Endothelial nitric oxide synthase is predominantly involved in Angiotensin II modulation of renal vascular resistance and norepinephrine release Short title NO modulates renal sympathetic neurotransmission

NO is mainly generated by endothelial nitric oxide synthase (eNOS) or neuronal nitric oxide synthase (nNOS). Recent studies indicate that Ang II generates NO release, which modulates renal vascular resistance and sympathetic neurotransmission. Experiments in wild-type [eNOS(+/+) and nNOS(+/+)], eNOS deficient [eNOS(-/-)] and nNOS decficient [nNOS(-/-)] mice were performed to determine which NOS isoform is involved. Isolated mice kidneys were perfused with Krebs-Henseleit solution. Endogenous norepinephrine (NE) release was measured by HPLC. Ang II dose dependently increased renal vascular resistance in all mice species. EC50 and maximal pressor responses to Ang II were greater in eNOS(-/-) than in nNOS(-/-) and smaller in wild type (WT) mice. The non-selective NOS inhibitor L-NAME (0.3mM) enhanced Ang II induced pressor responses in nNOS(-/-) and WT but not in eNOS(-/) mice. In nNOS(+/+) mice 7-nitroindazole monosodium salt (0.3mM), a selective nNOS inhibitor, enhanced Ang II induced pressor responses slightly. Ang II enhanced renal nerve stimulation induced NE release in all species. L-NAME (0.3mM) reduced Ang II mediated facilitation of NE release in nNOS(-/-) and WT but not in eNOS(-/-) mice. 7-NINA failed to modulate NE release in nNOS(+/+) mice. 8cPTC-cGMP (0.1nM) increased NE release. mRNA expression of eNOS, nNOS and iNOS did not differ between mice strains. In conclusion, Ang 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 Ang II mediated renal NE release.