Abstract P427: Inhibition of the Regulator of G Protein Signaling 14, a Novel Anti-Hypertensive Mechanism

Abstract

The Regulator of G Protein Signaling 14 (RGS14) knockout (KO) mouse is unique in that it not only extends longevity, but also enhances several aspects of healthful aging. The RGS14 KO mouse, compared with wild type (WT), is protected against obesity and diabetes, and has increased exercise capacity, similar to levels achieved with chronic exercise training, all potentially important anti-hypertensive mechanisms. The goal of this investigation was to test more directly that the RGS14 KO mouse is protected against hypertension. Accordingly, we chronically infused angiotensin II (1.44 mg/kg/day) by implanted osmotic pump for 14 days. Stroke volume was measured by cardiac echocardiography. Cardiac output was calculated as the product of stroke volume and heart rate. Heart rates were not different in WT and RGS14 KO prior to angiotensin II infusion or after infusion (425±11 beats/min in WT vs. 420±13 beats/min in KO). Prior to angiotensin II baseline values for mean arterial pressure were similar in WT (84±3 mmHg) and RGS14 KO (79±2 mmHg) and baseline values for systemic vascular resistance, calculated as mean arterial pressure/cardiac output, were also similar in WT (3.7±0.1 mmHg/mL/min) and RGS14 KO (2.2±0.2 mmHg/mL/min) before angiotensin II infusion. As expected, the angiotensin infusion for 14 days increased mean arterial pressure by 69±8 % and systemic vascular resistance by 43±9 % in WT. Surprisingly, angiotensin II failed to increase either mean arterial blood pressure or systemic vascular resistance significantly in RGS14 KO mice. Thus the increases in arterial pressure and vasoconstriction, pathognomonic of angiotensin II, were completely blocked in the RGS14 KO mouse, implicating this mechanism as a potential novel therapeutic modality for treating hypertension.