Abstract 1178: NO/cGMP Signaling and NOS-dependent Hydrogen Peroxide Production Maintain Vasorelaxation in Small Arteries from Hypertensive Rats
Three major endothelium-dependent pathways mediate relaxation in small arteries: nitric oxide synthase (NOS), cyclooxygenase (COX), and Ca2+-activated K+ channels (KCa). The first aim of this study was to determine the relative participation of these pathways in vasorelaxation of third order mesenteric arteries from hypertensive rats. Normotensive (NORM), angiotensin II-infused (ANG), placebo normotensive (Placebo), and deoxycorticosterone acetate-salt (DOCA) rats were studied. Systolic blood pressure increased in ANG (205 ± 5 mmHg) and DOCA (197 ± 2 mmHg) (n = 6–12). Arteries from ANG had decreased sensitivity to acetylcholine (ACh)-induced relaxation compared to NORM (logEC50: ANG: − 6.8 ± 0.1, NORM: − 7.2 ± 0.1; p < 0.05). Relaxation in DOCA was comparable to Placebo (logEC50: DOCA: − 6.8 ± 0.3, Placebo: − 7.3 ± 0.2; p = 0.11). Maximal relaxations to ACh were not different between groups (% maximal relaxation: NORM: 97.6 ± 1.6, ANG: 94.1 ± 2.9, Placebo: 98.4 ± 1.2, DOCA: 87.9 ± 10.8). NOS inhibition abolished ACh-mediated relaxation in arteries from ANG and DOCA, and decreased ACh sensitivity in NORM and Placebo (L-NAME logEC50: NORM: − 6.5 ± 0.3, Placebo: − 6.8 ± 0.5; p < 0.05). COX inhibition had no effect in any group. KCa inhibitors had no effect on arteries from ANG, and decreased ACh sensitivity in NORM (KCa inhibitors logEC50: NORM: − 6.8 ± 0.2; p < 0.05). SNP-induced relaxations were comparable between all groups. These data indicate that NOS is the primary pathway of vasorelaxation in small arteries from hypertensive rats. Next, we designed experiments to determine the activation of NO/cGMP signaling and examine a role for NOS-dependent H2O2 production in arteries from ANG. ACh stimulated, NOS dependent cGMP production was increased over basal in arteries from ANG (55.7 ± 6.9 vs. 30.5 ± 5.1 pmol/mg; p < 0.05; n = 8–12). H2O2 production was stimulated by ACh and was NOS dependent in arteries from ANG (2.8 ± 0.2 μmol/mg with ACh, 1.8 ± 0.1 μmol/mg with L-NAME + ACh; p< 0.05; n = 9–16). Catalase treatment decreased sensitivity to ACh in arteries from ANG (catalase logEC50: − 6.1 ± 0.2; p < 0.05; n = 6). In conclusion, vasorelaxation in small mesenteric arteries from hypertensive rats is maintained by NO/cGMP signaling and NOS-mediated H2O2 production.