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)

1. The effect of 5-hydroxytryptamine (5-HT) was studied on excitatory neurally mediated non-adrenergic non-cholinergic (NANC) contractions evoked by electrical field stimulation (EFS) in guinea-pig isolated bronchi. 2. 5-HT (0.1-100 microM) produced a concentration-dependent inhibition of the excitatory NANC response with 50.9 +/- 5.0% (n = 5, P < 0.01) inhibition at 100 microM. This inhibition was not significantly affected by the 5-HT2 antagonist, ketanserin (1 microM) when inhibitions (+/- ketanserin) at each concentration of 5-HT were compared by unpaired t tests; however, this concentration appeared to produce a leftward shift (approximately 10 fold) of the 5-HT concentration-inhibition curve. Ketanserin (1 microM) was effective in blocking bronchoconstriction evoked by activation of 5-HT2A receptors on airway smooth muscle. In the presence of ketanserin (1 microM) 5-HT (100 microM) evoked an inhibition of 57.4 +/- 5.9% (n = 5, P < 0.01) with an EC50 of 0.57 microM. 3. Inhibition evoked by 5-HT (0.1-100 microM) was unaffected by the alpha-adrenoceptor antagonist phentolamine (1 microM), the beta 2-adrenoceptor antagonist, ICI 118551 (0.1 microM), the 5-HT1A/B antagonist, cyanopindolol (1 microM) or the 5-HT3/4 antagonist, ICS 205-930 (1 microM). 4. Methiothepin (0.1 microM) produced an insurmountable inhibition of the effect of 5-HT (0.1-100 microM), reducing the maximum inhibition produced by 5-HT (100 microM) to 30.2 +/- 5.0% (n = 5, P < 0.001) and suggesting a non-competitive antagonism. Methiothepin inhibited the effect of 5-HT (10 microM) in a concentration-dependent manner with an IC50 of 81 nM. 5. Selective 5-HT receptor agonists were also tested on excitatory NANC responses. 5-Carboxamidotryptamine (5-CT, 0.1-100 MicroM) was the most potent, producing a concentration-dependent inhibition with an EC50 of 0.13 MicroM. Calculation of approximate IC25 values (concentration of the agonist required to give a 25% inhibition of the excitatory NANC response) gave a rank order of potency 5-CT > 5-HT> > 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) >alpha-methyl-5-hydroxytryptamine (alpha-Me-5HT). Sumatriptan, 5-methoxytryptamine (5-MeOT) and 2-methyl-5-hydroxytryptamine (2-Me-5HT) were essentially inactive with IC25> 100 MicroM.6. 5-HT (10 microM) did not significantly affect contractile responses to exogenously applied substance P(1 nM-10 Microm).7. The effect of 5-HT was unchanged after incubation with the nitric oxide (NO) synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 100 Microm). However, pretreatment with charybdotoxin (ChTX,0.1-30 nM), a blocker of the large conductance Ca2+-activated K+channel (K+ca), produced a concentration-dependent inhibition of the effect of 5-HT (10 MicroM).8. 5-HT evokes a concentration-dependent inhibition of e-NANC bronchoconstriction in guinea-pig isolated bronchi but does not affect cumulative concentration-dependent contractile responses to substance P, suggesting that inhibition is via a prejunctional receptor. Effects of selective antagonists and agonists suggest that an atypical 5-HT receptor mediates this inhibition. The inhibitory effect of 5-HT does not involve the production of NO, but may involve the opening a ChTX-sensitive K+ca channel.These data suggest that an atypical 5-HT receptor inhibits the release of neuropeptides from sensory C fibres and may act as other inhibitory neuromodulators via the opening of a common K'channel.
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PMID:Inhibition of excitatory non-adrenergic non-cholinergic bronchoconstriction in guinea-pig airways in vitro by activation of an atypical 5-HT receptor. 751 94

