Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bisoprolol, (+/-)1-(4-[(2-isopropoxyethoxy)-methyl]-phenoxy)-3-isopropyl-amino -2- propanol-hemifumarate, is a new, highly selective beta 1-adrenoceptor blocking agent without intrinsic sympathomimetic activity and low to moderate local anaesthetic activity. As demonstrated in binding experiments, and in classical pharmacological studies using rats, guinea pigs, cats, and dogs, bisoprolol markedly differentiated between beta 1-adrenoceptors of the heart, or the renal juxtaglomerular apparatus, and the beta 2-subtype in arterial blood vessels, bronchi, liver, or skeletal muscle. Up to concentrations nearly 100-fold higher than the therapeutic plasma levels in humans, bisoprolol did not affect the functional refractory period of the heart, and was devoid of a direct suppressive effect on myocardial contractility and of calcium antagonistic properties in heart and vascular muscle. The pattern of haemodynamic effects of bisoprolol was typical of beta-blockers and included decreases in blood pressure (BP), heart rate (HR), and cardiac output, concomitant with an increase in calculated total peripheral resistance. In contrast to other beta-blockers, bisoprolol increased renal blood flow in anaesthetized dogs. Bisoprolol lowered BP in hypertensive dogs and rats, attenuated the development of spontaneous hypertension in rats, decreased plasma renin activity and protected the heart from the sequelae of transient ischemia. It did not block presynaptic beta-adrenoceptors in blood vessels. Serum lipids and the serum lipoprotein profile remained unaltered after bisoprolol. Bisoprolol was devoid of affinity for autonomic receptors other than beta-adrenoceptors or for autacoid receptors. This is probably one of the reasons why bisoprolol did not affect the function of the central nervous, respiratory, and gastrointestinal systems in an obvious way. The high beta 1-selectivity of bisoprolol is linked with extremely favourable pharmacokinetic properties. These include nearly complete enteral absorption and virtual absence of liver first-pass metabolism, both resulting in high bioavailability, long plasma half-life, pharmacokinetics that are linear over a wide dose range and independent of age, food intake and hydroxylator status, low plasma protein binding, and a 1:1 ratio of hepatic metabolization to renal elimination of the unaltered substance. This sum of favourable pharmacological and pharmacokinetic properties characterize bisoprolol as an optimized beta-blocker.
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PMID:High beta 1-selectivity and favourable pharmacokinetics as the outstanding properties of bisoprolol. 243 93

The acute hemodynamic responses to beta-adrenoceptor blockade with the beta 1-selective antagonist metoprolol, and to combined alpha/beta-receptor blockade with labetalol, were compared intraindividually in a randomized single-blind, cross-over study. Fourteen patients with proved ischemic heart disease, aged 52-64 years, were studied at rest (supine) and during ischemia-inducing exercise (in the seated posture) using invasive percutaneous techniques. Metoprolol reduced heart rates and cardiac output greatly (p less than 0.001) and systemic arterial pressures slightly (p less than 0.001) under all conditions. Left ventricular filling pressures increased. Labetalol induced a slight decrease in heart rates during exercise, while cardiac output was unchanged. Systemic arterial pressures and vascular resistances, pressures and resistances in the pulmonary circulation, and left ventricular filling pressures were distinctly lower. During ischemia-inducing exercise, the differences between the effects of labetalol and metoprolol on heart rate, cardiac output, systemic vascular resistance, and left ventricular filling pressures were highly significant. The effects on the rate X pressure product and on angina were similar. It is concluded that combined alpha/beta-blockade with labetalol offsets or attenuates the potential adverse hemodynamic effects of beta-receptor blockade alone without loss of symptomatic efficacy.
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PMID:Hemodynamic effects at rest and during exercise of combined alpha/beta-receptor blockade and of beta-receptor blockade alone in patients with ischemic heart disease. 244 2

