Time-dependent systolic and diastolic function in mice overexpressing calcineurin.

Echocardiograms have been assessed only at 56 days in mice overexpressing calcineurin (CN mice). Age-dependent echocardiographic changes were evaluated because the development of sudden death is time dependent. Because cyclosporin A (CsA) reverses hypertrophy in CN mice, its effects on the time course of the development of sudden death and cardiac dysfunction were assessed. In wild-type (WT) mice, the left ventricular (LV) internal end-diastolic dimension (LVIDd) increased and the LV mass index (LVMI) decreased with age. In CN mice, two distinct phases of pathophysiology were found. After 14 days, in CN mice, the LVIDd and LVMI were significantly increased, but sudden death had not occurred. After 28 days, in CN mice, relative dilation of the left ventricle occurred, whereas the LVMI decreased. Sudden death developed during progressive dilation associated with systolic and diastolic dysfunction. CsA treatment reversed hypertrophy in CN mice but did not reverse systolic and diastolic dysfunction and exaggerated sudden death. Sudden cardiac death was associated with systolic and diastolic dysfunction but was not related to isolated cardiac hypertrophy in CN mice.

Acute effects of toborinone on vascular capacitance and conductance in experimental heart failure.

BACKGROUND: Toborinone (OPC-18790), a phosphodiesterase III inhibitor, enhances cardiac contractility and is an arterial dilator. However, its effects on the venous system have not yet been clearly defined. Because toborinone administration reduces left ventricular (LV) end-diastolic pressure, it is probably also a venodilator. Because of the known arterial effects and the hypothesized venous effects, we compared changes in systemic vascular conductance (the inverse of resistance) with changes in venous capacitance. METHODS AND RESULTS: In 15 anesthetized, splenectomized dogs (10 treatment, 5 control), pressures were measured in the right atrium, aorta, portal vein, and LV. A cuff constrictor was placed around the portal vein. Cardiac output was measured by thermodilution, and splanchnic vascular capacitance was measured by blood-pool scintigraphic methods. Data were collected at baseline, after induction of heart failure (microsphere embolization into the left coronary artery), and then after toborinone boluses of 0.1, 0.2, 0.4, and 0.8 mg/kg. Heart failure was associated with decreased capacitance and conductance (to 87+/-3% and 64+/-4% of baseline values, respectively, P<0.05). After administration of the lower doses of toborinone, capacitance increased more than conductance; however, the effects were more balanced at the higher doses. Compared with nitroglycerin, hydralazine, and enalaprilat (results of an earlier study) in the same model, toborinone increased capacitance to a degree similar to that with nitroglycerin, at higher doses increased conductance similarly to hydralazine, and increased both capacitance and conductance considerably more than did enalaprilat. CONCLUSIONS: Toborinone is a potent balanced venous and arterial dilator in experimental acute heart failure. These marked effects suggest that it may prove to be a clinically important alternative to other vasodilators.