Ž . European Journal of Pharmacology 318 1996 89–92 Short communication Lack of endothelin ET receptor-mediated smooth muscle B hyperpolarization in rat mesenteric resistance arteries Gareth J. Waldron a,1 , Alan G. Roach b , Christopher J. Garland a, ) a Department of Pharmacology, UniÕersity of Bristol, UniÕersity Walk, Bristol, BS8 1TD, UK b Rhone-Poulenc Rorer Ltd., Rainham Road South, Dagenham, Essex, UK Received 8 August 1996; revised 18 October 1996; accepted 22 October 1996 Abstract The presence of functional endothelin ET receptors was investigated in rat isolated mesenteric resistance arteries. Neither B Ž . Ž . endothelin-3 0.1–100 nM nor the endothelin ET selective agonists sarafotoxin S6c and BQ 3020 both 1–100 nM induced any B Ž . measurable hyperpolarization or relaxation in stimulated a -adrenoceptor agonist; phenylephrine or unstimulated arteries. In both cases, 1 Ž . the subsequent addition of acetylcholine 1 mM hyperpolarized the membrane potential by 10–20 mV and totally reversed any contraction which was present. These results indicate that the endothelin ET -mediated vasodilatation observed in the intact mesenteric B bed does not reflect hyperpolarization of smooth muscle cells in resistance arteries arising from the mesenteric artery. Keywords: Endothelium; Smooth muscle, vascular; Hyperpolarization; Endothelin 1. Introduction In addition to causing a long lasting increase in blood pressure, intravenous bolus doses of endothelin can also Ž stimulate an initial, transient reduction in pressure Yana- . gisawa et al., 1988a . Based on the relative potencies of endothelin-1 and endothelin-3 in vivo, it has been sug- gested that endothelin ET receptors mediate this transient B Ž decrease in blood pressure Gardiner et al., 1990a; Yanagi- . sawa et al., 1988b . Endothelin-induced vasodilatation has been demon- Ž strated in the isolated perfused rat mesenteric bed Douglas . and Hiley, 1990; Warner et al., 1989 and in anaesthetized Ž and pithed, but not conscious, rats Gardiner et al., 1990a,b; . Le Monnier de Gouville et al., 1990 . In the perfused bed, the vasodilator response was only partially attenuated by inhibitors of cyclooxygenase and nitric oxide synthase, suggesting the involvement of an additional, non-nitric oxide factor contributing to smooth muscle relaxation Ž Douglas and Hiley, 1990; Fukuda et al., 1991; Warner et ) Ž . Ž . Corresponding author. Tel.: 44-117 928-866; Fax: 44-117 925- 0168; e-mail: chris.garland@bris.ac.uk 1 Present address: Smooth Muscle Research Group, Department of Pharmacology and Therapeutics, University of Calgary, 3330, Hospital Drive, N.W., Calgary, Alberta, Canada T2N 4N1. . al., 1989 . Endothelin-3 evoked a monophasic hyperpolar- ization of 8 mV in the main isolated superior mesenteric artery from Wistar rats, which was unaffected by either nitro-arginine or the endothelin ET antagonist BQ123, A and was mimicked by the endothelin ET receptor-specific B agonist IRL 1620, suggesting a role for endothelium-de- Ž . rived hyperpolarizing factor EDHF released by endothe- Ž lin ET receptor stimulation Nakashima and Vanhoutte, B . 1993 . We investigated whether similar hyperpolarization, which could lead to smooth muscle relaxation, also occurs in small resistance arteries from the rat mesenteric bed, and if endothelin ET receptors are functionally linked to B the response. Previous experiments in the superior mesen- teric artery were performed in unstimulated artery seg- ments, making it impossible to determine if tension changes accompanied the increase in membrane potential and if the Ž hyperpolarization occurred in stimulated cells Nakashima . and Vanhoutte, 1993 . 2. Materials and methods 2.1. General Ž . Segments 1–2 mm in length of mesenteric artery from Ž male Wistar or Sprague-Dawley rats approximately 240– 0014-2999r96r$15.00 Copyright q 1996 Elsevier Science B.V. All rights reserved.