Selective inhibition of pinacidil effects by estrogen in guinea pig heart.
BACKGROUND
Recently, gender related differences in heart function have been extensively studied. Some of them, as differences in repolarization between males and females have been explained by direct effect of estrogen on delayed rectifier K+ channels and Ca2+ channels. It seems that estrogen induces overexpression of SUR2A subunits of ATP-sensitive K+ channels. The aim of this paper was to compare heart rate changes in male and female guinea pigs in the presence of different potassium channel openers (PCOs).


METHODS
We used spontaneously beating right atria from control and estrogen receptor modulator-treated male and female guinea pigs (17-beta-estradiol as a stimulator and tamoxifen as a blocker of estrogen receptor located in heart muscle).


RESULTS
In control females, rilmakalim and diazoxide, but not pinacidil elicited concentration-dependent decrease of heart rate. On the other hand, all three PCOs induced similar negative chronotropic action in hearts obtained from male control group (Emax was between -40 and -70 bpm, respectively). After two weeks of treatment with 17-beta-estradiol, pinacidil failed to significantly decrease heart rate in males however, tamoxifen-pretreated female group responded by decrease in automatism in the presence of rising concentration of pinacidil (Emax=-45+/-6 bpm, not significantly different from Emax in male control=-40+/-5 bpm, n=7). Interestingly, we observed lower blood concentration of the heart form of lactate dehydrogenase (H-LDH) in female than in male control group. Moreover, H-LDH concentration increased in tamoxifen-pretreated female group and decreased in 17-beta-estradiol-treated male group.


CONCLUSIONS
Our results indicate that estrogen downregulates H-LDH production and specifically modulate pinacidil action in guinea pig right atria, probably by changes of binding site for this drug in SUR2A receptor, but not for rilmakalim and diazoxide.
Kocić
Ivan
I
Department of Pharmacology, Medical University of Gdańsk, Debowa 23, 80-204 Gdańsk, Poland. ikocic@amg.gda.pl
Gruchała
Marta
M
Petrusewicz
Jacek
J
D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D015536:Down-Regulation; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D020110:Pinacidil / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D001993:Bronchodilator Agents; D002839:Chromans; D004965:Estrogen Antagonists; D004967:Estrogens; D015221:Potassium Channels; D011759:Pyrrolidines; D011960:Receptors, Estrogen; D014665:Vasodilator Agents; D013629:Tamoxifen; C075012:rilmakalim; D004958:Estradiol; D020110:Pinacidil; D007770:L-Lactate Dehydrogenase; D003981:Diazoxide