Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 is now known to synthesized in the kidney and influence the renal function. ET-1 mRNA was detected in glomerulus and inner medullary collecting ducts using RT-PCR technique. ETA receptor mRNA was detected only in glomerulus, vasa recta bundle, and arcuate artery. ETB receptor mRNA distributed mainly in glomerulus and collecting ducts. Endothelium derived relaxing factor (EDRF) was believed to be nitric oxide, was synthesized by nitric oxide (NO) synthase from L-arginine. NO stimulates soluble guanylate cyclase and increases cGMP level. NO synthase mRNA was detected in glomerulus and inner medulla. Soluble guanylate cyclase mRNA distributed widely along the nephron segments. NO and cGMP system seems to play some roles in modulating renal functions.
 ...
PMID:[Endothelin, EDRF, CGRP]. 128 17

Endothelin-1 (ET-1) elevated cyclic GMP levels in cultured porcine kidney epithelial cells (LLC-PK1) in a concentration-dependent manner with an EC50 value of about 5 x 10(-10) M. NG-methyl-L-arginine and NG-nitro-L-arginine inhibited cyclic GMP responses to 10(-8) M ET-1 with IC50 values of 1.2 x 10(-6) and 7.6 x 10(-8) M, respectively, and the inhibition was prevented with L-arginine. ET-1-induced cyclic GMP accumulation was enhanced with superoxide dismutase and diminished with oxyhemoglobin and methylene blue. Furthermore, the effect of ET-1 on the cyclic GMP levels was totally dependent on extracellular Ca2+. ET-3, but not big ET-1 and ET C-terminal hexapeptide16-21, elicited similar cyclic GMP responses as observed with ET-1 at the same concentration range. These data strongly suggest that, in LLC-PK1 cells, ET-1 stimulates formation of an endothelium-derived relaxing factor-like substance from L-arginine in a Ca(2+)-dependent fashion, which in turn activates soluble guanylate cyclase to elevate cellular cyclic GMP levels. The effects of ET on cyclic GMP accumulation in the kidney epithelial cells may be related to the natriuretic effects of ET in vivo.
 ...
PMID:Endothelin-1 stimulates cyclic GMP formation in porcine kidney epithelial cells via activation of the L-arginine-dependent soluble guanylate cyclase pathway. 172 46

Endothelin-1 (ET-1) evoked concentration-dependent contractions that were slow in onset and sustained in aortae from both normotensive (Wistar and Wistar-Kyoto rats) and spontaneously hypertensive rats. The presence of a functional endothelium reduced the contractions evoked by low concentrations of ET-1 in the aortae from normotensive rats and shifted the concentration-contraction curves to the right in the hypertensive rat. NG-monomethyl-L-arginine, a competitive inhibitor of nitric oxide (NO) synthase, inhibited the influence of the endothelium. Endothelin-3 (ET-3) evoked contractions in aortae from both normotensive and hypertensive rats at concentrations greater than 3 x 10(-8) M, which were reduced by the presence of a functional endothelium. ET-1 and ET-3 evoked concentration- and endothelium-dependent relaxations in aortae contracted submaximally with phenylephrine, from both types of rats. The relaxations were reversed by methylene blue, an inhibitor of soluble guanylate cyclase, and nitro-L-arginine, a competitive inhibitor of NO synthase. These observations demonstrate that the endothelium modulates the contractile response evoked by ET-1 and ET-3 in the aorta of the rat. This inhibition is more pronounced in aortas from hypertensive compared to normotensive rats and is mediated, at least in part, by an enhanced production of endothelium-derived NO.
 ...
PMID:The basal and stimulated release of EDRF inhibits the contractions evoked by endothelin-1 and endothelin-3 in aortae of normotensive and spontaneously hypertensive rats. 172 52

Changes with age in the coronary vascular response to endothelin-1 were investigated in perfused hearts isolated from 2-, 6- and 24-month-old (mo) male Fisher-344 rats. Endothelin-1 injected as a single bolus (0.3, 3 and 30 nmol) into the coronary artery supply caused dose-dependent vasoconstriction in all three age groups. While there was no age-related change in the vasoconstriction induced by the lower doses (0.3 and 3 nmol), the higher dose (30 nmol) elicited a more pronounced vasoconstriction in 6- and 24-mo rats than that in 2-mo rats. NG-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide formation, markedly enhanced the vasoconstriction induced by 30 nmol endothelin-1 in 2- and 6-mo rats but only slightly and non-significantly enhanced that vasoconstriction in 24-mo rats. Haemoglobin, which inhibits activation of guanylate cyclase by nitric oxide, enhanced the endothelin-1-induced vasoconstriction in 2-mo rats, but not in 6- and 24-mo rats. The acetylcholine-induced coronary vasodilation was more pronounced in 2- and 6-mo rats than in 24-mo rats and was attenuated by L-NNA in 2- and 6-mo rats. The coronary vasodilation induced by nitroprusside (0.1 mmol), a pharmacological precursor of nitric oxide, did not change with age. Endothelin-1 (30 nmol) markedly increased the release of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in all three age groups. The prostaglandin synthesis inhibitor indomethacin enhanced the endothelin-1-induced vasoconstriction in 2- and 6-mo rats to a similar extent.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Modulation by aging of the coronary vascular response to endothelin-1 in the rat isolated perfused heart. 837 44

