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

Acute occlusions of the left circumflex coronary artery were performed in open-chest dogs. A control group (n = 19) was compared with three groups (total n = 17) pretreated once daily with different doses of the cardioselective beta-blocking drug atenolol (ICI 66 082) given by mouth for 5 days. Only animals without coronary collateral vessels were examined, having a mortality rate of 100% in the control group. Arrhythmias and ventricular fibrillation during the first 30 min after coronary occlusion showed a biphasic distribution in time (phase 1a and 1b). A lower degree of beta-adrenoceptor blockade reduced the incidence of arrhythmias and ventricular fibrillation in phase 1a, but fibrillation occurred in all animals during phase 1b. A higher dose of the beta-blocking drug protected the animals from ventricular fibrillation, and arrhythmias in phase 1a were greatly reduced. At all times the ventricular fibrillation threshold in the group pretreated with atenolol was significantly higher than in the control group. In both groups a significant decrease in ventricular fibrillation threshold was found only during phase 1a. The greater sensitivity of phase 1a arrhythmias to beta-blockade and the lack of a decrease in ventricular fibrillation threshold during phase 1b might indicate differences in the genesis of arrhythmias and fibrillation in phases 1a and 1b.
Cardiovasc Res 1979 Oct
PMID:Prophylaxis of ventricular fibrillation after acute experimental coronary occlusion by chronic beta-adrenoceptor blockade with atenolol. 51 61

The present study investigated the effects of celiprolol a novel beta 1-antagonist with partial beta 2-agonist activity on the human failing heart. Experiments were performed on isolated electrically driven atrial and ventricular cardiac preparations and in membrane preparations from the left ventricles of nine patients (four with dilated cardiomyopathy; five with ischemic cardiomyopathy) undergoing cardiac transplantation for terminal heart failure. Celiprolol produced a negative inotropic effect in atrial and ventricular heart muscle. However, in the presence of forskolin--which activates the catalyst of the adenylate cyclase-or the cAMP phosphodiesterase inhibitor milrinone, celiprolol produced concentration-dependent positive inotropic effects and positive lusitropic effects. Experiments with the beta 1-and beta 2-selective antagonists CGP 207.12A and ICI 118.551, respectively, suggest that the positive inotropic response is mediated by beta 2-adrenoceptors. In radioligand binding experiments, a selectivity of 15.7 [-Gpp(NH)p] or 23.9 [+Gpp(NH)p] as judged from the Ki values--of binding to beta 2-adrenoceptors was measured in the failing human ventricular myocardium. Competition curves with celiprolol alone and in the presence of the guanine nucleotide Gpp(NH)p revealed no evidence for agonist activity at beta 1- or beta 2-adrenoceptors. It is concluded that amplification of the cAMP response is able to unmask partial agonist activity of celiprolol in the failing human heart at beta 2-adrenoceptors. The inotropic measurements are a more sensitive approach than radioligand binding studies. Whether the pharmacological profile of celiprolol will be useful in conditions like heart failure is questionable with respect to the potential downregulation of beta 2-adrenoceptors by its partial agonist activity.
J Cardiovasc Pharmacol 1992 Sep
PMID:Positive inotropic effects due to partial agonistic activity of the beta-adrenoceptor antagonist celiprolol following amplification of cAMP formation in failing human myocardium. 127 96

The role of beta 1-adrenoceptors in mediation of vasodilatation is not clear. The microsphere technique was used to compare the effects of mixed beta-, beta 1-, and beta 2-stimulation on blood flow and conductance changes in five groups of pentobarbital-anesthetized rats: I, vehicle; II, mixed beta-stimulation; III, beta 1-stimulation; IV, beta 2-stimulation; and V, mixed beta-blockade. Isoproterenol (32 ng/kg/min) was infused into rats either without (group II) or with ICI 118,551 (beta 2-blocker, 30 micrograms/kg, group III), atenolol (beta 1-blocker, 100 micrograms/kg, group IV), or both blockers (group V), respectively. At the doses selected, ICI 118,551 shifted the dose-vasodepressor response curve of salbutamol (beta 2-agonist) to the right but had no effect on the dose-chronotropic response curve of dobutamine (beta 1-agonist), whereas atenolol shifted the dose-chronotropic response curve of dobutamine to the right and had no effect on the dose-vasodepressor response curve of salbutamol. The results show that isoproterenol increased heart rate (HR) and arterial conductances in the coronary and skeletal muscle beds but had no effects in other beds. Combined with ICI 118,551, isoproterenol caused similar increases in HR and coronary arterial conductance but markedly less increase in skeletal muscle conductance. Atenolol abolished the increase in HR by isoproterenol but did not affect the increases in coronary and muscular arterial conductances. With both blockers, isoproterenol produced no increase in coronary and skeletal muscle conductance. Therefore, both beta 1- and beta 2-adrenoceptors play a role in coronary and skeletal muscle vasodilatation.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1990 May
PMID:Effects of beta 1- and beta 2-adrenoceptor stimulation on hemodynamics in the anesthetized rat. 169 31

