The influence of progesterone alone and in combination with estradiol on ventricular action potential duration and triangulation in response to potassium channel inhibition.
BACKGROUND
Females are at increased risk for torsades de pointes (TdP). Some evidence suggests that progesterone may protect against TdP, but few data exist regarding the effects of progesterone on cardiac repolarization. We determined the effects of progesterone alone and in combination with estradiol on ventricular action potential duration (APD) and triangulation in response to potassium channel inhibition.


RESULTS
Female New Zealand white rabbits (n = 30) underwent ovariectomy and were implanted with 21-day sustained release pellets (each n = 6): progesterone; estradiol; progesterone; & estradiol combined; dihydrotestosterone (DHT); and placebo. After 20 days, hearts were excised, mounted, perfused with modified Krebs-Henseleit buffer, and paced at 150 bpm. After baseline measurements, hearts were perfused with quinidine 3 μmol/L. The degree of quinidine-associated prolongation of ventricular APD at 90% repolarization (APD(90) ) in the progesterone group was significantly less than that in the estradiol and the combined estradiol and progesterone groups, and not significantly different than in the DHT group. The degree of prolongation of action potential triangulation (APD(90) - APD(30) ) in hearts from progesterone-treated rabbits was significantly less than that in the estradiol group, and not significantly different from that in hearts from DHT-treated rabbits. There were no significant differences in quinidine effects on ventricular APD(90) or action potential triangulation between hearts exposed to estradiol alone or those exposed to both estradiol and progesterone.


CONCLUSIONS
Progesterone protects against prolongation of APD(90) and triangulation associated with potassium channel inhibition. However, progesterone does not attenuate the effects of estradiol on prolongation of ventricular APD(90) associated with potassium channel inhibition.
Tisdale
James E
JE
Department of Pharmacy Practice, College of Pharmacy, Purdue University, 1001 West 10th Street, Indianapolis, IN 46202, USA. jtisdale@iupui.edu
Overholser
Brian R
BR
Wroblewski
Heather A
HA
Sowinski
Kevin M
KM
D000200:Action Potentials; D000818:Animals; D013196:Dihydrotestosterone / Q000008:administration & dosage; D004958:Estradiol / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects* / Q000503:physiopathology; D010052:Ovariectomy; D026902:Potassium Channel Blockers / Q000633:toxicity*; D011374:Progesterone / Q000008:administration & dosage* / Q000097:blood; D011802:Quinidine / Q000633:toxicity*; D011817:Rabbits; D018570:Risk Assessment; D012737:Sex Factors; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*
D026902:Potassium Channel Blockers; D013196:Dihydrotestosterone; D011374:Progesterone; D004958:Estradiol; D011802:Quinidine