Submitted on December 21, 2006
Accepted on January 18, 2007
Effect of the Na-K-2Cl Cotransporter NKCC1
on Systemic Blood Pressure and Smooth Muscle Tone
Puneet Garg1, Christopher F Martin1, Shawn Elms2, Frank J Gordon3, Susan M Wall1, Christopher J Garland4, Roy L Sutliff5, and W. Charles O'Neill6*
1 Renal Division, Emory University, Atlanta, Georgia, United States
2 Atlanta Veterans Affairs Medical Center, Decatur, Georgia, United States
3 Pharmacology, Emory University, Atlanta, Georgia, United States
4 Pharmacology, University of Bath, Bath, United Kingdom
5 Pulmonary and Critical Care Medicine, Emory University, Atlanta, Georgia, United States; Atlanta Veterans Affairs Medical Center, Decatur, Georgia, United States
6 Renal Division, Emory University Hospital, Atlanta, Georgia, United States
* To whom correspondence should be addressed. E-mail: woneill{at}emory.edu.
Studies in rat aorta have shown that the Na-K-2Cl cotransporter NKCC1 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 NKCC1 in systemic vascular resistance and hypertension, blood pressure was measured in rats before and after inhibition of NKCC1 with bumetanide. Intravenous infusion of bumetanide sufficient to yield a free plasma concentration above the IC50 for NKCC1 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 NKCC1 null mice, demonstrating that it was acting specifically through NKCC1. In third-order mesenteric arteries, bumetanide-inhibitable efflux of 86Rb 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 NKCC1 influences blood pressure through effects on smooth muscle tone in resistance vessels and that this effect is augmented in hypertension.
