Effect of the Na-K-2Cl cotransporter NKCC1 on systemic blood pressure and smooth muscle tone

Studies in rat aorta have shown that the Na-K-2Cl cotransporter NKCCl is activated by vasoconstrictors and inhibited by nitrovasodilators, contributes to smooth muscle tone in vitro, and is upregulated in hypertension. To determine the role of NKCCl in systemic vascular resistance and hypertension, blood pressure was measured in rats before and after inhibition of NKCCl with bumetanide. Intravenous infusion of bumetanide sufficient to yield a free plasma concentration above the IC50 for NKCCl produced an immediate drop in blood pressure of 5.2% (P < 0.001). The reduction was not prevented when the renal arteries were clamped, indicating that it was not due to a renal effect of bumetanide. Bumetanide did not alter blood pressure in NKCCl-null mice, demonstrating that it was acting specifically through NKCCl. In third-order mesenteric arteries, bumetanide-inhibitable efflux of Rb-86 was acutely stimulated 133% by phenylephrine, and bumetanide reduced the contractile response to phenylephrine, indicating that NKCC1 influences tone in resistance vessels. The hypotensive effect of bumetanide was proportionately greater in rats made hypertensive by a 7-day infusion of norepinephrine (12.7%, P < 0.001 vs. normotensive rats) but much less so when hypertension was produced by a fixed aortic coarctation (8.0%), again consistent with an effect of bumetanide on resistance vessels rather than other determinants of blood pressure. We conclude that NKCCl influences blood pressure through effects on smooth muscle tone. in resistance vessels and that this effect is augmented in hypertension.