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1 Department of Medicine, College of Medicine, University of California, Irvine, Irvine, CA 92697, USA
2 Department of Physiology and Biophysics, College of Medicine, University of California, Irvine, Irvine, CA 92697, USA
3 Department of Bioengineering, School of Engineering, University of California, Irvine, CA 92697, USA
4 Susan Samueli Center for Integrative Medicine, College of Medicine, University of California, Irvine, Irvine, CA 92697, USA
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Abstract |
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- and 47 C-fibres) were identified. Administration of histamine (10 µg kg–1) and BK (1 µg) in combination into the left atrium (LA) caused an additive response in 16 afferents compared with administration of either BK or histamine alone (2.62 ± 0.39 versus 1.67 ± 0.20 versus 1.24 ± 0.23 impulses s–1 (imp s–1), BK + histamine versus BK versus histamine). To further evaluate interactions between these mediators, we observed that injection of histamine (10 µg kg–1, LA) 4 min after the administration of BK (1 µg, LA) induced a significantly larger cardiac afferent response than the response to histamine before BK (1.24 ± 0.23 versus 1.96 ± 0.39 imp s–1, before versus after, n
= 10). In contrast, six other afferents responded reproducibly to repeated injections of histamine (10 µg kg–1, LA) in the absence of BK. BK sensitization of the afferent response to histamine lasted for less than 10 min. Cyclooxygenase blockade with indomethacin (5 mg kg–1, I.V.) abolished BK sensitization of the response to histamine (1.09 ± 0.11 versus 1.11 ± 0.10 imp s–1, n
= 10). Conversely, the response of most (7/9) cardiac afferents to repeat application of BK (1 µg, LA) 4 min after histamine (10 µg kg–1, LA) was attenuated compared with the BK response before histamine (1.84 ± 0.25 versus 1.31 ± 0.18 imp s–1, before versus after, P < 0.05). Repeat BK (1 µg, LA) induced a consistent response in five other afferents in the absence of histamine. Thus, BK interacts with histamine, and together they cause a larger response than either one alone. BK sensitizes cardiac afferents responding to histamine in a time-dependent fashion, and the BK sensitization effect is dependent on an intact cyclooxygenase pathway. Conversely, histamine reduces the response of most afferents to BK.
(Received 28 January 2005;
accepted after revision 16 March 2005;
first published online 17 March 2005)
Corresponding author L.-W. Fu: Department of Medicine, C240 Medical Sciences I, University of California at Irvine, Irvine, CA 92697, USA. Email: lwfu{at}uci.edu
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Introduction |
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Of the many ischaemic metabolites, BK, a potent nociceptive agent, excites somatic and visceral A- and C-fibre afferents, and sensitizes these sensory nerve endings to mechanical, thermal and chemical stimulation (Dray & Perkins, 1993; Rivera et al. 2000; Liang et al. 2001). For example, previous studies have demonstrated that BK activates cardiac and abdominal visceral afferents through stimulation of kinin B2 receptors leading to sympathoexcitatory reflex responses, including transient hypertension (Tjen-A-Looi et al. 1998; Guo et al. 2002). Also, several studies have shown that BK sensitizes somatic afferents to mechanical and thermal stimulation (Kumazawa et al. 1991; Rivera et al. 2000). Sensitization refers to an increase in the magnitude of response, sometimes accompanied by an increase in spontaneous activity and/or a decrease in response threshold (Gebhart, 2000). In contrast, other studies have concluded that BK desensitizes mechanically and chemically sensitive cardiac spinal afferents to chemical stimulation (Baker et al. 1980). Thus, there are conflicting conclusions regarding the influence of BK on somatic and visceral afferents in response to mechanical and chemical stimulation.
Histamine, another metabolite released during myocardial ischaemia, can also stimulate or sensitize somatic and visceral sensory nerve endings (Fu et al. 1997, 2005; Herbert et al. 2001; Koda & Mizumura, 2002). In this respect, we recently demonstrated that, during ischaemia, histamine activates visceral spinal afferents innervating the heart and the abdominal visceral organs (Fu et al. 1997, 2005). Others have shown that histamine also excites somatic and testicular afferents (Herbert et al. 2001; Koda & Mizumura, 2002). Furthermore, histamine enhances the responses of these afferents to heat and mechanical stimulation (Koda & Mizumura, 2002), implying that histamine can sensitize visceral afferents to chemical stimulation. There is no information, however, on the influence of histamine on the cardiac afferent responses to other chemical stimuli.
