Br. J. Pharmacol. (1990), 99, 152-156

kf--" Macmillan Press Ltd, 1990

Dual effects of capsaicin on responses of the rabbit ear artery to field stimulation Hideki Moritoki, Hideshi Takase & Asao Tanioka Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokushima, Shomachi, Tokushima 770, Japan 1 The effects of capsaicin (Cap) on contractions of ring segments of rabbit ear artery induced by field stimulation were studied. 2 At low concentrations (0.3-3 gM) Cap caused transient enhancement and at higher concentrations (above 3 pM) inhibition of stimulation-induced contractions, without affecting noradrenaline (NA)-induced contractions. 3 In the continuous presence of high concentrations of Cap, rebound facilitation was observed after inhibition, and at this stage, Cap elicited less inhibition of the response. 4 Repeated application of Cap at 60 min intervals irreversibly desensitized the artery to the inhibitory effect of Cap. 5 Functional removal of the endothelium enhanced the facilitatory effect of low concentrations of Cap and attenuated its inhibitory effect. 6 Pretreatment with indomethacin abolished the facilitatory effect of Cap and enhanced its inhibitory effect, indicating that prostaglandins are involved in the action of Cap. The effect of indomethacin was more marked in preparations from which the endothelium had been removed. 7 Desensitization to substance P (SP) or substance K (SK), did not affect either the inhibitory or the facilitatory effect of Cap. 8 These results suggest that the dual effects of Cap on stimulation-induced contractions of rabbit ear artery may arise from the release of multiple mediators that act prejunctionally to modulate NA release. The stimulant effect seems to be mediated by prostanoids, while the inhibitory effect seems to be caused by a substance(s) that is not SP or SK. The possibility that the mediator is calcitonin gene-related peptide requires further study.

Introduction

Methods

Capsaicin (Cap), a pungent ingredient of hot pepper, causes pain and releases peptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) from primary sensory neurones (Jessell et al., 1978; Gamse et al., 1981; Duckles & Buck, 1982; Saito & Goto, 1986). Acute release or depletion of peptides, such as SP, substance K (SK; neurokinin A) and CGRP (Lundberg et al., 1985) from peripheral neurones is thought to be responsible for several Cap-induced responses. In blood vessels, Cap has been shown to cause either dilatation or contraction, depending on the species and portion of the vessels used (Duckles, 1986). Cap-induced increase in intestinal blood flow is thought to be mediated by SP (Rozsa et al., 1984; 1985). However, in some preparations, such as guinea-pig atria (Lundberg et al., 1984; Zernig et al., 1984) and cat cerebral artery (Duckles, 1986), the role of SP as a mediator of the action of Cap is controversial. Duckles (1986) demonstrated that in cerebral arteries, Cap-induced contractions are due to its direct action, whereas the dilatation is triggered by an as yet unidentified substance released by Cap.

The middle portion of the central artery of the rabbit ear was excised with parallel razors, separated from adjacent tissue and cut into ring segments, 4mm long, under a dissecting microscope. Each segment was set up in a 1O ml siliconized (to prevent adsorption of peptides) organ bath essentially by the method described by Bevan et al. (1975). Briefly, a U-shaped stainless wire was passed through the lumen of the ring segment and the ends of this wire were anchored to a plastic holder. A second wire was also passed through the lumen and connected to an isometric transducer (Nihon Kohoden TB-1TH) to measure contractions. The preparation was then immersed in Krebs solution of the following composition (mM): NaCI 115.3, KCl 4.7, CaCl2 1.6, MgSO4 1.2, NaHCO3 25.0 and glucose 11.1, maintained at 350C and bubbled with 95% 02 and 5% CO2. The resting tension of the artery was maintained at 1.0g. In rings precontracted with the EC80 concentration of noradrenaline (NA), 10 yM acetylcholine (ACh) caused 76.9% dilatation, indicating that functional endothelium remained. After an equilibration period of 60 min, the artery was stimulated with trains of 6 pulses, of 0.5 ms duration and supramaximal voltage at 8 Hz every 2 min, from a stimulator (Nihon Kohoden SEN 3201) with a constant voltage modulator, through a pair of platinum electrodes placed on either side of the artery. For construction of dose-response curves, Cap, CGRP or NA was added in a volume of 10 to 20yl to the lOml organ bath. To test the effect of Cap or CGRP on NA-induced contractions, these agents were added 5 min before NA. The facilitatory effect of a single dose of Cap was studied.

