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MS 0680 Received 4 February 2000; accepted after revision 17 May 2000.
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ABSTRACT |
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This review will discuss current concepts regarding 'active' or neurally mediated vasodilatation in human skin and skeletal muscle vascular beds in response to the release of vasodilating substances from nerves. Active vasodilatation is distinct from the 'passive vasodilatation' that occurs during withdrawal of sympathetic vasoconstrictor tone. First, we will discuss the cutaneous circulation, where there clearly is a physiologically important neural vasodilatory system. Second, we will discuss the skeletal muscle circulation, in which recent studies have cast a strong shadow of doubt on the existence of a neural vasodilatory system in humans (Lindqvist et al. 1996; Halliwill et al. 1997; Reed et al. 2000). It is also important to recognise that in both skin and skeletal muscle there is a remarkable capacity to vasodilate. During whole body heat stress, skin blood flow can reach values of 7-8 l min-1. Considering that a typical individual has only 2-3 kg of skin, this indicates that skin blood flow can exceed 250 ml (100 g tissue)-1 min-1 (Rowell et al. 1969). With whole body exercise, it is estimated that skeletal muscle blood flow can exceed 100 ml (100 g tissue)-1 min-1 and blood flow values up to 300 ml (100 g tissue)-1 min-1 have been measured during small muscle mass exercise (Andersen & Saltin, 1985; Rowell et al. 1986; Rowell, 1997).
Sympathetic control of skin blood flow
Cutaneous blood flow in non-acral regions (i.e. the 'hairy' skin covering most of the body surface) is controlled by the autonomic nervous system and plays a key role in thermoregulation. This control is exerted in part by changes in the level of sympathetic adrenergic vasoconstrictor nerve activity to the skin. Such nerves release noradrenaline (predominantly) when activated and induce vasoconstriction via 
-adrenergic receptors (Kellogg et al. 1989). For example, when core temperature is reduced there is a rise in cutaneous vasoconstrictor nerve activity, noradrenaline release and vasoconstriction in the skin. However, during a rise in core temperature (such as might occur with exercise or environmental stress), the control of cutaneous blood flow becomes more complicated (Kenney & Johnson, 1992).
When an individual is passively heated and blood flow to a cool upper extremity is recorded, there are small increases in skin blood flow as core temperature rises by between 0·5 and 1·0°C due to the withdrawal of sympathetic vasoconstrictor tone (Kellogg et al. 1989). However, during further increases in core temperature, there is a marked and progressive rise in cutaneous blood flow that cannot be explained by sympathetic vasoconstrictor withdrawal (Roddie et al. 1957; Kellogg et al. 1989). This vasodilatation is a sympathetically mediated active vasodilatation, but at present the nerves involved and the substances that mediate the vasodilatation are poorly understood (Roddie et al. 1957). In acral skin (e.g. the palmar surface of the hand) vasodilatation during body heating occurs predominantly due to sympathetic withdrawal.
Evidence for active cutaneous vasodilatation in humans. What evidence do we have that this dilatation represents an active neurally mediated response? The increase in cutaneous blood flow can be abolished by surgical sympathectomy or by acute nerve block of the sympathetic nerves to the limb with local anaesthetics, suggesting that intact sympathetic neural pathways are necessary to produce the dilatation (Roddie et al. 1957). Along these lines, this dilatation is absent or impaired in various forms of peripheral neuropathy and autonomic failure. In addition, while administration of -adrenergic blocking agents abolishes sympathetically mediated vasoconstrictor responses, it has no effect on this dilatory response (Kenney et al. 1991). 
-receptor blockade also has little impact on the vasodilator responses (Freund et al. 1987). Finally, the magnitude of the dilatation is far greater than that achieved by removal of sympathetic vasoconstrictor tone (Roddie et al. 1957; Kellogg et al. 1989). Taken together, these findings indicate that the dilatation is not simply due to withdrawal of vasoconstrictor tone (i.e. passive vasodilatation) but instead is due to the activation of an active vasodilatory neural pathway. Figure 1 summarises these findings. The key question then revolves around the neurotransmitter responsible for the dilatation.
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Idealised representation of the forearm blood flow responses, which have been used as a surrogate for cutaneous blood flow responses to heating and cooling. A comparison is made between a control arm (continuous line) and a sympathectomised arm some months after a surgical sympathectomy (dashed line). With cooling there is cutaneous vasoconstriction and a reduction in forearm blood flow in the control arm. This vasoconstriction is mediated by an increase in noradrenaline release from sympathetic vasoconstrictor fibres. With whole body heating this vasoconstriction is eliminated, and after some period there is marked cutaneous vasodilatation and a progressive rise in forearm blood flow. This cutaneous vasodilatation occurs at about the same time (or slightly after) the onset of sweating. In the surgically sympathectomised arm the vasoconstrictor responses to whole body cooling, the vasodilator responses to whole body heating and sweating are absent. Data such as these were interpreted to suggest that there is an active vasodilator system in human skin. Adapted from Roddie (1983). | ||
What substance released by nerves mediates active cutaneous vasodilatation? The rise in skin blood flow during whole body heat stress occurs at about the same time as the onset of sweating (Roddie et al. 1957). This observation has raised the possibility that the same nerves regulating sweating also produce the active vasodilatation. Another possibility is that when the sympathetic nerves activate sweat glands, sweat glands produce or release some substance (bradykinin has been proposed) that causes the vasodilatation (Fox & Hilton, 1958). Several studies have addressed this issue. It is well established that sweating is mediated by acetylcholine released from sympathetic cholinergic nerves acting via muscarinic cholinergic receptors (Roddie et al. 1957; Kolka & Stephenson, 1987). Indeed, brachial artery infusion of the muscarinic receptor antagonist atropine eliminates sweating in the treated forearm during whole body heat stress (Roddie et al. 1957; Shastry et al. 2000). However, pretreatment with atropine only delays the onset of cutaneous vasodilatation and blunts the peak dilator responses modestly or not at all during whole body heat stress (see Fig. 2; Roddie et al. 1957; Kellogg et al. 1995). Likewise, when atropine is administered (either via a brachial artery catheter or using microdialysis fibres imbedded in the skin) during the peak of the cutaneous vasodilator response to whole body heat stress, sweating is arrested but there is no impact on the ongoing dilatation (Roddie et al. 1957; Shastry et al. 2000). These observations argue against the idea that some substance or metabolite released by the active sweat glands causes the dilatation. They further demonstrate that the neural pathway that mediates active cutaneous vasodilatation does not operate via muscarinic cholinergic receptors.
