Vasorelaxant and antihypertensive effects of ZCM298, a dihydropyridine derivative, are through inhibiting extracellular calcium influx

Abstract

BackgroundZCM298 is a novel 1,4-dihydropyridine derivative. The aim of the study was to investigate its vasodilation and hypotension, and the related mechanisms. MethodsThe isometric tension of artery ring segments was recorded using an in vitro myography system. The blood pressure of spontaneously hypertensive rats (SHRs) was measured in vivo using a non-invasive tail cuff blood pressure system. Changes in the intracellular calcium concentration ([Ca2+]i) in the mesenteric artery were surveyed using real-time confocal microscopy. Regional cerebral blood flow (rCBF) in the pia mater was monitored by laser-Doppler flowmetry (LDP). ResultsZCM298 (10−9–10−4 M) relaxed rat mesenteric artery obviously and concentration-dependently, which was not affected by the removal of the endothelium. ZCM298 shifted the concentration-contractile curves of mesenteric arteries in response to phenylephrine, U46619, KCl and CaCl2 towards the right in a non-parallel manner. The potency of ZCM298 on relaxing basilar artery was much higher than on mesenteric artery. ZCM298 did not depress the phenylephrine-induced vasoconstriction; however, it inhibited the contraction caused by the addition of CaCl2 in Ca2+-free solution. ZCM298 (10−6 M) inhibited the increase of [Ca2+]i induced by KCl in the artery. ZCM298 improved the rCBF in the pia mater of rats at 0.03 and 0.06mg/kg. ZCM298 depressed the systolic and diastolic blood pressure of SHRs in a dose-dependent manner. ConclusionsZCM298 relaxes arteries probably through inhibiting extracellular calcium influx and decreases the blood pressure of SHRs. ZCM298 is more potent in the basilar artery than in the mesenteric artery and improves rCBF in the pia mater of rats.