1. Regional haemodynamic responses to the homologous peptides, pituitary adenylate cyclase-activating peptide (1-27) (PACAP27) and vasoactive intestinal polypeptide (VIP) were assessed by giving 20 min infusions (1.5-15 nmol kg-1 h-1) in conscious, chronically-instrumented, Long Evans rats. 2. PACAP27 caused dose-dependent depressor and tachycardic effects associated with renal, mesenteric and hindquarters vasodilatations, although only in the latter vascular bed was there a sustained increase in flow. 3. VIP caused dose-dependent depressor and tachycardic effects that were not significantly different from those caused by equimolar doses of PACAP27. However, the hindquarters vasodilator effects of VIP (at 7.5 and 15 nmol kg-1 h-1) were greater than those of PACAP27 (at the same doses), and accompanied by reductions in renal and mesenteric flows and conductances. 4. In the presence of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 11 mumol kg-1 h-1), there was significant inhibition of the hindquarters vasodilator effects of PACAP27 and VIP (at 7.5 and 15 nmol kg-1 h-1). Under these circumstances the renal and mesenteric vasoconstrictor effects of VIP were abolished. 5. The beta 2-adrenoceptor antagonist, ICI 118551 (670 nmol kg-1 bolus, 335 nmol kg-1 h-1 infusion), reduced the matched hindquarters vasodilator responses to PACAP27 (15 nmol kg-1 h-1) and VIP (7.5 nmol kg-1 h-1), and also abolished the renal vasoconstrictor effects of VIP. 6. The AT1-receptor antagonist, losartan potassium (20 mumol kg-1), had no significant effect on the haemodynamic response to PACAP27 (15 nmol kg-1 h-1), but augmented the hypotensive action of VIP (7.5 nmol kg-1 h-1). This influence of losartan was associated with conversion of the renal and mesenteric vasoconstrictor effect of VIP to vasodilatation. 7. Our findings show that similar changes in mean systemic arterial blood pressure in response to PACAP27 and VIP conceal substantial differences in their regional haemodynamic actions. Although the hindquarters vasodilator effects of both peptides involve NO- and Beta2-adrenoceptor-mediated mechanisms,it appears that activation of the renin-angiotensin system contributes significantly to the haemodynamic effects of VIP, but not to those of PACAP27.
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PMID:Regional haemodynamic responses to pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal polypeptide in conscious rats. 791 21

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

1. Regulation of excitatory and inhibitory junction potentials (e.j.ps and i.j.ps) by opioid peptides was studied in isolated muscle strips from the pyloric sphincter of the dog. 2. Methionine enkephalin (MetEnk; 10(-10) to 10(-6) M) and [D-Ala2, D-Leu5] enkephalin (DADLE; 10(-11) to 10(-7) M), a delta-specific opioid agonist, inhibited i.j.ps and e.j.ps recorded from cells in the myenteric and submucosal regions of the circular muscle layer. These compounds had no effect on resting potential or slow wave activity suggesting that the effects on junction potentials were not due to direct effects on smooth muscle cells. 3. MetEnk and DADLE caused similar effects on junction potentials in preparations in which the myenteric plexus was removed, suggesting that opioids inhibit pre-junctional effects on nerve fibres within the muscularis externa. 4. Inhibition of junction potentials by MetEnk and DADLE was blocked by approximately the same extent by naloxone (10(-6) M) and ICI 174,864 (10(-6) M), a delta-specific antagonist. 5. MetEnk and DADLE blocked a portion of the i.j.p. that was sensitive to arginine analogues; after treatment with N omega-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), MetEnk and DADLE had no further effect on i.j.ps. These data suggest that opioids regulate nitric oxide-dependent neurotransmission. 6. Naloxone (10(-6) M) alone had no effect on i.j.ps elicited by short trains of electrical field stimuli. 7. I.j.p. amplitude was reduced after a period of conditioning stimulation (2 min, 30 Hz, 30 V). Naloxone blocked the post-stimulation inhibition. Repetitive stimulation at high frequencies (30 Hz) resulted in sustained hyperpolarization. Naloxone increased the amplitude of the hyperpolarization responses elicited by high frequency stimulation.8. These results show that e.j.ps and i.j.ps in the canine pylorus are inhibited by opioids. A portion of the inhibitory effects appears to be mediated via delta receptors.9. Although pyloric muscles are richly innervated by nerves containing opioid peptides, brief trains of stimuli do not appear to release concentrations of opioids that are effective in regulating junction potentials. Higher frequency stimulation (or longer durations of stimulation) appear to be necessary to release concentrations of opioids that are effective in modulating the amplitude of junction potentials.
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PMID:Regulation of neural responses in the canine pyloric sphincter by opioids. 848 15

