Recovery of vascular smooth muscle relaxation from nitroglycerin-induced tolerance following a drug-free interval. A time-course in vitro study.
Hemodynamic tolerance occurs upon continuous exposure of vascular tissues to nitroglycerin (NTG). This phenomenon is believed to be due to the depletion of the tissue sulfhydryl (SH) group, which is essential for NTG-induced increase in tissue cyclic GMP and vasorelaxation. To determine the effect of an NTG-free interval on recovery of tissue cyclic GMP accumulation and vasorelaxation following development of NTG tolerance, isolated rat aortic rings were kept in Krebs physiologic buffer at 37 degrees, precontracted with epinephrine, and exposed to NTG. The mean concentration of NTG, which relaxed the rings by 50% (EC50) upon first exposure, was 1.1 x 10(-7) M (N = 20), and vascular cyclic GMP levels after NTG increased from 21 to 46 fmol/mg (P less than 0.02). A second exposure to NTG 15 min later increased the EC50 to 1.3 x 10(-4) M and cyclic GMP levels did not change (P less than 0.001 vs first NTG exposure), indicating tolerance to NTG. However, acetylcholine-mediated relaxation of aortic rings was preserved even in NTG-tolerant rings. A second exposure of tissues to NTG separated by 30, 60, and 120 min from the first exposure progressively decreased the EC50, such that at 120 min the EC50 of NTG was 0.4 x 10(-7) M (P = NS vs first NTG exposure). Tissue cyclic GMP levels increased from 14 to 71 fmol/mg (P = NS vs first NTG exposure). These data confirm development of tolerance to the vasorelaxant effects of NTG following initial exposure. An interval of 2 hr between multiple exposures of tissues to NTG results in preservation of the smooth muscle relaxation and an increase in tissue cyclic GMP in response to NTG.
Mehta
J L
JL
University of Florida College of Medicine, Department of Medicine, Gainesville 32610.
Lawson
D L
DL
Nichols
W W
WW
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic; D006152:Cyclic GMP / Q000378:metabolism; D004361:Drug Tolerance; D004837:Epinephrine / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D005996:Nitroglycerin / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D005996:Nitroglycerin; D006152:Cyclic GMP; D000109:Acetylcholine; D004837:Epinephrine