Modifications by sumatriptan and acetylcholine of nitric oxide-mediated neurogenic dilatation in dog cerebral arteries

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Abstract

Canine cerebral arterial strips denuded of endothelium responded to nicotine and transmural electrical stimulation with relaxations, which were abolished by NG-nitro-l-arginine and methylene blue. Magnitudes of relaxation did not differ in the arteries contracted with prostaglandin F and sumatriptan, an effective therapeutic of migraine. Sumatriptan concentration-dependently contracted the arteries responding to 2 Hz stimulation with persistent relaxations, and the concentration of this 5-HT1B/1D/1F receptor agonist to overcome the relaxation averaged 1.06×10−7 M. Acetylcholine inhibited the response to nerve stimulation due possibly to its action on prejunctional nitroxidergic nerves; the inhibition did not differ in the arteries contracted with prostaglandin F and K+. It appears that sumatriptan does not interfere with the release of nitric oxide from nerves but counteracts the neurogenic relaxation by functional antagonistic action on smooth muscle. Prejunctional inhibition by muscarinic receptor activation is unlikely associated with opening of neuronal K+ channels.

Introduction

Sumatriptan, a 5-HT1B/1D/1F receptor agonist Hartig et al., 1996, Van den Broek et al., 2000, is regarded as a useful anti-migraine agent (Saxena and Tfelt-Hansen, 2000). Suppression of persistent intracranial vasodilatation, possibly responsible for cluster headache and migraine, by vasoconstriction via 5-HT receptor activation Humphrey and Feniuk, 1991, Ferrari and Saxena, 1993, especially 5-HT1B subtype Nilsson et al., 1999, Razzaque et al., 1999, is postulated to underlie the therapeutic action. Nitric oxide (NO) derived from the vasodilator nerve Toda and Okamura, 1990a, Toda and Okamura, 1992 and endothelium Katusic, 1992, Toda and Okamura, 1998 dilates cerebral arteries. Since l-NG-methylarginine hydrochloride, a non-selective NO synthase inhibitor, relieves headaches in migraine patients (Lassen et al., 1997), endogenous NO is suggested to participate in the pathogenesis. Intravenous infusion of nitroglycerin to healthy subjects evokes vascular headache (Iversen et al., 1989). Histamine that dilates primate cerebral arteries via a release of endogenous NO (Toda, 1990) is recognized to provoke migraine attacks (Krabbe and Olesen, 1980). Possibility of neurogenic NO to participate in the migraine headache is also suggested Ayajiki et al., 1997, Toda, 1997. Sumatriptan reportedly inhibits the release of norepinephrine from adrenergic nerves in the isolated rat kidney (Charlton et al., 1986) and of serotonin from the isolated superfused pig brain cortex (Schlicker et al., 1989) by acting on prejunctional 5-HT1-like receptors. Reduction by sumatriptan of the calcitonin gene-related peptide release from trigeminal nerve terminals is suggested to be attributed to activation of prejunctional 5-HT1-like receptors (Goadsby and Edvinsson, 1993). However, whether this 5-HT1B/1D/1F receptor agonist acts on prejunctional nitroxidergic nitrergic nerves in cerebral arteries and produces vasoconstriction by interfering with the release of NO remains to be determined.

Suppression by acetylcholine of cerebral vasodilatation caused by nitroxidergic nerve stimulation is mediated by prejunctional muscarinic receptor activation in canine, monkey and porcine cerebral arteries Toda et al., 1995, Toda et al., 1997, Tanaka et al., 1999, Liu and Lee, 1999, whereas α-adrenoceptor and VIP receptors in nerve terminals do not seem to participate in the modulation of neurogenic vasodilatation in cerebral arteries Toda et al., 1995, Toda et al., 1997. Decreased Ca2+ influx may be involved in the inhibitory effect of acetylcholine; however, further mechanisms of action have not been clarified. Recently, Jiang et al. (1999) have suggested that opening of neuronal K+ channels is involved in the acetylcholine-induced inhibition in isolated guinea pig basilar arteries, on the basis of data obtained with K+ channel inhibitors. Our preliminary study has indicated that this is not the case in dog and monkey cerebral arteries.

The present study was undertaken to determine the prejunctional action of sumatriptan and the interaction of neurogenic NO and sumatriptan in isolated dog cerebral arteries denuded of the endothelium, in which acetylcholine inhibits nitroxidergic nerve function prejunctionally. In addition, whether the prejunctional inhibitory effect of acetylcholine is ascribable to K+ channel opening was elucidated. Sumatriptan reportedly opens K+ channels (Le Grand et al., 1998).

Section snippets

Preparation and experimental protocol

Beagle dogs of either sex, weighing 9 to 14 kg, were used for the present study. The Animal Care and Use committee at our University approved the use of dog blood vessels.

Dogs were anesthetized with sodium pentobarbital (30 mg/kg, i. v.) and killed by bleeding from the carotid arteries. The brain was removed, and the middle cerebral and basilar arteries were isolated. The arteries were helically cut into strips of approx. 20 mm long, and the endothelium was removed by gently rubbing the intimal

Responses to nicotine or transmural electrical stimulation as affected by sumatriptan or K+

In helical strips of canine cerebral arteries contracted with prostaglandin F (10−6 M), nicotine (10−4 M) and NO (10−7 M) elicited moderate relaxations. The nicotine-induced relaxation was abolished by hexamethonium (10−5 M, n=4) and methylene blue (10−5 M, n=3), whereas the response to NO was unaffected by the ganglionic blocker but was abolished by methylene blue. NG-nitro-l-arginine (10−5 M) abolished only the relaxation induced by nicotine (n=4), and l-arginine (3×10−3 M) restored the

Discussion

Transmural electrical stimulation and nicotine produce relaxations of cerebral arteries from dogs, monkeys, humans and pigs Toda and Okamura, 1990a, Toda and Okamura, 1990b, Toda, 1993, Lee and Sarwinski, 1991, Tanaka et al., 1999, which are recognized to be mediated by NO released from vasodilator nerves. The fact that the nicotine-induced relaxation, being sensitive to hexamethonium, and the response to electrical stimulation, abolished by tetrodotoxin, were depressed by NG-nitro-l-arginine,

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