The actions of Cap on blood vessels described so far are postjunctional effects (Rozsa et al., 1984; 1985; Duckles, 1986): no prejunctional effects on blood vessels have yet been shown, although a prejunctional effect of Cap, irrespective of its direct or indirect action, is well documented for intestinal smooth muscle (Szolcsanyi & Bartho, 1979; Bartho et al., 1982; Chahl, 1982; Bartho & Vizi, 1985). We have shown that in rat vas deferens, Cap enhanced the stimulation-induced twitch response by a prejunctional mechanism (Moritoki et al., 1987). Hence, in the present work, we studied the effect of Cap on adrenergic transmission in the rabbit ear artery.

CAPSAICIN ON ADRENERGIC TRANSMISSION To investigate the function of the vascular endothelium, the endothelium of the artery was removed by rubbing the luminal surface of the artery with cotton thread. Removal of the endothelium was confirmed by the absence of a dilator response to ACh whilst the response to papaverine was unaffected. Pairs of preparations were used to study the effect of indomethacin and removal of the endothelium, because the artery was irreversibly desensitized to the inhibitory effect of Cap. A stock solution of 100 mm Cap in ethanol was diluted with Krebs solution immediately before use. The total amount of ethanol added to the organ bath (at most 1 gl) did not have any effect on the response of the preparation. Results are expressed as means + s.e.mean. Differences between values were examined by Student's t test, and a P value of less than 0.05 was considered significant. The drugs used were: capsaicin (Sigma Chemical Co., St Louis, Mo), calcitonin gene-related peptide and substance K (neurokinin A, gifts from Dr K. Kitagawa, University of Tokushima), substance P (Peptide Institute, Osaka, Japan), indomethacin (Sigma), caffeic acid (Sigma), tetrodotoxin (Sigma), guanethidine bitartrate (Sigma), clonidine hydrochloride (Sigma), acetylcholine chloride (Sigma) and noradrenaline bitartrate (Wako Chemical Co., Osaka, Japan).

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The effect of a low concentration of Cap (1 yM) is shown in Figure 1 (top left). A further stepwise increase in Cap concentration caused dose-dependent attenuation of the twitch-like response (Figure lb and Figure 2). The maximal inhibition caused by 20/IM Cap was 68.4 + 4.5% (n = 6). A single dose of a high concentration (20 pM) of Cap inhibited the response without showing an initial potentiating effect and the inhibition was followed by restoration and enhancement of the response (Figure 1, top right). The maximal inhibition caused by a single dose of 20pM Cap was 90.4 + 4.6% (n = 10), which was greater than that caused by the cumulative application of 20Mm Cap (68.4 + 4.7%, P < 0.01). The maximal inhibition induced by 20 Mm Cap decreased gradually with time in the continuous presence of Cap; half recovery was observed after about 10-20min, and thereafter the con-

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Dual effects of capsaicin

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Stimulation of ring segments of rabbit ear artery with trains of 6 pulses of 0.5 ms duration at 8 Hz every 2 min caused twitchlike contractions. The contractions were abolished by 0.1 Mm tetrodotoxin or lOpM guanethidine, indicating that the response was adrenergic. Cap 0.3 and 1 UM transiently enhanced the twitch-like contractions by 18.1 + 6.9% and 36.8 + 7.0% (n = 6, Figures 1 and 2), respectively, and the augmented response returned to the control level in 20min.

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Figure 1 Dual effects of capsaicin (Cap), and inhibitory effect of calcitonin gene-related peptide (CGRP) on the contractions of rabbit ear artery induced by field stimulation. Upper tracings show the potentiation at a low concentration (1 MM, upper left) and the inhibition followed by prolonged potentiation at a high concentration (20pM, upper right) of Cap administration at (0). The lower tracing shows the effects of cumulative addition of Cap (uM, 0) and CGRP (nM, 0). The ring segment was stimulated with trains of 6 pulses of 0.5 ms duration at 8 Hz every 2 min.

