Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00345 (ICI)
 5,388 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The portal-systemic collateral circulation of portal hypertensive rats was studied. The collaterals were perfused through the mesenteric vein with Krebs solution, which was allowed to escape through the jugular veins. The portal-collateral resistance can be quantitated from slopes of the pressure-flow relationships. In collaterals perfused at constant flow, both norepinephrine (NE) and 5-hydroxytryptamine (5-HT) increased the perfusion pressure. Phentolamine caused surmountable antagonism of the constrictor effects of NE, suggesting an involvement of alpha-adrenoceptors. The effects of 5-HT were competitively blocked by the 5-HT2 receptor-selective antagonist ICI 169,369. Isoproterenol dilated NE-preconstricted collaterals. The effect of isoproterenol was blocked by propranolol, demonstrating that the effect was mediated by beta-adrenoceptors. Acetylcholine (ACh) dilated NE-preconstricted collaterals. The dilatation effect of ACh was absent in collaterals in which the endothelium was removed. The competitive inhibitor of the nitric oxide synthase, N omega-nitro-L-arginine (L-NNA), increased collateral resistance and prevented the ACh-induced dilatation of the collaterals. The constrictor response to L-NNA and the blockade of the ACh-induced relaxation by both L-NNA and removal of endothelium are consistent with an involvement of nitric oxide. This experimental model can thus be used to explore the pathophysiological and the pharmacological properties of the collateral venous bed in portal hypertensive states.
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PMID:Pharmacology of portal-systemic collaterals in portal hypertensive rats: role of endothelium. 141 13

We determined the effects of isoproterenol (Iso) on parasympathetic neurotransmission in isolated equine trachealis strips by comparing the effects of Iso on the contractile response to electrical field stimulation (EFS) and acetylcholine (ACh), as well as by measuring EFS-induced ACh release. The interaction of Iso with muscarinic receptors and endogenous nitric oxide was also investigated. ACh release was measured by high-performance liquid chromatography with electrochemical detection. Iso (10(-7) M or greater) caused significantly more inhibition of EFS- than of ACh-induced contraction, an observation usually interpreted as evidence of prejunctional inhibition of ACh release. However, the latter conclusion was not supported by measurement of ACh release. Iso concentration dependently augmented ACh release, which was reversed by the beta 2-adrenoceptor antagonist ICI-118,551 but not by the beta 1-adrenoceptor antagonist CGP-20,712A. Our results indicate that activation of beta 2-adrenoceptors augments ACh release. Moreover, the comparison of inhibitory effects on EFS- and ACh-induced contraction does not provide correct information about the prejunctional actions of beta-agonists. ACh release was increased more by atropine (10(-7) M) than by Iso (10(-6) M), indicating the predominance of prejunctional inhibitory muscarinic autoreceptors over excitatory beta 2-adrenoceptors. Additionally, we found that inhibition of nitric oxide synthase by NG-nitro-L-arginine did not affect either the cholinergic contractile response or ACh release in both the absence and presence of Iso.
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PMID:Beta 2-adrenoceptor activation augments acetylcholine release from tracheal parasympathetic nerves. 761 36

1. We assessed regional haemodynamic responses to the vasodilator, MgSO4, in the absence and presence of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), in conscious chronically instrumented Long Evans rats (n = 9). 2. MgSO4 (loading dose 220 mumol kg-1 min-1 for 7 min, maintenance dose 56 mumol kg-1 min-1 for 7 min), alone, caused slight bradycardia and hypotension accompanied by reductions in renal and mesenteric flows, but a marked hyperaemic vasodilatation in the hindquarters (flow, delta 54 +/- 6%, vascular conductance, delta 77 +/- 5%). 3. L-NAME (183 nmol kg-1 min-1) caused hypertension (29 +/- 2 mmHg) accompanied by bradycardia (-51 +/- 6 beats min-1) and reductions in flow and vascular conductance in the renal (-18 +/- 4% and -35 +/- 3%, respectively), mesenteric (-35 +/- 3% and -49 +/- 3%, respectively), and hindquarters (-26 +/- 3% and -42 +/- 3%, respectively) vascular beds. In the presence of L-NAME, the hypotensive and bradycardic effects of MgSO4 were still apparent, but its hindquarters hyperaemic vasodilator effect was significantly attenuated. 4. In order to determine if the inhibitory action of L-NAME on the hindquarters hyperaemic vasodilator action of MgSO4 was a non-specific effect, due to the change in baseline conditions caused by L-NAME, we also examined responses to MgSO4 in the presence of endothelin-1 (12.5 pmol kg-1 min-1) or angiotensin II (50 pmol kg-1 min-1). In the presence of either peptide, the overall effects of MgSO4 on hindquarters flow and vascular conductance were unchanged. 5. In a separate experiment (n = 8) we determined that the inhibitory effect of L-NAME on the hyperaemic vasodilator response to MgSO4 was prevented by L-arginine, and also demonstrated that the Beta2-adrenoceptor antagonist, ICI 118551, caused significant inhibition of the hindquarters haemodynamic effects of MgSO4.6. We conclude that the hindquarters haemodynamic effects of MgSO4 in conscious rats involve a substantial L-NAME-sensitive component which depends on activation of Beta2-adrenoceptors, probably asa consequence of adrenal medullary adrenaline release.
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PMID:Effects of NG-nitro-L-arginine methyl ester on regional haemodynamic responses to MgSO4 in conscious rats. 801 14

