Neuronal nitric oxide synthase supports renin release during sodium restriction through inhibition of phosphodiesterase 3
2010 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1879-1905, Vol. 23, no 11, 1241-1246 p.Article in journal (Refereed) Published
Background: Mice with targeted deletion of neuronal nitric oxide synthase (nNOS‑/‑) display inability to increase plasma renin concentration (PRC) in response to sodium restriction. nNOS has a distinct expression at the macula densa, and it has been hypothesized that nNOS supports renin release by cGMP-mediated inhibition of cAMP-specific phosphodiesterase 3 (PDE3) in juxtaglomerular cells.
Objective: To test the hypothesis that nNOS-derived NO supports renin release by inhibition of PDE3.
Methods: The experiments were performed in conscious nNOS-/- and wild types after ten days on a low sodium diet by acute treatment with the PDE3 inhibitor milrinone, the PDE5 inhibitor zaprinast, or vehicle, using a crossover study protocol. PRC was measured with the antibody-trapping technique and blood pressure with telemetry. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were estimated by measurements of inulin- and Para-Amino Hippuric acid clearances, respectively.
Results: The basal PRC was reduced in nNOS-/- compared to the wild types. Administration of milrinone caused a more pronounced PRC increase in nNOS-/-, resulting in normalized renin levels, while PDE5 inhibition did not affect PRC in any genotype. The blood pressure was similar in both genotypes, and milrinone did not affect blood pressure compared to vehicle. GFR and RPF were similar at baseline and were reduced by milrinone.
Conclusions: The present study provides in vivo evidence supporting the view that NO, selectively derived from nNOS, mediates renin release during sodium restriction by inhibiting PDE3, which would increase renin release by elevating cAMP levels in the juxtaglomerular cells.
Place, publisher, year, edition, pages
2010. Vol. 23, no 11, 1241-1246 p.
IdentifiersURN: urn:nbn:se:uu:diva-113177DOI: 10.1038/ajh.2010.153ISI: 000283531900016OAI: oai:DiVA.org:uu-113177DiVA: diva2:290077