Endothelium-dependent relaxations in the aorta from K2p6.1 knockout mice

Abstract

K 2P 6.1 or TWIK-2, a two-pore domain K channel, is an important regulator of cardiovascular function. K 2P 6.1 is highly expressed in vascular smooth muscle and endothelium. Mice (8–12 wk) lacking functional K 2P 6.1 ( K 2P 6.1−/−) are hypertensive and have enhanced vascular contractility. It is not known whether the lack of functional K 2P 6.1 in endothelium has a role in the vascular dysfunction in K 2P 6.1−/− mice. We tested the hypothesis: K 2P 6.1−/− mice have impaired endothelium-dependent relaxations. K 2P 6.1−/− mice were ∼35 mmHg more hypertensive than WT mice at both 8–12 wk (young adult) and 20–24 wk (mature mice, P < 0.01; n = 8–10). Endothelium-dependent relaxations of the thoracic aorta were evaluated by isometric myography after contraction with phenylephrine (10−6 M). Maximal ACh-dependent relaxations were increased from 65 ± 1% to 73 ± 1% in the aorta from young adult ( P < 0.01; n = 6) and from 45 ± 1% to 74 ± 1% in the aorta from mature ( P < 0.001; n = 5) K 2P 6.1−/− mice compared with K 2P 6.1+/+ littermates. However, in the aorta from young adult and mature K 2P 6.1+/+ mice, 10−5 M indomethacin, a cyclooxygenase inhibitor, increased maximal ACh relaxations to knockout levels. Enhanced relaxation was also seen with ATP, a P 2Y purinergic agonist, and A23187, a nonreceptor-based agonist in mature K 2P 6.1−/− mice. Mature adult aorta from K 2P 6.1−/− showed an attenuated ACh-mediated contraction in the presence of nitro-l-arginine methyl ester (l-NAME) and without precontraction of 0.97 mN vs. 7.5 mN in K 2P 6.1−/− and K 2P 6.1+/+ ( P < 0.001; n = 5). In summary, K 2P 6.1−/− mice, which are hypertensive, have enhanced endothelium-dependent relaxations in the aorta due to the suppression of an indomethacin-sensitive constrictor component.