Abstract 2952: Sympathetic Renal Vasoconstriction in Rabbits With Pacing-induced Heart Failure is AT1R Dependent
The cardio-renal syndrome represents a major complication in the treatment of patients with chronic heart failure (CHF). The mechanisms that contribute to the deterioration in renal function in CHF are not clearly understood. To determine the interaction between sympathetic regulation of renal vascular tone and Angiotensin II (Ang II), we instrumented rabbits with a renal flow probe to measure renal blood flow and a radiotelemetry unit to measure blood pressure and calculated renal vascular resistance (RVR). CHF was induced by rapid ventricular pacing. We found a significant increase in RVR in rabbits with CHF (2.08±0.13, sham, vs. 2.69±0.15, CHF, P<0.05.) Losartan (10 mg/kg IV bolus), an Ang II type 1 receptor (AT1R) antagonist, decreased RVR in CHF rabbits (1.79±0.10, CHF + losartan, vs. 2.69±0.15, CHF, P<0.05.) In another group of animals, the left kidney was denervated. In these animals, RVR in CHF was not different from sham animals (2.26±0.45 vs. 2.08±0.13, P=ns.) In another group of animals, we assessed the response to intrarenal infusion of norepinephrine (5 ug/kg/min) to simulate sympathetic stimulation. The response to norepinephrine infusion was augmented in rabbits with CHF (RVR: 3.97±0.73, CHF vs. 2.73±0.22, sham, P<0.05) and was reduced by losartan administration (RVR: 2.43±0.47, CHF+losartan, vs. 3.97±0.73, CHF, P<0.05.) After tissues were harvested, we determined the expression of AT1R in sieved renal blood vessels. Kidneys from rabbits with CHF expressed higher AT1R than sham (1.02±0.11 vs. 0.35±0.03, P<0.05); renal denervation normalized the expression of AT1R (0.57±0.08 vs. 0.35±0.03, sham, P=ns.) This data suggests that AT1R activation contributes to the renal vasoconstriction in CHF at baseline and during sympathetic stimulation and that increased renal nerve activity may influence expression of AT1R in the kidney vasculature. The link between sympatho-excitation and renal function may implicate a future therapeutic target for patients suffering from the cardio-renal syndrome.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).