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)

Of 7 phosphodiesterase inhibitors tested for ability to induce a quasi-morphine withdrawal syndrome (QMWS) in opiate-naive rats, five were effective in a dose-related way. These, in descending order of potency, were IBMX, ICI-63197, RO-201724, theophylline and caffeine. Their potencies in inducing a QMWS correlated significantly (P less than 0.05) with those in inhibiting low Km cyclic AMP phosphodiesterase of rat brain homogenate. There was no correlation with potencies in inhibiting cyclic GMP phosphodiesterase.
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PMID:Mechanism of quasi-morphine withdrawal behaviour induced by methylxanthines. 21 99

The effects of nizatidine (a new H2-receptor antagonist) and of related compounds were studied on oxidative drug metabolism in the rat both in vivo and in vitro. Nizatidine is a structural analog of the H2-receptor antagonists ICI 125,211 (Tiotidine) and ranitidine (Zantac). Nizatidine (120 mg/kg, ip) had no effect on the [14C]aminopyrine (ABT) or [14C]caffeine breath (CBT) tests, nor on the clearance from plasma of aminopyrine despite high tissue and plasma concentrations of nizatidine. Binding of nizatidine (1 mM) to rat hepatic microsomal P-450 determined by spectral analysis was not observed. In vitro aminopyrine demethylation was inhibited by nizatidine only at high concentrations (Ki = 92 mM). Cimetidine, ICI 125,211, and imidazole bind avidly to rat hepatic microsomal cytochrome P-450 and are potent inhibitors of aminopyrine demethylation in vitro. Imidazole inhibited the aminopyrine breath test, while imidazole, ranitidine, and ICI 125,211 inhibited the caffeine breath in vivo. These data indicate that nizatidine has no acute inhibitory effect on hepatic oxidative drug metabolism in the rat, both in vitro and in vivo. The composite structural-activity data suggest that inhibition of in vivo oxidative drug metabolism by H2-antagonists may not depend primarily on either the imidazole ring side chain or the thiazole ring per se. Furthermore, the in vivo inhibition may not correlate with in vitro data.
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PMID:Nizatidine, a new histamine H2-receptor antagonist, and hepatic oxidative drug metabolism in the rat: a comparison with structurally related compounds. 285 33

A quasi-morphine withdrawal syndrome (QMWS) is a pattern of behavior closely resembling the true withdrawal syndrome in the opiate-dependent animal, which can be elicited acutely by a nonopiate drug in an opiate-naive animal. The main criteria proposed for the QMWS, in addition to its resembling the true withdrawal syndrome, are that the effects of opiates and of opiate antagonists on the QMWS should parallel those on true opiate withdrawal. Drugs that wholly or largely fulfill these criteria are 3-isobutyl-1-methylxanthine (IBMX), theophylline, caffeine, ICI 63197, and RO 201724. From the evidence given, it is concluded that these drugs act by inhibiting brain cyclic AMP phosphodiesterase, thus raising the level of cyclic AMP in appropriate neurons. These findings are consistent with the view that the molecular mechanisms of opiate dependence is the hypertrophy of a neuronal cyclic AMP system in compensation for the inhibition by opiate of an adenylate cyclase. Our studies and those of others suggest that: a) very rapid tests for opiate activity and for addictive liability can be devised by use of IBMX; b) opiates may be used clinically to counter poisoning by caffeine or theophylline; and c) a relationship may exist between caffeine consumption and opiate addiction.
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PMID:Character and meaning of quasi-morphine withdrawal phenomena elicited by methylxanthines. 616 62

