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CARDIOVASCULAR |
1 School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, UK
2 Prince of Wales Medical Research Institute, University of New South Wales, Baker Street, Randwick, NSW 2031, Australia
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Abstract |
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1-adrenoceptor antagonist prazosin (0.1 µM) vasoconstrictions at 90 mmHg were larger than those at 30 mmHg. At both pressures, the combination of prazosin and suramin virtually abolished constrictions. The purinergic component of vasoconstriction (prazosin-resistant) was almost abolished by the L-type Ca2+ channel antagonist nifedipine (1 µM). Increasing pressure from 30 to 90 mmHg decreased the resting membrane potential and increased the amplitude of purinergic excitatory junction potentials. These findings indicate that the contribution of ATP to neurovascular transmission increases when the pressure is raised from 30 to 90 mmHg, which is similar to the pressure second-order mesenteric arteries experience in vivo, and that Ca2+ influx through L-type Ca2+ channels is largely responsible for purinergic activation of the vascular smooth muscle.
(Received 19 April 2007;
accepted after revision 14 May 2007;
first published online 17 May 2007)
Corresponding author William Dunn: School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, UK. Email: william.dunn{at}nottingham.ac.uk
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Introduction |
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Analysis of contractions obtained in response to sympathetic nerve stimulation in rat small mesenteric arteries in vitro has produced conflicting data with regard to the importance of ATP as a sympathetic neurotransmitter. Angus et al. (1988) reported that the 1-adrenoceptor antagonist prazosin reduced the amplitude of contractions to 3 s trains of electrical stimuli at 25 Hz by about 90%, the remaining small contraction being blocked by desensitization of P2X1 receptors with ,
-methylene ATP. Subsequently, Sjoblom-Widfeldt et al. (1990) showed that the purinergic component of neurally evoked contraction increased when the perivascular axons were activated with shorter trains of stimuli at lower frequencies, with contractions to a single stimulus being due primarily to released ATP. Using the P2-receptor antagonist suramin, Gitterman & Evans (2001) reported that the contribution of ATP to neurally evoked contractions of mesenteric arteries increases as vessel diameter decreases. It has also been suggested that neurally released NA and ATP may act synergistically to produce contractions of mesenteric arteries (Brock et al. 2006; see also Ralevic & Burnstock, 1990), as prazosin and suramin reduced contractions to 20 stimuli at 10 Hz by 85 and 70%, respectively.
To date, most studies of neurally evoked contractions of isolated arteries have either used isometric recording techniques to measure the increase in force produced by activation of the vascular smooth muscle (Angus et al. 1988; Sjoblom-Widfeldt et al. 1990) or used diameter tracking of small arteries without any distending pressure (Gitterman & Evans, 2001). In vivo, arteries experience and contract against the background of force applied by intraluminal pressure. Despite the development of pressure myography systems that allow vasoconstriction to be monitored in pressurized small arteries in vitro, surprisingly few studies have examined responses to nerve stimulation using this technique. In pressurized rat mesenteric arteries, constrictions to sympathetic nerve stimulation have been demonstrated by both Pourageaud & De Mey (1998) and Parkington et al. (2004). While the nature of the neurotransmitter responsible for this constriction was not the main focus of either study, part of the response was resistant to prazosin, and so may have been mediated by ATP. In the present study we have used pressure myography to measure the noradrenergic and purinergic components of vasoconstriction in rat second-order mesenteric arteries following sympathetic nerve stimulation under physiologically relevant conditions.
