The alpha-adrenoceptor antagonist, zolertine, inhibits alpha(1D)- and alpha(1A)-adrenoceptor-mediated vasoconstriction in vitro

1 The antagonist effect of zolertine (4-phenyl-1-[2-(5-tetrazolyl)ethyl]pip erazine trihydrochloride), on vascular contraction elicited by noradrenalin e in aorta, carotid (alpha (1D)-adrenoceptors), mesenteric (alpha (1A,D)-ad renoceptors) and caudal arteries (alpha (1A)-adrenoceptors) from Wistar Kyo to (WKY) and spontaneously hypertensive (SHR) rats and rabbit aorta (alpha (1B)-adrenoceptors), was investigated in endothelium-denuded arterial rings . 2 The selective alpha (1D)-adrenoceptor agonist, noradrenaline, elicited co ncentration-dependent contractions in all arterial rings from both species. Noradrenaline selectivity was: carotid = aorta >> mesenteric = rabbit aort a > caudal arteries. 3 The contractile responses induced by noradrenaline were competitively ant agonized by zolertine in rat carotid and aorta arteries, yielding pA(2) val ues of WKY, 7.48 +/- 0.18; SHR, 7.43 +/- 0.13 and WKY, 7.57 +/- 0.24; SHR, 7.40 +/- 0.08, respectively. Zolertine was a non-competitive antagonist in some blood vessels as Schild plot slopes were lower than unity. The pk(b), estimates for zolertine were WKY, 6.98 +/- 0.16; SHR, 6.81 +/- 0.18 in the mesenteric artery, WKY, 5.73 +/- 0.11; SHR, 5.87 +/- 0.25 in the caudal art ery and 6.65 +/- 0.09 in rabbit aorta. 4 Competition binding experiments using the alpha (1)-adrenoceptor antagoni st [H-3]prazosin showed a zolertine pK(1) of 6.81 +/- 0.02 in rat liver (al pha (1B)-adrenoceptors) and 6.35 +/- 0.04 in rabbit liver (alpha (1A)-adren oceptors) membranes. 5 Zolertine showed higher affinity for alpha (1D)-adrenoceptors compared to alpha (1A)-adrenoceptors, while it had an intermediate affinity for alpha (1B)-adrenoceptors. The ability of the alpha (1)-adrenoceptor antagonist zo lertine to block alpha (1D)-adrenoceptor-mediated constriction in different vessels of WKY and SHR rats may explain its antihypertensive efficacy desp ite its low order of potency.