The new nitric oxide donor cyclohexane nitrate induces vasorelaxation, hypotension, and antihypertensive effects via NO/cGMP/PKG pathway

Abstract

We investigated the cardiovascular effects induced by the nitric oxide donor Cyclohexane Nitrate (HEX). Vasodilatation, NO release and the effects of acute or sub-chronic treatment with HEX on cardiovascular parameters were evaluated. HEX induced endothelium-independent vasodilatation (Maximum effect [efficacy, ME]= 100.4± 4.1%; potency [pD2]= 5.1± 0.1). Relaxation was attenuated by scavenging nitric oxide (ME= 44.9± 9.4% vs. 100.4± 4.1%) or by inhibiting the soluble guanylyl cyclase (ME= 38.5± 9.7% vs. 100.4± 4.1%). In addition, pD2 was decreased after non-selective blockade of K + channels (pD2= 3.6± 0.1 vs. 5.1± 0.1) or by inhibiting K ATP channels (pD2= 4.3± 0.1 vs. 5.1± 0.1). HEX increased NO levels in mesenteric arteries (33.2± 2.3 vs. 10.7± 0.2 au, p< 0.0001). Intravenous acute administration of HEX (1-20mg/kg) induced hypotension and bradycardia in normotensive and hypertensive rats. Furthermore, starting at 6 weeks after the induction of 2K1C hypertension, oral treatment with the HEX (10mg/Kg/day) for 7 days reduced blood pressure in hypertensive animals (134± 6 vs. 170± 4mmHg, respectively). Our data demonstrate that HEX is a NO donor able to produce vasodilatation via NO/cGMP/PKG pathway and activation of the ATP-sensitive K + channels. Furthermore, HEX acutely reduces blood pressure and heart rate as well as produces antihypertensive effect in renovascular hypertensive rats.