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Effects of inhibition of the Na⁺/K⁺/2Cl^– cotransporter on myogenic and angiotensin II responses of the rat afferent arteriole

Smooth Muscle Research Group, Department of Pharmacology and Therapeutics, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada

Submitted 30 August 2006 ; accepted in final form 29 October 2006

The Na⁺/K⁺/2Cl^– cotransporter (NKCC) plays diverse roles in the kidney, contributing sodium reabsorption and tubuloglomerular feedback (TGF). However, NKCC is also expressed in smooth muscle and inhibitors of this transporter affect contractility in both vascular and nonvascular smooth muscle. In the present study, we investigated the effects of NKCC inhibitors on vasoconstrictor responses of the renal afferent arteriole using the in vitro perfused hydronephrotic rat kidney. This preparation has no tubules and no TGF, eliminating this potential complication. Furosemide and bumetanide inhibited myogenic responses in a concentration-dependent manner. Bumetanide was 20-fold more potent (IC₅₀ 1.0 vs. 20 µmol/l). At 100 and 10 µmol/l, furosemide and bumetanide inhibited myogenic responses by 72 ± 4 and 68 ± 5%, respectively. The maximal level of inhibition by bumetanide was not affected by nitric oxide synthase inhibition (100 µmol/l N^G-nitro-L-arginine methyl ester). However, the time course for the dilation was slowed (from t_1/2 = 4.0 ± 0.5 to 8.3 ± 1.7 min, P = 0.04), suggesting either a partial involvement of NO or a permissive effect of NO on relaxation kinetics. Bumetanide also inhibited ANG II-induced afferent arteriolar vasconstriction at similar concentrations. Finally, NKCC1, but not NKCC2, expression was demonstrated in the afferent arteriole by RT-PCR and the presence of NKCC1 in afferent arteriolar myocytes was confirmed by immunohistochemistry. In concert, these results indicate that NKCC modulation is capable of altering myogenic responses by a mechanism that does not involve TGF and suggest a potential role of NKCC1 in the regulation of vasomotor function in the renal microvasculature.

renal autoregulation; tubuloglomerular feedback; vascular smooth muscle; chloride

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