1 To test the possibility that adenosine receptors exist within the trachea of the guinea-pig, an attempt has been made to identify a compound with adenosine antagonist activity in this tissue.2 Quinidine, phentolamine, phenoxybenzamine, 2-2'-pyridylisatogen tosylate (PIT) and caffeine were tested for antagonism of spasmolytic responses to adenosine, adenosine 5'-triphosphate (ATP) and adenine on the guinea-pig isolated trachea.3 Quinidine (10 and 25 mug/ml), phentolamine (10 and 30 mug/ml) and phenoxybenzamine (10 mug/ml) had little or no effect on response to adenosine, ATP and adenine. PIT (21 mug/ml) potentiated responses to adenosine, ATP and adenine by an unexplained mechanism.4 Caffeine (25 mug/ml) partially relaxed the trachea and inhibited spasmolytic responses to both adenosine and ATP, but not to adenine, isoprenaline, aminophylline or prostaglandin E(2) (PGE(2)).5 A number of compounds related to caffeine (xanthine, hypoxanthine, theophylline and theobromine) were tested for adenosine antagonist activity. Xanthine (300 mug/ml) and hypoxanthine (300 mug/ml) did not relax the trachea or antagonize spasmolytic responses to adenosine. Both theophylline (10 mug/ml) and theobromine (30 mug/ml) partially relaxed the trachea; theophylline, but not theobromine, antagonized spasmolytic responses to adenosine.6 pA(2) values for caffeine and theophylline as antagonists of adenosine were 4.3 and 4.7 respectively. However, the slopes of the Schild plot regressions were significantly less than 1.0 for both compounds.7 Four compounds, adenine, AH 8883, M30966 and ICI 63197, which like caffeine and theophylline, have phosphodiesterase inhibitory activity were tested for adenosine antagonist activity in the trachea. Adenine and AH 8883 had no effect and M30966 and ICI 63197 caused significant potentiation.8 The effects of caffeine and theophylline were also investigated on the non-adrenergic inhibitory response to nerve stimulation (NAIR). Both caffeine (100 mug/ml, n = 4) and theophylline (30 mug/ml, n = 4) enhanced the NAIR (20 Hz) while virtually abolishing matched responses to exogenous adenosine.9 The results support the existence of adenosine receptors in the guinea-pig trachea.
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PMID:Purine antagonists in the identification of adenosine-receptors in guinea-pig trachea and the role of purines in non-adrenergic inhibitory neurotransmission. 624 33

The effects of a chronic 14-day administration of a selective beta2-adrenergic-receptor antagonist (ICI-118551) on skeletal muscle were evaluated in female Sprague-Dawley rats. Chronic ICI-118551 treatment did not modify muscle mass, oxidative potential, or protein concentration of the medial gastrocnemius muscle, suggesting that maintenance of these skeletal muscle characteristics is not dependent on beta2-adrenergic-receptor stimulation. However, the drug treatment increased beta-adrenergic-receptor density of the lateral gastrocnemius (42%) and caused an increase in specific (g/g) isometric in situ contractile forces of the medial gastrocnemius [twitch, 56%; tetanic (200 Hz), 28%]. The elevated contractile forces observed after a chronic treatment with ICI-118551 were completely abolished when the beta2-adrenergic antagonist was also administered acutely before measurement of contractile forces, suggesting that this response is beta2-adrenergic-receptor dependent. Possible mechanisms for the increased forces were studied. Caffeine administration potentiated twitch forces but had little effect on tetanic force in control animals. Administration of dibutyryl adenosine 3',5'-cyclic monophosphate in control animals also resulted in small increases of twitch force but did not modify tetanic forces. We conclude that increases in beta-adrenergic-receptor density and the stimulation of the receptors by endogenous catecholamines appear to be responsible for increased contractile forces but that the mechanism remains to be demonstrated.
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PMID:Chronic beta-blockade increases skeletal muscle beta-adrenergic-receptor density and enhances contractile force. 926 41

The clinical observation that coronary heart disease is more common in men and postmenopausal women than in premenopausal women has suggested cardiovascular protective effects of female sex hormones including hormone-mediated coronary vasodilation. We investigated whether the sex hormones induced coronary relaxation is due to a decrease in [Ca(2+)](i) as measured in single coronary smooth muscle cells isolated from gonadectomized male and female pigs. In the presence of external Ca(2+), prostaglandin F(2alpha) (PGF(2alpha); 10(-5) M) and membrane depolarization by 51 mM KCl caused significant cell contraction and maintained increase in [Ca(2+)](i) to 297 +/- 4 and 341 +/- 20 nM, respectively. At 10(-9) to 6 x 10(-7) M, 17beta-estradiol, progesterone, and testosterone caused inhibition of PGF(2alpha)- and KCl-induced contraction and [Ca(2+)](i) with 17beta-estradiol being most effective. 17alpha-Estradiol did not affect PGF(2alpha)-induced contraction, and the inhibition of PGF(2alpha) contraction by 17beta-estradiol, progesterone, or testosterone was abolished by tamoxifen and ICI 182, 780, RU-486, or flutamide, respectively. 17beta-Estradiol caused similar inhibition of PGF(2alpha)- and KCl-induced contraction and [Ca(2+)](i). Progesterone and testosterone caused greater inhibition of PGF(2alpha)-induced cell contraction and [Ca(2+)](i) compared with the KCl responses. In Ca(2+)-free (2 mM EGTA) solution, caffeine (10 mM) and carbachol (10(-5) M), which activate Ca(2+) release from intracellular stores, caused small cell contraction and transiently increased [Ca(2+)](i) to 256 +/- 53 and 262 +/- 32 nM, respectively. Sex hormones did not significantly affect caffeine- or carbachol-induced contraction or [Ca(2+)](i). Thus, 17beta-estradiol, progesterone, and testosterone cause relaxation of coronary smooth muscle cells and decrease [Ca(2+)](i) mainly by inhibiting Ca(2+) entry from extracellular space but not Ca(2+) release from intracellular stores. The differences in potency of sex hormones in reducing cell contraction and [Ca(2+)](i) suggest differences in the sensitivity of the PGF(2alpha)- and depolarization-activated Ca(2+) entry pathways to inhibition by sex hormones.
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PMID:Decreased [Ca(2+)](i) during inhibition of coronary smooth muscle contraction by 17beta-estradiol, progesterone, and testosterone. 1049 Aug 85

