Possible protective effects of kinins and converting enzyme inhibitors in cardiovascular tissues.
The main objective of this study was to determine if the components of the kallikrein-kinin system are released into the venous effluent from isolated perfused rat hearts. To assess the contribution of kinins and the vascular and cardioprotective effects of the ACE inhibitor ramipril, we determined the status of cardiac kallikrein (CKK), potent kinin-generating enzyme, in rats with right ventricular hypertrophy induced by chronic volume overload and left ventricular hypertrophy by aortic banding. CKK was measured as previously described (Nolly, H.L., Carbini, L., Carretero, O.A., Scicli, A.G., 1994). Kininogen by a modification of the technique of Dinitz and Carvalho (1963) and kinins were extracted with a Sep-Pak C18 cartridge and measured by RIA. CKK (169 +/- 9 pg Bk/30 min), kininogen (670 +/- 45 pg Bk/30 min) and immunoreactive kinins (62 +/- 10 pg Bk/30 min) were released into the perfusate. The release was almost constant over a 120 min period. Pretreatment with the protein synthesis inhibitor puromycin (10 mg i.p.) lowered the release of kallikrein (42 +/- 12 pg Bk/30 min, p < 0.001) and kininogen (128 +/- 56 pg Bk/30 min, p < 0.001). Addition of ramiprilat (10 micrograms/ml) increased kinin release from 54 +/- 18 to 204 +/- 76 pg Bk/30 min (p < 0.001). Aortic banding of rats increased their blood pressure (BP) (p < 0.001), relative heart weight (RHW) (p < 0.001) and CKK (p < 0.001). Ramipril treatment induced a reduction in BP (p < 0.05) and RHW (p < 0.005) while CKK remained elevated. Aortocaval shunts increased their ANF plasma levels (p < 0.05), RHW (p < 0.001) and CKK (p < 0.01). Ramipril treatment induced a reduction in RHW (p < 0.05), while CKK and ANF increased significantly (p < 0.05). The present data show that the components of the kallikrein-kinin system are continuously formed in the isolated rat heart and that ramipril reduces bradykinin breakdown with subsequent increase in bradykinin outflow. The experiments with aorta caval shunt and aortic banding show that cardiac tissues increase their kinin-generating activity and this was even higher in ramipril-treated animals. This may suggest that the actual level of kinins is finely tuned to the local metabolic demands. In this experimental model of cardiac hypertrophy. ACE inhibitors potentiate the actions of kinins and probably try to normalise endothelial cell function.
Nolly
H
H
Laboratory of Experimental Hypertension and Vasoactive Substances, School of Medicine and National Council of Research, Mendoza, Argentina.
Miatello
R
R
Damiani
M T
MT
Abate
C D
CD
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000378:metabolism*; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016234:Kallikrein-Kinin System / Q000187:drug effects* / Q000502:physiology; D007610:Kallikreins / Q000378:metabolism; D007704:Kininogens / Q000302:isolation & purification / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011691:Puromycin / Q000494:pharmacology; D011863:Radioimmunoassay; D017257:Ramipril / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D000806:Angiotensin-Converting Enzyme Inhibitors; D007704:Kininogens; D011500:Protein Synthesis Inhibitors; D011691:Puromycin; D009320:Atrial Natriuretic Factor; D007610:Kallikreins; D017257:Ramipril; D001920:Bradykinin