Sex differences in myocardial infarct size are abolished by sarcolemmal K<sub>ATP</sub>channel blockade in rat

Johnson, M. S.; Moore, Russell L.; Brown, David A.

doi:10.1152/ajpheart.01291.2005

Cited by 73 publications

(71 citation statements)

References 25 publications

(31 reference statements)

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“…Selective blockade of the myocardial sarcK ATP channel completely abolished the infarct-sparing effect conferred by 5 days of exercise training in both male and female rats, indicating that an opening of the sarcK ATP channel is required for cardioprotection induced by short-term exercise training in both sexes. In addition, we have corroborated the findings of previous studies that have indicated that the female heart is intrinsically more resistant to myocardial infarction than the male heart (2,11,15,41) and that this sex difference is abolished by sarcK ATP channel blockade (29).…”

Section: Discussionsupporting

confidence: 90%

“…After a 10-min equilibration period, baseline LV pressures and coronary flow rate were recorded, and hearts were perfused with buffer containing a specific sarcK ATP channel antagonist (30 M HMR-1098, a gift from Dr. Heinz Gögelein, Aventis Pharma) (SedHMR and TrHMR) or with buffer containing no drug (Sed and Tr). This concentration of HMR-1098 has been previously used in Langendorf-perfused heart preparations in our laboratory (9,29) and others (12,35) and effectively has abolished the cardioprotective effect of chronic exercise in female rats (9). Five minutes following initiation of HMR-1098 or control buffer, LV pressures and coronary flow were recorded a second time to examine the acute effects of HMR-1098, and hearts were exposed to 1 h of regional ischemia induced by left coronary artery ligation using a reversible snare (10).…”

Section: Methodsmentioning

confidence: 99%

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Sex-specific and exercise-acquired cardioprotection is abolished by sarcolemmal K_ATP channel blockade in the rat heart

Chicco¹,

Johnson²,

Armstrong³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Chicco AJ, Johnson MS, Armstrong CJ, Lynch JM, Gardner RT, Fasen GS, Gillenwater CP, Moore RL. Sex-specific and exercise-acquired cardioprotection is abolished by sarcolemmal KATP channel blockade in the rat heart. Am J Physiol Heart Circ Physiol 292: H2432-H2437, 2007. First published January 19, 2007; doi:10.1152/ajpheart.01301.2006.-The present study was conducted to determine whether the infarct sparing effect of shortterm exercise is dependent on the operation of the myocardial sarcolemmal ATP-sensitive K ϩ (KATP) channel. Adult male and female Sprague-Dawley rats were exercised on a motorized treadmill for 5 days. Twenty-four hours following the training or sedentary period, hearts were isolated and exposed to 1 h of regional ischemia followed by 2 h of reperfusion on a modified Langendorf apparatus in the presence or absence of the sarcolemmal KATP channel antagonist HMR-1098 (30 M). Following the ischemia-reperfusion protocol, infarct size was determined as a percentage of the total ischemic zone at risk (ZAR). Short-term exercise reduced infarct size by 24% in males (32 Ϯ 2% of ZAR; P Ͻ 0.01) and by 18% in females (26 Ϯ 2% of ZAR; P Ͻ 0.05). Sarcolemmal KATP channel blockade abolished the training-induced cardioprotection in both males and females, increasing infarct size to 43 Ϯ 3% and 52 Ϯ 4% of ZAR, respectively. In the absence of HMR-1098, infarct size was significantly lower in sedentary females than in males (33 Ϯ 4% vs. 42 Ϯ 2% of ZAR, respectively; P Ͻ 0.01). However, the presence of HMR-1098 abolished this sex difference, increasing infarct size by 58% in the sedentary females (P Ͻ 0.01) but having no effect on infarct size in sedentary males. This study demonstrates that the sex-specific and exercise-acquired resistance to myocardial ischemia-reperfusion injury is dependent on sarcolemmal KATP activity during ischemia. ischemia; infarction; sex differences; gender ISCHEMIC HEART DISEASE is a leading cause of mortality in industrialized countries throughout the world. Myocardial infarction is often the initial manifestation of ischemic heart disease, and survival is inversely proportional to the size of the myocardial infarction sustained (13). A variety of preconditioning stimuli has proven to be effective at reducing myocardial infarct size when administered immediately before ischemia (e.g, ischemic preconditioning and adenosine receptor agonists), but the protective effect of these treatments is lost after repetitive administration (38, 53). Exercise training, however, has been consistently shown to confer sustainable protection against myocardial infarction in animal models (10,26,40,56,57) and has been associated with improved survival following an ischemic event in humans (27,43). Despite substantial efforts to characterize the cardioprotective phenotype evoked by exercise training over the past decade, the precise mechanisms by which exercise reduces infarct size have not been fully elucidated.The infarct-sparing effect of exercise has been reported following both long-term (Ͼ10 wk) (9...