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Figure 2 (a) The influence of endothelium and indomethacin on the dose-response curves for dual effects of capsaicin (Cap) on the field stimulation-induced contractions of rabbit ear artery. The doseresponse curve for the initial stimulant effect of Cap was constructed from responses to single applications of 0.1, 0.3 and 11MM Cap, whereas that for its inhibitory effect was obtained by cumulative application (above 3 gM). Paired preparations were incubated with or without 1OOMm indomethacin for 60min, and washed for 30min before dose-response curves to Cap were constructed as above. Preparations: (O), with endothelium; (0), without endothelium; (A), with endothelium, indomethacin-treated; (A), without endothelium, indomethacin-treated. (n = 5). (b) Contractions of field stimulated rabbit ear artery after (0) a single dose of 20Mm Cap applied at zero time and after removal of Cap (0) by washing (arrow). The ordinates indicate responses as percentages of the twitch-like contractions elicited before administration of Cap. Experimental conditions were as for Figure 1. Vertical lines show s.e.mean (n = 6). * P < 0.05, ** P < 0.01, compared with the value for the control preparations with intact endothelium (unpaired t test).

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Figure 4 Twitch-like responses of rabbit ear artery to field stimulation showing the development of desensitization of the artery to the inhibitory effect of capsaicin (Cap, 201uM applied at 0). The first application of Cap caused inhibition followed by rebound potentiation of the response. A further addition of 20pM Cap was less inhibitory. The preparation was washed repeatedly for 60min (W) before re-exposure to 20.uM Cap. Experimental conditions were as for Figure 1.

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Figure 3 Effects of (a) capsaicin (Cap, 20 Mm) and (b) calcitonin generelated peptide (CGRP, 30nM) on noradrenaline (NA)-induced contractions of rabbit ear artery. (a) (0) Control preparations; (A) Cap-treated preparations in which Cap-induced inhibition was maximally developed (5min after 20,uM Cap); (E) Cap-treated preparations in which the Cap-induced rebound potentiation was maximally developed (30min after 20Mm Cap). (b) (0) Control preparations; (0) preparations in which CGRP-induced inhibition was maximally developed (5min after 30nM CGRP). The ordinates indicate percentages of the maximal contractions induced by NA. Vertical lines show s.e.mean (n = 6).

Unlike the inhibitory effect, the facilitatory effects of both low (1 Mm) and high (20 gM) concentrations of Cap were reproducible and were still observable in preparations that had been desensitized to the inhibitory effect of Cap (Figure 4). When the rebound potentiation developed 30min after application of a single dose of 20Mm Cap (163.1 + 54.4%, n = 6), NA-induced contractions (Figure 3) were, by contrast, slightly attenuated (pD2 values: 7.24 + 0.06; vs 6.81 + 0.14, n = 3, P < 0.05).

Involvement of prostanoids tractions increased gradually and finally reached 188.1 + 14.4% (n = 6) of the control level (Figures 1 and 2). Pretreatment with 20MM Cap for 5 min (at the time when the inhibition reached a maximum) did not affect NA-induced contractions (Figure 3).

Effect of the endothelium Removal of the endothelium by rubbing the luminal surface of the artery, which abolished the dilator response to 1OpM ACh (68.0 + 4.3% to 3.6 + 1.9%, n = 5), enhanced the stimulant effect of low concentrations of Cap (0.1 MM to 3 uM; Figure 2a). Also, facilitation of the response induced by 3yM Cap was significantly greater in arteries after removal of the endothelium (182.0 + 24.8%) than in those with intact endothelium (118.1 + 6.9%, n = 6, P < 0.05). Furthermore, arteries from which the endothelium had been removed did not dilate in response to Cap at concentrations of up to lOMyM.

Desensitization When the rebound response induced by 20MM Cap reached a maximum, further addition of 20MM Cap caused less attenuation of the response (Figure 1, bottom, and Figure 4). Washing the preparation for 60min restored the augmented field stimulation-induced response towards the initial level. Further addition of 20MM Cap elicited progressively less inhibition of the response, and usually on the 3rd application, Cap no longer inhibited, but enhanced the response. Once developed, the loss of sensitivity of the artery to Cap was irreversible, even after repeated washing of the preparation for more than 5 h (data not shown). However, in this state, in comparison with untreated preparations, the prejunctional inhibitory effect of clonidine was unaltered (pD2 value: 7.88 + 0.10; vs 8.06 + 0.04, n = 6, NS), as was the postjunctional inhibitory effect of papaverine (pD2 value: 5.34 + 0.10; vs 5.25 + 0.05, n = 4, NS).