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This figure shows the sweating (relative humidity; A) and cutaneous vascular conductance (CVC; B) responses to whole body heat stress in a representative subject. Under control conditions, whole body heat stress caused marked sweating and concurrent vasodilatation. Atropine iontophoresis abolished sweating but only delayed and slightly attenuated the vasodilatation. In contrast, local administration of botulinum toxin abolished both sweating and cutaneous vasodilatation. Cutaneous vasodilatation in response to local warming was maintained after all three treatments, indicating that cutaneous blood vessel responsiveness was unaltered. These data suggest that some unknown co-transmitter released from cholinergic nerves evokes cutaneous vasodilatation during whole body heat stress in humans. For further discussion see text. Data adapted from Kellogg et al. (1995). Figure adapted from Joyner & Dietz (1997). | ||
Recently, the emergence of nitric oxide (NO) as a substance released by vasodilating nerves in the penile and cerebral circulation has raised questions about the possible role of neurally mediated NO release as a cause of active cutaneous vasodilatation in humans (Toda & Okamura, 1991; Burnett et al. 1992). This hypothesis was especially attractive because studies on active cutaneous vasodilatation in the rabbit ear demonstrated that selective administration of arginine analogues to inhibit NO synthase eliminated the vasodilator responses to whole body heat stress (Taylor & Bishop, 1993). However, more recent studies in the rabbit ear have suggested that NO is not functioning as a neurotransmitter, but that it plays a permissive role and is needed to achieve the full expression of this vasodilatation (Farrell & Bishop, 1995, 1997). Along these lines, several attempts have been made to study the contribution of NO to neurally mediated cutaneous vasodilatation during whole body heat stress in humans.
In studies in humans, arginine analogues (e.g. NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME)) have been administered via the brachial artery before and after the onset of cutaneous dilatation or administered directly into the skin using microdialysis fibres to produce a regional NO synthase inhibition (Dietz et al. 1994b; Shastry et al. 1998, 2000; Kellogg et al. 1998). The original study on this topic (Dietz et al. 1994b) found little evidence that NO played a role in the cutaneous vasodilator responses to whole body heat stress. However, this study was limited by the use of whole forearm blood flow as a surrogate for cutaneous blood flow and the possibility that the L-NMMA, given as a pretreatment before heat stress, might not have reached the nerves and blood vessels that become active during heat stress. In this context, subsequent studies that used more selective ways of measuring skin blood flow and administering study drugs (Shastry et al. 1998, 2000; Kellogg et al. 1998) have found that 
20-30 % of the dilator response to whole body heat stress can be reduced by inhibiting the synthesis of NO. These observations suggest that NO contributes to but is not the primary substance responsible for the active vasodilatation in the cutaneous circulation. It is possible that NO acts as an amplifier of active vasodilatation and its release is flow induced or triggered by mechanical factors acting on endothelial cells (Rubanyi et al. 1986). Another idea is that acetylcholine from the sympathetic cholinergic sudomotor nerves might stimulate the vascular endothelium to release NO. However, since the dilatation is relatively insensitive to atropine (in doses that completely block sweating), it is unlikely that cholinergic stimulation of the vascular endothelium via acetylcholine spillover from the sudomotor nerves is responsible for any NO production (Shastry et al. 2000).
While the role of NO in active cutaneous vasodilatation is modest, NO does appear to evoke the majority (> 50 %) of the cutaneous vasodilator responses observed in the forearm skin during local heating (Kellogg et al. 1999). Interestingly, when local temperature is raised to above 42 or 43°C, which subjects frequently report as painful, the dilator response to local heating is much less subject to blunting by NO synthase inhibitors (Kellogg et al. 1999).
What substance evokes active cutaneous vasodilatation in humans? The best evidence suggests that a co-transmitter released by the sympathetic cholinergic nerves causes neurally mediated cutaneous vasodilatation during whole body heat stress in humans (Kellogg et al. 1995). This idea comes from a clever series of experiments by Kellogg and colleagues that are summarised in Fig. 2. Using laser Doppler flowmetry to assess cutaneous blood flow, they demonstrated that local administration of botulinum toxin (which acts presynaptically to block neurotransmitter release from cholinergic nerves) eliminates both the cutaneous vasodilator response and sweating in the treated areas during whole body heat stress in humans. Using the same methods, local administration of atropine eliminates the sweat response but not the cutaneous vasodilator response to whole body heat stress in humans. Further, exogenous acetylcholine causes sweating and mild dilatation when applied at the same time as botulinum treatment, indicating that botulinum toxin does not abolish end-organ responsiveness (Kellogg et al. 1995). In contrast, exogenous acetylcholine did not cause vasodilatation (or sweating) in the presence of atropine, indicating that non-muscarinic receptors are not involved in these responses. Thus, these elegant observations have led to the hypothesis that an unknown substance is co-released from sympathetic cholinergic nerves and is responsible for active cutaneous vasodilatation. Research in several laboratories is currently focusing on the possibility that vasodilating peptides might be co-released from these sympathetic cholinergic nerves.
Sympathetic control of skeletal muscle blood flow
Skeletal muscle in humans is innervated by sympathetic vasoconstrictor nerves that release noradrenaline (Barcroft et al. 1943). In order to appreciate the arguments for and against the presence of vasodilator nerves in human skeletal muscle, and in order to place these arguments in both a historical and physiological context, it is first necessary to review the studies that established the existence of sympathetic vasodilator nerves in the skeletal muscle of several animal species.
