Modelling the changes due to the endothelium and hypertension in the a-adenoreceptor- mediated responses of rat aorta A. Tabernero 1 , J. Giraldo 2 & E. Vila 1 1 Departament de Farmacologia i Terape Áutica and 2 Laboratori de Medicina Computacional, Unitat de Bioestadõ Âstica. Facultat de Medicina. Universitat Auto Á noma de Barcelona, 08193 Bellaterra, Spain Summary 1 The present study focuses on the role of endothelium on a 1 -adrenoceptor-mediated vasoconstriction in aorta from Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). To define and quantify changes in the parameters governing agonism at a 1 -adrenoceptor by hypertension and/or endothelium, the operational model of analysis was used. 2 In either endothelium intact or denuded aorta, the sensitivity (P < 0.001) and the maximum contraction (P < 0.05) to phenylephrine were smaller in SHR than in WKY. 3 However, in each strain of rats, removal of endothelium increased the sensitivity (P < 0.001) to phenylephrine but reduced (P < 0.05) KCl-evoked vasoconstriction, suggesting a modulation of these responses by the endothelium. The observed differences in sensitivity and maximum contraction are interpreted in terms of the operational parameters: E m , the maximum possible effect; pK A , the agonist affinity; a, the agonist efficacy and n, the slope for the function relating receptor occupancy to pharmacological effect. The estimated parameters reflected differences, between strains, in the signal transduction processes linked to a 1 -adrenoceptor stimulation ascribed to the presence of the endothelium. 4 N G -nitro-l-arginine methyl ester (L-NAME), enhanced to a similar extend in both rat strains the sensitivity (P < 0.001) and the maximum contraction to phenylephrine. Indomethacin reduced the maximum contraction to phenylephrine by 56.85% in SHR and by 11.80% in WKY suggesting that contracting prostanoids play a more major role in this response in SHR than in WKY. Nevertheless, these inhibitors were without effect on denuded vessels from both strains suggesting that NO and cyclooxygenase products from the media or the adventitia do not play a role on the phenylephrine- mediated responses. 5 The studied endothelial factors partially explain the observed differences in modulation of a 1 - adrenoceptor responses by the endothelium but suggest the participation of other compounds released by the endothelium. Introduction Several studies have contributed to establish the role of the endothelium as a modulator of contractile responses induced by different vasoconstrictor sub- stances, including the a 1 -adrenoceptor agonists (God- fraind, Egleme & Alosachie, 1985; Topouzis, Schott & Stoclet, 1991; Doggrell, 1992; Tabernero & Vila, 1995). Endothelial regulation of vascular smooth muscle function and vascular tone relies in the various factors synthetized and released by the endothelial cells. Important vasodilator substances generated by the endothelium are nitric oxide (NO), prostacyclin, and the endothelium hyperpolarizing factor (EDHF). In addition to relaxing compounds, the endothelium is a source of potent vasoconstrictor factors, such as the peptide endothelin-1 and some prostanoids. Thus, thromboxane A 2 and prostaglandin H 2 produced from the cyclooxygenase pathway, both cause contraction via the thromboxane/endoperoxide receptor. Changes on the production and/or release of these factors may be involved in the altered vascular reactivity described in hypertension or other cardiovascular pathologies (Lu È scher, 1994; Nava & Lu È scher, 1995). Wide differences in the influence of the endothelium on a 1 -adrenoceptor-mediated responses have been observed in several blood vessels. In the rat aorta increases in sensitivity and/or in the maximum contractile responses to noradrenaline or other a 1 - adrenoceptor agonists after the removal of endothelial cells have been reported (Alosachie & Godfraind, Correspondence: Elisabet Vila ã 1999 Blackwell Science Ltd 219 Journal of Autonomic Pharmacology, 19, 219±228