Effects of halothane on EDRF/cGMP-mediated vascular smooth muscle relaxations.
BACKGROUND
Halothane has been reported to inhibit endothelium-dependent relaxation in a variety of vessels. These studies were done to determine whether this inhibition is caused by interference with synthesis, release, or action of endothelium-derived relaxing factor (EDRF) on cyclic guanosine monophosphate (cGMP) levels within the vascular smooth muscle.


METHODS
Rat aortic rings were suspended in aerated Krebs solution (37 degrees C) and were contracted to a stable plateau with EC60-70 norepinephrine (NE). Relaxations caused by acetylcholine (ACh; 1 x 10(-8)-1 x 10(-6) M), nitric oxide (NO; 5 x 10(-9)-1 x 10(-6) M), or nitroglycerin (NG; 2 x 10(-9)-3 x 10(-7) M) in rings contracted with NE were compared in the presence and absence of halothane. Tissue cGMP contents were measured using a radioimmunoassay method.


RESULTS
In the presence of halothane (0.5, 1.0, and 2.0 MAC), the ACh-induced relaxations were significantly attenuated in a concentration-dependent manner, an effect that was reversible. Halothane (2 MAC) significantly attenuated NO-induced relaxations at all concentrations and NG-induced relaxations at low concentrations (5 x 10(-9)-3 x 10(-8) M) but not at higher concentrations (1 x 10(-9)-3 x 10(-7) M) in denuded vessels. Nitric oxide-stimulated (5 x 10(-8)-5 x 10(-6) M) cGMP content was significantly attenuated by halothane (2 MAC) at NO concentrations between 1 x 10(-7) and 5 x 10(-6) M.


CONCLUSIONS
Nitric oxide, either endogenous or exogenous, interacts with the enzyme guanylate cyclase to stimulate the production of cGMP. Halothane interfered with the relaxations caused by NO (in rings without endothelium) and decreased the NO-stimulated cGMP content. These results suggest that the site of action of halothane in attenuating endothelium-dependent relaxation in the rat aorta is within the vascular smooth muscle, rather than on the synthesis, release, or transit of the EDRF from the endothelium and that its action may involve an interference with guanylate cyclase activation.
Biology Department, George Mason University, Fairfax, Virginia.
J L
JL
Hart
M
M
Jing
S
S
Bina
W
W
Freas
R A
RA
Van Dyke
S M
SM
Muldoon
D000818:Animals; D004347:Drug Interactions; D006157:Guanosine Monophosphate / Q000502:physiology*; D006221:Halothane / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D005996:Nitroglycerin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D009569:Nitric Oxide; D006157:Guanosine Monophosphate; D005996:Nitroglycerin; D006221:Halothane