Angiotensin II facilitates tricyclic antidepressant-induced changes in QRS-duration in the rat.
Experimental evidence indicates that angiotensin II can modulate sodium channel and gap junction function. This raises the possibility that variations in angiotensin II could alter the effect of drugs that act on these mechanisms. In this study, the influence of changing salt status and angiotensin II activity has been investigated by evaluating the QRS prolonging effects of the sodium channel blocking drug, desmethylimipramine. In control rats with a normal salt intake, intravenous infusion of desmethylimipramine (0.8 mg/kg/min) over 60 min increased QRS duration over time to 150% of control by 60 min; mean arterial blood pressure and pulse rate were decreased. In salt-deplete rats, the response to desmethylimipramine was similar to controls for 30 min. Thereafter, QRS duration increased more rapidly than controls. In rats on a high salt diet, the same desmethylimipramine infusion produced no change in QRS duration for 30 min, despite equivalent reductions in mean arterial blood pressure. Thereafter, QRS duration increased, reaching values similar to control by 60 min. In rats on a normal salt diet pretreated with captopril, there was a similar blunting of the QRS response to desmethylimipramine to that observed in salt-loaded rats. The QRS response to desmethylimipramine and salt-loaded rats on normal salt diets receiving captopril returned to the control pattern after a subpressor infusion of angiotensin II (3 ng/min), while a higher rate of angiotensin II (10 ng/min) further enhanced the QRS prolonging effect of desmethylimipramine. These data demonstrate that endogenous angiotensin II contributes to the regulation of the cardiac electro-physiological response to DMI.
Li
P
P
Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee.
Benitez
J
J
Roden
D
D
Branch
R A
RA
D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D003891:Desipramine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004562:Electrocardiography / Q000187:drug effects*; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012982:Sodium, Dietary / Q000008:administration & dosage
D012982:Sodium, Dietary; D000804:Angiotensin II; D002216:Captopril; D003891:Desipramine