ALTERATIONS IN ANGIOTENSIN-II RECEPTOR-MEDIATED SIGNAL-TRANSDUCTION SHORTLY AFTER CORONARY-ARTERY CONSTRICTION IN THE RAT

Objective: The aim of the study was to determine the effect of coronar y artery constriction on the density of angiotensin II receptors and o n the effector responses coupled with these receptors on myocytes one week after surgical induction of coronary artery stenosis in rats. Met hods: After induction of coronary artery stenosis and following the es timation of global cardiac performance, myocytes were enzymatically di ssociated and radioligand binding studies were performed. In addition, the isotonic contractile performance, cytosolic calcium transients, a nd angiotensin II stimulated inositol phosphate generation in myocytes were measured in the presence and absence of the angiotensin II recep tor subtype antagonist losartan. Results: After documenting left Ventr icular failure and right ventricular dysfunction, the expression and d ensity of angiotensin II receptors in left ventricular myocytes were e valuated and found to be increased 3.1-fold and 4.1-fold, respectively . Corresponding increases in right ventricular myocytes were 3.6-fold and 4.5-fold. In contrast, the quantity of the regulatory protein G(q alpha) was not altered in either Ventricle. Angiotensin LT did not inc rease the generation of total inositol phosphates in left and right ve ntricular myocytes at maximum stimulation. However, the threshold for the formation of inositol phosphates was lowered in left ventricular m yocytes of coronary narrowed rats. Measurements of single cell mechani cs indicated that angiotensin II stimulation markedly improved the dep ression in myocyte function biventricularly. This inotropic effect was coupled with the restoration of cytosolic calcium. Conclusions: The u pregulation of angiotensin II receptors on myocytes in this model of g lobal ischaemia may be a compensatory mechanism ameliorating myocyte c ontractility in an attempt to sustain ventricular pump function.