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

Cysteinyl-leukotrienes (CysLTs: LTC4, LTD4 and LTE4) are inflammatory mediators which significantly contribute to the airway obstruction in asthma. At least two distinct receptor subtypes exist for cysteinyl-leukotrienes, the CysLT1- and CysLT2-receptor. The purpose of this study was to test whether sheep trachealis muscle is a useful preparation for further characterization of CysLT2-receptors, previously implicated in contraction of human pulmonary veins. Leukotriene C4 and leukotriene D4 evoked contractile responses, leukotriene C4 being significantly more potent than leukotriene D4, whereas leukotriene E4 failed to elicit contractions. The response to leukotriene C4 exhibited tachyphylaxis upon repeated administration. There were no significant effects of epithelial denudation, NO-synthesis inhibition (L-NAME) or cyclooxygenase inhibition (indomethacin) on the responses to cysteinyl-leukotrienes or cholinergic agonists. Neither was responsiveness to different agonists changed by overnight storage. The responses to leukotriene C4 and leukotriene D4 were markedly potentiated when their metabolism was inhibited by S-hexyl glutathione and L-cysteine. The selective CysLT1-antagonist ICI 198,615 had no significant effect on these responses. However, the combined CysLT1- and CysLT2-antagonist BAY u9773 competitively antagonized leukotriene C4 and leukotriene D4 (pA2 values of 7.0 and 6.8 against leukotriene C4 and leukotriene D4, respectively). The findings support that leukotriene C4 and leukotriene D4 act predominantly on CysLT2-receptors in sheep trachea.
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PMID:Functional characterization of receptors for cysteinyl-leukotrienes in sheep trachealis muscle. 934 30

The compound 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha), a F2-isoprostane formed mainly via a non-cyclooxygenase pathway, has been shown to constrict both human and guinea pig airway smooth muscle in vitro. We investigated whether this compound has any activity on bronchial resistance and plasma exudation in tracheal tissue of anaesthetised guinea pigs. 8-Epi-PGF2 alpha (12.5, 25 and 50 micrograms kg-1 i.v.) elicited a dose-dependent increase in intratracheal pressure. Diphenhydramine (2 mg kg-1 i.v.), indomethacin (1 mg kg-1 i.v.) and NG-nitro-L-arginine methyl ester (L-NAME, 10 mg kg-1 i.v.) did not affect the 8-epi-PGF2 alpha (25 micrograms kg-1 i.v.)-induced bronchoconstriction. On the contrary, while atropine (0.5 mg kg-1 i.v.) injected 10 min prior to 8-epi-PGF2 alpha (25 micrograms kg-1 i.v.) significantly reduced to 55% (P < 0.05) the increase in intratracheal pressure induced by the isoprostane, the selective thromboxane A2 receptor antagonist, ICI-192,605 (0.5 mg kg-1 i.v.) abolished it (95%, P < 0.001). Furthermore, 8-epi-PGF2 alpha (50, 100 and 200 micrograms kg-1 i.v.) increased plasma leakage, measured according to the Evans Blue dye technique, in tracheal tissue. This effect was particularly evident when 8-epi-PGF2 alpha was injected at the dose of 200 micrograms kg-1 i.v. (105% increase; P < 0.01) and it was markedly reduced by ICI-192,605 (0.5 mg kg-1 i.v.) (36%; P < 0.01) but not by diphenhydramine (2 mg kg-1 i.v.). In isolated perfused lungs, 8-epi-PGF2 alpha (2.5 micrograms ml-1 min-1 perfused for 2 min) increased the thromboxane A2 formation which was significantly reduced by ICI-192,605 (16 micrograms ml-1 min-1 perfused for 5 min) and abolished by indomethacin (1 microgram ml-1 min-1 perfused for 15 min). These data indicate that 8-epi-PGF2 alpha induces bronchoconstriction in guinea pig in vivo and that this effect, which seems to be related to activation of thromboxane A2 receptor, is associated to an augment of vascular permeability with plasma leakage in airway smooth muscle.
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PMID:Bronchopulmonary effects of 8-epi-PGF2A in anaesthetised guinea pigs. 950 83

