Effect of chronic renal denervation on cardiac response to β-adrenergic stimulation in a diabetic nephropathy rat model

Abstract

Abstract Increased cardiac sympathetic drive as a consequence of increased renal sympathetic activity is an important contributor to the development of cardiovascular complications in patients with diabetic nephropathy. Bilateral renal denervation (BRD), by reducing systemic sympathetic output, has been shown to normalize blood pressure and reduce left ventricular hypertrophy in clinical and experimental studies of hypertension. Therefore, this study aimed to determine the effect of BRD on cardiac response to β-adrenergic stimulation in a diabetic model with underlying hypertension using the transgenic (mRen-2)27 rats. We hypothesize that BRD will improve cardiac response to β-adrenergic stimulation in a diabetic nephropathy rat model.

Following streptozotocin (STZ) induction of diabetes, BRD or sham surgeries were conducted repeatedly (at the 3rd, 6th, and 9th week following induction) in both non-diabetic and diabetic 6 week old female Ren-2 rats. Blood glucose was maintained at 25-30 mmol/L using s.c. insulin. Cardiac function was determined in isolated hearts perfused in the Langendorff mode at 12th week following STZ induction. Normalized left ventricular developed pressure (LVDP) was recorded in response to cumulative concentrations of isoproterenol (nonspecific β1- and β2-agonist) (10-10 to 5×10-8 M) and BRL 37344 (specific β3-agonist) (10-12 to 10-6 M).

No significant differences in basal cardiac characteristics were observed in non-diabetic and diabetic rats. LVDP response to isoproterenol stimulation was reduced in the diabetic compared to non-diabetic group. However, stimulation with BRL 37344 had no significant effect on LVDP response in both non-diabetic and diabetic rats. In addition, BRD had no effect on LVDP response to isoproterenol and BRL 37344 stimulations compared to the innervated animals in both non-diabetic and diabetic rats. Interestingly, there was a significant increase in diastolic pressure-volume and hence filling pressure in diabetic rats, but a significant increase in diastolic pressure-volume in non-diabetic rats, after renal denervation.

In conclusion, renal denervation did not restore the attenuated cardiac response to β-adrenergic stimulation in the diabetic hypertensive rats. This suggests that in the diabetic hypertensive rat hearts, reducing renal sympathetic activity does not decrease sympathetic drive to the heart, but may contribute to a reduction in underlying cardiac remodeling.