Previous observations suggest the possibility of interaction between BK and histamine on cardiac spinal afferents. First, the concentrations of these two mediators are increased simultaneously during brief myocardial ischaemia (Kimura et al. 1973; Kounis & Zavras, 1991; Frangogiannis et al. 1998). Second, both BK and histamine contribute to activation of cardiac spinal afferents during brief myocardial ischaemia (Tjen-A-Looi et al. 1998; Fu et al. 2005). However, earlier studies have reached different conclusions with respect to the interactions between BK and histamine on somatic and abdominal visceral afferents (Stebbins et al. 1992; Koppert et al. 2001). For instance, some studies have determined that BK and histamine reciprocally sensitize somatic and visceral afferents to the action of the other mediator (Brunsden & Grundy, 1999; Koppert et al. 2001). Another study suggested that histamine desensitizes visceral afferents to BK (Stebbins et al. 1992). Thus, it is unclear whether these mediators sensitize or desensitize visceral afferents to each other. Furthermore, the mechanism of interaction between these two mediators on ischaemically sensitive cardiac spinal afferents has not been investigated.
With respect to possible mechanisms, most studies agree that prostaglandins sensitize somatic sensory nerve fibres to thermal, mechanical and chemical stimulation (Schuligoi et al. 1994; Wang et al. 1996; Petho et al. 2001). In this respect, prostaglandins sensitize cardiac and testicular afferents to BK (Nerdrum et al. 1986; Mizumura et al. 1987). Importantly, both BK and histamine induce prostaglandin production through a mechanism that includes activation of phospholipase A2 (PLA2) to generate arachidonic acid from phospholipids; (Juan & Sametz, 1980; White & Kaliner, 1988; Prado et al. 1997). Therefore, neural interactions between BK and histamine, particularly those leading to altered sensitivity of afferent nerve endings, probably involve a prostaglandin mechanism.
The purpose of the present study was to evaluate interactions between BK and histamine in their influence on cardiac spinal afferents that respond to ischaemia. We hypothesized that BK sensitizes ischaemically sensitive cardiac afferents responding to histamine, and that histamine potentiates the response of these afferents to BK. Furthermore, we postulated that interaction between BK and histamine would be mediated through a cyclooxygenase mechanism. A preliminary report of this work has been presented (Fu & Longhurst, 2004).
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Methods |
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A total of 55 adult cats of either sex (2.1–4.7 kg) were anaesthetized by intramuscular injection of ketamine (20–30 mg kg–1; Phoenix Scientific, Inc., St Joseph, MO, USA) followed by intravenous injection of 
-chloralose (40–50 mg kg–1). Additional injections of -chloralose (5–10 mg kg–1, I.V.) were given as necessary to maintain an adequate depth of anaesthesia, which was assessed by observing the absence of a conjunctival reflex. The trachea of each animal was intubated, and respiration was maintained artificially (Harvard pump, model 661, Ealing, South Natick, MA, USA). Animals were ventilated by air supplemented with 100% O2 through the respirator. The femoral vein and artery were cannulated for administration of drugs and fluid, as well as for measurement of blood pressure. A PE 90 catheter was introduced into the left atrium (LA) through the left atrial appendage for intracardiac injection. Arterial blood pressure was measured by a pressure transducer (Statham P 23 ID; Gould) connected to the femoral arterial catheter. Arterial blood gases were assessed frequently by a blood gas analyser (ABL-5; Radiometer, Copenhagen, Denmark) and were maintained within physiological limits (PO2 > 100 mmHg, PCO2
= 28–35 mmHg, pH 7.35–7.45) by adjusting the respirator rate or tidal volume, or by intravenously administering 2–3 ml of 1 M NaHCO3 (8.4%, w/v). Body temperature was monitored by a rectal thermistor, and maintained at 36–38°C with a circulating water heating pad and a heat lamp. At the end of the experiment, animals were killed by administration of a solution of saturated potassium chloride into the femoral vein after being rendered insentient with a supplement of -chloralose (50 mg kg–1). Surgical and experimental protocols used in this study were approved by the Animal Use and Care Committee at the University of California at Irvine. The studies conformed to American Physiological Society's ‘Guiding Principles in the Care and Use of Animals’.
