Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca²⁺-sensitive K⁺ current in miniature swine with LV hypertrophy

Abstract

Emter CA, Tharp DL, Ivey JR, Ganjam VK, Bowles DK. Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca 2ϩ -sensitive K ϩ current in miniature swine with LV hypertrophy. Am J Physiol Heart Circ Physiol 301: H1687-H1694, 2011. First published August 12, 2011 doi:10.1152/ajpheart.00610.2011.-Coronary vascular dysfunction has been observed in several models of heart failure (HF). Recent evidence indicates that exercise training is beneficial for patients with HF, but the precise intensity and underlying mechanisms are unknown. Left ventricular (LV) hypertrophy can play a significant role in the development of HF; therefore, the purpose of this study was to assess the effects of low-intensity interval exercise training on coronary vascular function in sedentary (HF) and exercise trained (HF-TR) aortic-banded miniature swine displaying LV hypertrophy. Six months postsurgery, in vivo coronary vascular responses to endothelin-1 (ET-1) and adenosine were measured in the left anterior descending coronary artery. Baseline and maximal coronary vascular conductance were similar between all groups. ET-1-induced reductions in coronary vascular conductance (P Ͻ 0.05) were greater in HF vs. sedentary control and HF-TR groups. Pretreatment with the ET type A (ETA) receptor blocker BQ-123 prevented ET-1 hypersensitivity in HF animals. Whole cell voltage clamp was used to characterize composite K ϩ currents (IKϩ) in coronary smooth muscle cells. Raising internal Ca 2ϩ from 200 to 500 nM increased Ca 2ϩ -sensitive K ϩ current in HF-TR and control, but not HF animals. In conclusion, an ETA-receptor-mediated hypersensitivity to ET-1, elevated resting LV wall tension, and decreased coronary smooth muscle cell Ca 2ϩ -sensitive IKϩ was found in sedentary animals with LV hypertrophy. Low-intensity interval exercise training preserved normal coronary vascular function and smooth muscle cell Ca 2ϩ -sensitive IKϩ, illustrating a potential mechanism underlying coronary vascular dysfunction in a large-animal model of LV hypertrophy. Our results demonstrate the potential clinical impact of exercise on coronary vascular function in HF patients displaying pathological LV hypertrophy. coronary circulation; vascular smooth muscle; potassium channels; heart failure CORONARY VASCULAR DYSFUNCTION is a hallmark feature of the progression to heart failure (HF). Altered responsiveness to mediators of vascular tone, such as endothelin-1 (ET-1), have been observed and may contribute to this phenomena (8,21,32,33,46,49). Impaired coronary vascular function can have profound effects on myocardial oxidative capacity and function and may play a significant role in the inability of the failing heart to respond to situations of increasing stress. The mechanism by which this occurs remains unclear. Considerable evidence exists indicating that profound modulation of both cardiomyocyte and smooth muscle cell electrophysiological phenotype are involved in cardiovascular disease (36, 47, 51). Calcium-activated K ϩ (K Ca...

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“…45 Indeed, decreased BK Ca a-channel-induced vasodilation may impair the ability of vascular smooth muscle to buffer against excessive vasoconstrictor stimuli. 17,18,44,45 The underlying cause of the discrepancy in channel expression and vasomotor control observed in the current study remains unknown, but may be linked to function of the BK Ca channel b1-subunit. For example, reduced NO-mediated b1-subunit trafficking to the plasma membrane may influence kinetics, calcium sensitivity, and BK Ca channel activity in response to pharmacological modulators.…”

“…In line with the current study, data from the coronary vasculature of obese pigs with metabolic syndrome show a similar pattern of impaired BK Ca channel–dependent vasodilation in parallel with increased overall expression of the BK Ca channel itself . Indeed, decreased BK Ca α‐channel–induced vasodilation may impair the ability of vascular smooth muscle to buffer against excessive vasoconstrictor stimuli …”

Reduced vascular smooth muscle BK channel current underlies heart failure‐induced vasoconstriction in mice

“…Increased myogenic tone and reduced expression and function of BK channels are observed in hypertension, diabetes, and metabolic syndrome, diseases associated with an increased incidence and more rapid progression of HF (28, 29, 40–49). Reduced BK currents have also been proposed as a mechanism for the reduced coronary reserve in LV hypertrophy (50, 51). The reduced BK currents in LV hypertrophy, however, are unrelated to the level of expression of BK α and β1 subunits (51).…”

Function and regulation of large conductance Ca2+-activated K+ channel in vascular smooth muscle cells

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