Dissociation of tissue thiols content from nitroglycerin-induced cyclic-3',5'-guanosine monophosphate and the state of tolerance: in vivo experiments in rats.

The in vivo effects of nitroglycerin (GTN) on the biochemical response [cyclic-3',5'-guanosine monophosphate (cGMP) levels] of vascular (aorta and inferior vena cava, IVC) and other tissues (heart and lung) were studied. GTN caused dose and time-dependent increases in cGMP content of aorta and IVC. Compared to base line, maximal concentrations of 3- to 4-fold the basal levels of cGMP were measured in the aorta, IVC and lung of rats after 2 mg i.v. bolus doses of GTN. Tolerance to GTN, as assessed by the reduction in the cGMP increase in response to an i.v. GTN dose, developed 12 to 18 hr after continuous i.v. infusion (100-200 micrograms/hr) of the drug. Significant differences in the pattern of formation and degradation of cGMP were noted between tolerant and nontolerant rats. Unlike the control IVC tissue, where elevated cGMP was measured throughout the 5-min post GTN administration, in tolerant IVC, cGMP levels were not significantly different from the basal values at time points 3 and 5 min post GTN. These results suggest that IVC is more prone to (or less recoverable from) the state of tolerance than the aorta. Furthermore, when tissue thiols were measured in control and tolerant rats, a complete dissociation was observed between the state of tolerance and the endogenous glutathione and cysteine concentrations. These data constitute strong evidence against an in vivo depletion of tissue thiols as being the primary determinant underlying the development of tolerance during nitrate therapy.