Actions of endothelin-1 on cultured rat renomedullary interstitial cells are modulated by nitric oxide

1. Cultured renomedullary interstitial cells (RMIC) isolated from ii-week-o ld Sprague-Dawley rat kidneys possess ETA receptors, as identified by rever se transcription-polymerase chain reaction (RT-PCR), 2, Treatment with endothelin (ET)-1 (10(-6) mol/L) increases the intracellu lar inositol 1,4,5-trisphosphate concentrations within 10 s and intracellul ar calcium concentrations after 7 s, 3. Endothelin-l (10(-7) and 10(-10) mol/L) induced increases in intracellul ar cAMP concentrations, but only in the presence of N-omega-nitro-L-arginin e, a nitric oxide synthase (NOS) inhibitor, Addition of ET-1 (10(-10) mol/L ) to the RMIC culture led to increases in intracellular cGMP concentrations through activation of NOS, 4, In the presence of ET-1 (10(-7) and 10(-10) mol/L) and during NOS inhibi tion, RMIC responded with increased cell proliferation and extracellular ma trix (ECM) synthesis. These responses were abolished by BQ-123 (10(-6) mol/ L), suggesting mediation via the ETA receptor subtype, The proliferative ef fect of ET-1 was also abolished by atrial natriuretic peptide (10(-6) mol/L ), 5, The present study provides evidence that binding of ET-I to ETA receptor s on RMIC activates several intracellular second messenger systems that med iate cell proliferation and ECR I synthesis, 6, These results also highlight an important interaction between ET-1 and n itric oxide in the control of RMIC function.