The beta-adrenoceptor antagonist pindolol [10-1,000 micrograms/kg subcutaneously (s.c.)] caused dose-related decreases in mean arterial pressure (MAP) and increased heart rate (HR) in conscious spontaneously hypertensive rats (SHR). The lowest dose of pindolol (10 micrograms/kg) decreased MAP by 25 mm Hg (-16%) without affecting plasma norepinephrine (NE) or plasma renin concentration (PRC). However, higher doses of pindolol elicited dose-related increases in plasma NE concentration and PRC. Plasma epinephrine concentration was not altered by pindolol. The selective beta 2-adrenoceptor antagonist ICI 118,551 (3 mg/kg, s.c.) prevented the tachycardia but not the increase in PRC caused by 100 micrograms/kg pindolol. Treatment with ICI 118,551 completely eliminated the 45% increase in plasma NE elicited by 100 micrograms/kg of pindolol even though the decrease in MAP caused by this dose of pindolol was the same in the presence (-33 mm Hg) and absence (-34 mm Hg) of beta 2-adrenoceptor blockade. These results indicate that the vasodepressor action of pindolol in SHR does not result from an agonistic effect at postjunctional beta 2-adrenoceptors in the vasculature. In addition, the increases in plasma NE concentration produced by pindolol result from stimulation of beta 2-adrenoceptors. These beta 2-adrenoceptors may be located prejunctionally on sympathetic neurons.
J Cardiovasc Pharmacol 1990 Sep
PMID:Pindolol increases plasma norepinephrine concentration by stimulation of beta 2-adrenoceptors in conscious spontaneously hypertensive rats. 170 Feb 4

Peak III phosphodiesterase (PDE) inhibitors have combined positive inotropic and vasodilator effects. We studied 10 patients with chronic heart failure during and after infusion of intravenous (i.v.) ICI 153,110, an investigational peak III PDE inhibitor. Maximum hemodynamic response for the group occurred after cessation of infusion at a lower plasma drug concentration. At maximum hemodynamic response, cardiac index (CI) increased (2.4 +/- 0.5 vs. 3.2 +/- 0.37 L/min/m2, p less than 0.05) with a decrease in mean arterial pressure (MAP 91 +/- 5 vs. 80 +/- 3 mm Hg, p less than 0.05), pulmonary capillary wedge pressure (PCWP 25 +/- 2 vs. 17 +/- 3.1 mm Hg, p less than 0.01), systemic vascular resistance (SVR 1,422 +/- 106 vs. 983 +/- 97 dynes.s.cm-5, p less than 0.05) and pulmonary vascular resistance (PVR 227 +/- 39 vs. 16 +/- 31 dynes.s.cm-5, p less than 0.05). During the infusion, plasma renin activity (PRA) decreased from 6.34 +/- 2.53 to 3.6 +/- 3 ng/ml/h (NS). The five patients with high baseline PRA had a significant decrease (11.2 +/- 2.5 vs. 5.4 +/- 1.67 ng/ml/h, p less than 0.01) that preceded changes in CI and SVR by 1-2 h. These data suggest that reduction in PRA may have contributed to the hemodynamic effects of this peak III PDE inhibitor.
J Cardiovasc Pharmacol 1990 Sep
PMID:Acute neurohormonal and hemodynamic response to a new peak III phosphodiesterase inhibitor (ICI 153,110) in patients with chronic heart failure. 170 Feb 5