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Section: Discussionsupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Sex-specific and exercise-acquired cardioprotection is abolished by sarcolemmal K_ATP channel blockade in the rat heart

Chicco¹,

Johnson²,

Armstrong³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…Here, compared with age-matched K ATP channel-deficient males, females exhibited a higher propensity for calcium accumulation resulting in exaggerated diastolic dysfunction despite comparable parameters in ischemic indexes. 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).…”

Section: Discussionsupporting

confidence: 60%

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

Gumina¹,

O'Cochlain²,

Kurtz³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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knockout worsens myocardial calcium stress load in vivo and impairs recovery in stunned heart.. Am J Physiol Heart Circ Physiol 292: H1706 -H1713, 2007. First published December 22, 2006; doi:10.1152/ajpheart.01305.2006.-Gene knockout of the KCNJ11-encoded Kir6.2 ATP-sensitive K ϩ (KATP) channel implicates this stress-response element in the safeguard of cardiac homeostasis under imposed demand. K ATP channels are abundant in ventricular sarcolemma, where subunit expression appears to vary between the sexes. A limitation, however, in establishing the full significance of K ATP channels in the intact organism has been the inability to monitor in vivo the contribution of the channel to intracellular calcium handling and the superimposed effect of sex that ultimately defines heart function. Here, in vivo manganese-enhanced cardiac magnetic resonance imaging revealed, under dobutamine stress, a significantly greater accumulation of calcium in both male and female K ATP channel knockout (Kir6.2-KO) mice compared with sex-and age-matched wild-type (WT) counterparts, with greatest calcium load in Kir6.2-KO females. This translated, poststress, into a sustained contracture manifested by reduced end-diastolic volumes in K ATP channel-deficient mice. In response to ischemia-induced stunning, male and female Kir6.2-KO hearts demonstrated accelerated time to contracture and increased peak contracture compared with WT. The outcome on reperfusion, in both male and female Kir6.2-KO hearts, was a transient reduction in systolic performance, measured as rate-pressure product compared with WT, with protracted increase in left ventricular end-diastolic pressure, exaggerated in female knockout hearts, despite comparable leakage of creatine kinase across groups. Kir6.2-KO hearts were rescued from diastolic dysfunction by agents that target alternative pathways of calcium handling. Thus K ATP channel deficit confers a greater susceptibility to calcium overload in vivo, accentuated in female hearts, impairing contractile recovery under various conditions of high metabolic demand.ATP-sensitive K ϩ channel; Kir6.2; magnetic resonance imaging; myocardium; sex THE INWARDLY RECTIFYING K ϩ channel Kir6.2 is the pore-forming subunit of myocardial ATP-sensitive K ϩ (K ATP ) channels (21,22). In association with the regulatory sulfonylurea SUR2A receptor subunit, Kir6.2 generates functional adenine nucleotide-gated K ATP channels expressed in high density in the sarcolemma (34,38,39). K ATP channels are tightly coupled with intracellular energetic networks (1,7,10,25,58), and metabolic signals of distress are the primary inductors of channel activity with pore opening associated with regulation of action potential duration (48, 60). The property of signal decoding and translation of cellular energetic fluctuations implicates cardiac K ATP channels in the feedback regulation of membrane electrical activity (2, 12). In conjunction with an intrinsic ATPase activity, the tandem function of nucleotide binding domains within the SUR2A regulatory su...