Animal studies. Perhaps the first experiments to support the notion of vasodilator nerves in animal skeletal muscle were those of Bülbring and Burn in the 1930s (Bülbring & Burn, 1935) and Folkow and colleagues in Sweden in the 1940s (Folkow et al. 1948). These studies demonstrated that electrical stimulation of sympathetic nerves to an isolated perfused cat or dog hindlimb normally causes vasoconstriction, but that this vasoconstriction could be turned into an atropine-sensitive muscle vasodilatation by a number of pharmacological interventions that either blocked the breakdown of acetylcholine or blocked the release of noradrenaline. Later histochemical and physiological studies demonstrated that there were sympathetic cholinergic nerves in the skeletal muscle of many non-primate species (Uvnäs, 1966; Bolme & Fuxe, 1970). However, histochemical and physiological evidence for these nerves was absent in the primate species studied. The studies in non-primates suggested that, during stimulation of the sympathetic nerves, two sets of autonomic nerves to skeletal muscle are activated: adrenergic vasoconstrictor fibres and cholinergic vasodilator fibres. Furthermore, usually the actions of the vasodilator fibres were masked by the actions of the vasoconstrictor fibres. More recent observations in cats suggest that acetylcholine from sympathetic cholinergic nerves innervating skeletal muscle may stimulate the vascular endothelium to evoke NO release (Matsukawa et al. 1993). Other reports suggest that the sympathetic vasodilator nerves can directly release vasodilating nitrosyl factors (Davisson et al. 1994).
Early on, it was postulated that sympathetic vasodilator fibres in skeletal muscle might play a physiological role in the classic 'fight or flight' response when an animal is threatened. As Bülbring & Burn (1935) noted, 'A purely constrictor nerve supply to muscle blood vessels has always been difficult to understand, since in times of stress when the sympathetic system is fully active, the blood supply to the muscles requires to be increased, rather than diminished.' In theory, when an animal is threatened the sympathetic nervous system could produce a specific and targeted vasodilatation that would facilitate blood flow and oxygen delivery to skeletal muscle in anticipation of the metabolic demands associated with either fight or flight. This notion is supported by studies demonstrating that electrical stimulation of certain brain stem areas that evoke 'defence' or 'alerting' responses also produces skeletal muscle vasodilatation, in conjunction with hypertension and tachycardia (Abrahams et al. 1964; Bolme et al. 1967; Horeyseck et al. 1976).
Neurally mediated skeletal muscle dilatation in humans? The first clear suggestion that there might be neurally mediated vasodilatation in human skeletal muscle came from studies on syncope conducted by Henry Barcroft and Otto Edholm during World War II (Barcroft & Edholm, 1945). These investigators were interested in syncope because of the frequency of its occurrence in combatants as a result of injuries and in response to the psychological stress associated with life-threatening situations. In these studies it became clear that peripheral vasodilatation played a key role in syncopal responses, since cardiac output remained relatively constant. Based on their understanding of haemodynamics, Barcroft and Edholm hypothesised that skeletal muscle was one of the few tissues with sufficient vasodilatory reserve to account for the marked fall in blood pressure during syncope, and that a marked vasodilatation must be occurring in skeletal muscle.
To investigate this possibility, studies were performed in subjects who had undergone unilateral surgical sympathectomy (for a variety of reasons). In this patient group, responses from the sympathectomised forearm could be compared to responses in the opposite, presumably normal side. When forearm blood flow was measured during syncope, marked vasodilatation occurred in the normally innervated arm but not in the sympathectomised arm, and Barcroft and Edholm concluded that there was an active sympathetic vasodilatation in skeletal muscle during fainting.
During the 1950s and early 1960s a variety of experiments were conducted, expanding on these original observations. Many of these studies were conducted by Professor Barcroft's protégés (Roddie, 1977; Roddie & Shepherd, 1998). In these studies (Fig. 3), conducted before rigorous human studies review boards, severe mental or emotional stress evoked physiological changes similar to the 'defence reaction' and caused forearm blood flow to rise by up to 10-fold (for a discussion of the mental stress used see Roddie, 1977). The forearm vasodilatation was absent after surgical sympathectomy, and in most subjects a portion of the vasodilatation could be blunted by atropine (Fig. 3). These data provided strong evidence for the existence of sympathetic cholinergic vasodilator nerves to human skeletal muscle, and was seen as confirming that the vasodilatation seen during fainting was caused by these nerves.
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Individual records from two subjects during periods of severe mental stress. A, in a patient with a unilateral cervical sympathectomy, mental stress (hatched bar) evoked profound increases in forearm blood flow in the normal arm. These increases in forearm blood flow were absent in the sympathectomised forearm. B, a second subject was studied with normal innervation to both upper extremities. Atropine given selectively to one forearm blunted but did not eliminate the vasodilator responses to severe mental stress. Adapted from Blair et al. (1959). | ||
The existence of sympathetic cholinergic nerves to human skeletal muscle appeared to be confirmed in the 1960s when Abboud & Eckstein (1966) conducted experiments that paralleled the earlier studies of Bülbring & Burn (1935) and Folkow and colleagues (Folkow et al. 1948). In these experiments, a cold pressor test was used to produce sympathoexcitation while forearm blood flow was measured in both arms. Under control conditions, sympathetic activation evoked a bilateral forearm vasoconstriction. However, after treatment of one forearm with phentolamine, given to block the -adrenergic receptors, the vasoconstriction was converted to a vasodilatation. Further treatment of the forearm with guanethidine augmented the forearm vasodilatation during a cold pressor test, whereas treatment with atropine blunted it. Since the pharmacological agents used to demonstrate these responses were selectively administered to only one forearm via a brachial artery catheter, and the vasoconstrictor response in the untreated forearm remained unchanged, it appeared from these studies that the cold pressor test was producing co-activation of sympathetic vasoconstrictor and vasodilator fibres to the skeletal muscle of the forearm. It also appeared that the vasoconstrictor response normally masked the vasodilator response.
