This study tested whether leptin restores sympathetic-vagal balance, heart rate (HR) variability, and cardiac baroreflex sensitivity (BRS) in streptozotocin (STZ)-induced diabetes. Sprague-Dawley rats were instrumented with arterial and venous catheters, and a cannula was placed in the lateral ventricle for intracerebroventricular (ICV) leptin infusion. Blood pressure (BP) and HR were monitored by telemetry. BRS and HR variability were estimated by linear regression between HR and BP responses to phenylephrine or sodium nitroprusside and autoregressive spectral analysis. Measurements were made during control period, 7 days after induction of diabetes, and 7 days after ICV leptin infusion. STZ diabetes was associated with hyperglycemia (422 +/- 17 mg/dl) and bradycardia (-79 +/- 4 beats/min). Leptin decreased glucose levels (165 +/- 16 mg/dl) and raised HR to control values (303 +/- 10 to 389 +/- 10 beats/min). Intrinsic HR (IHR) and chronotropic responses to a full-blocking dose of propranolol and atropine were reduced during diabetes (260 +/- 7 vs. 316 +/- 6, -19 +/- 2 vs. -43 +/- 6, and 39 +/- 3 vs. 68 +/- 8 beats/min), and leptin treatment restored these variables to normal (300 +/- 7, -68 +/- 10, and 71 +/- 8 beats/min). Leptin normalized BRS (bradycardia, -2.6 +/- 0.3, -1.7 +/- 0.2, and -3.0 +/- 0.5; and tachycardia, -3.2 +/- 0.4, -1.9 +/- 0.3, and -3.4 +/- 0.3 beats.min(-1).mmHg(-1) for control, diabetes, and leptin) and HR variability (23 +/- 4 to 11 +/- 1.5 ms2). Chronic glucose infusion to maintain hyperglycemia during leptin infusion did not alter the effect of leptin on IHR but abolished the improved BRS. These results show rapid impairment of autonomic nervous system control of HR after the induction of diabetes and that central nervous system actions of leptin can abolish the hyperglycemia as well as the altered IHR and BRS in STZ-induced diabetes.