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1 Smooth Muscle Research Group, University of Calgary, Calgary, Canada
2 Smooth Muscle Research Group, University of Calgary, Calgary, Canada; Pharmacology and Therapeutics, University of Calgary, Calgary, Canada
* To whom correspondence should be addressed. E-mail: rloutzen{at}ucalgary.ca.
The Na+/K+/2Cl- cotransporter (NKCC) plays diverse roles in the kidney, contributing to Na+reabsorption and tubuloglomerular feedback (TGF) signaling. However, NKCC is also expressed in smooth muscle and inhibitors of this transporter affect contractility in both vascular and non-vascular 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 versus 20 µmol/L). Concentrations of 100 µmol/L furosemide and 10 µmol/L bumetanide inhibited myogenic responses by 72±4% and 68±5%, respectively. The maximal inhibition by bumetanide were not affected by nitric oxide synthase inhibition (100 µmol/L L-NAME). However the time course for the dilation was slowed (from t1/2 = 4.0±0.5 min 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 angiotensin II-induced afferent arteriolar vasoconstriction at similar concentrations. Finally, NKCC1, but not NKCC2, expression was demonstrated in the afferent arteriole was demonstrated 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 a modulation of TGF and suggest a potential role of NKCC1 in the regulation of vasomotor function in the renal microvasculature.
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