The calcium antagonists protect the myocardium against the deleterious effects of ischemia and postischemic reperfusion provided that they are used prophylactically. This requires chronic therapy. Experiments were undertaken to establish whether chronic verapamil therapy alters the cardiac noradrenaline reserves or provokes a change in beta 1 adrenoceptor density. Sprague-Dawley (SD) rats were fed a diet containing placebo, or placebo plus dl verapamil (V) to provide plasma V levels of around 100 ng/ml. After 6 weeks of therapy the hearts were excised and assayed for noradrenaline (NA), adrenaline (A), and dopamine (DA) using high performance liquid chromatography. In addition, cardiac membranes were isolated in the presence of Tris, 10 mM MgCl2 and 9 microM phenylmethylsulfoxylfluoride and assayed for beta 1 adrenoceptor density (Bmax) and affinity (KD), using [3H]dihydroalprenolol as the ligand. Three days of therapy reduced left ventricular NA by 45%. Asymptote was reached within 11 days, when the NA content has decreased (p less than 0.001) to only 0.9 +/- 0.1 mu/g dry wt, mean +/- SEM, n = 6. The tissue level of DA was also reduced from 0.14 +/- 0.02 to 0.08 +/- 0.01 microgram/g dry weight (p less than 0.02). Further treatment for up to 6 weeks caused no further change in NA, A, or DA. Even after 6 weeks of therapy the density (35.5 +/- 1.9 before and 31.2 +/- 2.3 fmol/mg protein after therapy) and affinity (0.24 +/- 0.02 and 0.21 +/- 0.02 nM) of the beta 1 adrenoceptors were unchanged. These results show that although chronic verapamil therapy depletes the cardiac reserves of NA, beta-adrenoceptor density remains constant.
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PMID:Chronic calcium antagonist therapy: some unexpected results. 246 14

Symptom-limited exercise testing (SLET) makes it possible to appraise in a reproducible manner both the extent of ischemia and the circulatory profile. Therefore, repeated SLET with either one or another drug, or a combination of both allows a proper comparison and avoids the quite impractical trials lasting several weeks, far too complicated in the case of combination of drugs. From the knowledge of the components of myocardial oxygen demand and of the pharmacological properties of different drugs, it is easy to predict what combinations will be complementary, harmful, or redundant. The application of these principles to the individual patient is made easier by the determination of the circulatory profile and of the severity of ischemia. From that, the logical proposal for whichever combination is obvious. The more effective and less costly combination appears to be the association of beta 1-selective blockers and preventive sublingual nitroglycerin. beta-Blockers and nifedipine and diltiazem and molsidomine are also effective and well tolerated.
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PMID:Mono- or combination therapy for stable angina pectoris. 248 Nov 68

Celiprolol, a long-acting, beta 1-selective adrenergic blocking drug, with peripheral beta 2-stimulatory and peripheral alpha 2-inhibitory action, has a unique pharmacologic profile. Its antianginal properties have been evaluated in comparison with those of propranolol and atenolol. Efficacy was assessed by improvement in time to exercise-limiting angina and to onset of ST-segment depression, as well as by symptomatic improvement. Celiprolol has been demonstrated to have antianginal and anti-ischemic effects comparable with both propranolol and atenolol, with a decreased incidence of bradycardia noted in the celiprolol-treated cohorts. No significant adverse effects or laboratory abnormalities were noted in these cohorts. Current indications for beta-blocker therapy are numerous. Cardioprotective effects and reduction in ischemic potential have been identified in a variety of clinical settings. Decreased morbidity and mortality in the postinfarct period have been well documented. Effects on supraventricular and ventricular arrhythmias, in the presence or absence of ischemia, are well known. Favorable hemodynamic effects in the peri- and postoperative period of coronary artery bypass surgery are described. More recently, beta-blocker therapy that is effective against angina has also been demonstrated effective in the reduction of silent ischemia. The different hemodynamic properties of the newer beta-blockers may provide additional therapeutic effects in many clinical situations.
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PMID:Clinical performance and therapeutic potential of celiprolol in angina pectoris. 248 91

