Acute antihypertrophic actions of bradykinin in the rat heart: importance of cyclic GMP.
The antihypertrophic action of angiotensin (Ang)-converting enzyme (ACE) inhibitors in the heart is attributed in part to potentiation of bradykinin. Bradykinin prevents hypertrophy of cultured cardiomyocytes by releasing nitric oxide (NO) from endothelial cells, which increases cardiomyocyte guanosine 3'5'-cyclic monophosphate (cyclic GMP). It is unknown whether cyclic GMP is essential for the action of bradykinin, or whether findings in isolated cardiomyocytes apply in whole hearts, in the presence of other cell types and mechanical/dynamic activity. We now examine the contribution of cyclic GMP to the antihypertrophic action of bradykinin in cardiomyocytes and perfused hearts. In adult rat isolated cardiomyocytes cocultured with bovine aortic endothelial cells, the inhibitory action of bradykinin (10 micromol/L) against Ang II (1 micromol/L)-induced [3H]phenylalanine incorporation was abolished by the soluble guanylyl cyclase inhibitor [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (10 micromol/L). In Langendorff-perfused rat hearts, Ang II (10 nmol/L)-induced increases in [3H]phenylalanine incorporation and atrial natriuretic peptide mRNA expression were prevented by bradykinin (100 nmol/L), the NO donor sodium nitroprusside (3 micromol/L), and the ACE inhibitor ramiprilat (100 nmol/L). The acute antihypertrophic action of bradykinin was accompanied by increased left ventricular cyclic GMP, and the ramiprilat effect was attenuated by HOE 140 (1 micromol/L, a B2-kinin receptor antagonist) or [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (100 nmol/L). In conclusion, bradykinin exerts a direct inhibitory action against the acute hypertrophic response to Ang II in rat isolated hearts, and elevation of cardiomyocyte cyclic GMP may be an important antihypertrophic mechanism used by bradykinin and ramiprilat in the heart.
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D006332:Cardiomegaly / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003326:Coronary Circulation; D006152:Cyclic GMP / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009924:Organ Culture Techniques; D010649:Phenylalanine / Q000378:metabolism; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000806:Angiotensin-Converting Enzyme Inhibitors; D020030:Nitric Oxide Donors; D010649:Phenylalanine; C052549:ramiprilat; D006152:Cyclic GMP; D017257:Ramipril; D001920:Bradykinin