Perfusion with ([N-Me-Phe3,D-Pro4]morphiceptin (PL017)), [D-Pen2,5]enkephalin (DPDPE) and MEt5 and Leu5 enkephalin induced circular muscle contractions and decreased immunoreactive vasoactive intestinal polypeptide (VIP) venous output in canine ileal segments. Motility and VIP responses to PL017 were abolished by the mu antagonist CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) and unchanged by the delta antagonist ICI 174,864 ([N,N-dially-Tyr1,Aib2,3]Leu-enkephalin) which abolished DPDPE motility and VIP responses. The VIP response to DPDPE was unchanged by CTAP, which reduced motility responses, suggesting a DPDPE interaction with endogenous mu opioids, at a mu/delta(complexed) receptor. ICI 174,864 abolished Met5 and Leu5 enkephalin motility responses and Leu5 enkephalin VIP responses while CTAP was ineffective on Leu5 enkephalin motility responses or on both enkephalin VIP responses. CTAP increased Met5 enkephalin motility responses suggesting mu actions to inhibit excitatory nerves. ICI 174,864 reduced Met5 enkephalin VIP output decrements requiring CTAP addition for abolition, suggesting actions at mu/delta(complexed) receptors. Inhibition of nitric oxide synthase with N-omega-L-arginine methyl ester (L-NAME) abolished delta opioid and reduced by 30% mu opioid motility responses, leaving the VIP response intact. Hexamethonium and atropine abolished tonic VIP output, leaving intact motility responses to PL017 and DPDPE. Subsequently L-NAME eliminated delta opioid and reduced by 1/3 mu opioid motility responses. All opioids reduced the NO-mediated IJPs in myenteric plexus-free ileal circular muscle. Thus mu or delta opioids inhibit both NO and VIP release but removal of NO, not VIP, disinhibits circular muscle motility.
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PMID:Identification of mechanisms and sites of actions of mu and delta opioid receptor activation in the canine intestine. 811 80

Ultrasonic probes were placed around dog femoral arteries to record blood flow. Hind paw scalding with boiling water (5 s) caused a marked increase in ipsilateral femoral blood flow that persisted for the 2-h observation period. Contralateral femoral blood flow and systemic and pulmonary vascular resistances were unchanged. Compared to scald only animals, methysergide pretreatment diminished and shortened the femoral vasodilator response to scald (109 +/- 14 vs 243 +/- 27 ml/min at 5 min; 59 +/- 14 vs 191 +/- 31 ml/min at 2 h). Pretreatment with ritanserin, BW A1433U83, atropine, ICI 118551, diphenhydramine, ranitidine, meclofenamate, L-nitro-arginine methyl ester, 3-amino-1,2,4-triazine, and U 37883A had no effect on the increased femoral blood flow response to scald, suggesting this vasodilator response is not dependent upon activation of serotonergic2, adenosineA1, muscarinic, beta 2-adrenergic, histaminergic1 or histaminergic2 receptors, on cyclooxygenase products, endothelium-derived relaxing factor derived from nitric oxide (NO) synthase III, NO derived from NO synthase II, or KATP channels, respectively. Methysergide given after burn immediately reduced the augmented femoral blood flow to preburn levels, suggesting the vasodilator response to scald is mediated through continual activation of local serotonergic1-like receptors, which may be target site(s) for therapeutic interventions to influence burn-induced hemodynamic alterations.
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PMID:Analysis of regional hemodynamic regulation in response to scald injury. 828 81

