Differential Role of K _ATP Channels Activated by Conjugated Estrogens in the Regulation of Myocardial and Coronary Protective Effects

Abstract

Background-We have demonstrated that estrogen can reduce myocardial injury in ischemia-reperfusion via activation of ATP-sensitive potassium (K ATP ) channels. We sought to determine whether the protective effect of estrogen extends to epicardial coronary artery with attenuated vasoconstriction in patients after angioplasty by activation of such channels. Methods and Results-The study was designed to prospectively investigate 41 consecutive patients scheduled for elective coronary angioplasty. Pretreatment with estrogen limited myocardial ischemia during coronary occlusion and attenuated postangioplasty coronary vasoconstriction at the dilated and distal segments. An inhibitor of K ATP channels, glibenclamide, did not affect coronary vasomotor response, although it abolished the beneficial effect of estrogen on myocardial ischemia. Patients to whom estrogen was administered after the second balloon deflation experienced a similar magnitude of myocardial ischemia as controls but showed significantly attenuated vasoconstriction compared with controls (Pϭ0.0001). Endothelin-1 levels from the great cardiac vein rose significantly from 1.9Ϯ0.4 to 3.1Ϯ0.6 pg/mL (Pϭ0.001) 15 minutes after angioplasty in the control group; this was attenuated after estrogen was administered. Significant correlation was found between the changes in coronary vasomotion of the dilated segment and endothelin-1 levels (rϭ0.65, PϽ0.0001). Conclusions-These results demonstrate that estrogen is protective against both myocardial ischemia and coronary vasoconstriction through different mechanisms. The myocardial effect of estrogen was abolished by glibenclamide, which suggests that the cardioprotective effect of estrogen may result from activation of K ATP channels. In contrast, estrogen-induced attenuated vasoconstriction is associated with an attenuated release of endothelin-1, independent of K ATP activation.

KATP channel knockout worsens myocardial calcium stress load in vivo and impairs recovery in stunned heart

“…The present findings thus provide further evidence for the suggested gender-specific resistance to metabolic stress associated with higher levels of K ATP channels in females compared with males and a reduction in infarct size following ischemia-reperfusion injury (6,23,43). The protective action of estrogen on the ischemic myocardium is abolished by K ATP channel blockade (32), whereas treatment with 17␤-estradiol appears to stimulate K ATP channel expression (44) and prevent stress-induced calcium loading (26). Conversely, male-derived cardiac cells appear to accumulate higher levels of intracellular calcium in response to metabolic stress compared with femalederived cells (9).…”

Acute effects of 17β-estradiol on myocardial pH, Na+, and Ca2+ and ischemia-reperfusion injury

“…2 fit this paradigm in that acute E2 limitation of Na i ϩ and Ca i ϩ accumulation (see Figs 3 and 4) is associated with a smaller decrease in pH i during ischemia, and, again, this effect of E2 was diminished by L-NAME. We cannot rule out the possibility that E2 inhibits proton production, e.g., by stimulating ATP-dependent K ϩ channels (29), independently of that due to inhibition of NHE1 (and thus limits stimulation of NHE1), but the data in Fig. 1 provide strong evidence that E2 inhibits the response of NHE1 to acidification under conditions in which the acidification is not E2 dependent.…”

KMUP‐3 attenuates ventricular remodelling after myocardial infarction through eNOS enhancement and restoration of MMP‐9/TIMP‐1 balance

“…ATPdependent potassium (KATP) channels are expressed in cardiomyocytes at high levels and exert cardioprotective effects (Noma, 1983). In acute situations, for example, the opening of KATP channels results in cardioprotection against ischaemia/reperfusion injury with decreased cell death and reduced infarction size (Lee et al, 2003). Recently, longterm administration of KATP channel activators has also been shown to attenuate the ventricular remodelling after MI (Lee et al, 2008).…”