Cardiac spinal afferent recording
Single-unit cardiac spinal afferent activity was recorded as previously described (Tjen-A-Looi et al. 1998; Fu & Longhurst, 2002b). In brief, a midline sternotomy was performed, and the first through to the seventh left ribs and the left lung were removed. The left paravertebral sympathetic chain was isolated, then draped over a plexiglass platform and covered with warm mineral oil. Small nerve filaments were dissected gently from the chain or rami communicantes between T2 and T5 under an operating microscope (Zeiss, Germany), and the rostral ends were placed across one pole of a recording electrode. The other pole of the recording electrode was grounded with a cotton thread to the animal. The recording electrode was attached to a high-impedance probe (model HIP511; Grass Instruments, Quincy, MA, USA). Action potentials were amplified (model P511 preamplifier; Grass Instruments) and processed through an audioamplifier (AM8B, audiomonitor; Grass Instruments) and an oscilloscope (model 2201; Tektronix, Beavertown, OR, USA). Nerve activity and blood pressure were recorded simultaneously on a chart recorder (K2G; Astro-Medical, West Warwich, RI, USA). Afferent activity also was processed with a Pentium computer through an analog-to-digital converter (CED micro 1401 mkII; CED, Cambridge, UK) for subsequent off-line analysis. Discharge frequency of afferents was analysed with data acquisition and analysis software (Spike 2; CED) and a rate histogram was created for each afferent. Accurate assessment of impulse activity was verified for each afferent by comparing the constructed histogram with the original neurogram.
The receptive field of each afferent was located by mechanical stimulation of the heart. This included constricting the thoracic aorta as well as gently probing the heart with a cotton swab. The location of the afferent nerve ending was confirmed by placing a stimulating electrode directly on the surface of the myocardium to evoke the afferent's action potential. In the present study, each afferent had a single receptive field that could be located precisely in one of the ventricles. Conduction velocity (CV) of each afferent fibre was calculated by dividing conduction distance by conduction time. The conduction time was determined by measuring the time interval from electrical stimulation and the evoked afferent's action potential. The conduction distance was estimated by measuring the length of a wet thread between the receptive field and recording electrode (Fu & Longhurst, 2002b). C- and A-fibre afferents were classified as those with CVs of <2.5 and 2.5–30 m s–1, respectively (Fu & Longhurst, 2002a).
Myocardial ischaemia was induced by complete occlusion of the appropriate coronary artery supplying the receptive field of the cardiac afferent nerve with a thread placed around the vessel. Ischaemia was confirmed by observing a regional change in the colour of the myocardium, which has been closely correlated with the production of lactic acid, as indicated by a reduction in tissue pH (Pan et al. 1999). Afferents were considered to be ischaemically sensitive if their discharge activity during 3–5 min of myocardial ischaemia was increased at least twofold above baseline activity (Fu & Longhurst, 2002a,b).
Experimental protocols
Influence of BK on responses of cardiac afferents to histamine. Ten cats were subjected to 3–5 min of myocardial ischaemia followed by 2–3 min of reperfusion. After identifying an ischaemically sensitive cardiac afferent, we injected histamine (10 µg kg–1) into the LA and recorded discharge activity of cardiac afferent as previously described (Fu & Longhurst, 2002a). BK (1 µg, LA) then was administrated (Fig. 1). Repeat stimulation with histamine (10 µg kg–1, LA) was conducted 4 min after administration of BK, and 25 min after the first application of histamine. Thirty minutes later, the response of the afferent to LA injection of histamine (10 µg kg–1) + BK (1 µg) together was evaluated. Histamine and BK (Sigma) were dissolved in 0.9% NaCl and were prepared fresh daily.
