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)

In perinatal lungs, veins contribute substantially to total pulmonary vascular resistance. The present study was designed to determine the role of endothelium-derived nitric oxide (EDNO) in modulating the responsiveness of pulmonary veins and arteries in newborn lambs. Fourth-order pulmonary arterial and venous rings of newborn lambs were suspended in organ chambers filled with modified Krebs-Ringer bicarbonate solution (95% O2/5% CO2, 37 degrees C), and their isometric force was measured. Nitro-L-arginine had no effect on the resting tension of pulmonary arteries but caused an endothelium-dependent contraction of pulmonary veins. During contraction to endothelin-1 or U46619, acetylcholine, bradykinin, and calcium ionophore A23187 induced larger endothelium-dependent relaxation in pulmonary veins than in arteries. The endothelium-dependent relaxation of pulmonary vessels was abolished by nitro-L-arginine. In vessels without endothelium, nitric oxide induced significantly greater relaxation in pulmonary veins than in arteries. All vessels relaxed similarly to 8-bromo-cGMP. Radioimmunoassay showed that the basal level of intracellular cGMP of pulmonary veins with endothelium was higher than that of arteries with endothelium. Acetylcholine, bradykinin, and calcium ionophore A23187 induced a significantly larger endothelium-dependent increase in the intracellular content of cGMP in pulmonary veins than in arteries. In vessels without endothelium, nitric oxide induced a larger increase in cGMP content in pulmonary veins than in arteries. The present study suggests that EDNO may play a larger role in modulation of pulmonary venous than arterial reactivity, which may be mainly due to a difference in the activity of soluble guanylate cyclase in vascular smooth muscle.
 ...
PMID:Endothelium-derived nitric oxide plays a larger role in pulmonary veins than in arteries of newborn lambs. 789 31

We examined the effects of endothelium-dependent responses on coronary perfusion pressure (CPP) in isolated, blood-perfused neonatal pig hearts under conditions of controlled coronary flow. Baseline CPP was increased 8%-21% by the cyclooxygenase inhibitor indomethacin (10-100 microM), and 30%-92% by NG-monomethyl-L-arginine (L-NMMA, 10-100 microM), an inhibitor of nitric oxide (NO) synthase, suggesting that both prostaglandin and nitric oxide synthesis contribute to basal coronary tone. Both acetylcholine (ACh) and bradykinin (BK) decreased CPP. These effects were enhanced by preconstriction with endothelin-1. L-NMMA markedly attenuated BK-induced coronary vasodilation and converted the ACh response to constriction, indicating a significant role for NO release in these responses. After 1 h of total, global normothermic ischemia and 45 min of reperfusion, vasoconstrictor responses to endothelin-1 and ACh were enhanced, while BK-induced dilation was significantly reduced. L-Arginine supplementation during reperfusion did not restore vasodilatory responses to ACh or BK. The magnitude of L-NMMA-induced coronary vasoconstriction during reperfusion was similar to that observed without ischemia-reperfusion. Coronary vasodilation in response to sodium nitroprusside, a NO precursor that causes endothelium-independent vasodilation by directly activating smooth muscle guanylate cyclase, was unaffected by ischemia-reperfusion. We conclude that NO production in the neonatal coronary circulation contributes to both basal tone and the response to ACh and BK. After ischemia-reperfusion, basal NO production and smooth muscle relaxation mediated by guanylate cyclase are intact, whereas agonist-stimulated dilation is significantly impaired.
 ...
PMID:Endothelium-dependent regulation of coronary tone in the neonatal pig. 797 31