In summary, by the 1960s there was a clear line of physiological and pharmacological evidence in support of the existence of sympathetic cholinergic vasodilator nerves to skeletal muscle in humans.
However, it must be noted that there was a lack of histological or anatomical evidence in humans (or other primates) to support this notion (Bolme & Fuxe, 1970). There were also several major inconsistencies that had yet to be explained. First, the vasodilator response to mental stress in adrenalectomised patients appeared to be markedly lower than that in normal individuals (Barcroft et al. 1960). While mental stress responses are notoriously variable across individuals, this observation raised the possibility that adrenaline released from the adrenal glands in response to mental stress might play a role in producing vasodilatation. Additionally, acute local anaesthetic blockade of the sympathetic nerves to the forearm at the stellate ganglion could not consistently reproduce the blunting of vasodilator responses seen in surgically sympathectomised limbs (Barcroft et al. 1960). The forearm vasodilatation during mental stress could also be blunted by brachial artery administration of an early -blocking drug (Glover et al. 1962). These observations all suggested that limb vasodilatation during mental or emotional stress might be caused by non-neural mechanisms.
Early observations with microneurography. With the development of microneurography it became possible to directly measure the peripheral sympathetic nerve responses to various manoeuvres in humans (Sundlöf & Wallin, 1977). Several investigators have measured sympathetic nerve activity during vasovagal syncope (Wallin & Sundlöf, 1982; Smith et al. 1993). These important studies have shown that sympathetic nerve activity from bundles innervating skeletal muscle vascular beds in the lower leg becomes profoundly silent during syncope. This suggests that at least a portion of the skeletal muscle vasodilatation that occurs during vasovagal syncope may represent sympathetic withdrawal (i.e. a passive vasodilatation) instead of a neurally mediated active vasodilatation.
In contrast to this observation, one early study on sympathetic traffic to the skeletal muscle vascular bed failed to show any change in sympathetic nerve activity to the arm during mental stress, suggesting that sympathetic withdrawal did not play a role in this vasodilatation (Anderson et al. 1987). However, blood flow to the forearm was not measured concurrently in this study, so it is impossible to say whether blood flow in the arm changed in response to mental stress in these individuals. In general, these early observations with microneurography did little to favour active vasodilatation in human skeletal muscle, as they provided no discrete evidence for vasodilator nerve traffic, and they suggested that in some conditions (e.g. vasovagal syncope) sympathetic withdrawal might explain some or all of the vasodilatation.
Early observations on the role of nitric oxide. In the early 1990s we became interested in whether NO might be mediating the forearm vasodilator responses seen during mental stress. Our interest was stimulated by observations in a variety of animal models that were consistent with the presence of nitroxidergic vasodilator nerves (Toda & Okamura, 1991; Burnett et al. 1992; Snyder, 1992). We were also aware of studies in the coronary circulation demonstrating that acetylcholine from autonomic nerves can stimulate NO release from the vascular endothelium and evoke vasodilatation (Broten et al. 1992).
In our first study (Dietz et al. 1994a), we used brachial artery administration of a NO synthase inhibitor to selectively blunt NO production in one forearm while leaving the other forearm unaffected. This allowed us to study the effect that NO synthase blockade had on the forearm blood flow response to mental stress in the treated arm while the untreated arm served as a 'control', overcoming the limitations imposed by the highly variable individual response to mental stress. We found that NO synthase inhibition reduced the vasodilator response to mental stress by about 70 % (Fig. 4). In additional experiments, we confirmed the early observations that the dilator response was also blunted by atropine
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Tracings of the forearm blood flow responses to mental stress in an individual in which one forearm was treated with the NO synthase inhibitor L-NMMA via a brachial artery catheter. In the control arm, mental stress evoked marked skeletal muscle vasodilatation. This vasodilatation was absent in the arm treated with L-NMMA. These data indicated that NO is involved in the forearm vasodilator response to sympathoexcitatory manoeuvres in humans. From Dietz et al. (1994a). | ||
In our next investigation on NO and sympathetic vasodilatation (Dietz et al. 1997), we adapted the strategy used in the early animal studies and later by Abboud & Eckstein (1966). We had subjects perform ischaemic handgrip exercise to fatigue as a means of producing sympathoexcitation while blood flow responses were measured in the contralateral (non-exercising) forearm. Ischaemic handgrip exercise produces marked and consistent increases in sympathetic nerve traffic to non-exercising limb skeletal muscles (Seals & Enoka, 1989). This increase in nerve traffic normally evokes pronounced vasoconstriction in the contralateral non-exercising forearm, although sometimes modest vasodilatation can be seen due to unintended contractions in this 'resting' limb (Cotzias & Marshall, 1993). We reasoned that if we blocked sympathetic vasoconstriction in the forearm we might unmask the actions of sympathetic vasodilator fibres. When subjects performed ischaemic handgrip exercise to fatigue after treatment of the contralateral forearm with phentolamine and bretylium to eliminate the -adrenergically mediated vasoconstriction in the non-exercising forearm, we observed a marked vasodilatation in the non-exercising forearm. This vasodilatation could be blunted in part by intra-arterial administration of atropine, propranolol or L-NMMA.
We interpreted these studies in the context of the studies performed in surgically sympathectomised humans, and postulated that during these stressful manoeuvres (both mental stress and ischaemic exercise) sympathetic cholinergic nerves to skeletal muscle are activated and release acetylcholine. Furthermore, in the light of animal studies, we speculated that the acetylcholine was stimulating NO release from the vascular endothelium or perhaps NO was released directly by sympathetic vasodilator nerves (Matsukawa et al. 1993; Davisson et al. 1994).