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Methods |
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Male Wistar rats (180–220 g) were stunned by a blow to the cranium and killed by exsanguination. After removal of the mesentery, the tissue was maintained in physiological salt solution containing (mM): NaCl, 118; NaHCO3, 25; KCl, 4.8; MgSO4, 2.5; KH2PO4, 1.2; glucose, 11.1; CaCl2, 1.25; and gassed with 95% O2–5% CO2 (pH 7.4). A first-order mesenteric artery was identified and followed to the point where its second-order branches further divided into the third-order branches. This part of the vascular tree was isolated, and adherent fat and connective tissue were removed from the primary and the secondary branches, except at the branch point where it was left intact. One of the secondary branches of the mesenteric artery was tied off just distal to the branch point. The perivascular axons were activated electrically through a stimulating electrode that consisted of a polyethylene tube (
400 µm lumen diameter) with a silver wire electrode within the lumen that was filled with physiological salt solution and another electrode wrapped around the outside, close to the mouth. The first-order artery was drawn into the stimulating electrode and the fat left intact at the branch point was used to create a tight seal at the mouth of the electrode. Electrical stimuli (1 ms pulse width, 20 V) were supplied by a stimulus isolation unit (DS2; Digitimer Ltd, Welwyn Garden City, UK). The distal end of the secondary artery was then mounted onto a glass cannula containing physiological saline and connected to a pressure servo controlled peristaltic pump (Living Systems, Burlington, VT, USA), allowing precise control of intraluminal pressure. The tissues were superfused with physiological saline and maintained at 36–37°C. Vessels were pressurized to either 30 or 90 mmHg, and allowed to equilibrate for 30 min.
Pressure myography
Arteries were visualized using a CCD camera attached to an inverted microscope and their inner diameter was continually monitored using an edge tracking device (video dimension analyser model V94; Living Systems, Burlington, VT, USA). Following equilibration, arteries were stimulated at 5 min intervals with 50 pulses at 10 Hz for a period of 30 min during which the amplitude of the constrictions increased to reach a plateau level. Frequency response curves (FRCs) to 50 pulses at frequencies of 0.5, 1, 2, 4, 6, 8 and 10 Hz were then constructed. Following each train of stimuli, the diameter of the artery was allowed to return to the baseline value before the next train of stimuli was applied. FRCs produced by increasing the frequencies of stimulation from 0.5 to 10 Hz were similar to those produced by decreasing the frequencies of stimulation from 10 to 0.5 Hz.
Separate arteries were used to study neurally evoked constrictions at distending pressures of 30 and 90 mmHg. In each artery, three FRCs were obtained at intervals of 30 min: the first in the absence of drugs (control); the second in the presence of either the 1-adrenoceptor antagonist prazosin (0.1 µM), or the P2-receptor antagonist suramin (0.1 mM); the third in presence of both antagonists. These concentrations of antagonists were chosen since they have previously been shown to selectively abolish 1-adrenoceptor and P2-receptor-mediated functional responses in mesenteric arteries (Angus et al. 1988; Sjoblom-Widfeldt et al. 1990; Gitterman & Evans, 2001; Brock et al. 2006). In control experiments, three consecutive FRCs were performed in the absence of drugs to determine the effects of time alone. In some experiments, after obtaining an initial control FRC, responses to nerve stimulation were obtained in the presence of the Na+ channel blocker tetrodotoxin (0.3 µM). In other experiments, responses to a single application of ,-methylene ATP (0.1 µM) were determined in vessels held at either 30 or 90 mmHg. This concentration of ,-methylene ATP (0.1 µM) was chosen because it was submaximal for activating mesenteric arteries. A full concentration–response curve to ,-methylene ATP was not produced since higher concentrations caused P2X1-receptor desensitization.
To determine the involvement of voltage-activated Ca2+ channels in mediating vasoconstrictions, FRCs were performed in the absence and in the presence of the L-type Ca2+ channel blocker nifedipine (1 µM). To assess the contribution of L-type Ca2+ channels to the purinergic component of the vasoconstriction, the effects of nifedipine were also assessed in tissues pretreated with prazosin (0.1 µM) to block 1-adrenoceptors.
In the experiments assessing the effects of neurotransmitter antagonists or nifedipine, these agents were added to the superfusing solution and allowed to circulate for approximately 25 min before the FRC was obtained.
Electrophysiology of pressurized arteries
Intracellular recordings from smooth muscle cells located 0.5–1 mm from the end of the stimulating electrode were made using sharp microelectrodes (120–200 M
) filled with 0.5 M KCl and connected to an Axoclamp 2A (Axon Instruments, Union City, CA, USA). Impalements were only accepted if the following criteria were satisfied: (1) the cell penetration was abrupt, (2) the membrane potential increased to a value more negative than the initial potential, (3) the membrane potential was stable. In each preparation recordings were made from three or four cells at 30 and 90 mmHg and it was not possible to maintain impalements during the change in pressure. EJPs were evoked by single stimuli and we assume that the stimuli used (1 ms pulse width, 20 V) were supramaximal as, at 30 mmHg, increasing the stimulus voltage did not increase EJP amplitude. At 90 mmHg, impalements were often lost shortly following a single stimulus and it was not possible to maintain recordings during repetitive activation of the perivascular axons. Resting membrane potentials were determined upon withdrawal of the microelectrode. In some experiments, arteries were held at either 30 or 90 mmHg, and the effects of suramin (0.1 mM) on EJPs were determined. In others, the effect of nifedipine (1 µM) on EJPs was determined at 90 mmHg.
