Degradation of bradykinin, a cardioprotective substance, during a single passage through isolated rat-heart.
Angiotensin converting enzyme (ACE) inhibitors have cardioprotective effects in different species including human. This cardioprotective effect is mainly due to the inhibition of bradykinin (BK) degradation rather than inhibition of the conversion of angiotensin I to angiotensin II. Bradykinin, a nonapeptide, has been considered to be the potential target for various enzymes including ACE, neutral endopeptidase 24.11, carboxypeptidase M, carboxypeptidase N, proline aminopeptidase, endopeptidase 24.15, and meprin. In the present study, the coronary vascular beds of Sprague Dawley rat isolated hearts were perfused (single passage) with Krebs solution alone or with different concentrations of BK i.e. 2.75x10(-10), 10(-7), 10(-6) and 10(-5) M solution. Percent degradation of BK was determined by radioimmunoassay. The degradation products of BK after passing through the isolated rat-hearts were determined using RP-HPLC and mass spectroscopy. All the four doses of BK significantly decreased the perfusion pressure during their passage through the hearts. The percentage degradation of all four doses was decreased as the concentration of drug was increased, implying saturation of a fixed number of active sites involved in BK degradation. Bradykinin during a single passage through the hearts degraded to give [1-7]-BK as the major metabolite, and [1-8]-BK as a minor metabolite, detected on HPLC. Mass spectroscopy not only confirmed the presence of these two metabolites but also detected traces of [1-5]-BK and arginine. These findings showed that primarily ACE is the major cardiac enzyme involved in the degradation of bradykinin during a single passage through the coronary vascular of bed the healthy rat heart, while carboxypeptidase M may have a minor role.
Ahmad
M
M
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, UK. maqsood_mul@yahoo.com
Zeitlin
I J
IJ
Parratt
J R
JR
Pitt
A R
AR
D000818:Animals; D001920:Bradykinin / Q000378:metabolism* / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000378:metabolism* / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects; D058851:GPI-Linked Proteins; D066298:In Vitro Techniques; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D015260:Neprilysin / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D002316:Cardiotonic Agents; D058851:GPI-Linked Proteins; D007703:Peptidyl-Dipeptidase A; C058479:carboxypeptidase M; D008666:Metalloendopeptidases; D015260:Neprilysin; D001920:Bradykinin