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1 Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT, USA
* To whom correspondence should be addressed. E-mail: donald.kohan{at}hsc.utah.edu.
Endothelin-1 (ET-1) inhibition of vasopressin (AVP)-stimulated cAMP accumulation in the collecting duct has been hypothesized to be mediated, at least in part, by nitric oxide (NO). To examine this, the effect of ET-1 on NO production by acutely isolated rat inner medullary collecting duct (IMCD) cell suspensions, and its role in mediating ET-1 effects on AVP-stimulated cAMP accumulation, were studied. ET-1 dose-dependently (first evident at 100 pM ET-1) increased IMCD NO production as determined by DAF-FM fluorescence. ETB receptor (BQ788), but not ETA receptor (BQ123), antagonism blocked this effect. Non-specific NOS inhibitors (L-NAME or L-NMMA) or NOS-1 inhibitors (SMTC or VNIO) inhibited the ET-1 response, while NOS-2 or NOS-3 inhibitors (L-NAA or 1400W) were ineffective. ET-1 also increased cGMP accumulation. ET-1 caused a 35% reduction in AVP-stimulated cAMP levels, however this response was not affected by L-NAME or SMTC. Addition of L-arginine, NADPH, tetrahydrobiopterin, or tempol (to reduce superoxide-dependent conversion of NO to peroxynitrate) did not affect the response. NO donors (SNAP or spermine NONOate), at concentrations that stimulated DAF-FM fluorescence and increased cGMP levels, did not alter AVP-stimulated cAMP accumulation in the IMCD cell suspensions. In conclusion, ET-1 stimulates IMCD NO production through activation of the ETB receptor and NOS-1. However, neither ET-1-mediated NO production nor NO donors inhibit AVP-stimulated cAMP accumulation, indicating that NO does not mediate ET-1 inhibition of cAMP in the IMCD.
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