Canine renovascular responses to sumatriptan and 5‐carboxamidotryptamine: modulation through endothelial 5‐HT₁‐like receptors by endogenous nitric oxide

Abstract

1 In anaesthetized dogs, intra-left atrial (i.l.a.) administration of the 5-HTI-like receptor agonists, sumatriptan (1-10 gkg-') and 5-carboxamidotryptamine (0.03-0.3plgkg-') produced dose-related reductions in renal blood flow and vascular conductance, which were characterized by their rapid onset and recovery. 2 In these animals, i.v. administration of the inhibitor of nitric oxide (NO) synthase, N0-nitro-Larginine methyl ester (L-NAME; 10 mg kg-') significantly augmented the renal vasoconstrictor responses to i.l.a. sumatriptan and 5-carboxamidotryptamine. 3 The effects of L-NAME upon these responses to sumatriptan and 5-carboxamidotryptamine were significantly reversed by subsequent i.v. administration of L-arginine (1000mgkg-'). 4 L-NAME-significantly attenuated the systemic hypotensive responses to i.v. acetylcholine (0.3-3 ,tg kg-') and this effect was also reversed by L-arginine. 5 L-NAME had no effect upon the renal vasoconstrictor response to i.l.a. administration of angiotensin II, nor did it affect the renal vascular conductance recovery response to brief mechanical occlusion of the renal artery. 6 These data suggest that sumatriptan and 5-carboxamidotryptamine stimulate the release of NO through the activation of a 5-HTI-like receptor located on the endothelial cells.7 It is concluded that in canine renal vasculature, 5-HT,-like agonists (and presumably endogenous 5-hydroxytryptamine) can cause simultaneous activation of a 5-HT,-like receptor on both vascular smooth muscle and endothelial cells. The net renal vascular response to these agonists is therefore a function of both the vascular smooth muscle vasoconstriction and the concurrent vasodilator influence of NO released from the endothelium.

Vasodilator and vasoconstrictor responses induced by 5-hydroxytryptamine in the in situ blood autoperfused hindquarters of the anaesthetized rat

“…This is possibly because at certain doses simultaneous vasodilator and vasoconstrictor responses could occur. Indeed, this would be consistent with observations suggesting that, in the renal vascular bed, some 5-HT agonists exert a dual vasoconstrictor and vasodilator action at the same doses (Cambridge et al 1991a(Cambridge et al , 1991bWhiting and Cambridge 1995). Doses higher than 50 ng/kg produced a dose-dependent vasoconstrictor effect, whose activity maximum was higher than that of the maximum vasodilator responses.…”

“…However, only methiothepin, but not mesulergine (Villalon et al 1998;Centurion et al 2000), blocked the vasodilator effect of 5-HT or 5-CT. Therefore, as has been previously reported for canine kidney vasculature (Cambridge et al 1991a(Cambridge et al , 1991bWhiting and Cambridge 1995), 5-HT 1 receptor activation could be responsible for the vasodilator activity observed in the hindquarter vascular bed of the anaesthetized rat with intra-arterial administration of 5-HT agonists.…”

“…By contrast, in the rat hindquarter vascular bed model, as observed in this study, 5-HT induced both vasodilator and vasoconstrictor responses, depending on the dose administered. Some studies, carried out in other animal species and using different vascular bed models, have proposed the occurrence of both vasoconstrictor and vasodilator 5-HT-induced responses, which would be mediated by simultaneous activation of heterogeneous 5-HT receptor subtypes (Cambridge et al 1991a(Cambridge et al , 1991bWhiting and Cambridge 1995).…”

Vascular 5‐HT1‐like receptors mediating vasoconstriction and vasodilatation: their characterization and distribution in the intact canine cardiovascular system

“…In this respect the renal vasculature appears to be devoid of the vasodilator subtype, for unlike the carotid vasculature, the renal vasculature exhibits only vasoconstrictor responses to the tryptamine analogues. It should be noted that in the canine renal vasculature we have found evidence for endothelial 5-HT1-like receptors coupled to the endogenous vasodilator, nitric oxide (see the following paper, Whiting & Cambridge, 1995).…”

Influence of the endothelium and nitric oxide on the contractile responses evoked by 5‐HT1D receptor agonists in the rabbit isolated saphenous vein

“…According to the vascular endothelium (E) and NO in the constrictor responses to Sum hypothesis of migraine, the therapeutic efficacy of Sum may be has recently been proposed in vitro in isolated pulmonary ardue to constriction of cerebral blood vessels following activa-teries McCulloch et al, 1994;Sweeney tion of post-junctional 5-HTID receptors (Humphrey & Fe-et al, 1995) and in vivo in the renal vasculature of the anniuk, 1991; Ferrari & Saxena, 1993;Medhurst et al, 1993). esthetized dog (Whiting & Cambridge, 1995 Pharmacology (1996) 119, [35][36][37][38][39][40][41][42] Endothelium & 5-HTlD receptor-mediated contracdons properties of 5-HTID receptor agonists, in particular in de-termining their potency and efficacy (Martin & MacLennan, 1990;Van Heuven-Nolsen et al, 1990;Razzaque et al, 1995 (Clitherow et al, 1994;Skingle et al, 1994 Nw-nitro-L-arginine methyl ester (L-NAME; 0 or 10-5 …”