The mechanisms regulating leptin secretion were investigated in isolated rat white adipocytes. Insulin (1-100 nM) linearly stimulated leptin secretion from incubated adipocytes for at least 2 h. The adrenergic agonists norepinephrine, isoproterenol (two nonselective beta-agonists), or CL-316243 (potent beta3) all inhibited insulin (10 nM)-stimulated leptin release. The inhibitory effects of norepinephrine and isoproterenol could be reversed not only by the nonselective antagonist propranolol but also by the selective antagonists ICI-89406 (beta1) or ICI-118551 (beta2), the beta2-antagonist being less effective than the beta1. Insulin-stimulated leptin secretion could also be inhibited by a series of agents increasing intracellular cAMP levels, such as lipolytic hormones (ACTH and thyrotropin-stimulating hormone), various nonhydrolyzable cAMP analogs, pertussis toxin, forskolin, methylxanthines (caffeine, theophylline, IBMX), and specific inhibitors of phosphodiesterase III (imazodan, milrinone, and amrinone). Significantly, antilipolytic agents other than insulin (adenosine, nicotinic acid, acipimox, and orthovanadate) did not mimic the acute stimulatory effects of insulin on leptin secretion under these conditions. We conclude that norepinephrine specifically inhibits insulin-stimulated leptin secretion not only via the low-affinity beta3-adrenoceptors but also via the high-affinity beta1/beta2-adrenoceptors. Moreover, it is suggested that 1) activation of phosphodiesterase III by insulin represents an important metabolic step in stimulation of leptin secretion, and 2) lipolytic hormones competitively counterregulate the stimulatory effects of insulin by activating the adenylate cyclase system.
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PMID:Mechanisms of leptin secretion from white adipocytes. 1205 93

We have investigated the intracellular signaling mechanisms underlying the release of nitric oxide (NO) evoked by beta-adrenoceptor (AR) agonists in urinary bladder strips and cultured bladder urothelial cells from adult rats. Reverse transcription-PCR revealed that inducible NO synthase and endothelial NOS but not neuronal NOS genes were expressed in urothelial cells. NO release from both urothelial cells and bladder strips was decreased (37-42%) in the absence of extracellular Ca2+ (100 microm EGTA) and was ablated after incubation with BAPTA-AM (5 microm) or caffeine (10 mm), indicating that the NO production is mediated in part by intracellular calcium stores. NO release was reduced (18-24%) by nifedipine (10 microm) and potentiated (29-32%) by incubation with the Ca2+ channel opener BAYK8644 (1-10 microm). In addition, beta-AR-evoked NO release (isoproterenol; dobutamine; terbutaline; 10(-9) to 10(-5) m) was blocked by the NOS inhibitors N(G)-nitro-L-arginine methyl ester (30 microm) or N(G)-monomethyl-L-arginine (50 microm), by beta-adrenoceptor antagonists (propranol, beta1/beta2; atenolol, beta1; ICI 118551; beta2; 100 microm), or by the calmodulin antagonist trifluoperazine (50 microm). Incubating cells with the nonhydrolyzable GTP analog GTPgammaS (1 microm) or the membrane-permeant cAMP analog dibutyryl-cAMP (10-100 microm) directly evoked NO release. Forskolin (10 microm) or the phosphodiesterase IBMX (50 microm) enhanced (39-42%) agonist-evoked NO release. These results indicate that beta-adrenoceptor stimulation activates the adenylate cyclase pathway in bladder epithelial cells and initiates an increase in intracellular Ca2+ that triggers NO production and release. These findings are considered in light of recent reports that urothelial cells may exhibit a number of "neuron-like" properties, including the expression of receptors/ion channels similar to those found in sensory neurons.
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PMID:Beta-adrenoceptor agonists stimulate endothelial nitric oxide synthase in rat urinary bladder urothelial cells. 1222 60