1. Endothelin-3 (ET-3) at concentrations below those which caused contraction (30 nM) elicited endothelium-dependent relaxation followed by rebound contraction in rat isolated thoracic aorta. 2. Endothelin-1 also relaxed the rat aorta with a similar potency. 3. The nitric oxide (NO) synthase inhibitor, NG-nitro L-arginine, the radical scavenger, haemoglobin and the soluble guanylate cyclase inhibitor, methylene blue, each inhibited the ET-3-induced relaxation. 4. The calmodulin inhibitor, calmidazolium, considerably attenuated the relaxation caused by ET-3 without affecting that to nitroprusside. 5. Concentrations of ET-3 that were necessary to induce the relaxation also caused concentration-dependent elevation of guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels. 6. NG-nitro L-arginine, haemoglobin, methylene blue, calmidazolium and removal of the endothelium completely abolished ET-3-stimulated cyclic GMP production. 7. These results suggest that ET-3 triggers NO formation possibly via ETB receptors on the endothelium to activate soluble guanylate cyclase, which in turn stimulates cyclic GMP production and smooth muscle relaxation. The enzyme contributing to the NO formation may be of the calcium/calmodulin-dependent, constitutive type.
 ...
PMID:Endothelin-3-induced relaxation of rat thoracic aorta: a role for nitric oxide formation. 838 84

Increasing vasoconstriction and vascular remodeling of pulmonary vasculature are main characteristics of hypoxic pulmonary hypertension (HPH). Basal pulmonary circulatory tone is maintained by a dynamic balance of vasoconstrictors and vasodilators acting on the pulmonary vascular smooth muscle cells. Endothelin-1 (ET-1) and nitric oxide (NO) are the most important endothelium-derived vasoconstrictor (EDCF) and vasodilator (EDRF). In this report, we studied the effect of ET-1 and NO on hypoxic pulmonary vascular remodeling. We observed that ET-1 dose dependently increased DNA synthesis of pulmonary artery smooth muscle cells (PASMC), SNP, a NO generating drug, inhibited DNA synthesis of PASMC and its inhibitory effect was mediated by cGMP. Hypoxia increased the proliferative response of PASMS to ET-1 by stimulating autocrine of PASMC and decreased the inhibitory effect of SNP by reducing the activity of intra-cellular soluble guanylate cyclase. Based on the result, it is suggested that the balance of ET-1 and NO and regulation of hypoxia play important roles in hypoxic pulmonary vascular remodeling.
 ...
PMID:[Study on the effect of endothelin and nitric oxide on DNA synthesis of pulmonary artery smooth muscle cells and modulation of hypoxia]. 870 50

Endothelin-1 (ET-1) is synthesized within the wall of the ductus arteriosus (DA) and is a potent constrictor of the DA in vitro. However, the role of endogenous ET-1 in closure of the DA at birth remains unclear. Therefore, we studied the effects of a selective ETA-receptor antagonist (PD-156707), or its vehicle, on DA closure in 13 late-gestation fetal lambs during the first 5 h after birth. We also studied the effects of ETA-receptor blockade on DA constriction induced by oxygen, indomethacin (a cyclooxygenase inhibitor), and LY-83583 (a soluble guanylate cyclase inhibitor) in vitro (n = 9 ductus arteriosus rings). In vehicle-treated lambs in vivo, the DA constricted during the 5-h study period after birth: DA resistance increased (from 0.007 +/- 0.01 to 3.406 +/- 4.15 mmHg. ml-1. min. kg-1; P < 0.05); the pressure gradient across the DA increased (from 1.4 +/- 2.1 to 25.2 +/- 9.4 mmHg; P < 0.05); and DA blood flow decreased (from 193.5 +/- 48.0 to 19.3 +/- 14.3 ml. kg-1. min-1; P < 0.05). In vitro, the DA was constricted by exposure to 30% oxygen (23 +/- 14% net active tension; P < 0.05), indomethacin (5 x 10(-6) M, 22 +/- 5% net active tension; P < 0.05), LY-83583 (10(-5) M, 24 +/- 10% net active tension; P < 0.05), and ET-1 (10(-7) M, 19 +/- 4% net active tension; P < 0.05). Although PD-156707 blocked both the in vivo and in vitro effects of exogenous ET-1, it had no effect on postnatal ductus constriction nor on in vitro ductus contractile responses to oxygen, indomethacin, or LY-83583. This study suggests that endogenous ET-1 does not play an important role in closure of the DA at birth.
 ...
PMID:Endothelin-receptor blockade does not alter closure of the ductus arteriosus. 981 69