Guinea pig papillary muscles were preincubated in the presence of 5 x 10(-9) mol/L unlabeled noradrenaline or adrenaline then incubated with (3H)-noradrenaline and superfused. Electrical field stimulation with 180 pulses delivered at 1 or 3 Hz was used to induce overflow of radioactivity. Comparison of the effects of preexposure of the tissue to adrenaline or noradrenaline revealed that adrenaline incubation caused an enhancement of stimulation-evoked overflow of (3H)noradrenaline and a reduction of the effect of exogenously added isoprenaline. Furthermore, the selective beta 2-adrenoceptor antagonist ICI 118,551 (10(-7) mol/L), but not the selective beta 1-adrenoceptor antagonist ICI 89,406 (10(-7) mol/L), reduced electrically evoked overflow of (3H)noradrenaline in tissue preincubated with adrenaline but not in tissue preincubated with noradrenaline. The overflow-reducing effect of ICI 118.551 occurred at stimulation with 3 Hz but not at stimulation with 1 Hz. The present results support the hypothesis that noradrenergic transmission in guinea pig papillary muscle is facilitated via beta 2-adrenoceptors, and that adrenaline may serve as transmitter in this positive feedback mechanism after its incorporation into sympathetic nerves.
J Cardiovasc Pharmacol 1991 Feb
PMID:Presynaptic beta-adrenoceptors in guinea pig papillary muscle: evidence for adrenaline-mediated positive feedback on noradrenergic transmission. 170 30

The present study was undertaken to investigate the effects of endothelin (ET) isopeptides on the pulmonary vascular bed of the intact, spontaneously breathing cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by intralobar infusion of U46619, intralobar bolus injections of ET-1 (1 micrograms), ET-2 (1 micrograms), and ET-3 (3 micrograms) produced marked reductions in pulmonary and systemic vascular resistances. The pulmonary vasodilator response to each ET isopeptide was not altered by atropine (1 mg/kg i.v.), indomethacin (2.5 mg/kg i.v.), or ICI 118551 (1 mg/kg i.v.), but was significantly inhibited by an intra-arterial (i.a.) infusion of glybenclamide at 5 mg/kg. This dose of glybenclamide significantly inhibited the decrease in lobar arterial and systemic arterial pressures in response to intralobar injection of pinacidil (30 and 100 micrograms), whereas the pulmonary vasodilator responses to acetylcholine (0.03 and 0.1 micrograms) and prostaglandin I2 (0.1 and 0.3 micrograms) were not altered. The systemic vasodilator response to each ET isopeptide was not changed by glybenclamide or by the other blocking agents studied. The present data demonstrate for the first time that ET-1, ET-2, and ET-3 dilate the pulmonary vascular bed in vivo. The present data suggest that the pulmonary vasodilator response to ET isopeptides depends, in part, on activation of potassium channels and is mediated differently from the systemic vasodilator response to these substances. Contrary to earlier work, the present data indicate the pulmonary vascular response to ET isopeptides depends on the pre-existing level of pulmonary vasomotor tone. Furthermore, the present data suggest that in the lung ET-1, ET-2, and ET-3 may serve as endogenous agonists for potassium channels, a newly described vasodilator mechanism in the pulmonary vascular bed of intact adult animals.
J Cardiovasc Pharmacol 1991
PMID:Evidence for distinct endothelin receptors in the pulmonary vascular bed in vivo. 172 83

