NKCC1 and hypertension: role in the regulation of vascular smooth muscle contractions and myogenic tone.

High-ceiling diuretics (HCD), known potent inhibitors of housekeeping Na(+),K(+),2Cl cotransporter (NKCC1) and renal-specific NKCC2, decrease [Cl(-)](i), hyperpolarize vascular smooth muscle cells (VSMC), and suppress contractions evoked by modest depolarization, phenylephrine, angiotensin II, and UTP. These actions are absent in nkcc1 (/) knock-out mice, indicating that HCD interact with NKCC1 rather than with other potential targets. These findings also suggest that VSMC-specific inhibitors of NKCC1 may be considered potential pharmacological therapeutic tools in treatment of hypertension. It should be underlined that side by side with attenuation of peripheral resistance and systemic blood pressure, HCD blocked myogenic tone (MT) in renal afferent arterioles. Keeping this in mind, attenuation of MT might be a mechanism underlying the prevalence of end-stage renal disease documented in hypertensive African-Americans with decreased NKCC1 activity and in hypertensive patients subjected to chronic HCD treatment. The role of NKCC1-mediated MT in protection of the brain, heart, and other encapsulated organs deserves further investigation.