Captopril-Induced Reversal of Nitroglycerin Tolerance: Role ... : Journal of Cardiovascular Pharmacology (original) (raw)

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Role of Sulfhydryl Group vs. ACE-Inhibitory Activity

Department of Medicine, University of Florida College of Medicine, and the Veterans Affairs Medical Center, Gainesville, Florida. U.S.A.

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Abstract

The angiotensin-converting enzyme (ACE) inhibitor captopril has been shown to reverse vascular tolerance to nitroglycerin (NTG). Whether captopril reverses NTG tolerance by providing sulfhydryl (SH) groups or by inhibiting ACE is not clear. To examine this issue, we treated rat aortic rings with buffer, captopril (SH +, ACE inhibitory activity+), enalaprilat (SH –, ACE inhibitory activity+), or N-acetylcysteine (NAC, SH+, ACE inhibitory activity –) prior to their contraction with epinephrine and subsequent relaxation with NTG. Previous exposure of NTG-treated rings resulted in marked resistance to the vasorelaxant effect of a subsequent exposure to NTG in buffer-treated rings. Both N AC and captopril, but not enalaprilat, potentiated the vasorelaxant effects of NTG during the first exposure of vascular rings to NTG and also prevented the development of tolerance to NTG during a second exposure. Buffer-treated rings showed an inability to accumulate cyclic guanosine monophosphate (GMP) in response to a second exposure to NTG. In contrast, both NAC and captopril-pretreated rings demonstrated a persistence of cyclic GMP accumulation during the second NTG exposure. The endothelium-dependent vasodilator acetylcholine (ACh) caused relaxation of the NTG-tolerant rings and also induced cyclic GMP accumulation in these rings. In other experiments, we found that prior exposure of vascular rings to ACh did not cause resistance to the subsequent vasorelaxant effects of ACh. NAC, captopril, and enalaprilat did not modulate the effects of ACh during either the first or subsequent exposures to ACh. In addition, indomethacin did not influence the “protective” effects of NAC or captopril against NTG tolerance. These data show that NTG tolerance does not cause cross-tolerance to ACh. The availability of the SH group, as in NAC and captopril, and not the ACE-inhibitory activity alone, as in enalaprilat, modifies NTG tolerance, and these effects of NAC or captopril are not modified by prostaglandin inhibition. Lastly, these agents do not modulate the vasorelaxant effects of ACh.