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Cardiovascular phenotype of intermediate‐conductance KCa‐channel(KCa3.1)‐knockout mice.

The endothelium plays a key role in the control of vascular tone and endothelial alterations contribute to several cardiovascular disease states. Endothelium‐dependent dilation is mediated by NO, prostacyclin, and an endothelium‐derived hyperpolarizing factor (EDHF). EDHF‐signalling is thought to be initiated by activation of endothelial Ca2+‐activated K+ channels (KCa) leading to hyperpolarization of the endothelium and subsequently to hyperpolarization and relaxation of vascular smooth muscle. In the present study, we tested the functional role of the endothelial intermediate‐conductance KCa (KCa3.1) in endothelial hyperpolarization, EDHF‐mediated dilation, and in the control of arterial pressure in KCa3.1‐deficient mice (KCa3.1−/−) by patch‐clamp analysis, myography and intravital microscopy. Disruption of the KCa3.1 gene abolished endothelial KCa3.1 currents and significantly diminished overall current through KCa channels. As a consequence, endothelial and smooth muscle hyperpolarization in response to acetylcholine (ACh) was reduced in KCa3.1−/− mice. ACh‐induced dilations were impaired in the carotid artery and in the cremaster microcirculation due to a substantial reduction of EDHF‐mediated dilation in KCa3.1−/− mice. Moreover, the loss of KCa3.1 led to a significant increase in arterial blood pressure and to mild left ventricular hypertrophy. These results indicate that the endothelial KCa3.1 is a fundamental determinant of endothelial hyperpolarization, EDHF‐signalling and thereby a crucial factor in the control of vascular tone and overall circulatory regulation.