Inhibition of nitric oxide synthase by L-NAME improves ventricular performance in streptozotocin-diabetic rats.
The overall goal of this study was to determine if activation of the nitric oxide synthetic pathway suppressed basal ventricular performance and the responsiveness to beta-adrenergic stimulation characteristic of cardiac function in the 8-week streptozotocin (60 mg/kg, i.v.) diabetic (STZ-Db) rat. Left ventricular performance was measured in isolated working hearts, before and at the peak response to 0.8 microM dobutamine, in the absence or presence of NG-nitro-L-arginine methyl ester (L-NAME, 1 mM), a non-selective inhibitor of nitric oxide synthase (NOS). Ventricular performance was suppressed in the STZ-Db heart under basal (decreased heart rate, cardiac output, aortic flow -dP/dt) and dobutamine-stimulated (diminished rise in +dP/dt and maximum systolic pressure) conditions. L-NAME had minimal effects on basal or dobutamine-stimulated ventricular performance in control hearts. In contrast, L-NAME infusion in hearts from STZ-Db returned the depressed heart rate to control values, which was correlated with an increase in aortic flow. In addition, the dobutamine-stimulated rise in maximum systolic pressure and +dP/dt were similar in the control and STZ-Db rats in the presence of l-NAME. Western blot analysis detected the presence of inducible nitric oxide synthase (NOS) and a significant (P<0.001) increase in the constitutive NOS in ventricular myocytes from STZ-Db rats. These data suggest that an increased production of nitric oxide by NOS in ventricular myocytes from STZ-Db animals suppressed basal ventricular performance and the responsiveness to beta-adrenergic stimulation in diabetic hearts.
Smith
J M
JM
Department of Physiology, Midwestern University, Downers Grove, IL 60515, USA.
Paulson
D J
DJ
Romano
F D
FD
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D004280:Dobutamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000633:toxicity; D016276:Ventricular Function
D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D004280:Dobutamine; D013311:Streptozocin; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester