cyclic-gmp and 1-ethyl-2-benzimidazolinone

We examined the involvement of nitric oxide (NO) and/or endothelium-derived hyperpolarizing factor (EDHF) in decreasing peripheral vascular resistance in the rat hind limb perfusion model and analyzed the identity of EDHF in this model. The potency of carbachol (CCh) to produce relaxation was quantitatively similar to sodium nitroprusside (SNP). CCh-induced relaxation was abolished after endothelial denudation, but resistant to nitroarginine and indomethacin. The relaxation was inhibited by tetraethylammonium, ouabain, charybdotoxin plus apamin, and under depolarization. SNP-induced relaxation was accompanied by increased cGMP production, which was inhibited by ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-l-one). Although CCh produced a similar extent of relaxation to SNP, the cGMP level was 24 times lower than that with SNP. Low KCl produced a definite relaxation, which was inhibited by ouabain, but independent of NO, prostacyclin, and endothelium. 1-EBIO (1-ethyl-2-benzimidazolinone) as an activator of IK(Ca) channel also produced a concentration-dependent relaxation, which was inhibited by charybdotoxin, ouabain, and depolarization, but independent of NO and prostacyclin. Clotrimazole and 17-octadecynoic acid as inhibitors of P(450) monooxygenase inhibited the CCh-induced relaxation. Meanwhile, catalase at a concentration sufficient to inhibit H(2)O(2)-induced relaxation did not exert definite inhibition of the CCh-induced relaxation. These results suggest that CCh produces an endothelium-dependent, EDHF-dependent, and NO-cGMP-independent relaxation and that K(+) and metabolite(s) of P(450) monooxygenase possibly play an important role for this relaxation.

Topics: Animals; Benzimidazoles; Carbachol; Cyclic GMP; Endothelium, Vascular; Female; Gap Junctions; Hindlimb; Nitric Oxide; Nitroarginine; Nitroprusside; Perfusion; Potassium Chloride; Rats; Rats, Sprague-Dawley; Vascular Resistance; Vasodilation

Nitric oxide (NO) is continuously produced and released in human airways, but the biological significance of this process is unknown. In this study, we have used Calu-3 cells to investigate the effects of NO on transepithelial anion secretion. An inhibitor of NO synthase, NG-nitro-L-arginine methyl ester, reduced short- circuit current (I(sc)), whereas an NO donor, S-nitrosoglutathione (GSNO), increased I(sc), with an EC50 approximately 1.2 microM. The NO-activated current was inhibited by diphenylamine-2-carboxylate, clotrimazole, and charybdotoxin. Selective permeabilization of cell membranes indicated that NO activated both apical anion channels and basolateral potassium channels. An inhibitor of soluble guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, prevented activation of I(sc) by NO but not by 8-bromo-cGMP, suggesting that NO acts via a cGMP-dependent pathway. Sequential treatment of cells with forskolin and GSNO or 1-ethyl-2-benzimidazolinone and GSNO showed additive effects of these chemicals on I(sc). Interestingly, GSNO elevated intracellular Ca2+ concentration ([Ca2+]i) but had no effect on I(sc) activated by thapsigargin. These results show that NO activates transepithelial anion secretion via a cGMP-dependent pathway that involves cross talk between NO and [Ca2+]i.

Topics: Anions; Benzimidazoles; Bronchi; Calcium Channel Agonists; Cell Line; Colforsin; Cyclic GMP; Cystic Fibrosis Transmembrane Conductance Regulator; Electric Conductivity; Glutathione; Humans; Ion Channels; Nitric Oxide; Nitric Oxide Synthase; Nitroso Compounds; Respiratory Mucosa; S-Nitrosoglutathione

1. In pre-eclampsia, a functional change occurs in the role played by endothelium-derived nitric oxide (NO) in the regulation of smooth muscle contraction in resistance arteries. We investigated the underlying mechanism in human omental resistance arteries from normotensive pregnant and pre-eclamptic women in the presence of diclofenac (an inhibitor of cyclo-oxygenase). 2. In endothelium-intact strips, the sensitivity to 9,11-epithio-11,12-methano-thromboxane A2 (STA2) was significantly higher in pre-eclampsia, and this was not modified by either NG-nitro-L-arginine (L-NNA, an inhibitor of NO synthase) or removal of the endothelium. 3. Bradykinin and substance P each produced an endothelium-dependent relaxation of the STA2-induced contraction in both groups, although the relaxation was significantly smaller for pre-eclampsia. L-NNA markedly attenuated the endothelium-dependent relaxation in the normotensive pregnant group but not in the pre-eclamptic group. 4. In the presence of L-NNA, the relaxation induced by sodium nitroprusside (SNP) on the STA2 contraction was significantly smaller for pre-eclamptic than for normotensive pregnant women. 5. In endothelium-denuded strips, the relaxation induced by 8-para-chlorophenyl thio-guanosine-3', 5'-cyclic monophosphate (8-pCPT-cGMP) on the STA2 contraction was significantly less for pre-eclampsia. 6. In beta-escin-skinned strips from both groups of women, 8-pCPT-cGMP (1-10 microM) concentration-dependently attenuated the contraction induced by 0.5 microM Ca2+. However, its relaxing action was significantly weaker in pre-eclampsia. 7. It is suggested that the weaker responsivene to NO seen in strips from pre-eclamptic women may be partly due to a reduced smooth muscle responsiveness to cyclic GMP.

Topics: Adult; Benzimidazoles; Bradykinin; Calcium; Calcium Channel Agonists; Cyclic GMP; Cyclooxygenase Inhibitors; Endothelium, Vascular; Female; Humans; In Vitro Techniques; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth; Nitric Oxide; Nitric Oxide Synthase; Nitroprusside; Omentum; Potassium; Pre-Eclampsia; Pregnancy; Substance P; Thromboxane A2; Vasodilation