Contribution of electromechanical coupling between KV and CaV1.2 channels to coronary dysfunction in obesity

Abstract

Previous investigations indicate that diminished functional expression of voltage-dependent K+ (KV) channels impairs control of coronary blood flow in obesity/metabolic syndrome. The goal of this investigation was to test the hypothesis that KV channels are electromechanically coupled to CaV1.2 channels and that coronary microvascular dysfunction in obesity is related to subsequent increases in CaV1.2 channel activity. Initial studies revealed that inhibition of KV channels with 4-aminopyridine (4AP, 0.3 mM) increased intracellular [Ca2+], contracted isolated coronary arterioles and decreased coronary reactive hyperemia. These effects were reversed by blockade of CaV1.2 channels. Further studies in chronically instrumented Ossabaw swine showed that inhibition of CaV1.2 channels with nifedipine (10 μg/kg, iv) had no effect on coronary blood flow at rest or during exercise in lean swine. However, inhibition of CaV1.2 channels significantly increased coronary blood flow, conductance, and the balance between coronary flow and metabolism in obese swine (P < 0.05). These changes were associated with a ~50 % increase in inward CaV1.2 current and elevations in expression of the pore-forming subunit (α1c) of CaV1.2 channels in coronary smooth muscle cells from obese swine. Taken together, these findings indicate that electromechanical coupling between KV and CaV1.2 channels is involved in the regulation of coronary vasomotor tone and that increases in CaV1.2 channel activity contribute to coronary microvascular dysfunction in the setting of obesity.

KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

“…4) We investigated the role of KV7 channels in coronary metabolic vasodilation (using a subset of animals; n ϭ 2) by pacing the heart to higher rates before and during intracoronary infusion of 10 M linopirdine. In this experiment, arterial and coronary venous blood were sampled simultaneously at each heart rate to calculate myocardial oxygen consumption by the Fick principle (5). We assessed the role of K V7 channels in endothelium-dependent vasodilation by performing intracoronary bradykinin concentration-response protocols before (control) and during simultaneous infusion of 30 M linopirdine.…”

“…The specific redox-sensitive targets mediating H 2 O 2 -induced vasodilation of coronary vascular smooth have not been firmly established. Our previous findings suggest that voltage-dependent K ϩ (K V ) channels may play an important role, but the identities of individual K V channels involved remain elusive (4,5,12,38,39). K V 7 channels are expressed in a variety of vascular smooth muscle cell types, including those from the coronary circulation (20,23).…”

Biphasic alterations in coronary smooth muscle Ca2+ regulation in a repeat cross-sectional study of coronary artery disease severity in metabolic syndrome

“…Witczak et al and others 37 also demonstrated decreases in VGCC function with disease. However, Neeb et al 22 demonstrated a decrease in SERCA function with disease, and several studies 20, 38, 39 reported an increase in VGCC function with disease. One possible explanation for the apparent discrepancy in the data is duration of diet and/or severity of disease.…”

“…An additional factor in these discrepancies may be the swine model. Witczak 19 and Hill 21 utilized diabetic dyslipidemic Yucatan swine that had no primary insulin resistance, while Berwick 20 utilized MetS Ossabaw swine with primary insulin resistance, hypertension, and increased aldosterone as major characteristics. Neeb 22 used both Ossabaw and Yucatan swine.…”

“…Therefore, alteration in CSM Ca 2+ regulation in CAD is an important area of study. Alterations in many Ca 2+ transporters, including voltage-gated Ca 2+ channels 19, 20 , sarco-endoplasmic reticulum Ca 2+ ATPases 19, 21, 22 , transient receptor potential channels 23 , plasma membrane Ca 2+ ATPases 19 , and Na + /Ca 2+ exchangers 19 , have been described in CAD 24 . However, there is a paucity of data regarding time-dependent changes in CSM Ca 2+ handling in the setting of obesity/MetS.…”