Hypotension Due to Kir6.1 Gain‐of‐Function in Vascular Smooth Muscle

Abstract

BackgroundKATP channels, assembled from pore‐forming (Kir6.1 or Kir6.2) and regulatory (SUR1 or SUR2) subunits, link metabolism to excitability. Loss of Kir6.2 results in hypoglycemia and hyperinsulinemia, whereas loss of Kir6.1 causes Prinzmetal angina–like symptoms in mice. Conversely, overactivity of Kir6.2 induces neonatal diabetes in mice and humans, but consequences of Kir6.1 overactivity are unknown.Methods and ResultsWe generated transgenic mice expressing wild‐type (WT), ATP‐insensitive Kir6.1 [Gly343Asp] (GD), and ATP‐insensitive Kir6.1 [Gly343Asp,Gln53Arg] (GD‐QR) subunits, under Cre‐recombinase control. Expression was induced in smooth muscle cells by crossing with smooth muscle myosin heavy chain promoter–driven tamoxifen‐inducible Cre‐recombinase (SMMHC‐Cre‐ER) mice. Three weeks after tamoxifen induction, we assessed blood pressure in anesthetized and conscious animals, as well as contractility of mesenteric artery smooth muscle and KATP currents in isolated mesenteric artery myocytes. Both systolic and diastolic blood pressures were significantly reduced in GD and GD‐QR mice but normal in mice expressing the WT transgene and elevated in Kir6.1 knockout mice as well as in mice expressing dominant‐negative Kir6.1 [AAA] in smooth muscle. Contractile response of isolated GD‐QR mesenteric arteries was blunted relative to WT controls, but nitroprusside relaxation was unaffected. Basal KATP conductance and pinacidil‐activated conductance were elevated in GD but not in WT myocytes.ConclusionsKATP overactivity in vascular muscle can lead directly to reduced vascular contractility and lower blood pressure. We predict that gain of vascular KATP function in humans would lead to a chronic vasodilatory phenotype, as indeed has recently been demonstrated in Cantu syndrome.

K ATP channel gain-of-function leads to increased myocardial L-type Ca 2+ current and contractility in Cantu syndrome

“…Kir6.1 and SUR2 are prominently expressed in vascular smooth muscle (VSM). VSM expression of K ATP GOF under smooth muscle (SM)-MHC promoter control reduces vascular contractility, resulting in a chronically vasodilated state with low systolic and diastolic BP (9). Young vGOF mice, induced with tamoxifen at 2 mo and studied by echocardiography 1 mo later, revealed no significant changes in cardiac structural parameters, but did exhibit enhanced cardiac contractility (Fig.…”

“…In contrast, older vGOF animals exhibited increased diastolic volume, as observed in CS patients. Vascular K ATP GOF results in increased smooth muscle K ATP current and diminished BP (9), providing a potentially direct explanation for the markedly lowfor-age BPs in CS patients; this also provides a systemic mechanism that may link the primary vGOF phenotype to secondary consequences in the heart: vascular K ATP GOF expression results in vasodilation that will ultimately result in a long-standing volume load, evidenced by LV chamber dilation. Early after transgene induction (6 wk), vGOF hearts exhibit increased contractility and increased ejection fraction (Fig.…”

“…This constellation of features is distinct from both typical hypertrophic cardiomyopathies (where LVPWD is increased) and typical dilated cardiomyopathies (where there is chamber dilation with diminished cardiac function). In part, this dilated hypercontractile phenotype could be a secondary response to chronically elevated blood volume as a result of vasodilation-a directly predicted consequence of vascular K ATP GOF (9). Pulsed-wave velocity testing offers a noninvasive correlate of vascular tone.…”

KATPChannels in the Cardiovascular System

“…Conditional knockout mice that lack Kir6.1 specifically in smooth muscle cells are hypertensive, and the vascular smooth muscle cells fail to respond to vasodilators (35), underscoring the important role of Kir6.1 in blood flow control. Hypotension was also noted in mice with transgenic expression of Kir6.1 gain-of-function subunits in vascular smooth muscle (492). Despite the significance of these findings, the Kir6.1 Ϫ/Ϫ mice or vascular Kir6.1 overexpression approaches have not been employed to investigate its role of blood flow in pathophysiological conditions, such as in the context of cardiac ischemia, reperfusion, ischemic preconditioning, and the no-reflow phenomenon, where maintaining adequate blood flow is expected to beneficial.…”

Verdict in the Smooth Muscle K ATP Channel Case

“…Mice expressing smooth muscle-specific Kir6.1 gain-of-function mutants have low blood pressure, consistent with the influence of overactive K ATP channels, 8 and now in the current issue, Aziz et al 3 have used the Cre-Lox system to produce mice that lack functional K ATP channels in smooth muscle while retaining these channels in heart and brain. These mice are hypertensive but, unlike global Kir6.1 knockouts, show no obvious ECG abnormalities and no sudden death, even in the presence of the vasoconstrictor ergonovine.…”