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Time course of influence of BK on response of afferents to histamine. The time course of the influence of BK on the histamine-induced discharge of cardiac afferents was evaluated. After identification of an ischaemically sensitive cardiac afferent, histamine (10 µg kg–1) was injected into the LA, and afferent activity was recorded. Subsequently BK (1 µg, LA) was administered. Repeat injection of histamine (10 µg kg–1, LA) was conducted 4, 7 or 10 min in 10, 5 and 5 animals after administration of BK, and 30 min after the first application of histamine, respectively (Fig. 1).
Response of BK–histamine interaction to cyclooxygenase blockade. In 10 other animals, we examined the influence of cyclooxygenase inhibition with indomethacin (5 mg kg–1, I.V.) on the interaction between BK and histamine in 10 ischaemically sensitive cardiac afferents. This dose of indomethacin effectively abolishes the visceral afferent response to prostaglandins (Longhurst et al. 1991). Indomethacin (Sigma) was dissolved in 8.4% sodium bicarbonate solution, diluted with 0.9% NaCl to a concentration of 10 mg ml–1. After identifying an ischaemically sensitive unit, the afferent response to histamine (10 µg kg–1, LA) was evaluated (Fig. 1). Indomethacin then was administered intravenously. We repeated histamine 30 min after its initial application and 15 min after treatment with indomethacin. Then, BK (1 µg, LA) was injected, and histamine (10 µg kg–1, LA) was injected again 4 min after treatment with BK and 25 min after the second administration of histamine.
An identical procedure was conducted in a time control group of animals (n = 5), with the exception that saline (1 ml, I.V.) was substituted for indomethacin (Fig. 1).
Influence of histamine on response of afferents to BK. We examined the effect of histamine on the BK-evoked discharge activity of nine cardiac afferents. After identification of an ischaemically sensitive fibre, the response of the afferent to BK (1 µg, LA) was evaluated (Fig. 1). Histamine (10 µg kg–1, LA) was then administered. Repeat stimulation with BK (1 µg, LA) was conducted 4 min after histamine and 25 min after the first application of BK. Thirty minutes later, the response to LA injection of histamine (10 µg kg–1) + BK (1 µg) was examined. Since these responses were similar to those obtained with BK + histamine in the first protocol, the data were combined.
To determine consistency of response of the afferents to BK, we studied six other ischaemically sensitive cardiac afferents as time controls (Fig. 1). After identification of an ischaemically sensitive unit, each animal in this group was treated identically, with the exception that histamine was replaced by saline (0.2 ml, LA).
Data analysis
Discharge activity of cardiac spinal afferents, expressed in impulses per second (imp s–1), was averaged during 3–5 min of pre-ischaemia and 5 min of ischaemia. We measured the responses of cardiac afferent nerve endings to histamine, BK, and histamine + BK by averaging discharge rates of the afferents during the entire period of response, defined as the time during which sustained activity exceeded baseline activity by 20%. Baseline activity was determined over the 1–2 min period immediately preceding chemical injection, or the 3–5 min period immediately preceding ischaemia.
Data are expressed as means ± S.E.M. The Kolmogorov–Smirnov test was used to determine if the data were distributed normally. Normally distributed data in all protocols were compared with a one-way repeated-measures analysis of variance (ANOVA) with Tukey's post hoc test. Non-normally distributed data in all protocols were compared with the Friedman repeated-measures analysis of variance on ranks with a Dunnett's post hoc test. All statistical calculations were performed with Sigmastat software (Jandel Scientific Software, San Rafael, CA, USA). Values were considered to be significantly different when P < 0.05.
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Results |
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The activities of 55 ischaemically sensitive cardiac afferents were recorded in the present study. Endings of most (91%) afferents were located in the anterior (n
= 18) and posterior (n
= 34) wall of the left ventricle (Fig. 2). Three afferents were located on the posterior wall of the right ventricle. The conduction velocity for these afferents ranged from 0.2 to 5.6 m s–1. Eighty-five per cent (47 fibres) of these afferents were classified as C-fibres (CV = 0.82 ± 0.07 m s–1). The remaining units (eight afferents) were classified as A-fibres (CV = 3.94 ± 0.13 m s–1). No obvious association was found between CV and the responsiveness of the fibres to chemical stimulation or ischaemia.
