NEGATIVE INOTROPIC ACTIONS OF NITRIC-OXIDE REQUIRE HIGH-DOSES IN RAT CARDIAC-MUSCLE

Initial experiments were designed to determine if vasoactive concentra tions of nitric oxide (NO) alter contractility in rat heart. Contracti le function was monitored in left atrial and papillary muscles (30 deg rees C) paced at 0.5 Hz during cumulative addition of 3-morpholino-syd nonimine-HCl(SIN-1), an agent that releases NO. At concentrations betw een 10(-7) and 10(-4) M (NO concentrations of approximately 10(-8)-3 x 10(-7) M), SIN-1 did not affect contractility in either tissue. Simil arly, 10(-4) M SIN-1 did not alter the positive inotropic responses to isoproterenol or increasing extracellular [Ca+2] ([Ca+2](o)). To obta in higher concentrations of NO. additional studies were conducted usin g authentic NO. NO-saturated stock solutions and a corresponding contr ol solvent were adjusted to pH 1.6 with HCl. Dose-dependent effects of NO were examined by adding aliquots of the stock solutions (or contro l solvent) to the bathing solution. At final concentrations of 1 x 10( -5)-5 x 10(-4) M, NO produced transient, concentration-dependent decre ases in contractility that were paralleled by reductions in buffer pH. Control solvent elicited similar reductions in pH(o) and transient de creases in contractility; however, the negative inotropic action elici ted by the NO-containing solution was approximately 20% so greater tha n that observed in control conditions. These data demonstrate that onl y high concentrations of NO depress contractility in isolated rat card iac muscle. and suggest that this effect is mediated by both acidosis and a pH(o)-independent mechanism.