Evidence from recent studies: sympathetic vasodilatation in human muscle revisited. A major turning point in our thinking occurred when Lindqvist and colleagues (Lindqvist et al. 1996) reported that the forearm vasodilator responses to mental stress were still present in subjects who had undergone local anaesthetic block of the nerves to the upper extremity at the brachial plexus in the axilla. These observations indicated that local or circulating factors and not sympathetic vasodilator nerves were responsible for the vasodilatation during mental stress. At the same time, we were simultaneously recording muscle sympathetic nerve activity to the forearm and forearm blood flow during mental stress (Halliwill et al. 1997). We also evaluated the impact of local anaesthetic block of the sympathetic nerves at the stellate ganglion on the vasodilator response to mental stress (Halliwill et al. 1997). In these experiments, several key observations were made. First, in subjects who showed marked vasodilatation during mental stress there was also sympathetic withdrawal in the forearm (i.e. some of the 'neurally mediated' vasodilatation was passive dilatation due to removal of vasoconstrictor tone) (Fig. 5). Second, we found no evidence of increased nerve activity that might be related to activation of sympathetic vasodilator fibres. Third, the vasodilator responses to mental stress were still present after local anaesthetic block of the stellate ganglion indicating that non-neural mechanisms were involved. Finally, we found that, after stellate ganglion block, the vasodilatation that occurred during mental stress could be attenuated by -adrenergic blockade.
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Representative data from one subject showing arterial blood pressure (ABP), muscle sympathetic nerve activity (MSNA) recorded from the radial nerve, forearm blood flow and skin blood flow before (Baseline), during (Mental stress) and after (Recovery) mental stress evoked by the Stroop word-colour conflict test. Concurrent with the rise in forearm blood flow there was inhibition of muscle sympathetic nerve activity, indicating that a portion of the forearm vasodilatation was attributable to sympathetic withdrawal (i.e. passive vasodilatation). These data represented a major turning point in our understanding of the mental stress response. Adapted from Halliwill et al. (1997). | ||
Putting the pieces together. We now had results that appeared internally conflicting. To address this conflict, we revisited our study with ischaemic handgrip exercise and used stellate ganglion block to see if the vasodilatation we had unmasked with phentolamine and bretylium was neurally mediated (Reed et al. 2000). In this study we demonstrated that contralateral ischaemic handgripping to fatigue evokes profound skeletal muscle vasodilatation in the resting forearm after the sympathetic nerves to that forearm have been acutely blocked with local anaesthetics. As with the dilatation seen during mental stress, propranolol or L-NMMA given alone blunted this vasodilatation, and in combination virtually eliminated it (Fig. 6). Taken together, we now believe that our findings indicate that circulating catecholamines stimulating 2-receptors on vascular smooth muscle and endothelial cells in combination with locally mediated NO release are the probable mechanism of the forearm vasodilatation elicited during sympathoexcitatory manoeuvres in humans (Freyschuss et al. 1988; Dawes et al. 1997; Reed et al. 2000). Additionally, during mental stress sympathetic withdrawal appears to contribute as well (Halliwill et al. 1997). This conclusion is also supported by the failure to find histochemical evidence for sympathetic dilator fibres in humans, and the physiology studies from non-human primates (Uvnäs, 1966; Bolme & Fuxe, 1970).
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Individual forearm blood flow (FBF) responses to contralateral ischaemic handgripping to fatigue. These responses were recorded after the subject had received a stellate ganglion block which eliminated the sympathetic outflow to the resting forearm. In this subject handgripping to fatigue caused forearm blood flow to increase by 2·5-fold. Propranolol, given via a brachial artery catheter, did not affect baseline blood flow but the increase in flow during contralateral ischaemic handgripping to fatigue and post-exercise ischaemia (PEI) was blunted. After this second bout of handgripping, the NO synthase inhibitor L-NMMA was given and a third bout of exercise was performed. L-NMMA caused a marked reduction in the resting forearm blood flow. It also eliminated the rise in forearm blood flow seen during the previous two bouts of handgripping. Adapted from Reed et al. (2000). | ||
How do we reconcile these observations and conclusions with those showing that chronic surgical sympathectomy eliminates the forearm vasodilator responses to mental stress (Blair et al. 1959; Roddie, 1977)? First, it must be remembered that sympathetic withdrawal can account for some of the vasodilatation during mental stress - and perhaps most of the dilatation during syncope (Wallin & Sundlöf, 1982; Smith et al. 1993; Halliwill et al. 1997). Thus, differences between a sympathectomised limb and an innervated limb would be partly attributed to the loss of this passive vasodilatation. Second, since at least a portion of the vasodilator responses to these manoeuvres is eliminated by NO synthase inhibition, -blockade, or atropine, it is likely that chronic changes in autonomic receptors on the vascular endothelium or vascular smooth muscle that occur after surgical sympathectomy might underlie the different responses in sympathectomised limbs. Along these lines, recent observations in animals indicate that chronic sympathectomy eliminates endothelial NO synthase expression in sympathectomised blood vessels (Aliev et al. 1996). This suggests that normal NO-mediated responses to local and circulating factors would be present following acute sympathectomy with local anaesthetics or drugs injected into the brachial artery, but that these responses would be absent in the months and years following surgical sympathectomy. So, while chronic sympathectomy studies are important, they must be interpreted with caution.
A final puzzle is the atropine sensitivity of many of these responses (Blair et al. 1959; Abboud & Eckstein, 1966; Dietz et al. 1994a, 1997). If cholinergic vasodilator nerves do not exist in humans, then why are many of these dilator responses attenuated by atropine? One explanation is that a small fraction of the vascular endothelial cells may synthesise and release acetylcholine (Milner et al. 1990). In this context, mechanically stimulated NO release from the canine femoral artery (and subsequent vasodilatation) is absent when the femoral artery is treated with either atropine or exogenous acetylcholinesterase (Martin et al. 1996).
In view of the evidence discussed above, we believe that the most likely mechanisms involved in the forearm vasodilator responses to sympathoexcitatory manoeuvres including mental stress centre around sympathetic withdrawal, local release of NO and 2-mediated stimulation (via circulating adrenaline) acting on receptors on the vascular endothelium and smooth muscle. One physiological role for this local vasodilator mechanism might be consistent with the ideas advanced by Pohl and colleagues (de Wit et al. 1998) who have shown that when blood pressure increases during periods of increased sympathetic traffic to skeletal muscle there is also a myogenic response in the resistance vessels. However, the vasoconstriction associated with the increased sympathetic traffic and the myogenic response are partially offset by local NO release (de Wit et al. 1998). Perhaps the forearm dilatation seen during mental stress or contralateral ischaemic handgrip exercise after acute local anaesthetic block or pharmacological sympathectomy normally opposes these powerful constrictor mechanisms.