Arterial segments were exposed to 100mm indomethacin, a cyclo-oxygenase inhibitor, for 60min, and then washed for 30 min to prevent a direct effect of indomethacin. The stimulation-induced twitch-like contractions were not affected by this treatment. However, treatment with indomethacin inhibited the facilitatory effect of Cap, i.e. the potentiation induced by low concentrations of Cap (0.3-1 gM), the rebound potentiation caused by higher concentrations of Cap (above 20 M) and Cap-induced potentiation observed in preparations desensitized to Cap (Figure 2). The effect of indomethacin persisted for up to 4 h after its washout from the bath. Indomethacin, while suppressing the potentiating action of Cap, slightly but not significantly affected the inhibitory effect. In preparations from which the endothelium had been removed, treatment with 100M indomethacin reversed the facilitation of the response induced by 3 gM Cap (182.0 + 24.8%) to inhibition (73.5 + 4.1% of the control contraction, n = 6). The extent of the reversal was greater than that in preparations with intact endothelium (104.7 + 8.5% to 83.6 + 6.6%, n = 6). However, after treatment with indomethacin, the extent of the Cap-induced inhibition in preparations with and without intact endothelium became almost the same. Unlike indomethacin, the lipoxygenase inhibitor caffeic acid (1O Mm) had no effect on either the inhibition or the rebound potentiation elicited by Cap (data not shown).

Effect of CGRP CGRP dose-dependently inhibited the field stimulationinduced contractions (Figure 5), its threshold concentration for inhibition was over 0.6nm, and its pD2 value 8.81 + 0.10 (n = 8). In the continuous presence of a high concentration of CGRP (30nM), the twitch-like contractions were restored to the level before CGRP addition in 30min, when further addition of this concentration of CGRP again caused inhibition. Hence, desensitization of the artery to CGRP did not develop under these experimental conditions. Furthermore, even when the artery had been irreversibly desensitized to Cap by its

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CGRP (nM) Figure 5 Inhibitory effect of calcitonin gene-related peptide (CGRP) on the contractions of rabbit ear artery induced by field stimulation. Responses are plotted as percentages of the initial contraction induced by field stimulation. Experimental conditions were as for Figure 1. Vertical lines show s.e.mean (n 8). =

repeated application, CGRP showed the

same inhibitory before desensitization (Figure 1). Like Cap (20pM, 30min treatment), higher concentrations of CGRP slightly attenuated NA-induced contractions: in the presence of 30 nm CGRP, the dose-response curve for NA was shifted 3.6 times to the right (Figure 3).

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Effects of substance P and substance K SP or SK (neurokinin A) at a concentration of 0.1 m transiently inhibited the field stimulation-induced response, and repeated application of these peptides did not inhibit the response any further: the inhibitions by 1 gm SP and SK were only 2.4% and 3.7% (n 3), respectively. The dual effects of Cap were virtually unaffected by development of desensitization to these peptides. =

Discussion was found to have dual actions on the twitch-like contractions of ring segments of rabbit ear artery induced by field stimulation at 8 Hz (Figure 1). Similar dual effects have been noted for guinea-pig ureter (Hua & Lundberg, 1986). The inhibitory effect of Cap on the field stimulation-induced contractions of rabbit ear artery was not due to a postjunctional action, unlike that obtained in guinea-pig arteries (Duckles, 1986), because Cap did not affect NA-induced contractions of the ear artery when its inhibitory effect was maximally developed. The results indicate that it acts prejunctionally and may inhibit the release of NA. The Cap-induced inhibition was not mediated through arachidonic acid metabolites, as it was not attenuated by compounds affecting the arachidonic acid cascade such as indomethacin and caffeic acid. The fact that the stimulant effect of Cap on field stimulation-induced contractions of the ear artery was abol-

