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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/R421    most recent 00481.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Stegbauer, J. Articles by Rump, L. C. PubMed PubMed Citation Articles by Stegbauer, J. Articles by Rump, L. C.

RENAL HEMODYNAMICS AND CARDIORENAL INTEGRATION

Endothelial nitric oxide synthase is predominantly involved in angiotensin II modulation of renal vascular resistance and norepinephrine release

¹Department of Nephrology, Marienhospital Herne, Ruhr-University Bochum, Herne; ²Department of Nephrology, Heinrich-Heine-University Düsseldorf, Düsseldorf; ³Institute of Vegetative Physiology, University-Hospital Charité, Humboldt-University of Berlin, Berlin; and ⁴Institute for Medical Neurobiology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

Submitted 4 July 2007 ; accepted in final form 22 November 2007

Nitric oxide (NO) is mainly generated by endothelial NO synthase (eNOS) or neuronal NOS (nNOS). Recent studies indicate that angiotensin II generates NO release, which modulates renal vascular resistance and sympathetic neurotransmission. Experiments in wild-type [eNOS(+/+) and nNOS(+/+)], eNOS-deficient [eNOS(–/–)], and nNOS-deficient [nNOS(–/–)] mice were performed to determine which NOS isoform is involved. Isolated mice kidneys were perfused with Krebs-Henseleit solution. Endogenous norepinephrine release was measured by HPLC. Angiotensin II dose dependently increased renal vascular resistance in all mice species. EC₅₀ and maximal pressor responses to angiotensin II were greater in eNOS(–/–) than in nNOS(–/–) and smaller in wild-type mice. The nonselective NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME; 0.3 mM) enhanced angiotensin II-induced pressor responses in nNOS(–/–) and wild-type mice but not in eNOS(–/–) mice. In nNOS(+/+) mice, 7-nitroindazole monosodium salt (7-NINA; 0.3 mM), a selective nNOS inhibitor, enhanced angiotensin II-induced pressor responses slightly. Angiotensin II-enhanced renal nerve stimulation induced norepinephrine release in all species. L-NAME (0.3 mM) reduced angiotensin II-mediated facilitation of norepinephrine release in nNOS(–/–) and wild-type mice but not in eNOS(–/–) mice. 7-NINA failed to modulate norepinephrine release in nNOS(+/+) mice. (4-Chlorophrnylthio)guanosine-3', 5'-cyclic monophosphate (0.1 nM) increased norepinephrine release. mRNA expression of eNOS, nNOS, and inducible NOS did not differ between mice strains. In conclusion, angiotensin II-mediated effects on renal vascular resistance and sympathetic neurotransmission are modulated by NO in mice. These effects are mediated by eNOS and nNOS, but NO derived from eNOS dominates. Only NO derived from eNOS seems to modulate angiotensin II-mediated renal norepinephrine release.

eNOS-deficient mice; nNOS-deficient mice; pressor response; L-NAME