In vitro vasorelaxant and in vivo cardiovascular effects of S-nitrosothiols: comparison to and cross tolerance with standard nitrovasodilators.
The in vitro vasorelaxant and in vivo cardiovascular effects of synthetic S-nitrosothiols (RSNOs) were compared to standard nitrovasodilators. S-Nitroso-glutathione (GSNO), S-nitroso-N-acetylcysteine (NACysNO), S-nitroso-galactopyranose (GPSNO), S-nitroso-thioglycerol (TGSNO) and S-nitroso-homocysteine (HCysNO) relaxed phenylephrine (PE) contracted rabbit aorta at 50% effective concentrations (EC50s) of 3-46 nM. While nitroglycerin (GTN) exhibited in vitro tolerance after preincubation, the RSNOs were considerably less cross tolerant to GTN. In conscious dogs, GSNO, NACysNO and GPSNO (1-20 mcg/kg/min i.v.) paralleled nitroprusside (SNP) in reducing mean arterial and central venous pressure (MAP; CVP) with mild tachycardia. GSNO, NACysNO and SNP were more hypotensive and more resistant to isosorbide dinitrate (ISDN) cross tolerance than GTN. NACysNO showed mild self tolerance with low infusion (2.5 mcg/kg/min x 4h x 3 days) and blunted GTN's hypotension. These studies demonstrate that GSNO and NACysNO are SNP-like vasodilators in conscious dogs, which exhibit less cross tolerance to ISDN than GTN. Further, RSNOs relax vascular smooth muscle seemingly independent of nitric oxide (NO) liberation, and nitrate tolerance may involve reduced RSNO formation or NO release rather than desensitized guanylate cyclase (GC).
Smith
M P
MP
Cardiovascular Diseases Unit, Upjohn Laboratories, Upjohn Company, Kalamazoo, MI.
Humphrey
S J
SJ
Kerr
S W
SW
Mathews
W R
WR
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D004285:Dogs; D004361:Drug Tolerance; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008623:Mercaptoethanol; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D009603:Nitroso Compounds / Q000494:pharmacology*; D011817:Rabbits; D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*
D009603:Nitroso Compounds; D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds; D014665:Vasodilator Agents; D009569:Nitric Oxide; D008623:Mercaptoethanol; C032635:S-nitrosomercaptoethanol