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We observed a larger response to histamine and BK in the 16 ischaemically sensitive cardiac afferents compared to either histamine or BK response alone (2.62 ± 0.39 versus 1.67 ± 0.20 versus 1.24 ± 0.23 imp s–1, BK + histamine versus BK versus histamine, Fig. 3). The simultaneous presentation of the two algogenic substances evoked a simple additive effect (Fig. 3).
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An example of the response of an ischaemically sensitive afferent (CV = 0.66 m s–1), innervating the posterior wall of the left ventricle to histamine (10 µg kg–1, LA, Fig. 4B1), BK (1 µg, LA, Fig. 4B(2)), and repeat histamine (10 µg kg–1, Fig. 4B(3)) 4 min after BK is shown in Fig. 4. Discharge activity of this cardiac afferent increased from 0.85 to 2.91 imp s–1 during ischaemia (Fig. 4A). Both histamine (Fig. 4C, trace 1) and BK (Fig. 4C, trace 2) caused reversible bursts of afferent activity. BK augmented the response to histamine by 55% compared with the initial histamine response (Fig. 4C, trace 3).
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, CV = 5.57 m s–1; 9 C-fibres, CV = 0.81 ± 0.24 m s–1) to histamine by 58% (Fig. 5). The activity of these afferents was increased from 0.65 ± 0.16 to 2.78 ± 0.32 imp s–1 during brief myocardial ischaemia. In a pilot study, we administered histamine and BK first, and then examined the sensitivity of the afferent to ischaemia in two fibres. Alternatively, we identified an ischaemically sensitive unit, and 20 min later we examined the response to histamine and BK in two other fibres. We observed that the responses of the four afferents to histamine and BK before and after ischaemia were similar. Thus, in the present study we injected histamine or BK 20 min after ischaemia. We found that histamine (10 µg kg–1, LA) and BK (1 µg, LA) stimulated all 10 afferents, significantly increasing their activity from 0.49 ± 0.14 to 1.24 ± 0.23, and 0.65 ± 0.11 to 2.26 ± 0.21 imp s–1 (Fig. 5A), respectively. Compared with the initial response to histamine, this group of afferents responded more robustly to histamine after BK (1.24 ± 0.23 versus 1.96 ± 0.39 imp s–1, initial versus repeat, P < 0.05). In contrast, the response of the six other cardiac afferents (1 A, CV = 2.96 m s–1; 5 C-fibres, CV = 0.87 ± 0.08 m s–1) to repeat histamine, in the absence of BK, was unchanged during the same time period (Fig. 5B).
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The influence of BK on histamine-evoked activity of ischaemically sensitive cardiac spinal afferents was relatively short-lived (Fig. 6). In this respect, we observed that histamine (10 µg kg–1, LA) and BK (1 µg, LA) stimulated all afferents, significantly increasing their discharge activity. Compared with the initial response to histamine (defined as 100% response), the responses to repeat application of histamine 4 and 7 min after BK treatment were augmented by 173 and 123%, respectively. Conversely, the response to histamine 10 min after BK was not significantly different from the initial response to histamine (Fig. 6).