1. The selective oestrogen (ER) receptor modulator, raloxifene, is widely used in the treatment of postmenopausal osteoporosis, but may also possess cardioprotective properties. We investigated whether it directly suppresses myocyte contractility through Ca(2+) channel antagonism in a similar way to 17beta-oestradiol. 2. Cell shortening and Ca(2+) transients were measured in single guinea-pig ventricular myocytes field-stimulated (1 Hz, 37 degrees C) in a superfusion chamber. Electrophysiological recordings were performed using single electrode voltage-clamp. 3. Raloxifene decreased cell shortening (EC(50) 2.4 microm) and the Ca(2+) transient amplitude (EC(50) 6.4 microm) in a concentration-dependent manner. At a concentration of 1 microm, raloxifene produced a 33+/-2% (mean+/-s.e.m) and 24+/-2% reduction, respectively (P<0.001, n=14 for both parameters). 4. These inhibitory actions were not observed in myocytes that had been incubated with the specific antagonist, ICI 182,780 (10 microm) (n=11). 5. Raloxifene (1 microm) shortened action potential durations at 50 and 90% repolarisation (P<0.05 and <0.001, respectively; n=27) and decreased peak L-type Ca(2+) current by 45%, from -5.1+/-0.5 pA/pF to -2.8+/-0.3 pA/pF (P<0.001, n=18). 6. Raloxifene did not significantly alter sarcoplasmic reticulum Ca(2+) content, as assessed by integrating the Na(+)/Ca(2+) exchanger currents following rapid caffeine application. 7. The present study provides evidence for direct inhibitory actions of raloxifene on ventricular myocyte contractility, mediated through Ca(2+) channel antagonism.
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PMID:Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L-type calcium current. 1502 59

The present study characterises the vasorelaxant response to raloxifene in isolated rings of porcine coronary artery. Tissues precontracted either with KCl (30 mM) or prostaglandin F(2alpha) (PGF(2alpha); 3 microM) were concentration-dependently relaxed by raloxifene (0.1-10 microM). Relaxation was not inhibited by the estrogen receptor antagonist 7alpha-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17beta-diol (ICI 182,780; 1 microM). Preincubation with raloxifene (1-3 microM) caused an inhibition of the KCl or PGF(2alpha)-induced contraction. The effects of raloxifene were independent of the endothelium. The relaxant response to raloxifene was slow in the onset and could not be reversed after repeated washings. Raloxifene did not affect Ca(2+) release from intracellular stores since it failed to inhibit a transient contraction induced by caffeine (10 mM). Raloxifene-induced relaxation was not influenced by the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM; 10-20 microM). Calcium-induced contractions in Ca(2+)-free high K(+) (60 mM) depolarising medium were concentration-dependently inhibited by raloxifene (0.3-3 microM). If arterial rings were incubated with the L-type Ca(2+) channel activator (S)-(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridine carboxylic acid methyl ester ((S)-(-)-Bay K 8644; 0.1 microM), cumulative concentration-response curves to Ca(2+) were shifted to the left. Raloxifene (0.3-3 microM) inhibited the effect of (S)-(-)-Bay K 8644 in a concentration-dependent manner. 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB 203580; 10 microM), an inhibitor of p38 mitogen-activated protein kinase (MAPK), diminished raloxifene-induced relaxation in endothelium-denuded arterial rings. Western blot analysis demonstrated that raloxifene stimulated p38 MAPK. It is concluded that raloxifene has an inhibitory effect on voltage-gated and receptor-operated L-type Ca(2+) channels in porcine coronary arteries, thus inducing vascular relaxation independent of the endothelium. p38 MAPK is, at least in part, involved in the relaxant response to raloxifene.
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PMID:Characterisation of the relaxant response to raloxifene in porcine coronary arteries. 1685 68


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