Prolongation by captopril of action potential duration in the normal and hypertrophied rat ventricle: direct action or inhibition of the local angiotensin converting enzyme?
OBJECTIVE
The aims were: (1) to study the acute effects of captopril on the action potential characteristics of ventricular fibres from the normal rat, (2) to compare the effects of captopril with those of perindoprilat, a non-thiol angiotensin I converting enzyme (ACE) inhibitor, (3) to determine the electrophysiological properties of the peptide substrates of converting enzyme, bradykinin and angiotensin I, and (4) to investigate whether the effects of captopril occurring in the healthy heart also occur in two models of ventricular hypertrophy.


METHODS
Action potentials were recorded with the standard glass microelectrode technique in right ventricular preparations excised from rat hearts and superfused under baseline conditions and with drug containing or peptide containing Tyrode solution. Ventricular hypertrophy was induced in response to hypertension (unilaterally nephrectomised, DOCA-salt model) or 4 week old left ventricular infarction.


RESULTS
In preparations from normal rat hearts, captopril increased action potential duration in a concentration dependent fashion [EC50 = 3.5 x 10(-8) M; maximum effect = 44(SEM 5.1)% prolongation at 10(-5) M for action potential duration at 90% repolarisation, APD90]. Perindoprilat similarly caused a dose dependent increase in action potential duration, but with 100 times greater potency [EC50 = 3.1 x 10(-10) M; maximum effect = 71(11)% prolongation at 10(-5) M for APD90]. SQ 14,534, a stereoisomer of captopril with one hundredth the ACE inhibitor potency, had no significant effect on action potential duration at 10(-5) M. Angiotensin I and bradykinin caused concentration dependent prolongation of action potential, but angiotensin II (10(-6) M) had no effect. Captopril (10(-5) M) had no significant effect in the hypertrophied right ventricle from DOCA-salt hypertensive rats, but significantly increased APD90 [39(4.9)%] in right ventricular preparations from rats with 4 week old anterior left ventricular infarction.


CONCLUSIONS
In the rat, captopril prolongs action potential duration, an effect possibly due to local accumulation of bradykinin and angiotensin I.
Ribuot
C
C
Research Centre, Hôpital sur Sacré-Coeur, Montreal, Québec, Canada.
Cardinal
R
R
Gouin
L
L
Moreau
P
P
Godin
D
D
Vermeulen
M
M
de Champlain
J
J
Rochette
L
L
Nadeau
R
R
D000200:Action Potentials / Q000187:drug effects*; D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002216:Captopril / Q000031:analogs & derivatives / Q000494:pharmacology*; D006332:Cardiomegaly / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D009203:Myocardial Infarction / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; C053500:perindoprilat; D000803:Angiotensin I; D002216:Captopril; D001920:Bradykinin