The selective alpha 1- and alpha 2-adrenoceptor agonists St 587 and BHT 933, respectively, and the antagonists prazosin (alpha 1) and WY 25309 (alpha 2) have been used in combination with the selective beta 2-adrenoceptor agonist pirbuterol, and the antagonists atenolol (beta 1) and ICI 118551 (beta 2), to analyse the effects of individual types of adrenoceptor stimulation in various parts of the rabbit heart. In the sinus node, beta 1-, but not beta 2-adrenoceptor stimulation increased the fast phase of depolarisation. Both beta 1- and beta 2-adrenoceptor stimulation increased the slope of the slow diastolic depolarisation, accelerated repolarisation, and increased maximum diastolic potential. Beta 1- and beta 2-adrenoceptor stimulation also accelerated repolarisation in Purkinje cells and papillary muscle. After blockade of both beta 1- and beta 2-adrenoceptors, alpha 1-adrenoceptor stimulation caused bradycardia, owing exclusively to delayed repolarisation. Alpha 2-adrenoceptor stimulation had no effect. Beta 1-, but not beta 2-adrenoceptor stimulation augmented peak contractions three- to fivefold, and reduced the time-to-peak tension. In contrast, alpha 1-adrenoceptor stimulation only moderately (up to 47%) increased peak tension, but increased time-to-peak and duration of contractions. The results would be consistent with beta 1-adrenoceptor stimulation increasing inward calcium current, and with stimulation of alpha 1-adrenoceptors delaying the decline of [Ca]i rather than increasing its magnitude. Both beta 1- and beta 2-stimulation increased repolarising current, but alpha 1-stimulation decreased it.
J Cardiovasc Pharmacol 1985
PMID:Cardiac electrophysiological effects of selective adrenoceptor stimulation and their possible roles in arrhythmias. 241 Jul 38

We characterized the beta-adrenoceptor subtype in isolated ring preparations of small intramyocardial flow-regulating (resistance) arteries (i.d. congruent to 239 micrometers) from rats by using beta 2 adrenoceptor agonists and beta-adrenoceptor antagonists exhibiting selectivity towards either beta 1- (pafenolol) or beta-adrenoceptors (ICI 118,551). The relative order of potency of selected agonists in producing beta-adrenoceptor-mediated relaxation of prostaglandin F2 alpha (10(-5) M) contracted coronary vessels was: isoprenaline greater than noradrenaline = adrenaline. ICI 118,551, but not pafenolol, relaxed coronary resistance vessels precontracted with prostaglandin F2 alpha (10(-5) M) or high potassium (125 mM) solutions. The IC50 values were 8.59 x 10(-6) M and 2.96 x 10(-5) M, respectively (p less than 0.0005). This indicates that ICI 118,551 had membrane-stabilizing effects. Both ICI 118,551 and pafenolol antagonized in a concentration-dependent manner the isoprenaline-induced relaxation of prostaglandin F2 alpha (10(-5) M) contracted coronary resistance vessels. The slopes and regression lines of the Schild plots were not significantly different from unity and the calculated pA2 values were 7.55 and 6.59 (p less than 0.005) for pafenolol and ICI 118,551, respectively. The results are compatible with the suggestion that beta-adrenoceptors mediating relaxation in rat coronary resistance vessels belong to the beta 1-adrenoceptor subtype.
J Cardiovasc Pharmacol
PMID:Characterization of beta-adrenoceptor subtype in isolated ring preparations of intramural rat coronary small arteries. 241 97

Pharmacological and radio-ligand binding studies have recently indicated the existence of beta 2-adrenoceptors in the human heart. Their physiological role, however, remains to be elucidated. The present study investigated in 17 normal, young volunteers the effect on resting left ventricular (LV) function of two types of beta-blockers; a predominant beta 1-adrenoceptor antagonist (atenolol, 50 mg once daily) and ICI 118,551 (20 mg t.i.d.), a new, predominant beta 2-antagonist. LV function was assessed using M-mode echocardiograms and systolic time intervals. Atenolol, ICI 118,551, and placebo were given according to a randomized, double-blind, cross-over protocol. As compared with placebo, both drugs caused a decrease in resting heart rate, but the reduction by ICI 118,551 was less pronounced. Systolic blood pressure was only reduced by atenolol 8 mm Hg on average. Cardiac output was decreased to the same extent following treatment with atenolol (-20%) as after ICI 118,551 (-17%). These decreases in cardiac output were related to the beta-blocker-induced bradycardia, since stroke volumes were not affected during either selective beta 1- or beta 2-blockade. In addition, all other echocardiographic variables reflecting LV pump function, such as fractional shortening, velocity of diameter change and of displacements, pre-ejection period, and the ratio of PEP/LVET, were not different from placebo. We conclude that in normal young subjects, global LV pump function is not affected by beta 1- or by beta 2-blockade, despite the negative chronotropic effect of both drugs.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol
PMID:Influence of beta 1- versus beta 2-adrenoceptor blockade on left ventricular function in humans. 242 84


1 2 3 4 5 6 7 8 9 Next >>