Effect of nitric oxide synthase inhibitor N(omega) nitro-L-arginine methyl ester on relaxant responses to calcium channel antagonists in isolated aortic rings from Dahl normotensive and hypertensive rats.

Abstract

Differences exist between the pharmacological actions of calcium channel antagonists in blood vessels from hypertensive versus normotensive animals. In this investigation, we have examined the impact of nitric oxide synthase inhibitor N(omega) nitro-L-arginine methyl ester (L-NAME) on relaxant responses produced by the calcium channel antagonists (nifedipine, diltiazem, and mibefradil) in isolated aortic rings from Dahl salt-resistant normotensive (SRN) and salt-sensitive hypertensive (SSH) rats on a 4% salt diet. Morphological examination of the aortic rings revealed significantly larger lumen area, smooth muscle wall thickness, and perimeter in vessels of SSH rats versus SRN rats. Rank order potency for the antagonists was nifedipine > mibefradil > or = diltiazem in aortic rings from SRN rats, but mibefradil was found to be the most efficacious. The rank order potency for the antagonists in aortic rings from SSH rats was nifedipine > diltiazem > mibefradil, although all three drugs showed similar efficacy. The presence of L-NAME attenuated relaxations elicited by the antagonists in aortic rings from SRN rats. Treatment of tissues with L-NAME significantly reduced maximal response and decreased pIC(50). The presence of L-NAME had no effects on concentration-response curves to nifedipine and diltiazem in aortic rings from SSH rats, but it significantly attenuated relaxant responses of mibefradil. Our current results support the view that these calcium channel antagonists produce relaxations by mechanisms that are sensitive and insensitive to L-NAME. Moreover, the component insensitive to L-NAME was lacking in tissues from SSH rats for nifedipine and diltiazem but not mibefradil.