Endothelial cells have been shown to modulate function of normal myocardium. The role of such endothelial control in hypertrophied myocardium and its interaction with the renin-angiotensin system (RAS) which is upregulated in hypertrophied hearts, are not known.
The specific aims are to test the following hypotheses: 1) local cardiac angiotensin (Ang) II generation and its adverse effects on contractility and relaxation in left ventricular hypertrophy (LVH) are modulated by endothelial cells; 2) nitric oxide (NO) enhances LV relaxation to a greater extent in LVH than in control hearts due to basal upregulation of cardiac RAS; 3) exogenous NO donor prevents adverse effects of Ang II generation on contractility and relaxation in LVH; 4) beneficial effects of angiotensin-converting enzyme (ACE) inhibition on preventing diastolic LV dysfunction are blocked by inhibition of bradykinin and NO. Male Wistar rats with LVH due to ascending aortic stenosis and sham operated rats will be used for an isolated heart preparation. To study the role of endothelium as a mediator of adverse effects of Ang II on cardiac function, LVH and control hearts with normal and dysfunctional endothelium (disabled by Triton x-100 in concentration of 1:200) will be per-fused with increasing doses of Ang I. Fractional conversion of Ang I to II and its effects on cardiac function will be measured. To investigate effects of NO on LV function, sodium nitroprusside (SNP) will be infused during constant coronary flow and dose response curves will be investigated in groups of LVH and control hearts. To investigate if exogenous NO donor can prevent adverse effects of Ang II on cardiac function, both groups of hearts will receive infusion of Ang I and SNP. To examine whether the beneficial effects of ACE-inhibition on diastolic function depend in part on inhibition of bradykinin breakdown, hypertrophied hearts will be per-fused with enalaprilat and Ang I and either with saline or specific bradykinin inhibitor Hoe 140. The present proposal will provide new insight into the interaction of endothelium and cardiac RAS in the pathophysiology and prevention of diastolic dysfunction in heart failure due to pressure overload LVH.
| Bartunek, J; Weinberg, E O; Tajima, M et al. (2000) Chronic N(G)-nitro-L-arginine methyl ester-induced hypertension : novel molecular adaptation to systolic load in absence of hypertrophy. Circulation 101:423-9 |
| Bartunek, J; Weinberg, E O; Tajima, M et al. (1999) Angiotensin II type 2 receptor blockade amplifies the early signals of cardiac growth response to angiotensin II in hypertrophied hearts. Circulation 99:22-5 |
| Bartunek, J; Dempsey, S; Weinberg, E O et al. (1998) Chronic L-arginine treatment increases cardiac cyclic guanosine 5'-monophosphate in rats with aortic stenosis: effects on left ventricular mass and beta-adrenergic contractile reserve. J Am Coll Cardiol 32:528-35 |