Transient cerebral ischemia results in selective neuronal cell death. The mechanisms underlying this selective vulnerability to ischemia are only beginning to be elucidated. We studied the effect of ischemia on alpha 1-adrenergic receptor binding by measuring [3H]prazosin binding in gerbil forebrain membranes after 10 min of bilateral carotid occlusion. Binding was reduced from 62 +/- 3 to 33 +/- 4 fmol/mg protein. Binding in the same membranes to beta 2-adrenergic receptors were also decreased, but not to the extent of that to alpha 1-adrenergic receptors. Binding to muscarinic cholinergic [( 3H]quinuclydil benzilate) and beta 1-adrenergic receptors were only slightly depressed. Surprisingly, the protein content was significantly increased in the membrane fraction studied from ischemic forebrain (68 +/- 4 mg/g wet weight) compared with sham operated controls (57 +/- 4). The dramatic decrease in alpha 1-adrenergic receptor binding during ischemia is consistent with receptor binding studies of membranes pretreated with phospholipase A2 in vitro. It is not clear what effect this change in alpha 1-adrenergic receptor binding has on subsequent selective neuronal death. The recent demonstration that catecholamines and locus ceruleus neurons influence the loss of CA1 neurons in the hippocampus suggests that it may play an important modulatory role.
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PMID:Rapid reduction in [3H]prazosin binding to gerbil forebrain membranes during bilateral common carotid artery occlusion. 254 Nov 47

1) The primary receptor mechanism of catecholamine-induced myocardial potassium uptake is beta 1-adrenoceptor stimulation. Thus, K+ uptake seems to be a general effect of beta-adrenergic stimulation, dominated by beta 1-receptors in heart and by beta 2-receptors in skeletal muscle according to subtype preponderance in either tissue. In the myocardium there is also an effect of alpha 1-adrenoceptor stimulation which causes a significantly smaller uptake and requires higher catecholamine concentrations. 2) Both humoral and nervous adrenergic stimulation of the heart induce a significant potassium uptake which transiently reduces coronary sinus K+ concentration. It is likely that these changes affect cardiac functioning in vivo. During intense endogenous sympathetic activity and by high dose pharmacological interventions, the magnitude of change in coronary sinus concentration suggests that the reduction in extracellular K+ within the myocardium could be up to 1 mM. Under vulnerable conditions like hypokalemia and localized ischemia such changes might contribute to the risk for malignant arrhythmias. 3) Presumably net myocardial K+ accumulation is accompanied by a reciprocal reduction of intracellular Na+ concentration, which tends to reduce myocardial contractility and contribute to impaired cardiac function after a period of strong adrenergic stimulation. In vivo the negative inotropic effect could not be detected as long as catecholamines were supplied, but it occurred after stimulation was stopped. 4) In the intact beating heart beta-adrenergic stimulation increases Na,K-pumping 2.5 fold, from 15% of the maximum possible pump rate in control to 40% of maximum at high inotropy. These findings imply the presence of a substantial spare Na,K-pump capacity of the non-ischemic myocardium, even during intense sympathetic activity. Comparison of changes in pump rate and accumulated ionic shifts indicates that catecholamine-induced stimulation of Na,K-ATPase might be due to increased sensitivity for intracellular sodium.
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PMID:Myocardial potassium balance during adrenergic stimulation. 254 22

Pharmacologic intervention is critical to the management of myocardial ischemia. Four classes of drugs are now used in therapeutic regimens for ischemia. beta-Adrenergic blockers decrease ischemia by blocking beta 1-mediated inotropic and chronotropic effects, thereby decreasing myocardial oxygen consumption. Calcium channel blockers alter fast- and slow-response action potentials by decreasing transmembrane calcium flux, resulting in decreased conduction velocity and heart rate and prolonged effective refractory period. These effects positively influence ischemia and atrial dysrhythmias. Additionally, these agents decrease excitation-contraction coupling in vascular smooth muscle, resulting in coronary and peripheral vasodilation. Organic nitrates and nitrites decrease vascular smooth muscle contraction and preload, and afterload, precipitating a decrease in myocardial oxygen consumption and ischemia. They also improve blood flow to areas of compromised flow. Thrombolytic agents are administered in acute situations to dissolve the occluding thrombus, but they must be used within a few hours of the injury. These drugs activate the conversion of plasminogen to plasmin, which breaks down the clot into fibrin degradation products. The choice of agents is determined by the etiology of the patient's ischemia, his or her response to the drug, and the presence of concomitant disease processes.
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PMID:Pharmacologic management of myocardial ischemia. 257 Jan 35

