Interaction between endogenously produced carbon monoxide and nitric oxide in regulation of renal afferent arterioles

Abstract

Heme oxygenases (HO-1 and HO-2) catalyze the conversion of heme to carbon monoxide (CO), iron, and biliverdin. CO causes vasorelaxation via stimulation of soluble guanylate cyclase (sGC) and/or activation of calcium-activated potassium channels. Because nitric oxide (NO) exerts effects via the same pathways, we tested the interaction between CO and NO on rat afferent arterioles (AAs) using the blood-perfused juxtamedullary nephron preparation. AAs were superfused with either tricarbonyldichlororuthenium (II) dimer, known as CO releasing molecule (CORM-2), 10 μmol/l CO solution, or 15 μmol/l chromium mesoporphyrin (CrMP, HO inhibitor). AAs were also superfused with 1 mmol/l Nω-nitro-l-arginine (l-NNA) to inhibit NO synthase (NOS) or 10 μmol/l 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one to inhibit sGC, and then CrMP was superfused during NOS inhibition or sGC inhibition. Treatment with 150 and 300 μmol/l CORM-2 or with CO (10 μmol/l) significantly dilated AAs (22.0 ± 0.9 and 22.8 ± 0.9 vs. 18.3 ± 0.9 μm, n = 5, P < 0.05; and 26.0 ± 1.4 vs. 18.8 ± 0.7 μm, n = 5, P < 0.05). In untreated vessels, HO inhibition did not alter AA diameter (17.5 ± 0.7 vs. 17.2 ± 0.6 μm, n = 7, P > 0.05); however, during inhibition of NO production, which constricted arterioles to 14.6 ± 1.2 μm, n = 6, P < 0.05, concurrent HO inhibition led to further vasoconstriction (11.7 ± 1.6 μm, n = 6, P < 0.05). CORM-2 attenuated the l-NNA-induced vasoconstriction. Inhibition of sGC caused significant constriction (15.7 ± 0.4 vs. 18.8 ± 0.4 μm, n = 6, P < 0.05). HO inhibition during sGC inhibition did not cause further change in AAs (15.5 ± 0.7 μm, n = 6). We conclude that endogenously produced CO does not exert a perceptible influence on AA diameter in the presence of intact NO system; however, when NO production is inhibited, CO serves as an important renoprotective reserve mechanism to prevent excess afferent arteriolar constriction.