1. The purpose of the present experiments was to study the underlying mechanisms responsible for the relaxant action of endothelin-1 (ET-1) in the guinea-pig trachea in vitro. 2. In tracheal strips precontracted (60-70% of the maximum) with carbachol, ET-1 (1-100 nM) evoked slowly developing concentration-dependent relaxations. Preincubation of the tissues with the thromboxane A2/prostaglandin H2 receptor antagonist, BM 13505 (5 microM) significantly potentiated the relaxant response to ET-1. 3. Removal of the epithelium changed the response of precontracted tracheal preparations to ET-1 from a relaxation to a sustained contraction. 4. ET-1-induced relaxations were abolished by methylene blue (10 microM) and were almost completely attenuated by oxyhaemoglobin (5 microM) and NG-monomethyl-L-arginine (L-NMMA, 100 microM), an inhibitor of nitric oxide synthesis, but were not altered by indomethacin (10 microM). 5. In tracheal strips under passive tension, ET-1 (1-100 nM) elicited dose-dependent contractions. The sensitivity of tissues to ET-1 was significantly enhanced by removal of the epithelium (apparent EC50 values were 28.1 +/- 4.1 and 12.5 +/- 0.8 nM in intact and rubbed trachea, respectively, n = 7, P < 0.01). 6. Preincubation of intact tracheal strips with methylene blue, oxyhaemoglobin or L-NMMA did not mimic the effect of epithelium removal on ET-1-induced contractions. 7. There was a concentration-dependent increase in thromboxane A2 but not in PGE2 and prostacyclin release from intact tracheal strips following stimulation with ET-1 (5-100 nM). 8. These results show that ET-1 exerts a dual action on guinea-pig isolated trachea: it evokes contractions at low resting tone, whereas it induces relaxations at higher resting tone. The relaxant action of ET-1 may be mediated by nitric oxide released from epithelial cells and resultant activation of smooth muscle guanylate cyclase.
 ...
PMID:Induction by endothelin-1 of epithelium-dependent relaxation of guinea-pig trachea in vitro: role for nitric oxide. 810 33

Nitric oxide (NO) released from nonadrenergic-noncholinergic (NANC) nerves seems to be a principal mediator of the relaxation of penile erectile tissue necessary for erection, and drugs acting by release of NO have been shown to produce erection when injected intracorporeally into impotent patients. By producing hyperpolarization, K+ channel openers are effective in relaxing isolated penile erectile tissue from rabbit and man, and can produce tumescence and erection when injected intracorporeally into animals. Nicorandil is classified as a K+ channel opener, but it also acts as a donor of NO. In the present study, the effects of nicorandil on isolated preparations from human corpus cavernosum (CC) and deep cavernous artery (Acc) were compared with those of cromakalim (K+ channel opener) and SIN-1 (NO donor). Nicorandil produced a concentration-dependent relaxation of CC and Acc preparations. The relaxations obtained at the highest nicorandil concentration used (10(-4) M.) were 75 +/- 3% and 66 +/- 4% in CC preparations contracted by noradrenaline and endothelin-1, respectively. The corresponding effects in Acc preparations were 70 +/- 14% and 73 +/- 5%. Glibenclamide (blocking ATP-dependent K+ channels) significantly reduced the nicorandil-induced relaxation in CC, but not in Acc. Methylene blue (believed to block soluble guanylate cyclase) reduced nicorandil's relaxant effect in CC, although statistical significance was not obtained. NG-nitro-L-arginine 10(-4) M. (NO synthase inhibitor) did not significantly influence the effect of nicorandil on precontracted preparations in either tissue. In CC preparations contracted by electrical field stimulation, nicorandil and cromakalim concentration dependently inhibited the responses. This effect was significantly counteracted by glibenclamide. It is concluded that nicorandil is effective in relaxing human CC chiefly by its K+ channel opening action, and to some extent by its ability to release NO. For nicorandil's relaxing effect on Acc, ATP dependent K+ channels seem to be of limited importance. If effective in impotent patients, the drug may represent a new, interesting approach to the treatment of erectile dysfunction.
 ...
PMID:Effects of nicorandil on human isolated corpus cavernosum and cavernous artery. 812 2

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

To clarify the interaction between endothelin-1 (ET-1) and atrial natriuretic peptide (ANP), the effects of ET-1 on ANP secretion were investigated in isolated perfused rat hearts and in conscious unrestrained rats. Perfusion with 10(-9) M ET-1 stimulated ANP secretion from the isolated perfused rat heart. However, 10(-10) M ET-1 significantly decreased ANP secretion for the initial 15 min of the perfusion period. The perfusion with 10(-11) M ET-1, which is near the plasma level of ET-1 (2 x 10(-12) M), inhibited ANP secretion throughout the perfusion period. The perfusion of 10(-12) M ET-1 slightly decreased ANP secretion. After the ET-1 perfusion period, ANP secretion increased in proportion to ET-1 dose. The inhibitory action of ET-1 on ANP secretion was almost abolished by simultaneous perfusion of indomethacin, a cyclooxygenase inhibitor, but not by methylene blue, an inhibitor of soluble guanylate cyclase. In conscious unrestrained rats the iv infusion of 1 pmol/kg.min ET-1, which doubled the plasma ET-1 level, slightly but significantly decreased the plasma ANP level 5 and 10 min after the initiation of the infusion. The infusion of 10 and 30 pmol/kg.min ET-1 increased the plasma ANP level. These results demonstrate that low doses of ET-1 exert an inhibitory and short-acting action on ANP secretion from the heart, although high doses of ET-1 exert stimulating and long-lasting action, and suggest that prostanoids are involved in this inhibitory action.
 ...
PMID:Low doses of endothelin-1 inhibit atrial natriuretic peptide secretion. 847 43