In the context of vasovagal responses, passive vasodilatation due to sympathetic withdrawal is a very consistent finding (Wallin & Sundlöf, 1982; Morillo et al. 1997; Mosqueda-Garcia et al. 1998) but the roles of circulating adrenaline and NO are less clear (de Jong-de Vos van Steenwijk et al. 1995; Dietz et al. 1997) than their role during mental stress. Perhaps during syncope there is an element of reactive hyperaemia that contributes to the limb vasodilatation following the sudden loss of sympathetic vasoconstrictor tone, subsequent to the presyncopal period that is associated with very low limb blood flow (Barcroft & Edholm, 1945; Hainsworth et al. 1983; Dietz et al. 1997).
Summary/conclusions
In summary, the evidence for active dilatation in non-acral human skin is sound. However, it appears that the once convincing evidence for active dilatation in human skeletal muscle can be explained by other mechanisms. This apparent difference between humans (and perhaps primates) and most other mammalian species is puzzling. When Bülbring & Burn (1935) noted differences in sympathetic vasodilatation in dogs and cats they too were puzzled and commented that, 'Why should the mechanism of the dilatation be completely changed in the two species?' In this context, perhaps humans, with our upright posture and its associated challenges to blood pressure regulation and our relatively small hearts, 'need' vasoconstriction in our skeletal muscle far more than active vasodilatation.
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REFERENCES |
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| Abboud, F. M. & Eckstein, J. W. (1966). Active reflex vasodilatation in man. Federation Proceedings 25, 1611-1617 | [Medline] |
| Abrahams, V. C., Hilton, S. M. & Zbrozyna, A. W. (1964). The role of active muscle vasodilatation in the alerting stage of the defence reaction. The Journal of Physiology 171, 189-202. | |
| Aliev, G., Ralevic, V. & Burnstock, G. (1996). Depression of endothelial nitric oxide synthase but increased expression of endothelin-1 immunoreactivity in rat thoracic aortic endothelium associated with long-term, but not short-term, sympathectomy. Circulation Research 79, 317-323 | [Abstract/Full Text] |
| Andersen, P. & Saltin, B. (1985). Maximal perfusion of skeletal muscle in man. The Journal of Physiology 366, 233-249 | [Abstract] |
| Anderson, E. A., Wallin, B. G. & Mark, A. L. (1987). Dissociation of sympathetic nerve activity in arm and leg muscle during mental stress. Hypertension 9, 114-119. | |
| Barcroft, H., Bonnar, McK. W., Edholm, O. G. & Effron, A. S. (1943). On sympathetic vasoconstrictor tone in human skeletal muscle. The Journal of Physiology 102, 21-31. | |
| Barcroft, H., Brod, J., Hejl, Z., Hirsjärvi, E. A. & Kitchin, A. H. (1960). The mechanism of the vasodilation in the forearm muscle during stress (mental arithmetic). Clinical Science 19, 577-586. | |
| Barcroft, H. & Edholm, O. G. (1945). On the vasodilatation in human skeletal muscle during post-haemorrhagic fainting. The Journal of Physiology 104, 161-175. | |
| Blair, D. A., Glover, W. E., Greenfield, A. D. M. & Roddie, I. C. (1959). Excitation of cholinergic vasodilator nerves to human skeletal muscles during emotional stress. The Journal of Physiology 148, 633-647. | |
| Bolme, P. & Fuxe, K. (1970). Adrenergic and cholinergic nerve terminals in skeletal muscle vessels. Acta Physiologica Scandinavica 78, 52-59 | [Medline] |
| Bolme, P., Nagai, S. H., Uvnäs, B. & Wallenberg, L. R. (1967). Circulatory and behavioural effects on electrical stimulation of the sympathetic vasodilator areas in the hypothalamus and the mesencephalon in unanesthetized dogs. Acta Physiologica Scandinavica 70, 334-346 | [Medline] |
| Broten, T. P., Miyashiro, J. K., Moncada, S. & Feigl, E. O. (1992). Role of endothelium-derived relaxing factor in parasympathetic coronary vasodilation. American Journal of Physiology 262, H1579-1584 | [Medline] |
| Bülbring, E. & Burn, J. H. (1935). The sympathetic dilator fibres in the muscles of the cat and dog. The Journal of Physiology 83, 483-501. | |
| Burnett, A. L., Lowenstein, C. J., Bredt, D. S., Chang, T. S. & Snyder, S. H. (1992). Nitric oxide: A physiologic mediator of penile erection. Science 257, 401-403 | [Medline] |
| Cotzias, C. & Marshall, J. M. (1993). Vascular and electromyographic responses evoked in forearm muscle by isometric contraction of the contralateral forearm. Clinical Autonomic Research 3, 21-30 | [Medline] |
| Davisson, R. L., Johnson, A. K. & Lewis, S. J. (1994). Nitrosyl factors mediate active neurogenic hindquarter vasodilation in the conscious rat. Hypertension 23, 962-966 | [Abstract] |
| Dawes, M., Chowienczyk, P. J. & Ritter, J. M. (1997). Effects of inhibition of the L-arginine/nitric oxide pathway on vasodilation caused by -adrenergic agonists in human forearm. Circulation 95, 2293-2297 |
[Abstract/Full Text] |
| de Jong-de Vos van Steenwijk, C. C. E., Wieling, W., Johannes, J. M., Harms, M. P., Kuis, W. & Wesseling, K. H. (1995). Incidence and hemodynamic characteristics of near-fainting in healthy 6- to 16-year old subjects. Journal of the American College of Cardiology 25, 1615-1621 | [Medline] |
