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Inhibition of nitric oxide synthase by L-NAME improves ventricular performance in streptozotocin-diabetic rats
J M Smith1, D J Paulson, F D Romano
1Department of Physiology, Midwestern University, Downers Grove, IL 60515, USA.
Abstract:
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.
Insights
Diabetic rat hearts show suppressed function due to increased nitric oxide (NO) production. Inhibiting nitric oxide synthase (NOS) with L-NAME restored cardiac performance, suggesting NO
Area of Science:
- Cardiovascular Physiology
- Endocrinology
- Biochemistry
Background:
- Diabetic cardiomyopathy is characterized by impaired cardiac function.
- The role of nitric oxide (NO) in diabetic heart dysfunction is not fully understood.
Purpose of the Study:
- To investigate if nitric oxide synthase (NOS) activation suppresses cardiac function in diabetic rats.
- To assess the impact of NO on beta-adrenergic stimulation responsiveness in diabetic hearts.
Main Methods:
- Isolated working hearts from streptozotocin-induced diabetic (STZ-Db) rats and control rats were studied.
- Ventricular performance was measured under basal conditions and during dobutamine stimulation.
- Effects of NG-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, were evaluated.
Main Results:
- STZ-Db hearts exhibited suppressed basal function (reduced heart rate, cardiac output) and blunted dobutamine response.
- L-NAME treatment improved heart rate and aortic flow in STZ-Db hearts.
- L-NAME normalized the dobutamine-stimulated increase in systolic pressure and contractility in STZ-Db rats.
- Increased expression of inducible and constitutive NOS was observed in STZ-Db ventricular myocytes.
Conclusions:
- Increased nitric oxide production contributes to suppressed cardiac function in diabetic rats.
- Inhibition of NOS can ameliorate cardiac dysfunction and restore beta-adrenergic responsiveness in diabetic hearts.
- These findings highlight the detrimental role of NO in diabetic cardiomyopathy.