1. Cysteinyl-leukotrienes cause contractions and/or relaxations of human isolated pulmonary vascular preparations. Although, the localization and nature of the receptors through which these effects are mediated have not been fully characterized, some effects are indirect and not mediated via the well-described LT1 receptor. 2. In human pulmonary veins (HPV) with an intact endothelium, leukotriene D4 (LTD4) induced contraction above basal tone. This response was observed at lower concentrations of LTD4 in the presence of nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NOARG). Contractions (in the absence and presence of L-NOARG) were partially blocked by the LT1 antagonists (MK 571 and ICI 198615). 3. LTD4 relaxed HPV previously contracted with noradrenaline. This relaxation was potentiated by LT1 antagonists, but was abolished by removal of the endothelium. LTD4 also relaxed human pulmonary arteries (HPA) precontracted with noradrenaline but this effect was not modified by LT1 antagonists. 4. The results suggest that contraction of endothelium-intact HPV by LTD4 is partially mediated via LT1 receptors. Further, in endothelium-intact HPV, this contraction was opposed by a relaxation induced by LTD4, dependent on the release of nitric oxide, which was mediated, at least in part, via a non-LT1 receptor. In addition, LTD4 relaxation on contracted HPA was not mediated by LT1 receptors. 5. The mechanical effects of LTD4 on human pulmonary vasculature are complex and involve both direct and indirect mechanisms mediated via at least two types of cysteinyl-leukotriene receptors.
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PMID:Leukotriene receptors on human pulmonary vascular endothelium. 856 95

In rat aortic rings, the mechanism of endothelium-dependent relaxation induced by isoproterenol is examined. Pretreatment with (+/-)-1-[2,3]-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methyleth yl)amino] -2-butanol (ICI-118,551), a beta 2-adrenoceptor antagonist, or atenolol, a beta 1-adrenoceptor antagonist, partly inhibited the relaxing response to isoproterenol. The relaxing response to isoproterenol in the presence of ICI-118,551 or atenolol was markedly inhibited by removal of endothelium. In the aorta pretreated with ICI-118,551 or atenolol, residual relaxing response to isoproterenol was also inhibited by 2-methyl-1,2-di-3-pyridyl-1-propanone (metyrapone), alpha-naphthoflavone or 8-methoxypsoralen, cytochrome P-450 monoxygenase inhibitors, and methylene blue, but not by indomethacin, a cyclooxygenase inhibitor, 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1, 4-benzoquinone (AA861), a 5-lipoxygenase inhibitor, NG-nitro-L-arginine (NOARG), a nitric oxide synthase inhibitor, Zn protoporphyrin IX, a heme oxygenase inhibitor, or yohimbine, a alpha 2-adrenoceptor antagonist. In the aorta denuded of endothelium, metyrapone did not affect the residual relaxing response to isoproterenol in the presence of atenolol. These results suggest that the cytochrome P-450 system may be involved in the endothelium-dependent relaxation induced by isoproterenol through beta 1- and beta 2-adrenoceptor activation.
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PMID:Endothelium- and cytochrome P-450-dependent relaxation induced by isoproterenol in rat aortic rings. 903 Aug 95

1. 8-Iso prostaglandin F2 alpha (8-iso PGF2 alpha) is one of a series of prostanoids formed independently of the cyclo-oxygenase pathway. It has been shown to be upregulated in many conditions of oxidant stress where its formation is induced by free radical-catalysed actions on arachidonic acid. As 8-iso PGF2 alpha is formed in vivo in diseases in which oxidant stress is high such as septic shock, we have assessed the relative potency and efficacy of this compound in pulmonary arteries from control and lipopolysaccharide (LPS)-treated rats. 2. Several studies have characterized the contractile actions of 8-iso PGF2 alpha on various smooth muscle preparations, but its potential dilator actions have not been addressed. Thus these studies examined both the contractile and dilator actions of 8-iso PGF2 alpha in rat pulmonary artery rings. The thromboxane mimetic U46619, PGE2 sodium nitroprusside (SNP) and acetyl choline (ACh) were used for comparison. Each prostanoid had to be dissolved in ethanol to a maximum concentration of 1 x 10-2 M. At high concentrations, ethanol directly contracted pulmonary vessels. We were therefore limited by the actions of the vehicle such that we were unable to add prostanoids at concentrations higher than 1 x 10-4 M. In some cases this meant that maximum responses were not achieved and in these cases the Emax and pD2 values are apparent estimates. 3. The following rank order of potency was obtained from contractile studies; U46619 > 8-iso PGF2 alpha > PGE2, each prostanoid producing concentration-dependent contractions (10(-10)-3 x 10(-4) M, 10(-9)-10(-4) M, 10(-8)-10(-4) M, respectively). As has been shown previously for other smooth muscle preparations, the thromboxane receptor (TP) antagonist ICI 192605, (1 x 10(-6), 1 x 10(-5) and 1 x 10(-4) M), inhibited the contractions of 8-iso PGF2 alpha in a concentration-dependent fashion. 4. The nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 1 x 10(-4) M), enhanced the contractile function of both 8-iso PGF2 alpha and PGE2, but had no effect on that caused by U46619. Similarly, L-NAME inhibited the dilator function of all agents tested except the exogenous nitric oxide (NO) donor SNP indicating that PGE2 and 8-iso PGF2 alpha like ACh, act through the release of NO. The specificity of the effects of L-NAME were confirmed in studies with the inactive enantiomer D-NAME (1 x 10(-4) M), which did not affect the contractile or the dilator actions of 8-iso PGF2 alpha. Furthermore, ICI 192605 enhanced the dilator actions of 8-iso PGF2 alpha, suggesting that the dilator component of 8-iso PGF2 alpha was achieved via activation of a non-TP receptor. 5. Isoprostanes may modulate vascular tone by a direct action on TP receptors to cause contraction and via a distinct receptor leading to the release of NO to cause dilation.
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PMID:Evidence for a dilator function of 8-iso prostaglandin F2 alpha in rat pulmonary artery. 910 3