| de Wit, C., Jahrbeck, B., Schäfer, C., Bolz, S. S. & Pohl, U. (1998). Nitric oxide opposes myogenic pressure responses predominantly in large arterioles in vivo. Hypertension 31, 787-794 | [Abstract/Full Text] |
| Dietz, N. M., Engelke, K. A., Samuel, T. T., Fix, R. T. & Joyner, M. J. (1997). Evidence for nitric oxide-mediated sympathetic forearm vasodilatation in humans. The Journal of Physiology 498, 531-540 | [Abstract] |
| Dietz, N. M., Rivera, J. M., Eggener, S. E., Fix, R. T., Warner, D. O. & Joyner, M. J. (1994a). Nitric oxide contributes to the rise in forearm blood flow during mental stress in humans. The Journal of Physiology 480, 361-368 | [Abstract] |
| Dietz, N. M., Rivera, J. M., Warner, D. O. & Joyner, M. J. (1994b). Is nitric oxide involved in cutaneous vasodilation during body heating in humans? Journal of Applied Physiology 76, 2047-2053 | [Medline] |
| Farrell, D. M. & Bishop, V. S. (1995). Permissive role for nitric oxide in active thermoregulatory vasodilation in rabbit ear. American Journal of Physiology 269, H1613-1618 | [Medline] |
| Farrell, D. M. & Bishop, V. S. (1997). The roles of cGMP and cAMP in active thermoregulatory vasodilation. American Journal of Physiology 272, R975-981 | [Medline] |
| Folkow, B., Haeger, K. & Uvnäs, B. (1948). Cholinergic vasodilator nerves in the sympathetic outflow to the muscles of the hind limbs of the cat. Acta Physiologica Scandinavica 15, 401-411. | |
| Fox, R. H. & Hilton, S. M. (1958). Bradykinin formation in human skin as a factor in heat vasodilatation. The Journal of Physiology 142, 219-232. | |
| Freund, B. J., Joyner, M. J., Jilka, S. M., Kalis, J., Nittolo, J. M., Taylor, J. A., Peters, H., Feese, G. & Wilmore, J. H. (1987). Thermoregulation during prolonged exercise in heat: alterations with beta-adrenergic blockade. Journal of Applied Physiology 63, 930-936 | [Medline] |
| Freyschuss, U., Hjemdahl, P., Juhlin-Dannfelt, A. & Linde, B. (1988). Cardiovascular and sympathoadrenal responses to mental stress: influence of -blockade. American Journal of Physiology 255, H1443-1451 |
[Medline] |
| Glover, W. E., Greenfield, A. D. M. & Shanks, R. G. (1962). The contribution made by adrenaline to the vasodilatation in the human forearm during emotional stress. The Journal of Physiology 164, 422-429. | |
| Hainsworth, R., Karim, F., McGregor, K. H. & Wood, L. M. (1983). Hind-limb vascular-capacitance responses in anaesthetized dogs. The Journal of Physiology 337, 417-428 | [Abstract] |
| Halliwill, J. R., Lawler, L. A., Eickhoff, T. J., Dietz, N. M., Nauss, L. A. & Joyner, M. J. (1997). Forearm sympathetic withdrawal and vasodilatation during mental stress in humans. The Journal of Physiology 504, 211-220 | [Abstract] |
| Horeyseck, G., Janig, W., Kirchner, F. & Thamer, V. (1976). Activation and inhibition of muscle and cutaneous postganglionic neurones to hindlimb during hypothalamically induced vasoconstriction and atropine-sensitive vasodilation. Pflügers Archiv 361, 231-240 | [Medline] |
| Joyner, M. J. & Dietz, N. M. (1997). Nitric oxide and vasodilation in human limbs. Journal of Applied Physiology 83, 1785-1796 | [Abstract/Full Text] |
| Kellogg, D. L. Jr, Crandall, C. G., Liu, Y., Charkoudian, N. & Johnson, J. M. (1998). Nitric oxide and cutaneous active vasodilation during heat stress in humans. Journal of Applied Physiology 85, 824-829 | [Abstract/Full Text] |
| Kellogg, D. L. Jr, Johnson, J. M. & Kosiba, W. A. (1989). Selective abolition of adrenergic vasoconstrictor responses in skin by local iontophoresis of bretylium. American Journal of Physiology 257, H1599-1606 | [Medline] |
| Kellogg, D. L. Jr, Liu, Y., Kosiba, I. F. & O'Donnell, D. (1999). Role of nitric oxide in the vascular effects of local warming of the skin in humans. Journal of Applied Physiology 86, 1185-1190 | [Abstract/Full Text] |
| Kellogg, D. L. Jr, Pérgola, P. E., Piest, K. L., Kosiba, W. A., Crandall, C. G., Grossmann, M. & Johnson, J. M. (1995). Cutaneous active vasodilation in humans is mediated by cholinergic nerve cotransmission. Circulation Research 77, 1222-1228 | [Abstract/Full Text] |
| Kenney, W. L. & Johnson, J. M. (1992). Control of skin blood flow during exercise. Medicine and Science in Sports and Exercise 24, 303-312 | [Medline] |
| Kenney, W. L., Tankersley, C. G., Newswanger, D. L. & Puhl, S. M. (1991). Alpha 1-adrenergic blockade does not alter control of skin blood flow during exercise. American Journal of Physiology 260, H855-861 | [Medline] |
| Kolka, M. A. & Stephenson, L. A. (1987). Cutaneous blood flow and local sweating after systemic atropine administration. Pflügers Archiv 410, 524-529 | [Medline] |
| Lindqvist, M., Davidsson, S., Hjemdahl, P. & Melcher, A. (1996). Sustained forearm vasodilation in humans during mental stress is not neurogenically mediated. Acta Physiologica Scandinavica 158, 7-14 | [Medline] |
| Martin, C. M., Beltran-del-Rio, A., Albrecht, A., Lorenz, R. R. & Joyner, M. J. (1996). Local cholinergic mechanisms mediate nitric oxide-dependent flow-induced vasorelaxation in vitro. American Journal of Physiology 270, H442-446 | [Medline] |