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We observed that inhibition of cyclooxygenase activity with indomethacin prevented the BK-induced augmentation of the responses to histamine in 10 cardiac spinal afferents (2 A, CV = 3.98 and 4.21 m s–1; 8 C-fibres, CV = 0.84 ± 0.20 m s–1, Fig. 7). Thus, initial administration of histamine (10 µg kg–1, LA) increased the activity of each of the afferents from 0.43 ± 0.07 to 1.62 ± 0.12 imp s–1 (Fig. 7A). The influence of histamine after indomethacin (5 mg kg–1, I.V.) was reduced by 33% (1.62 ± 0.12 versus 1.09 ± 0.11 imp s–1, first versus second histamine response, P < 0.05, Fig. 7A). The response to histamine 4 min after BK (1 µg, LA) in the presence of indomethacin was similar to the second histamine response (1.09 ± 0.11 versus 1.11 ± 0.1 imp s–1, second versus third histamine response, Fig. 7A). Thus, indomethacin reduced the afferent response to histamine and to histamine following BK sensitization. In a control group of afferents (5 C-fibres, CV = 0.76 ± 0.21 m s–1), we observed consistent responses to repeat histamine in the absence of indomethacin and an enhanced response to a third histamine stimulation following BK (1.29 ± 0.17 versus 2.01 ± 0.12 imp s–1, second versus third histamine response, P < 0.05, Fig. 7B), similar to our earlier protocol (Fig. 5A). The histogram and neurograms in the Fig. 8 show the response of an ischaemically sensitive afferent (CV = 2.47 m s–1) to repeated stimulation with histamine (10 µg kg–1, LA) before (Fig. 8B, trace 2) and 4 min after (Fig. 8B, trace 3) BK (1 µg, LA) in the presence of indomethacin (5 mg kg–1, I.V.). Discharge activity of this cardiac afferent increased from 1.05 to 2.01 imp s–1 during ischaemia. Following treatment with indomethacin, before and after BK (Fig. 8B, traces 2 and 3) histamine evoked similar afferent responses (0.66–2.11 versus 0.75–2.25 imp s–1, before versus after BK), confirming that cyclooxygenase inhibition abolished the BK-related sensitization of this afferent to the action of histamine (Fig. 8).
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Seven of nine cardiac afferents (2 A, CV = 3.84 and 4.47; 5 C-fibres, CV = 0.77 ± 0.18 m s–1) responded less to repeat BK after histamine compared with the initial BK response (1.84 ± 0.25 versus 1.31 ± 0.18 imp s–1, initial versus repeat BK, P < 0.05, Fig. 9A). Conversely, two other C-fibre cardiac afferents (CV = 0.51 and 2.1 m s–1) displayed an enhanced response to the second BK stimulation following histamine (0.04–1.53 versus 0.1–1.84, and 0.1–1.02 versus 0.08–2.3 imp s–1, initial versus repeat BK for each afferent). Five other ischaemically sensitive afferents (1 A, CV = 3.38; 4 C-fibres, CV = 0.84 ± 0.26 m s–1) responded consistently to repeat BK in the absence of histamine (Fig. 9B).
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Discussion |
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The possibility that BK potentiates the response of cardiac spinal afferents to histamine was proposed more than a decade ago (Meller & Gebhart, 1992). Several lines of evidence support this suggestion. For instance, we and others have demonstrated that brief coronary artery occlusion activates cardiac spinal afferents (Tjen-A-Looi et al. 1998; Fu & Longhurst, 2002b). Brief ischaemia causes simultaneous release of both BK and histamine (Kimura et al. 1973; Kounis & Zavras, 1991; Frangogiannis et al. 1998). Both mediators contribute to activation of cardiac spinal afferents during myocardial ischaemia (Tjen-A-Looi et al. 1998; Fu et al. 2005). Also, previous in vitro studies of somatic and testicular sensory nerve fibres have shown that BK sensitizes these fibres to thermal and mechanical stimulation (Liang et al. 2001; Koda & Mizumura, 2002). Thus, BK potentially has the capability of enhancing the response of cardiac spinal afferents to histamine. However, earlier studies have shown that the influence of BK on the response of sensory nerve fibres to histamine stimulation is controversial. For example, studies have shown that BK potentiates histamine-evoked reflex bronchospasm and the response of polymodal cutaneous afferents in vitro (Koppert et al. 2001; Mazzone & Canning, 2002). Conversely, other studies have suggested that BK reduces the response of the cutaneous afferents to histamine and may desensitize chemically sensitive cardiac spinal afferents (Baker et al. 1980; Koppert et al. 2001). In addition, most previous studies of BK's influence on histamine response have been conducted in vitro and have used pharmacological concentrations of BK (Koppert et al. 2001; Liang et al. 2001). There have been no studies of the influence of BK on the response of ischaemically sensitive cardiac spinal afferents to histamine. The present in vivo study provides the first neurophysiological data demonstrating that BK in pathophysiological concentrations (Fu et al. 1997) enhances the response of ischaemically sensitive cardiac spinal afferents to histamine.
