Adaption of the heart to chronic pressure overload leads to cardiac hypertrophy and alterations in signal transduction-second messenger cascades. Responsiveness to catecholamine can be maintained despite receptor down regulation and loss of flow reserves, but this does not always occur. The positive compensation is achieved by readjusting intracellular post receptor systems. The objective of this proposal is first to determine the positive and negative compensatory changes in the second messenger cGMP in relation to cAMP in cardiac hypertrophy, and to evaluate the effect of these changes on local myocardial function and its 02 costs. Secondly, the goal is to enhance compensation and efficiency by chronic pharmacological modulation of receptor mediated changes in cAMP/cGMP pathways. All experiments will be conducted in anesthetized, open-chest dogs 6 months after induction of hypertrophy (aortic stenosis model), and on cells from similar animals. Regional myocardial work will be assessed from segment length measurements using ultrasonic dimension crystals and contractile force determinations by miniature force gauges. O2 consumption of the same segment will be determined from regional myocardial blood flow (radioactive microspheres) and regional O2 saturation of hemoglobin (microspectrophotometry) and with a p02 electrode in isolated cell suspensions. These physiological measurements will be combined with biochemical assays of beta adrenergic and muscarinic receptor number and affinity, adenyl and guanyl cyclase activity, cAMP, cGMP levels as well as cAMP and cGMP specific phosphodiesterase in vitro and in vivo.
The aim i s to determine the response of the hypertrophied heart to receptor mediated and direct changes in cGMP levels in terms of cAMP control of local function and 02 costs. Beta adrenergic and muscarinic receptor specific antagonists and agonists will be used to up and down regulate receptor numbers in order to improve compensation and restore efficiency through modulation of the cAMP/cGMP pathways. The ultimate goal is to gain a better understanding of the cellular mechanisms that control compensation in hypertrophy. Improving the ability of the hypertrophied heart to preserve function at lower 02 costs should impact positively on the development of congestive heart failure and survival in patients with cardiomyopathy of pressure overload.
