Role of voltage-sensitive calcium-channels in nitric oxide-mediated vasodilation in spontaneously hypertensive rats.

This study demonstrates that the vasodilator potencies of nitric oxide (NO) donors such as sodium nitroprusside are increased in conscious Spontaneously Hypertensive (SH) as compared to Wistar Kyoto (WKY) rats. For example, the NO donors do not dilate hindlimb resistance arteries in WKY rats whereas they elicit pronounced vasodilator responses in SH rats. This study also demonstrates that the NO-mediated vasodilator responses in WKY and SH rats were markedly diminished after blockade of voltage-sensitive Ca2+-channels (CaVS2+-channels) with nifedipine, diltiazem or verapamil. These findings suggest that NO dilates resistance arteries in vivo via direct and/or hyperpolarization-induced closure of CaVS2+-channels and that the increased potency of NO in SH rats may be due to the augmented CaVS2+-channel activity reported in this strain.

Potential role of nitration and oxidation reactions in the effects of peroxynitrite on the function of beta-adrenoceptor sub-types in the rat.

This study examined the hemodynamic responses elicited by the beta-adrenoceptor agonist, isoproterenol (1 and 10 microg/kg, i.v.) before and after administration of (i) peroxynitrite (10 x 10 micromol/kg, i.v.), (ii) the thiol chelator, para-hydroxymercurobenzoic acid (pHMBA, 75 micromol/kg, i.v.), and (iii) the electron acceptor, nitroblue tetrazolium (NBT, 10 micromol/kg, i.v.) in pentobarbital-anesthetized rats. The tachycardia elicited by the lower dose of isoproterenol was diminished whereas the tachycardia elicited by the higher dose was not attenuated after administration of peroxynitrite. The falls in hindquarter and renal vascular resistances elicited by both doses of isoproterenol were substantially diminished whereas the isoproterenol-induced falls in mesenteric vascular resistance were not changed after administration of peroxynitrite. All of the isoproterenol-induced responses were markedly attenuated after administration of pHMBA or NBT. These findings suggest that the oxidation and/or nitration of beta-adrenoceptors impair the ability of isoproterenol to bind to and/or activate these G protein-coupled receptors. beta1-, beta2- and beta3-adrenoceptors contain extracellular cysteine residues susceptible to oxidation (i.e., disulfide-bridge formation) whereas only the beta1- and beta2-adrenoceptors contain extracellular tyrosine residues susceptible to nitration. These findings also suggest that sustained impairment of beta1- and beta2-adrenoceptor function by peroxynitrite is due to nitration of extracellular tyrosine residues in these receptors. By analogy, beta3-adrenoceptors may not be permanently affected by peroxynitrite because these receptors are devoid of extracellular tyrosine residues.