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“…K ATP channels have been implicated in the sex-based responses to ischemic injury (12). Known sex differences are present in SUR2 mutant mice, as male SUR2 mutant mice have a shorter lifespan than female SUR2 mutant mice (3).…”

Section: Discussionmentioning

confidence: 99%

Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice

Stoller

Pytel²,

Katz³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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EM. Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice. Am J Physiol Regul Integr Comp Physiol 297: R1144 -R1153, 2009. First published August 12, 2009 doi:10.1152/ajpregu.00081.2009.-By sensing intracellular energy levels, ATP-sensitive potassium (K ATP) channels help regulate vascular tone, glucose metabolism, and cardioprotection. SUR2 mutant mice lack full-length K ATP channels in striated and smooth muscle and display a complex phenotype of hypertension and coronary vasospasm. SUR2 mutant mice also display baseline cardioprotection and can withstand acute sympathetic stress better than normal mice. We now studied response to a form of chronic stress, namely that induced by 4 wk of daily exercise on SUR2 mutant mice. Control mice increased exercise capacity by 400% over the training period, while SUR2 mutant mice showed little increase in exercise capacity. Unexercised SUR2 mutant showed necrotic and regenerating fibers in multiple muscle skeletal muscles, including quadriceps, tibialis anterior, and diaphragm muscles. Unlike exercised control animals, SUR2 mutant mice did not lose weight, presumably due to less overall exertion. Unexercised SUR2 mutant mice showed a trend of mildly reduced cardiac function, measured by fractional shortening, (46 Ϯ 4% vs. 57 Ϯ 7% for SUR2 mutant and control, respectively), and this decrease was not exacerbated by chronic exercise exposure. Despite an improved response to acute sympathetic stress and baseline cardioprotection, exercise intolerance results from lack of SUR2 K ATP channels in mice.K ATP channel; sulfonylurea receptor; SUR2; skeletal myopathy; exercise intolerance THE MECHANISMS THAT UNDERLIE the beneficial effects of regular exercise on metabolism and endurance are incompletely understood. ATP-sensitive potassium channels (K ATP channels) are found in muscle and the cardiovascular system and serve as cellular energy sensors. K ATP channels include a regulatory subunit, sulfonylurea receptor (SUR) 1 or 2, and a poreforming potassium channel, Kir6.1 or 6.2. Genetic deletion of the gene encoding Kir6.2 affects K ATP channels in the pancreas, heart, and skeletal muscle due to the lack of the poreforming subunit of K ATP channels (18). Two previous studies have investigated the role of K ATP channels in adaptation to chronic stress and exercise, and both demonstrated an impaired response in Kir6.2-null mice (15,24). Although defects in skeletal muscle and cardiovascular function were reported, the role of K ATP channel involvement is complicated by the ability of Kir6.2 to couple with either sulfonylurea receptor 1 (SUR1) or 2 (SUR2).In the heart, K ATP channels play critical roles during periods of sympathetic stress and protect the heart against ischemia (16,23,27). Kir6.2-null mice stressed with 21 days of experimental hypertension had significantly increased mortality compared with control mice (14). Cardiac function was impaired at baseline and after dobutamine exposure, and hypertensive Kir6.2-null mice developed ...

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Sex differences in myocardial infarct size are abolished by sarcolemmal K_ATPchannel blockade in rat

Cited by 73 publications

References 25 publications

Sex-specific and exercise-acquired cardioprotection is abolished by sarcolemmal K_ATP channel blockade in the rat heart

Sex-specific and exercise-acquired cardioprotection is abolished by sarcolemmal K_ATP channel blockade in the rat heart

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

Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice

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Sex differences in myocardial infarct size are abolished by sarcolemmal KATPchannel blockade in rat

Cited by 73 publications

References 25 publications

Sex-specific and exercise-acquired cardioprotection is abolished by sarcolemmal KATP channel blockade in the rat heart

Sex-specific and exercise-acquired cardioprotection is abolished by sarcolemmal KATP channel blockade in the rat heart

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

Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice

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Sex differences in myocardial infarct size are abolished by sarcolemmal K_ATPchannel blockade in rat

Sex-specific and exercise-acquired cardioprotection is abolished by sarcolemmal K_ATP channel blockade in the rat heart

Sex-specific and exercise-acquired cardioprotection is abolished by sarcolemmal K_ATP channel blockade in the rat heart

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