Abstract 641: Hypertension and Cardiac Dysfunction in Male Mice Deficient in the Alpha 1 Subunit of Soluble Guanylate Cyclase
Introduction. Nitric oxide (NO) plays a major role in regulating both vascular tone and myocardial function, but the contribution of the NO receptor, soluble guanylate cyclase (sGC), is less certain. We previously reported that deficiency of one sGC subunit, α1, is associated with hypertension in male but not female mice. The objective of this study was to further investigate the role of sGC in cardiac function.
Methods. Two to 4 month old male and female wild-type (WT) and sGCα1 knockout (sGCα1−/−) mice were studied using echocardiography (unanesthetized mice) and invasive hemodynamic methods (anesthetized mice). Mean arterial pressure (MAP) and heart rate (HR) were recorded in unrestrained animals with implanted telemetry devices.
Results. Telemetric and hemodynamic measurements confirmed that male but not female sGCα1−/− mice are hypertensive (Table⇓). HR measured with telemetry was elevated in both male and female sGCα1−/− mice. The ratio of the maximum first derivative of the developed LV pressure to the isovolumic pressure (dP/dtmax/IP), a relatively load-independent measure of systolic function, was decreased in male but not female sGCα1−/− mice. The time constant of isovolumic relaxation (τ), a measure of diastolic function, was similarly increased in male but not female sGC −/− mice. Echocardiography of male WT and sGCα1 −/− mice (n=19 and 23, respectively) revealed similar LVEF (80±4 vs 82±3, respectively) and wall thickness (0.7±0.1 mm for both), but LV end-systolic and diastolic volumes and stroke volume were decreased in male sGCα1−/− mice (19±4 vs 24±6 μl, 4±1 vs 5±2 μl, and 16±3 vs 19±4 μl, respectively, P<0.05 for all).
Conclusions. Deficiency of sGCα1 is associated with hypertension and cardiac dysfunction in male but not female mice suggesting a complex, gender-dependent role for sGCα1 in regulating blood pressure and cardiac function and providing a model to study the mechanisms by which NO regulates vascular relaxation and cardiac function.