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 KATP 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 (1-20 mg/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 (10 mg/Kg/day) for 7 days reduced blood pressure in hypertensive animals (134 +/- 6 vs. 170 +/- 4 mmHg, 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.

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Blood Pressure

Pressure Telemeter