Data analysis
All data was collected using the PowerLab recording system (ADInstruments, Chalgrove, UK) and analysed using GraphPad Prism (GraphPad Software Inc., San Diego, CA, USA) or Igor Pro (Wavemetrics, Lake Oswego, OR, USA) software. Resting membrane potentials and EJPs recorded in individual tissues were averaged for each experimental condition before comparisons were made. For EJPs, their rise time was measured between 10 and 90% of the rising phase, and their duration was measured between 10% of the rising phase and 90% of the decaying phase. Repeated measures analysis of variance (ANOVA) with a single independent variable was used to assess the effects of pressure on FRCs. The effects of the sequential addition of the neurotransmitter antagonists at each pressure were made by repeated-measured ANOVA and subsequent pairwise comparisons were made with Student's paired t tests with P values corrected using Bonferroni's method. All other pairwise comparisons were made with Student's paired or unpaired t tests, as appropriate. P values of <0.05 were regarded as indicating a significant difference.
Drugs
Prazosin HCl, suramin (Na+ salt), ,-methylene ATP and nifedipine were obtained from Sigma (Gillingham, UK). TTX was obtained from TCS Biologicals (Bath, UK). Nifedipine was prepared as a 10 mM stock solution in ethanol, and prazosin and ,-methylene ATP were prepared as 1 mM stock solutions in distilled water. Suramin was dissolved directly in the physiological saline solution.
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Results |
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The inner diameter of the second-order mesenteric arteries pressurized to 30 mmHg was 197 ± 4.5 µm (n = 32), while that of arteries pressurized to 90 mmHg was significantly larger at 277 ± 3.5 µm (n = 51, P < 0.001, Student's unpaired t test). There was no decrease in vessel diameter at either pressure during the equilibration period.
Frequency–response curves
Electrical stimulation of the perivascular axons evoked constrictions that increased in amplitude with the increase in stimulation frequency (Fig. 1A and B). Over the entire range of stimulation frequencies studied, the absolute amplitude of the vasoconstrictor responses was larger at 90 mmHg than at 30 mmHg (n = 8, P < 0.001, repeated measures ANOVA; Fig. 1C). In addition, there was a significant interaction between the effects of pressure and stimulation frequency (P < 0.001), indicating that the slope of their relationship differed between 30 and 90 mmHg. Furthermore, the percentage reduction in diameter (i.e. relative to the baseline value) was larger at the higher pressure when stimulated at both 2 Hz (30 mmHg, 1.4 ± 0.03%; 90 mmHg, 5.8 ± 0.08%; P < 0.05, Student's unpaired t test) and 10 Hz (30 mmHg, 9.2 ± 0.2%; 90 mmHg, 16.7 ± 0.2%; P < 0.05, Student's unpaired t test). In control experiments, in which no drugs were added, there were no significant differences in the amplitude of vasoconstrictions for the three successive frequency response curves (n = 6, P > 0.05, repeated-measures ANOVA).
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The contribution of noradrenergic and purinergic mechanisms to neurally evoked vasoconstriction was assessed for responses to trains at 2 and 10 Hz. Figure 2 shows the absolute amplitude of the neurally evoked vasoconstrictor response at 30 and 90 mmHg before and during the sequential addition of either the 1-adrenoceptor antagonist prazosin (0.1 µM), or the P2-receptor antagonist suramin (0.1 mM), followed by the combination of both agents. At 90 mmHg, the amplitude of the prazosin-resistant (purinergic) vasoconstrictor response to stimulation at 2 and 10 Hz was significantly greater than that at 30 mmHg (Fig. 2A and C). By contrast, the amplitude of the suramin-resistant vasoconstrictor response to stimulation at either 2 or 10 Hz did not differ between 30 and 90 mmHg (2 Hz, P
= 0.28; and 10 Hz, P
= 0.23; Student's unpaired t tests; Fig. 2B and D). In combination, prazosin and suramin almost abolished the vasoconstrictor response to trains at 2 and 10 Hz.
