T he guanylate cyclase cyclic GMP (cGMP) signaling cascade is a key vasodilator pathway involved in regulating vascular smooth muscle tone. 1 In vascular smooth muscle, an increase in cGMP is produced by 2 primary mechanisms: activation of soluble guanylate cyclase by agents including nitric oxide (NO) or activation of guanylate cyclase-linked transmembrane natriuretic peptide receptors (NPR-A and NPR-B), which are stimulated endogenously by atrial, B-type, or C-type natriuretic peptides (ANP,

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... NP, or CNP, respectively). 2 NPR-A is preferentially activated by ANP>BNP>>CNP, whereas NPR-B has a rank order of potency of CNP>>ANP=BNP. 2,3 ANP and BNP are potent vasodilators synthesized predominantly in cardiac tissues, and raised levels are associated with heart failure and myocardial infarction. 4 CNP, like ANP and BNP, is formed as a propeptide but far lower levels circulate compared with the other 2 natriuretic peptides. However, CNP is released by the endothelium, which has led to speculation that CNP may act in a localized manner to contribute to vasodilations on a regional basis. 5 espite their pronounced effects in the vasculature, the effect of natriuretic peptides in hypertension and the mechanisms underlying regional vasodilation remain unknown. Recently, KCNQ-encoded potassium channels (termed Kv7.1-7.5) have been identified as important regulators of vascular tone. 6 In the vasculature Kv7.1, 7.4 and 7.5 isoforms are consistently expressed with little or no contribution from Kv7.2 or Kv7.3, 6,7 and the dominant molecular species in cerebral and mesenteric arteries is a Kv7.4/7.5 heterotetramer. 8, 9 lockade of Kv7 channels results in the contraction of vessels at rest, whereas Kv7 activators relax precontracted arterial vessels or inhibit vasoconstrictions. 7, 10, 11 A reduction in Kv7.4 protein has been described in hypertensive models, where Kv7-dependent relaxations are attenuated. 12, 13 ] [15] However, the role of Kv7 channels in mediating the effects of other endogenous vasodilator signaling pathways has yet to be investigated. The aim of this study was to determine whether cGMP-dependent vasorelaxations produced by ANP and CNP, as well as the NO donor sodium nitroprusside (SNP), were affected by Kv7 channel blockade or impaired in arteries from hypertensive rats, where Kv7.4 abundance is reduced. Methods Experimental protocols are available in the online-only Data Supplement. All experiments were performed in accordance with the UK Animal (Scientific Procedures) Act 1986.