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 n itric 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.) diab etic (STZ-Db) rat. Left ventricular performance was measured in isolat ed working hearts, before and at the peak response to 0.8 mu M dobutam ine, in the absence or presence of N-G-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 ba sal (decreased heart rate, cardiac output, aortic flow -dP/dt) and dob utamine-stimulated (diminished rise in +dP/dt and maximum systolic pre ssure) conditions. L-NAME had minimal effects on basal or dobutamine-s timulated ventricular performance in control hearts. In contrast, L-NA ME infusion in hearts from STZ-Db returned the depressed heart rate to control values, which was correlated with an increase in aortic now. In addition, the dobutamine-stimulated rise in maximum systolic pressu re and +dP/dt were similar in the control and STZ-Db rats in the prese nce of L-NAME. Western blot analysis detected the presence of inducibl e nitric oxide synthase (NOS) and a significant (P<0.001) increase in the constitutive NOS in ventricular myocytes from STZ-Db rats. These d ata suggest that an increased production of nitric oxide by NOS in ven tricular myocytes from STZ-Db animals suppressed basal ventricular per formance and the responsiveness to beta-adrenergic stimulation in diab etic hearts. (C) 1997 Academic Press Limited.