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Pressure-induced changes in the response to ,-methylene ATP
Vasoconstriction to ,-methylene ATP (0.1 µM) was significantly larger at 90 mmHg compared with 30 mmHg when expressed either in absolute terms (n
= 7, P < 0.05, Student's unpaired t test; Fig. 3) or as a percentage reduction in diameter (30 mmHg, 7.0 ± 0.9%; 90 mmHg, 16.2 ± 3.8%, P < 0.05, Student's unpaired t test).
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The L-type Ca2+ channel blocker nifedipine (1 µM) significantly reduced vasoconstrictions to stimulation at 2 and 10 Hz in arteries held at 90 mmHg (Fig. 4A and B). In arteries held at 30 mmHg, nifedipine significantly reduced vasoconstrictions to stimulation at 10 Hz only (Fig. 4C and D). In arteries pretreated with prazosin (0.1 µM) to block the noradrenergic component of the neurally evoked response, nifedipine almost completely abolished vasoconstriction to trains at 2 and 10 Hz at both pressures (Fig. 4C and D).
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Increasing the pressure from 30 to 90 mmHg produced a significant decrease in the resting membrane potential (Fig. 5A and B). In addition, the rise in pressure caused an increase in the amplitude of EJPs evoked by single stimuli (Fig. 5A and C) and a reduction in EJP duration (30 mmHg, 516 ± 59 ms; 90 mmHg, 381 ± 37 ms; P < 0.05, Student's paired t test). As increasing the pressure did not change the rise time of EJPs (30 mmHg, 40 ± 5 ms; 90 mmHg, 37 ± 5 ms; P = 0.63, Student's paired t test), the reduction in EJP duration at 90 mmHg results from a marked speeding in their rate of decay. Increasing the pressure also revealed a small amplitude transient hyperpolarization that followed the EJP (Figs 5A and 6B). EJPs evoked by electrical stimulation were abolished by suramin (0.1 mM) at both 30 and 90 mmHg (Fig. 6A and B), confirming that they result from neurally released ATP. In addition, suramin abolished the transient hyperpolarization at 90 mmHg.
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Nifedipine (1 µM, n = 6) reduced the amplitude of the transient hyperpolarization that followed EJPs evoked at 90 mmHg (control, –1.4 mV ± 0.2; nifedipine, –0.3 ± 0.2 mV; P < 0.05, Student's paired t test). This change occurred without any alteration in the amplitude (control, 7.2 ± 0.9 mV; nifedipine, 7.6 ± 1.0 mV; P = 0.69, Student's paired t test) or the duration (control 241 ± 17 ms; nifedipine 254 ± 37 ms, P = 0.61, Student's paired t test) of EJPs.
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Discussion |
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,-methylene ATP at 90 mmHg.
Comparisons between isometrically and isobarically mounted rat and rabbit second-order mesenteric arteries have demonstrated that pressurization increases the sensitivity of the vascular smooth muscle to NA, histamine and angiotensin II (Dunn et al. 1994; Buus et al. 1994). Furthermore, the sensitivity to NA has been shown to increase as the intraluminal pressure is increased from 20 to 60 mmHg (Dunn et al. 1994). A similar pressure-related increase in vasoconstriction to ,-methylene ATP was obtained in the present study. These effects of increasing pressure on agonist sensitivity can, at least in part, be explained by an amplifying effect of increasing wall tension on agonist potency (VanBavel & Mulvany, 1994). It is also possible that the pressure-induced increase in wall tension contributes to the increased amplitude of neurally evoked vasoconstrictions at 90 mmHg. However, increasing pressure from 30 to 90 mmHg did not increase the amplitude of the suramin-resistant component of the vasoconstriction (i.e. the noradrenergic component) but it did increase the amplitude of the prazosin-resistant component of vasoconstriction (i.e. the purinergic component). These findings indicate that raising pressure selectively increases the purinergic component of neurally evoked vasoconstriction.
In mesenteric arteries, activation of 1-adrenoceptors by neurally released NA produces contraction through the release of Ca2+ from intracellular stores (Lamont et al. 2003; Zacharia et al. 2007), whereas neurally released ATP activates P2X1-ligand-gated channels, leading to membrane depolarization and opening of voltage-gated Ca2+ channels (Brock & van Helden, 1995; Xi et al. 2002)). Furthermore, as the P2X1-receptor channels are Ca2+ permeable, Ca2+ from this source may contribute to activation of the smooth muscle (Lamont et al. 2003). Indeed, Gitterman & Evans (2001) have suggested that Ca2+ entry through P2X1-receptor channels is primarily responsible for purinergic contractions of isometrically mounted second-order mesenteric arteries, as they found that nifedipine only slightly reduced neurally evoked contractions of these arteries in the presence of prazosin. This finding contrasts with that of the present study where the purinergic component of neurally evoked contraction was almost abolished by nifedipine, suggesting that activation of the vascular smooth muscle by ATP is primarily dependent on Ca2+ entering through voltage-activated L-type Ca2+ channels. It should be noted that Mg2+ was not included in the physiological salt solution used by Gitterman & Evans (2001) in order to increase the amplitude of neurally evoked contractions. The absence of Mg2+ would increase neurotransmitter release from sympathetic nerve terminals (Shimosawa et al. 2004) and this would explain the increased response of the arteries but it does not explain the increased dependence of neurally evoked contraction on Ca2+ entering through P2X1-receptor channels. However, Xi et al. (2002) demonstrated that EJPs in second-order mesenteric arteries activate nifedipine-resistant Ca2+ channels (T-type), and it is possible that the contribution of these channels to activation of the arteries increases in the absence of Mg2+. Studies in other arteries using Mg2+-containing physiological solutions have demonstrated that neurally evoked contractions mediated by P2X-receptors are abolished by nifedipine (Omote et al. 1989; Bulloch et al. 1991).
Raising intraluminal pressure has previously been reported to produce a depolarization of the vascular smooth muscle in rat mesenteric arteries (Schubert et al. 1996). A similar pressure-induced depolarization of the vascular smooth muscle has also been reported in a range of other small arteries and arterioles, and this depolarization can lead to a pressure-induced increase in myogenic activity that depends on voltage-dependent Ca2+ channels (Davis & Hill, 1999). Such pressure-induced myogenic activity is rarely observed in rat second-order mesenteric arteries, but is present in smaller arteries in this vascular bed, where pressure-induced constriction depends primarily on activation of L-type Ca2+ channels (Wesselman et al. 1996). Nonetheless, the pressure-induced depolarization of the resting membrane potential will increase the level of depolarization attained during EJPs, which would be expected to increase activation of voltage-gated Ca2+ channels. Furthermore, the pressure-induced increase in EJP amplitude would also be expected to increase activation of voltage-gated Ca2+ channels. Together, these changes can probably account for the selective augmentation of purinergic transmission. Similarly, the level of depolarization produced by ,-methylene ATP is likely to be increased at 90 mmHg, contributing to the increased postjunctional reactivity to this agent.
A pressure-induced increase in the size of EJPs similar to that observed in the present study has previously been reported by Keef & Neild (1982) in small arteries isolated from guinea-pig ears. These EJPs are also purinergic (Morris et al. 1998), but the mechanisms whereby pressure increases EJP amplitude have not been established. However, as pressurization did not produce depolarization of the guinea-pig ear arteries, the increase EJP amplitude does not appear to depend on membrane depolarization. Because increasing pressure increases postjunctional sensitivity to exogenously applied NA and ,-methylene ATP, but selectively increases the purinergic component of neurally evoked contraction, we cannot exclude the possibility that increasing pressure increased the concentration of ATP at the postjunctional receptors. In guinea-pig submucosal arterioles, increasing intraluminal pressure has been shown to change the relationship between the innervating axons and the vascular smooth muscle, decreasing the distance between the pre- and postjunctional membranes (Luff et al. 1987). This change could potentially increase EJP amplitude. It is also possible that pressure-induced stretching of the nerve terminal axons increases neurotransmitter release, as integrins mediate a stretch-induced increase in neurotransmitter release at frog skeletal neuromuscular junctions (Grinnell et al. 2003).