In man a close interrelationship exists between hyperadrenergic states, myocardial ischemia, necrosis, infarction and sudden cardiac death. Persistent high catecholamine levels may also be associated with increased vascular endothelial turnover and permeability to calcium and lipoproteins, increased blood velocity, abnormal blood flow patterns and atheroma formation. There are thus good reasons to predict a cardiovascular protective effect of beta-blockers. Animal data indicate that in spite of apparently adverse plasma lipoprotein changes beta-blockers retard atheromatous plaque formation under conditions of high cholesterol diet with or without stress. A slow heart rate, as well as a reduction in calcium influx and inhibition of both esterification of arterial wall cholesterol (by ACAT) and endothelial permeability to lipoproteins, may be central to this process. Beta-blockers benefit a spectrum of conditions related to the atheromatous process and myocardial necrosis. These are silent ischemia; stable (including mixed), unstable and preinfarction angina; periinfarction events (including myocardial rupture and dissection of the ascending aorta); and myocardial necrosis associated with stress conditions such as head injuries and subarachnoid hemorrhage. In one study coronary deaths in hypertensive men, particularly in smokers, were significantly reduced by metoprolol (a beta 1-selective blocker) compared to a diuretic. In contrast in the MRC study of mild hypertension only nonsmoking men with mild to moderate hypertension who received a nonselective beta-blocker appeared to experience fewer myocardial infarctions. Recent clinical data showed that moderate-severe hypertensives who were optimally controlled by atenolol-based treatment over a 10-year period were less likely to die from myocardial infarction than those suboptimally controlled, irrespective of a rise in serum triglyceride levels. Thus the net effect of acute beta-blockade in hyperadrenergic states, including myocardial infarction, is to limit cardiovascular damage. Chronic beta-blockade inhibits atheroma formation (in animals) and beneficially modifies the incidence of stroke and myocardial infarction, which in man are the long-term consequences of hypertension.
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PMID:The beta-receptor, atheroma and cardiovascular damage. 257 Apr 26

Extended (72-hour) ambulatory electrocardiographic monitoring was used to enable time series analysis of heart rate and asymptomatic ST-segment depression in 9 patients with severe coronary artery disease. The effects of beta 1-adrenergic blockade with optimal dose metoprolol were then assessed. Data were analyzed using Fourier transformation, autocorrelation and cross-correlation to examine possible coupling between heart rate and ischemic electrocardiographic changes. A marked circadian pattern was observed for both heart rate and ambulatory myocardial ischemia, with a period of approximately 24 hours by both Fourier and autocorrelation methods. Cross-correlation revealed heart rate and ischemia to be tightly coupled with a lag of 0 hours during placebo. During beta 1 adrenergic blockade the marked circadian variation in heart rate was diminished, although some periodicity in the 24-hour region remained. Ambulatory ischemia was also markedly diminished during beta 1-adrenergic blockade; however, some residual ischemia remained that was characterized by a peak spectral activity shifted to a period of 5 to 7 hours. Heart rate and ischemia were not coupled during beta 1-adrenergic blockade, as evidenced by lack of significant cross-correlation. Thus, time series analysis suggests close coupling between the variation in heart rate and ambulatory ischemia in patients with severe coronary artery disease. Beta 1-adrenergic blockade can markedly alter the periodic characteristics of and coupling between heart rate and ischemia. Ischemia remaining during beta 1-adrenergic blockade may have different spectral characteristics than that predominating during placebo administration. These differences may be manifestations of the heterogenous pathophysiologic mechanisms responsible for ambulatory ischemia and may have therapeutic implications.
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PMID:Influence of beta-adrenergic blockade defined by time series analysis on circadian variation of heart rate and ambulatory myocardial ischemia. 280 49


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