Previous studies have reached different conclusions regarding the duration of the BK sensitization of sensory nerve fibres to stimulation (Koltzenburg et al. 1992; Koppert et al. 2001). For instance, several in vitro studies concluded that BK provides short-lived (<5–10 min) potentiation of rat cutaneous polymodal afferents to thermal or chemical stimulation (Koltzenburg et al. 1992; Koppert et al. 2001; Liang et al. 2001). In contrast, an in vivo study suggested that BK sensitizes rat cutaneous nociceptive sensory fibres to mechanical stimulation leading to hyperalgesia for more than 20 min (Taiwo et al. 1987). There have been no studies of the duration of BK's potentiation of the response of visceral afferents to histamine. Although we anticipated from the previous in vivo study that the duration of BK-induced sensitization of cardiac spinal afferents to histamine would be prolonged, the present study suggests that the potentiation of BK is short-lived, at least with respect to histamine and its action on cardiac spinal afferents.
The mechanism underlying the interaction between BK and histamine on cardiac spinal afferents has not been elucidated previously (Koppert et al. 2001; Mazzone & Canning, 2002). Cyclooxygenase products as well as the protein kinase C (PKC) signalling pathway are potentially involved. BK stimulates visceral spinal afferents originating from the heart or the abdominal visceral organs partially through a cyclooxygenase mechanism as well as through a PKC signalling pathway (Tjen-A-Looi et al. 1998; Guo et al. 1999). Also, BK sensitizes polymodal somatic C-fibre afferents to thermal stimulation through the cyclooxygenase production mechanism (Petho et al. 2001). Through an intracellular PKC pathway, BK potentiates cutaneous nociceptors responding to heat stimulation (Cesare & McNaughton, 1996; Sugiura et al. 2002). Our present data show that indomethacin is able to eliminate fully the BK-related facilitation of histamine's action on cardiac spinal afferent. As such, this study demonstrates that the BK sensitization of the afferent response to histamine is mediated by cyclooxygenase products.
We proposed that histamine could potentiate the cardiac afferent response to BK, since previous studies either directly or indirectly implied this possibility. In this respect, in vitro experiments have shown that histamine sensitizes testicular polymodal afferents to thermal and mechanical stimulation (Koda et al. 1996; Koda & Mizumura, 2002), and in high concentrations (100 M) it facilitates the response of visceral afferents to BK stimulation (Mizumura et al. 1995; Brunsden & Grundy, 1999). However, other studies of testicular polymodal afferents and abdominal visceral afferents have reported that histamine suppresses the afferent response to BK (Stebbins et al. 1992; Mizumura et al. 1995). As such, the results of previous studies are contradictory. In the present investigation we have observed that histamine reduces the responses of most cardiac spinal afferents to BK, indicating that histamine desensitizes cardiac spinal afferents to BK stimulation.
As a point of particular interest, we also found that the net result of the sensitization of the histamine response by BK and the desensitization of the BK response by histamine led to an additive response when both mediators were administered simultaneously. This net response is probably most relevant to the intact animal experiencing myocardial ischaemia, since BK and histamine are released within the same time period during ischaemia (Kimura et al. 1973; Kounis & Zavras, 1991; Frangogiannis et al. 1998). The combined action reflects the individual influences of histamine and BK on each other.
In conclusion, this study is the first to demonstrate that BK sensitizes ischaemically sensitive cardiac spinal afferents to histamine in a time-dependent fashion, and that such sensitization requires an intact cyclooxygenase pathway. In contrast, histamine reduces the response of most cardiac afferents to BK. However, when cardiac spinal afferents are exposed to BK and histamine simultaneously, a condition that occurs under the usual circumstance of ischaemia, the afferent response reflects summation of the individual responses to the two mediators.
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P < 0.05 compared with either BK or histamine.
P < 0.05 post-BK versus pre-BK.