In the mesenteric arteries, EJPs evoked at 90 mmHg had shorter durations than those evoked at 30 mmHg and this change was due to speeding in their rate of decay. As the junctional current that underlies the EJP is much briefer than the change in membrane potential (Åstrand & Stjärne, 1989), the rate of EJP decay is determined primarily by the smooth muscle membrane time constant (see Tan et al. 2007). As the membrane time constant is the product of membrane resistance and capacitance, speeding in the rate of decay of EJPs is most likely to reflect a decrease in membrane resistance (i.e. assuming the specific membrane capacitance does not change). This change may reflect a pressure-induced increase in ion channel activity or depolarization-induced activation of voltage-dependent ion channels. Speeding in EJP time course cannot be attributed to activation of L-type Ca2+ channels, as nifedipine had no effect on EJP duration at 90 mmHg. Furthermore, the increase in amplitude of EJPs at 90 mmHg cannot be attributed to activation of L-type Ca2+ channels, as it was also unaffected by nifedipine, but this agent did reduce the transient hyperpolarization that followed EJPs at this pressure. The simplest explanation is that the hyperpolarization results from activation of Ca2+-activated K+ channels by Ca2+ entering through L-type Ca2+ channels. Suramin abolished both the EJP and the hyperpolarization, supporting the view that it is triggered by depolarization-induced Ca2+ entry.
Membrane depolarization would be expected to reduce the driving force for the ions generating the junctional current. However, when the membrane conductance change is brief compared to the potential change, the reduction in the drive force produced by depolarizing the membrane by 5–10 mV from 60 mV (when the reversal potential for the junctional current is 0 mV; Finkel et al. 1984) would produce only a small reduction in the amplitude of EJPs (<5%; McLachlan & Martin, 1981). In addition, reducing membrane resistance would have a relatively small effect on the amplitude of EJPs generated by the junctional current, as the effects of changing membrane resistance are largely compensated for by speeding in the membrane time constant (see Tan et al. 2007). Nonetheless, the pressure-induced increase in EJP amplitude would be expected to slightly underestimate the increase in the underlying junctional current.
The findings of this study are consistent with previous reports that ATP plays a role in neuroeffector transmission in rat mesenteric arteries (Sjoblom-Widfeldt et al. 1990; Gitterman & Evans, 2001; Brock et al. 2006), but in addition indicate that the contribution of this neurotransmitter is selectively increased when the distending pressure is increased. While the precise pressure experienced by the second-order mesenteric arteries in vivo is not known, Fenger-Gron et al. (1995) have shown in conscious rats that the pressure in arteries at the base of the mesenteric arcade (near the distal end of the tertiary/quaternary mesenteric artery branches) is approximately 65% of mean arterial pressure (MAP), while the pressure at the superior mesenteric artery is around 95% of MAP. Since the MAP in conscious rats is approximately 120 mmHg (Fenger-Gron et al. 1995), the second-order mesenteric arteries used in the present study will experience a mean pressure somewhere between about 80 and 115 mmHg. Thus, at physiological pressure (90 mmHg), the present data indicate that ATP is the predominant sympathetic neurotransmitter in mesenteric arteries. It is worth noting that most studies of neurotransmission in isometrically mounted mesenteric arteries have set the vessel lumen circumference at 90% of that measured when the distending pressure estimated using Laplace's equation is 100 mmHg (Angus et al. 1988; Sjoblom-Widfeldt et al. 1990; Brock et al. 2006) and at this setting the distending pressure under basal conditions is approximately 50 mmHg (see Brock et al. 2006).
In conclusion, raising intraluminal pressure selectively increases the contribution of neurally released ATP to activation of rat mesenteric arteries. The simplest explanation for this change is that the pressure-induced depolarization of the vascular smooth muscle, together with the increased amplitude of EJPs, augments the neurally evoked influx of Ca2+ through L-type Ca2+ channels leading to an increase in the purinergic component of vasoconstriction. These findings indicate that the physiological importance of ATP as a functional sympathetic neurotransmitter increases as intraluminal pressure increases. The increased responses produced by ATP at higher pressures could contribute to or exacerbate the raised pressure observed in hypertension.
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P < 0.05, comparison between the constrictions of the tissues maintained at 30 and 90 mmHg (Student's unpaired t tests).