In the present studies, Cap

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ished by indomethacin (Figure 2), but not by caffeic acid strongly suggests that the stimulant effect of Cap is mediated by cyclo-oxygenase-generated arachidonic acid metabolites. Cap has been found to stimulate prostaglandin formation (Collier et al., 1976) and to induce release of prostaglandins from the rabbit perfused ear artery (Juna et al., 1980) by activation of calcium-dependent phospholipase A2. Moreover, SP release induced by Cap showed tachyphylaxis, but Capinduced prostaglandin formation persisted. These phenomena seem analogous to the present findings that the rabbit ear artery became irreversibly desensitized to the inhibitory effect of Cap, but not to its potentiating effect. The potentiating effect of Cap on field stimulation-induced contractions is likely to be a prejunctional event, because when Cap-induced rebound potentiation developed 30 to 60min after the application of Cap, NA-induced contractions were not enhanced, but rather slightly attenuated (Figure 3). This idea is further supported by the findings of Toda et al. (1985) that prostaglandin D2 (PGD2) and PGF2a, increased [3H]-NA-efflux caused by nerve stimulation and enhanced the contractile response of isolated arteries to nerve stimulation, without affecting NA-induced contractions. The effects of Cap were at least in part influenced by the endothelium, which is a probable site for the production of arachidonic acid metabolite(s) in response to Cap. After removal of the endothelium, the facilitatory effect of Cap became dominant and masked its inhibitory effect (Figure 2), indicating that some inhibitory mediator(s), possibly endothelium-derived relaxing factor (EDRF) or an inhibitory prostanoid(s), is released from the endothelium and counteracts the stimulant effect of Cap. In contrast, treatment with indomethacin abolished the facilitatory effect and unmasked the inhibitory effect of Cap, especially in preparations in which the endothelium had been removed. Therefore, it is hypothesized that an arachidonic acid metabolite(s) with a stimulant effect is released by Cap from vascular smooth muscle and acts on the nerve to facilitate the response. These results imply that the endothelium does not play a primary role in inhibiting field stimulation-induced contractions, but that the function of the endothelium is to counteract the stimulant effect of Cap. The rabbit ear artery was easily desensitized to the inhibitory effect of Cap by 3-4 treatments with high concentrations of Cap (Figure 1), whereas rebound facilitation was longlasting and still observed after the artery had been desensitized to the inhibitory effect of Cap (Figure 4). This desensitization was irreversible and specific for Cap, and was not secondary to an increase in contractile tension due to a rebound phenomenon. Thus after desensitization, when Cap at concentrations as high as 100yM did not inhibit the field stimulation-induced contractions, the prejunctional a2-mediated inhibitory effect of clonidine and the postjunctional inhibitory effect of papaverine were unaffected. This desensitization suggests that repeated application of Cap may deplete the neurones of some substance that inhibits NA release and thereby mediates the inhibitory action of Cap. Two possible mediators are SP and SK (Duckles & Buck, 1982; Duckles & Levitt, 1984; Moskowitz et al., 1983; R6sza et al., 1984; 1985; Lundberg et al., 1985). However, in the present experiments, when the preparation had been desensitized to SP or SK, the inhibitory effect of Cap was not affected, making these substances unlikely candidates for mediating the inhibitory effect of Cap in this tissue. Recently CGRP was located in primary sensory neurones and Cap was shown to release CGRP-like immunoreactivity (Lundberg et al., 1985; Hua & Lundberg, 1986; Saito & Goto, 1986). In addition, CGRP has been shown to be present in cerebrovascular nerves (Edvinson, 1985; Hanko et al., 1985). CGRP induces dilatation of thoracic aorta (Brain et al., 1985; Duckles, 1986), and cat cerebral artery (Edvinson et al., 1985; Hanko et al., 1985; Verrecchia et al., 1986), and attenuates stimulation-induced contractions of rabbit ear artery (Hanko et al., 1985; 1986).

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Hua & Lundberg (1986) assumed that the dual effects of Cap on the ureter were due to the release of CGRP, which acts as an inhibitor, and tachykinin, as a stimulant. In the present studies, CGRP inhibited field stimulation-induced contractions dose-dependently just as Cap did (Figure 1), allowing us to suggest that the action of Cap on the ear artery could be mediated by CGRP. However, the effect of CGRP differed from that of Cap: CGRP (treatment for 5 min), but

not Cap, slightly inhibited NA-induced contractions (Figure 3). Moreover, the fact that the artery did not show desensitization to CGRP made it difficult to judge whether CGRP is involved in the inhibitory action of Cap. Further studies need to be performed before any definite conclusion can be made on the possible involvement of CGRP in the inhibitory action of Cap.

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(Received September 28, 1988 Revised August 14, 1989 Accepted September 6, 1989)

Dual effects of capsaicin on responses of the rabbit ear artery to field stimulation.

1. The effects of capsaicin (Cap) on contractions of ring segments of rabbit ear artery induced by field stimulation were studied. 2. At low concentra...
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