Levels of calcitonin gene-related peptide (CGRP), a vasodilator peptide present in nerves and airway endocrine cells of the rat respiratory tract, are increased in hypoxic lung and decreased in plasma, suggesting impaired CGRP release. We wanted to determine whether there was an adaptive functional response to reduced CGRP levels in hypoxia. Density of binding sites for CGRP were compared with its vascular actions following hypoxia, and with binding following administration of the sensory neurotoxin capsaicin to deplete neural CGRP. Autoradiography of lung sections incubated with 125I-labelled CGRP and other vasoactive peptides was used to quantify their binding sites, in male Wistar rats exposed to periods of hypoxia (inspiratory oxygen fraction (FI,O2) = 0.1) ranging 0-10 days (n = 5 each), in controls, and in rats treated neonatally with capsaicin. Relaxation to CGRP was compared in pulmonary artery of control and hypoxic rats. CGRP binding was seen in the vascular endothelium and was significantly elevated after 5 days of hypoxia (mean +/- SEM: control 4.6 +/- 0.4 versus hypoxic 16.6 +/- 2.4 amol.mm-2). CGRP-induced (5 x 10(-7)M) relaxation of pulmonary artery was reduced, compared with controls, following 8 and 21 days of hypoxia (mean +/- SEM) percentage of relaxation to phenylephrine: 78 +/- 3, 36 +/- 5 and 32 +/- 3, respectively) and was abolished by removal of endothelium. Capsaicin treatment also significantly elevated vascular CGRP binding. Atrial natriuretic peptide (ANP) binding levels were decreased in smooth muscle of all blood vessels after 7 days of hypoxia, but endothelin-1 (ET-1) and vasoactive intestinal peptide (VIP) binding was unchanged. We conclude that the vasodilator effects of CGRP are endothelium-dependent and, whilst they are reduced in hypoxic lung, this is not due to reduction in receptors, thereby implicating alterations in the nitric oxide guanylyl cyclase system. Furthermore, adaptive responses in some peptide binding sites occur in hypoxia, which may be due to changes in endogenous peptide levels.
 ...
PMID:Decreased endothelium-dependent pulmonary vasodilator effect of calcitonin gene-related peptide in hypoxic rats contrasts with increased binding sites. 866 97

We investigated the vasorelaxant effects of MCI-154, a cardiotonic agent designed to target thin filaments in cardiac muscles in intact and skinned vessels from guinea pigs. In normal Krebs-Henseleit solution, MCI-154 (10(-7)-10(-4) M) inhibited the contractions induced by angiotensin II, (Ang II), endothelin-1 (ET-1), phenylephrine, and phorbol 12-myristate 13-acetate (PMA) in a concentration-dependent manner in guinea pig aorta. In Ca(2+)-free solutions, ET-1 and PMA caused slowly developing and sustained contractions in guinea pig aorta, whereas phenylephrine and caffeine induced transient contractions due to Ca2+ release from the sarcoplasmic reticulum (SR). MCI-154 (10(-7)-10(-4) M) inhibited the contractile responses to ET-1 and PMA. MCI-154 also reduced the contraction induced by Ca2+ release from phenylehrine- and caffeine-sensitive Ca2+ store sites. On the other hand, the relaxation response to MCI-154 was not affected by the presence of methylene blue, a guanylate cyclase inhibitor or by the removal of endothelial cells. MCI-154 decreased the Ca(2+)-activated tension development in saponin-treated skinned fibers from guinea pig femoral arteries. The effects of MCI-154 were not potentiated in the presence of protein kinase A (PKA), whereas those of cyclic AMP were potentiated, possibly because of lack of protein kinase A. The present experiments demonstrate that MCI-154 inhibits vascular contraction when the contractions are produced by any of three mechanisms: protein kinase C (PKC) activation, Ca2+ mobilization from store sites, or sensitization of contractile elements by Ca2+.
 ...
PMID:MCI-154-induced relaxation in vascular smooth muscles of guinea pig. 884 68