The effects of various spontaneous nitric oxide (NO) donors and NO synthase inhibitors on endothelin- production were examined using porcine cultured aortic endothelial cells. NO donors such as (+/-)-(E)-4-methyl-2-[(E)-hydroxyimino]-5-nitro-3-hexanamide (NOR 2), (+/-)-(E)-4-ethyl-2-[( E)-hydroxyimino]-5-nitro-3-hexanamide (NOR 3) and (+/-)-N-[(E)-4-ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexen-1- yl]-3-pyridine carboxamide (NOR 4) suppressed effectively the release of endothelin-1 from the cells. Endothelin-1 mRNA expression was also attenuated by these compounds. Other NO donors such as 3-[2-hydroxy-1-(1-methylethyl)-2-nitrosohydrazino]-1-propanamin e (NOC 5), 2,2'-(hydroxynitrosohydrazino)bis-ethanamine (NOC 18), s-nitroso-n-acetyl-DL-penicillamine, N-morpholino sydnonimine (SIN-1) had no effects on endothelin-1 production. Endothelial intracellular cyclic guanosine monophosphate (cGMP) levels were significantly increased by all NO donors. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective soluble guanylyl cyclase inhibitor, had no effect on the NOR 3-induced decrease in endothelin-1 secretion, although cGMP production was abolished by ODQ. NOR 3 also inhibited endothelin-1 secretion even in the presence of 2-(4-carboxyphenyl)-4,4,5,5-tetrametylimidazole-1-oxyl 3-oxide (carboxy-PTIO), a NO scavenger. NOR 3-induced inhibitory effects on endothelin-1 secretion were abolished by preincubation of the compound in phosphate-buffered saline (37 degrees C, 4 h), a procedure by which about 98% of the parent compound's ability to release NO was lost. NO synthase inhibitors such as N(G)-nitro-L-arginine, N(G)-monomethyl-L-arginine and N(G)-nitro-L-arginine methyl ester (L-NAME) enhanced prepro endothelin-1 mRNA expression and significantly increased endothelin-1 release from endothelial cells. Endothelin-1 secretion was also increased effectively by carboxy-PTIO or ODQ. When the cells were exposed to L-NAME with carboxy-PTIO or ODQ, no significant further increase in endothelin-1 release was observed. These results suggest that endogenous NO inhibits endothelin-1 production through guanylyl cyclase/cGMP-dependent mechanisms. In contrast, it seems unlikely that exogenous NO has an inhibitory effect on endothelin-1 production in endothelial cells. NOR compounds inhibit endothelin-1 production perhaps through NO/cGMP-independent mechanisms, i.e., through an unknown effect of the parent compound itself.
 ...
PMID:Effects of endogenous and exogenous nitric oxide on endothelin-1 production in cultured vascular endothelial cells. 992 Jan 86

Escherichia coli endotoxin (LPS) when infused through the renal artery of the rabbit isolated perfused kidney prepared as constant pressure mode, caused a decrease in flow rate and kidney weight indicating its primary vasoconstrictor effect. This effect was predominant in kidneys from rabbits pretreated with LPS. Endothelin-1 at a concentration of 10(-10) M and big endothelin-1 at a concentration of 10(-8) M produced equal vasoconstrictor effects in kidney. Addition of endotheHn converting enzyme inhibitor, phosphoramidon, to the perfusion medium at a concentration of 10(-6) M caused a reduction in the effects of both LPS and big ET-1 without altering the vasoconstrictor effect of ETol. However, addition of methylene blue (10(-5) M), a soluble guanylate cyclase inhibitor and N(G)-nitro-L-arginine-methyl ester (10(-6) M) to the perfusion medium caused a potentiation in the vasoconstrictor effect of LPS. Indomethacin at a concentration of 10(-6) M did not alter the effect of LPS. These results were taken as evidence for the participation of endothelin peptides and the L-arginine-nitric oxide pathway in the effect ofLPS in rabbit isolated perfused kidney.
 ...
PMID:Possible involvement of endothelin peptides and L-arginine-nitric oxide pathway on the effect of endotoxin in the rabbit isolated perfused kidney. 1847 44