While estrogen is known to prevent the development of atherosclerosis, the mechanism is not completely understood. We investigated the effects of superoxide dismutase, acetylcholine, and other compounds on the release of nitric oxide (NO) by measuring the relaxation responses of aortic rings, with and without intact endothelium, taken from rabbits under various experimental conditions. The aorta of female rabbits released a greater amount of NO than did that of oophorectomized females and male rabbits. The greater basal release of NO in female rabbits was decreased in animals with atherosclerosis induced by a high cholesterol diet. We also investigated the effect of estrogen on endothelial, neuronal and inducible NO synthase (NOS), NOS-3, NOS-1 and NOS-2, respectively. Preincubation with a physiologic concentration of 17 beta-estradiol (10(-12) to 10(-8) M) over 8 h significantly enhanced the activity of NOS-3 in the endothelial cells of cultured human umbilical vein and bovine aortas. 17 beta-Estradiol also enhanced the release of NO from endothelial cells as measured by an NO selective meter and NO2-/N/3-, metabolites of NO. Western blot showed a similar effect of 17 beta-estradiol on NO. Estrogen increased NOS-3 via a receptor-mediated system. Low concentrations of 17 beta-estradiol (10(-10) to 10(-8) M) enhanced the activity of crude NOS-1 in the cytosolic fraction of rabbit cerebella. Partially purified NOS-1, obtained from the cytosolic fraction by DEAE column chromatography, had a similar response to estrogen. Estrogen at a low dose enhanced the fluorescence of dansyl calmodulin and augmented it in high doses. We also investigated the effect of estrogen on NOS-2. When J774 cells, a murine macrophage cell line, were incubated with interferon-r and lipopolysaccharide, NOS-2 was induced and a large amount of NO was released. Pre- or co-incubation of 17 beta-estradiol inhibited the induction of NOS-2 protein and NO release. The estrogen receptor antagonists, tamoxifen and ICI 182780, inhibited that effect of 17 beta-estradiol. 17 beta-Estradiol inhibited the induction of NOS-2 by a receptor-mediated system. These results may offer a new mechanism for the anti-atherosclerotic effect of 17 beta-estradiol.
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PMID:Effect of estrogen on isoforms of nitric oxide synthase: possible mechanism of anti-atherosclerotic effect of estrogen. 918 36

Estrogen (E) has nitric oxide (NO)-mediated effects in certain vascular beds, and fetal E levels rise acutely with parturition, suggesting that E may be involved in NO-mediated pulmonary vasodilation at birth. We tested the hypothesis that E acutely stimulates NO synthase (NOS) activity in ovine fetal pulmonary artery endothelial cells (PAEC) by measuring L-[3H]arginine conversion to L-[3H]citrulline in intact cells. NOS activity in the presence of 17 beta-estradiol (E2 beta) rose in a dose-dependent manner, increasing 70-100%, with a threshold concentration of 10(-10) M. This effect was detectable within 5 min of E2 beta exposure, and the maximal response was comparable to that obtained with acetylcholine, which had a threshold concentration of 10(-8) M. Ca2+ removal completely inhibited E2 beta-stimulated NOS activity, and activity with E2 beta and the Ca2+ ionophore A-23187 was not additive. In addition, the expression of the endothelial isoform of NOS (eNOS) was not altered, and the inducible and neuronal NOS isoforms were not detected by immunoblot analysis. These findings indicate that E2 beta acutely stimulates eNOS by Ca2+ influx. Furthermore, E2 beta-stimulated NOS activity was fully inhibited by the E receptor (ER) antagonists tamoxifen and ICI-182,780, and ER mRNA expression was evident in reverse transcription-polymerase chain reaction assays. Thus E acutely stimulates eNOS activity in fetal PAEC via the activation of endothelial ER and increases in intracellular Ca2+.
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PMID:Estrogen acutely stimulates nitric oxide synthase activity in fetal pulmonary artery endothelium. 925 48


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