title: Clinical tolerance to nitroglycerin is due to impaired biotransformation of nitroglycerin and biological counterregulation, not to desensitization of guanylate cyclase.
abstract: We studied the effect of nitroglycerin (NTG), endothelium-derived relaxing factor (EDRF), sydnonimine SIN-1, and sodium nitroprusside (SNP) on vascular tone, cyclic GMP content and activity of soluble guanylate cyclase (GC) (in homogenates) of tolerant (1 h 0.55 mM NTG) and non-tolerant (1 h vehicle) de-endothelialized rabbit aortae (RA) as well as on cyclic GMP content of cultured smooth muscle cells (SMC) from RA. Nitrate tolerance significantly attenuated NTG-induced vasodilation of precontracted (1.0 microM norepinephrine) RA, increase in cyclic GMP in RA and SMC, and activation of guanylate cyclase in homogenates as compared to controls. In contrast, vasodilation and cyclic GMP increases to NNP, SIN-1, and EDRF (from cultured bovine aortic endothelial cells) were not affected in RA and SMC, despite desensitization of guanylate cyclase to activation with SNP and SIN-1 in homogenized tolerant RA.
  
  
  CONCLUSIONS
  A desensitization of soluble guanylate cyclase to activation with NO can be demonstrated under non-physiological conditions (disrupted cells) in homogenates from nitrate tolerant RA. However, in intact cells (in situ or in culture) soluble guanylate cyclase is not desensitized to EDRF, SIN-1 or SNP. Therefore reduced generation of NO from NTG because of impaired biotransformation of NTG must be regarded as the basis of nitrate tolerance.
authors.affiliation: Department of Applied Physiology, University of Freiburg, FRG.
authors.forename: A
authors.initials: A
authors.lastname: Mülsch
authors.forename: R
authors.initials: R
authors.lastname: Busse
authors.forename: E
authors.initials: E
authors.lastname: Bassenge
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000378:metabolism*; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology; D005996:Nitroglycerin / Q000493:pharmacokinetics / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology*; D011817:Rabbits; D014655:Vascular Resistance / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D011355:Prodrugs; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D006152:Cyclic GMP