Electrical stimulation of the preganglionic superior cervical nerve produced a frequency-dependent vasoconstrictor response in the anterior choroidal blood vessels of the eye of anesthetized rats. Systemic administration of phentolamine (5 mg kg(-1)) reversed the vasoconstriction to a vasodilator response. This sympathetic-evoked vasodilation was not antagonized by inhibition of nitric oxide synthase with N(G)-nitro-L-arginine methyl ester (L-NAME) (20 mg kg(-1)) or by inhibition of cyclo-oxygenase with indomethacin (20 mg kg(-1)). Intravenous administration of propranolol (1 mg kg(-1)), as well as selective beta(1)-adrenoceptor antagonists atenolol (3 mg kg(-1)), timolol (0.3 mg kg(-1)), and betaxolol (0.1 mg kg(-1)), totally abolished the sympathetic nerve evoked ocular vasodilation. In contrast, the selective beta(2)-adrenoceptor antagonist, ICI-118, 551 ((+/-)-1-[2, 3-(Dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2- butanol) (0.3 mg kg(-1), i.v.), was without effect. These results support the conclusion that the residual sympathetic ocular vasodilation observed in the rat anterior choroid after alpha-adrenoceptor blockade is mediated exclusively by neurogenic release of norepinephrine acting on vascular beta(1)-adrenoceptors.
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PMID:Sympathetic vasodilation in the rat anterior choroid mediated by beta(1)-adrenoceptors. 1061 74

1. Accumulating evidence suggests that plasma levels of interleukin-6 (IL-6), a major cytokine stimulating the synthesis of acute phase proteins, are intimately regulated by the central nervous system (CNS). 2. In the present study, effects of intracerebroventricular (i.c. v) injection of N(G)-nitro-L-arginine methyl ester (L-NAME) or 7-nitroindazole, nitric oxide synthase (NOS) inhibitors, on plasma IL-6 levels and peripheral IL-6 mRNA expression were examined in mice. 3. L-NAME (0.1 - 2 microg per mouse i.c.v.) and 7-nitroindazole (0.2 - 2 microg per mouse i.c.v.) induced a dose-dependent increase in plasma IL-6 levels and a subsequent increase in circulating serum amyloid A, a liver acute-phase protein. In contrast, an intraperitoneal (i.p.) injection of L-NAME up to the dose of 25 microg per mouse had no effect. 4. Pretreatment with yohimbine (alpha(2)-adrenergic antagonist; 1 mg kg(-1) i.p.), or ICI-118,551 (beta(2)-adrenergic antagonist; 2 mg kg(-1) i.p.), but not with prazosin (alpha(1)-adrenergic antagonist; 1 mg kg(-1) i.p.), nor betaxolol (beta(1)-adrenergic antagonist; 2 mg kg(-1) i.p.), significantly inhibited the central L-NAME-induced plasma IL-6 levels. 5. I.c.v. (50 microg per mouse) or i.p. (100 mg kg(-1)) pretreatment with 6-hydroxydopamine had no effect on central L-NAME-induced plasma IL-6 levels. However, intrathecal (i.t.) pretreatment with 6-hydroxydopamine (20 microg per mouse) markedly inhibited central L-NAME-induced plasma IL-6 levels. Both yohimbine (1.5 microg per mouse i.t.) and ICI-118,551 (1.5 microg per mouse i. t.) were effective in inhibition of central L-NAME-induced plasma IL-6 levels. 6. There was an elevation of base-line plasma IL-6 levels in adrenalectomized animals. The adrenalectomy-enhanced levels were not further increased by central L-NAME. 7. L-NAME (2 microg per mouse i.c.v.) induced an increase in IL-6 mRNA expression in liver, spleen, and lymph node. 8. These results suggest that NOS activity in the brain tonically down-regulates peripheral IL-6 by inhibiting adrenaline release from the adrenal medulla.
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PMID:Central injection of nitric oxide synthase inhibitors increases peripheral interleukin-6 and serum amyloid A: involvement of adrenaline from adrenal medulla. 1078 Sep 96


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