The long-term goal is to determine whether alpha1 adrenergic blockade medication, in addition to angiotensin converting enzyme inhibition in the post-myocardial infarction treatment regimen, is indicated in preventing myocardial remodelling following a large myocardial infarction. Firstly, evidence will be sought for synergism between activation of the alpha1-adrenergic receptor and the receptor for angiotensin II (AT-II), the angiotensin-1 (A1) receptor with regard to myocardial hypertrophy. This will be studied-by stimulating myocardial cells in culture (neonatal and adult) with phenylephrine and AT II-in the presence and absence of appropriate blockers for varying durations, and studying the effect on cell growth and proliferation, changes in respective receptor density and affinity, gene expression of growth factors, and changes in signal transduction of each respective signalling pathway. Secondly, an in vivo study will be undertaken to study whether alpha1-adrenergic blockade with prazosin and WB 4101 has an additional advantage to inhibition of the AT1 receptor with losartan. Myocardial infarction will be induced in adult rats, and the effect of treatment with alpha1 adrenergic and AT1 receptor blockers will be compared with appropriate controls with regard to hemodynamic and morphometric parameters (remodelling), alpha1- and AT1 receptor density and affinity, and expression of growth genes. In additional to expanding our understanding of the mechanisms involved in the pathophysiology of post-myocardial infarction remodelling, the results of this study-may have an important effect on clinical practice.