| Matsukawa, K., Shindo, T., Shirai, M. & Ninomiya, I. (1993). Nitric oxide mediates cat hindlimb cholinergic vasodilation induced by stimulation of posterior hypothalamus. Japanese The Journal of Physiology 43, 473-483 | [Medline] |
| Milner, P., Kirkpatrick, K. A., Ralevic, V., Toothill, V., Pearson, J. & Burnstock, G. (1990). Endothelial cells cultured from human umbilical vein release ATP, substance P and acetylcholine in response to increased flow. Proceedings of the Royal Society B 241, 245-248 | [Medline] |
| Morillo, C. A., Eckberg, D. L., Ellenbogen, K. A., Beightol, L. A., Hoag, J. B., Tahvanainen, K. U. O., Kuusela, T. A. & Diedrich, A. M. (1997). Vagal and sympathetic mechanisms in patients with orthostatic vasovagal syncope. Circulation 96, 2509-2513 | [Abstract/Full Text] |
| Mosqueda-Garcia, R., Fernandez-Violante, R., Tank, J., Snell, M., Cunningham, G. & Furlan, R. (1998). Yohimbine in neurally mediated syncope: pathophysiological implications. Journal of Clinical Investigation 102, 1824-1830 | [Abstract/Full Text] |
| Reed, A. S., Tschakovsky, M. E., Minson, C. T., Halliwill, J. R., Torp, K. D., Nauss, L. A. & Joyner, M. J. (2000). Skeletal muscle vasodilatation during sympathoexcitation is not neurally mediated in humans. The Journal of Physiology 525, 253-262 | [Abstract/Full Text] |
| Roddie, I. C. (1977). Human responses to emotional stress. Irish Journal of Medical Science 146, 395-417 | [Medline] |
| Roddie, I. C. (1983). Circulation to skin and adipose tissue. In Handbook of Physiology, section 2, The Cardiovascular System, vol. III, Peripheral and Organ Blood Flow, ed. Shepherd, J. T. & Abboud, F. M., pp. 285-317. American Physiological Society, Bethesda, MD, USA. | |
| Roddie, I. C. & Shepherd, J. T. (1998). Recollections of Professor Henry Barcroft, F.R.S. Clinical Autonomic Research 8, 317-327 | [Medline] |
| Roddie, I. C., Shepherd, J. T. & Whelan, R. F. (1957). The contribution of constrictor and dilator nerves to the skin vasodilatation during body heating. The Journal of Physiology 136, 489-497. | |
| Rowell, L. B. (1997). Neural control of muscle blood flow: importance during dynamic exercise. Clinical and Experimental Pharmacology and Physiology 24, 117-125 | [Medline] |
| Rowell, L. B., Brengelmann, G. L. & Murray, J. A. (1969). Cardiovascular responses to sustained high skin temperature in resting man. Journal of Applied Physiology 27, 673-680 | [Medline] |
| Rowell, L. B., Saltin, B., Kiens, B. & Christensen, N. J. (1986). Is peak quadriceps blood flow in humans even higher during exercise with hypoxemia? American Journal of Physiology 251, H1038-1044 | [Medline] |
| Rubanyi, G. M., Romero, J. C. & Vanhoutte, P. M. (1986). Flow-induced release of endothelium-derived relaxing factor. American Journal of Physiology 250, H1145-1149 | [Medline] |
| Seals, D. R. & Enoka, R. M. (1989). Sympathetic activation is associated with increases in EMG during fatiguing exercise. Journal of Applied Physiology 66, 88-95 | [Medline] |
| Shastry, S., Dietz, N. M., Halliwill, J. R., Reed, A. S. & Joyner, M. J. (1998). Effects of nitric oxide synthase inhibition on cutaneous vasodilation during body heating in humans. Journal of Applied Physiology 85, 830-834 | [Abstract/Full Text] |
| Shastry, S., Minson, C. T., Wilson, S. A., Dietz, N. M. & Joyner, M. J. (2000). Effects of atropine and L-NAME on cutaneous blood flow during body heating in humans. Journal of Applied Physiology 88, 467-472 | [Abstract/Full Text] |
| Smith, M. L., Carlson, M. D. & Thames, M. D. (1993). Naloxone does not prevent vasovagal syncope during simulated orthostasis in humans. Journal of the Autonomic Nervous System 45, 1-9 | [Medline] |
| Snyder, S. H. (1992). Nitric oxide: First in a new class of neurotransmitters? Science 257, 494-496 | [Medline] |
| Sundlöf, G. & Wallin, B. G. (1977). The variability of muscle nerve sympathetic activity in resting recumbent man. The Journal of Physiology 272, 383-397 | [Medline] |
| Taylor, W. F. & Bishop, V. S. (1993). A role for nitric oxide in active thermoregulatory vasodilation. American Journal of Physiology 264, H1355-1359 | [Medline] |
| Toda, N. & Okamura, T. (1991). Role of nitric oxide in neurally induced cerebroarterial relaxation. Journal of Pharmacology and Experimental Therapeutics 258, 1027-1032 | [Abstract] |
| Uvnäs, B. (1966). Cholinergic vasodilator nerves. Federation Proceedings 25, 1618-1622 | [Medline] |
| Wallin, B. G. & Sundlöf, G. (1982). Sympathetic outflow to muscles during vasovagal syncope. Journal of the Autonomic Nervous System 6, 287-291 | [Medline] |
The time and effort put forth by the subjects who participated in our studies are greatly appreciated. The authors also appreciate the excellent secretarial assistance of Janet Beckman. Further, we would like to thank our co-investigators and laboratory team and also the nursing staff of the Mayo General Clinical Research Center for their assistance with our studies. This work was supported by NIH grants HL 46493, NS32352 and NRSA DK09826 (J. R. Halliwill). Further support was provided by the Mayo General Clinical Research Center (grant RR00585).
Corresponding author
M. J. Joyner: Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Email: joyner.michael{at}mayo.edu
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