Pressure‐dependent Reversal of Cerebral Vasoconstriction by a KCNQ4/5 (Kv7.4/7.5) Potassium Channel Activator

Appropriate regulation of cerebral arterial diameter is crucial for ensuring adequate blood flow to the brain. Enhanced cerebral vasoconstriction is a hallmark of cardiovascular diseases such as hypertension and subarachnoid hemorrhagic stroke(SAH). Pharmacological enhancement of K+ channel gating may be a viable approach to reverse abnormal vasoconstriction. Here, we report that S‐1 ((S)‐N‐[1‐(3‐morpholin‐4‐yl‐phenyl)‐ethyl]‐3‐phenyl‐acrylamide)), a selective Kv7.4/7.5 (KCNQ4/5) activator, reversed vasoconstriction of pressurized rat middle cerebral arteries due to: 1) inhibition of Kv2.1/9.3 or activation of voltage‐gated Ca2+ channels, and 2) treatment with angiotensin II, 5‐HT, or oxyhemoglobin that contribute to abnormal vasoconstriction in hypertension or SAH. The extent of vasodilatation evoked by S‐1 was pressure‐dependent, increasing in magnitude between 10 and 120 mmHg. The ability of S‐1 to evoke vasodilation, but preserve the myogenic response differs from the effect of ATP‐sensitive K+ channel activators that evoke pressure‐independent dilation. Our findings indicate that Kv7.4/7.5 channels may be a viable therapeutic target to suppress abnormal cerebral arterial vasoconstriction in disease while maintaining the myogenic response, a crucial physiological mechanism of cerebral blood flow autoregulation. (Support CIHR MOP‐13505; Andrew Family Professorship to WCC)