Patients with diabetes, hypertension, and heart failure have increased vascular tone, which adversely impacts their cardiovascular outcomes. Increased vascular tone in peripheral vessels increases the workload of the heart, impairing cardiac output and ventricular remodeling, and accelerating the progression to decompensated heart failure. Decreasing vascular tone, thereby unloading the heart and improving coronary perfusion, is an important therapeutic approach in patients with diseases associated with increased vasoconstriction.
The diameter of resistance vessels, which fundamentally regulates blood flow within an organ as well as the systemic vascular resistance and arterial pressure, is primarily determined by the contraction of vascular smooth muscle cells. Depolarization of the smooth muscle cell membrane potential and elevated cytosolic calcium increase contractility causing vasoconstriction, whereas hyperpolarization and decreased calcium reduce contractility causing vasodilation. Strong hyperpolarizing currents are required both to prevent excessive smooth muscle cell depolarization and vascular contractility in response to intraluminal pressure and vasoconstrictors as well as to enable smooth muscle cell hyperpolarization and vascular relaxation in response to vasodilators.
We found that six weeks after sham or permanent ligation of the left anterior descending artery, myogenic constriction, in the absence of systemic factors such as short-acting circulating neurohormones and neural inputs, is markedly increased in resistance vessels isolated from mice with heart failure. We demonstrate that reduced expression and activity of the large conductance calcium-activated potassium channel (BK channels) sensitize the vascular smooth muscle cells to depolarization, causing increased cytosolic calcium and myogenic tone in mice with heart failure. We are now exploring whether pharmacological activation of BK channels, which we have identified, can specifically blunt the abnormal vasoconstriction and consequently slow or prevent the frequently inevitable clinical decompensation of patients with heart failure.
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