The α‐adrenoceptor antagonist,zolertine, inhibits α1D‐ and α1A‐adrenoceptor‐mediated vasoconstriction in vitro

1 The antagonist effect of zolertine (4‐phenyl‐1‐[2‐(5‐tetrazolyl)ethyl]piperazine trihydrochloride), on vascular contraction elicited by noradrenaline in aorta, carotid (α1D‐adrenoceptors), mesenteric (α1A/D‐adrenoceptors) and caudal arteries (α1A‐adrenoceptors) from Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats and rabbit aorta (α1B‐adrenoceptors), was investigated in endothelium‐denuded arterial rings.
2 The selective α1D‐adrenoceptor agonist, noradrenaline, elicited concentration‐dependent contractions in all arterial rings from both species. Noradrenaline selectivity was: carotid=aorta>>.Gt;mesenteric=rabbit aorta>caudal arteries.
3 The contractile responses induced by noradrenaline were competitively antagonized by zolertine in rat carotid and aorta arteries, yielding pA2 values 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 pKb 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 artery and 6.65±0.09 in rabbit aorta.
4 Competition binding experiments using the α1‐adrenoceptor antagonist [³H]prazosin showed a zolertine pKi of 6.81±0.02 in rat liver (α1B‐adrenoceptors) and 6.35±0.04 in rabbit liver (α1A‐adrenoceptors) membranes.
5 Zolertine showed higher affinity for α1D‐adrenoceptors compared to α1A‐adrenoceptors, while it had an intermediate affinity for α1B‐adrenoceptors. The ability of the α1‐adrenoceptor antagonist zolertine to block α1D‐adrenoceptor‐mediated constriction in different vessels of WKY and SHR rats may explain its antihypertensive efficacy despite its low order of potency.