BRADYKININ BLOCKS ANGIOTENSIN-II-INDUCED HYPERTROPHY IN THE PRESENCE OF ENDOTHELIAL-CELLS

Angiotensin-converting enzyme inhibitors block left ventricular hypert rophy in vivo. A component of this effect has been attributed to tissu e accumulation of bradykinin. Little is known regarding the effect of bradykinin on cardiomyocytes, The objectives oi the present study were to define the effects oi bradykinin on isolated ventricular cardiomyo cytes (from adult and neonatal rat hearts) and to determine the extent to which bradykinin blocks hypertrophy in vitro. Bradykinin was found to be a hypertrophic agonist, as defined by increased protein synthes is and atrial natriuretic peptide secretion and expression, Bradykinin (10 mu mol/L) increased [H-3]phenylalanine incorporation by 23+/-3% i n adult and by 36+/-10% in neonatal cardiomyocytes. Constitutive atria l natriuretic peptide secretion by neonatal myocytes was increased 357 +/-103%. All effects of bradykinin were abolished by the B-2-kinin rec eptor antagonist Hoe 140. These increases were similar in magnitude to those observed with phenylephrine (20 mu mol/L) and angiotensin II (1 mu mol/L). However, in cardiomyocytes cocultured with endothelial cel ls, bradykinin did not increase protein synthesis. Angiotensin II incr eased [H-3]phenylalanine incorporation by 24+/-3% in adult cardiomyocy tes in monoculture and by 22+/-2% in adult rat cardiomyocytes cocultur ed with endothelial cells. Bradykinin abolished this angiotensin II-in duced hypertrophy in myocytes cultured with endothelial cells but not in myocytes studied in the absence of endothelial cells, In conclusion , bradykinin has a direct hypertrophic effect on ventricular myocytes. The presence of endothelial cells is required for the antihypertrophi c effects of bradykinin. The results suggest that the increase in loca l concentration of bradykinin associated with angiotensin-converting e nzyme inhibition is an important mechanism by which hypertrophy can be blocked, Manifestation of this mechanism appears to require bradykini n-stimulated release of paracrine factor(s) from endothelial cells, wh ich are also able to block the hypertrophic effects of Ang II.