Development of vascular tolerance to nitroglycerin (NTG) has been attributed to sulfhydryl (SH) depletion, guanylate cyclase desensitization, or both. Controversy regarding the precise contribution of these mechanisms may be due to variations in experimental design. To examine further the biochemical basis of NTG tolerance, norepinephrine (NE)-precontracted rat aortic rings were exposed to NTG (10(-5)M), which resulted in 84 +/- 6% relaxation. Other rings were first superfused with NTG (10(-6)M) and then contracted with NE. These rings showed a marked tolerance to the vasorelaxant effects of NTG (maximal relaxation 20 +/- 5%, n = 15, p < 0.001 vs. control rings). Similar tolerance to NTG was observed when the vascular rings were first superfused with acetylcholine (ACh 10(-6)M), indicating cross-tolerance between ACh and NTG. Treatment of NTG-tolerant rings with N-acetylcysteine (NAC) (10(-5)M) did not restore vascular smooth muscle (VSM) relaxation in response to NTG (maximal relaxation 23 +/- 5%, n = 8), suggesting that SH depletion may not be the basis of NTG tolerance in these experiments. Parallel sets of NTG-tolerant aortic rings were contracted with endothelin-1 (ET-1, n = 5) or the endothelium-derived relaxing factor (EDRF) synthase inhibitor NG-monomethyl L-arginine (L-NMMA, 10(-4)M, n = 8). In both ET-1- and L-NMMA-contracted rings, vascular relaxation in response to NTG was preserved (80 +/- 6 and 88 +/- 8% relaxation, respectively). Measurement of cyclic GMP in aortic rings showed marked accumulation on initial exposure of tissues to NTG (310 +/- 10 fmol/mg), whereas the NTG-tolerant rings showed much less cyclic GMP accumulation (48 +/- 29 fmol/mg). Rings contracted with L-NMMA or ET-1, but not NE, accumulated cyclic GMP when exposed to NTG (280 +/- 20 fmol/mg). These data indicate that NTG tolerance develops on exposure of vascular rings superfused with NTG or ACh and is probably not related to tissue SH depletion. Contraction of NTG-tolerant rings with ET-1 or L-NMMA restores NTG-mediated relaxation.
 ...
PMID:Studies of vascular tolerance to nitroglycerin: effects of N-acetylcysteine, NG-monomethyl L-arginine, and endothelin-1. 887 89

Atrial natriuretic peptide (ANP) has been shown to counteract the response of endothelin-1 (ET-1), but whether endogenous ANP actually inhibits the systemic release of ET-1 in vivo has not yet been determined. We administered HS-142-1 (HS), a specific antagonist of the guanylate cyclase-coupled ANP receptor, to conscious dogs with severe congestive heart failure (CHF) produced by rapid right ventricular pacing (n = 5, for 22 days) at doses of 0.3, 1.0, and 3.0 mg/kg at 30-minutes intervals. In the present study, plasma ANP and ET-1 levels were significantly elevated in CHF(348 +/-58 and 4.54 +/- 0.60 pg/ml, respectively compared with those in control dogs (65 +/- 4, P < 0.01, 1.30 +/- 0.17 pg/ml, P < 0.001). HS inhibited plasma guanosine 3',5'-cyclic monophosphate (cGMP) levels, a biological market of endogenous ANP activity, in a dose-dependent manner from 21.8 +/- 2.2 to 7.2 +/- 1.4 pmol/ml (P < 0.001), with concomitant significant increases in plasma ET-1 levels from 4.54 +/- 0.60 to 6.60 +/- 0.72 pg/ml (P < 0.05). There was a significant negative correlation between the decrease in plasma cGMP and the increment in plasma ET-1 (r = -0.64, P < 0.01). Despite these responses, mean arterial pressure and pulmonary arterial pressure did not change significantly. Plasma angiotensin II and arginine vasopressin levels, both of which have been reported to stimulate ET-1 secretion in vitro, also showed no significant changes. These results strongly suggest that endogenous ANP directly inhibits endogenous ET-1 secretion through a cGMP-mediated pathway in chronic severe CHF.
 ...
PMID:Endogenous atrial natriuretic peptide inhibits endothelin-1 secretion in dogs with severe congestive heart failure. 892 91


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>