Nitroglycerin-Induced Release of Calcitonin Gene-Related Peptide From Sensory Nerves Attenuates the Development of Nitrate Tolerance

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Abstract
The present study was designed to determine if endogenous calcitonin gene-related peptide (CGRP) affects the process of nitrate tolerance development in blood vessels. Rat aortic rings were suspended in organ chambers and relaxations to nitroglycerin (10(-9) -10(-6) M) were obtained in nitrate tolerant and nontolerant rings contracted with norepinephrine (10(-7) M). Tolerance was induced by incubating the rings with (tolerant) or without (nontolerant) nitroglycerin (10(-4) M) for 90 minutes, followed by repeated rinsing for 1 hour. Some rings were treated with CGRP8-37 (10(-6) M), glyburide (10(-6) M), or iberiotoxin (10(-7) M) during the 90-minute desensitization period with nitroglycerin (10(-4) M), and were then washed out during the 1-hour rinsing period. Other rings were treated with capsaicin (10(-5) M) prior to the 90-minute desensitization period. Calcitonin gene-related peptide release was measured by radioimmunoassay. Relaxation to nitroglycerin was markedly reduced in tolerant rings, as compared with nontolerant. Incubation with CGRP8-37 (10(-6) M) specifically during the 90-minute desensitization period with nitroglycerin resulted in even greater impairment in the response to nitroglycerin in tolerant rings, even though the calcitonin gene-related peptide antagonist had been washed out before completion of the nitroglycerin dose-response curve. Similar results were obtained following depletion of calcitonin gene-related peptide stores in sensory nerves by treatment with capsaicin (10(-5) M) prior to the 90-minute desensitization period with nitroglycerin. Prior treatment with CGRP8-37 or capsaicin had no effect on the response to nitroglycerin in nontolerant rings. Incubation with glyburide (10(-6) M), but not iberiotoxin (10(-7) M), specifically during the 90-minute desensitization period, mimicked the effect of CGRP8-37 and capsaicin in tolerant rings, suggesting a role for KATP channels in the effect of calcitonin gene-related peptide. Nitroglycerin (10(-4) M) caused a greater than twofold increase over basal levels in calcitonin gene-related peptide release in nontolerant rings, which was abolished in rings treated with capsaicin and in nitrate tolerant rings. These results suggest that nitroglycerin releases calcitonin gene-related peptide from sensory nerves during the process of desensitization to nitrovasodilators, and that interference with either the release or action of endogenous calcitonin gene-related peptide during this period enhances the extent to which nitrate tolerance occurs. The finding that nitroglycerin-induced release of calcitonin gene-related peptide from sensory nerves attenuates the desensitizing effect of nitroglycerin represents a heretofore unknown event in the development of nitrate tolerance, and demonstrates a novel role for calcitonin gene-related peptide in the vasculature.