Angiotensin converting enzyme and the arrhythmogenic action of angiotensin I: cardiac cell membrane as a site of angiotensin I conversion.
The influence of angiotensin I (Ang I) on heart excitability and refractoriness was investigated in isolated right ventricular muscle of adult rats as well as in isolated ventricular myocytes. The results indicated that Ang I (10(-8) M) added to the bath solution, decreased the action potential duration from 50.4 +/- 3.6 to 33.9 +/- 3.9 ms (P < 0.05) and reduced significantly the cardiac refractoriness. Consequently, a discharge of spontaneous action potentials was elicited when a second stimulus was applied during the relative refractory period. Moreover, the conduction velocity was reduced from 56.9 +/- 2.9 to 40 +/- 3.2 cm/s (P < 0.05). The question whether the effect of Ang I was related to its conversion to Ang II, was investigated on tissues exposed to enalapril maleate (10(-8) M). Under these conditions, the effect of Ang I was totally suppressed. Similar results were found with losartan (10(-7) M). To investigate if the conversion of Ang I to Ang II occurs at the level of surface cell membrane, measurements of inward calcium current (ICa) were performed in myocytes isolated from the rat ventricle. ICa was measured before and after the administration of Ang I (10(-8) M). The results indicated that Ang I (10(-8) M), added to the bath solution, reduced the peak ICa density by 26.3 +/- 2.6% (P < 0.05), an effect abolished by enalapril maleate (10(-8)M).


CONCLUSIONS
Evidence is presented for the first time, that Ang I is converted to Ang II at the surface cell membrane in cardiac muscle with consequent generation of cardiac arrhythmias which are elicited by Ang II.
De Mello
Walmor C
WC
Department of Pharmacology, Medical Sciences Campus, UPR, P.O. Box 365067, San Juan, PR 00936-5067, USA. wmello@rcm.upr.edu
D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats
D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D002118:Calcium