Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acute systemic hemodynamic effects of the calcium antagonist nisoldipine and the pyridazinone-derivative pimobendan, a phosphodiesterase inhibitor with vasodilating as well as positive inotropic properties, were studied in conscious pigs with chronic heart failure. Left ventricular (LV) dysfunction, manifested by a 25% decrease in cardiac output (CO), a 35% increase in systemic vascular resistance (SVR), and a doubling of the left ventricular filling pressure, was induced by a proximal ligation of the left circumflex coronary artery. Two to three weeks after myocardial infarction, cumulative 10-min infusions of either nisoldipine (0.05, 0.1, 0.25, and 0.5 micrograms/kg/min), pimobendan (2.5, 5, 12.5, and 25 micrograms/kg/min) or the solvents were administered. Infusion of the solvents did not affect any of the hemodynamic variables. Both nisoldipine and pimobendan normalized CO and exhibited a similar cardiac profile [systemic vasodilatation, reduction in left ventricular filling pressure, and an increase in heart rate (HR)] except for the significantly (p less than 0.05) larger increase in LVdP/dtmax with pimobendan (85%) than with nisoldipine (45%). In animals with heart failure, lower doses of both nisoldipine (twice) and pimobendan (four times) were needed to elicit a 30% reduction in SVR than in animals with normal pump function. For both drugs, the slope of the line describing the vasodilatory and positive inotropic properties shifted more in favor of the vasodilatory actions during heart failure (p less than 0.05). We conclude that in swine with chronic LV dysfunction nisoldipine, despite its lack of inotropic properties, appeared to improve ventricular function to the same extent as the primary positive inotropic agent pimobendan.
J Cardiovasc Pharmacol 1989 Oct
PMID:Acute hemodynamic effects of nisoldipine and pimobendan in conscious pigs with chronic heart failure. 247 81

Using antimony-bismuth myothermal equipment, we measured simultaneously the initial heat liberated from and the stress-time integral developed by guinea pig papillary muscles before and after application of UD-CG 115 BS (200 microM) at an experimental temperature of 21 degrees C. By means of the shortening method, the initial heat was subdivided into the activation heat, which is associated with the calcium turnover, and the tension-dependent heat, which represents the ATP splitting by contractile proteins. The activation heat increased slightly but not significantly from 0.24 +/- 0.05 to 0.34 +/- 0.09 mcal/g. The increase in the tension-dependent heat (from 0.23 +/- 0.07 to 0.49 +/- 0.22 mcal/g) was directly proportional to the increase in the developed stress-time integral (from 0.95 +/- 0.24 to 2.37 +/- 0.76 g.s/mm2). The data indicate that the economy of force generation by contractile proteins is unchanged by UD-CG 115 BS, whereas the activation heat may be slightly increased by this compound. A comparison of UD-CG 115 BS with other substances like isoproterenol or classic phosphodiesterase inhibitors reveals that UD-CG 115 BS increases myocardial force in a more economical way that may have clinical implications. The mode of action of this compound is attributed to its calcium-sensitizing effect on the contractile proteins.
J Cardiovasc Pharmacol 1989
PMID:Influence of the positive inotropic substance pimobendan (UD-CG 115 BS) on contractile economy of guinea pig papillary muscles. 247 86

The current therapeutic interest in specific phosphodiesterase (PDE) inhibition involves patients with severe congestive heart failure (CHF) whose symptoms are not controlled by diuretics, nitrates, angiotensin converting enzyme (ACE) inhibitors, and digitalis. Maximal exercise capacity is limited in these patients by an inadequate rise in cardiac output and a fixed capacity to dilate the skeletal muscle vasculature, which is perhaps compounded by disorders of the skeletal muscle metabolism. To improve maximal exercise capacity, the increase in cardiac performance produced by specific phosphodiesterase inhibitors must, in turn, reverse the abnormalities present in the periphery, and more specifically augment the capacity to dilate the skeletal muscle vasculature. Increased vasodilatory response to maximal exercise probably depends on the regression of structural changes in the skeletal muscle vasculature. Such regression may be mediated by a reduction in neurohormonal vasoconstrictor stimuli and/or chronic augmentation in resting limb blood flow. Submaximal exercise capacity, at work loads equivalent to less than 70% of peak aerobic capacity, appears to be directly limited by depressed cardiac output and high sympathetic vasoconstrictor activity. Specific phosphodiesterase inhibition, which consistently increases left ventricular performance during exercise, is more likely to improve exercise capacity at submaximal work loads than at maximal work loads.
J Cardiovasc Pharmacol 1989
PMID:Specific phosphodiesterase inhibition and maximal and submaximal exercise performance in patients with congestive heart failure. 247 92

Many newly developed positive inotropic agents are phosphodiesterase inhibitors. In the heart at least four phosphodiesterases (PDE I-IV) have been isolated. Depending on the species investigated, the positive inotropic effects of the PDE inhibitors appear to be correlated to the inhibition of a soluble or particulate PDE III or to a particulate PDE bound to the sarcoplasmic reticulum. In human ventricular tissue isolated from hearts with end-stage heart failure due to idiopathic dilated cardiomyopathy the positive inotropic effect of phosphodiesterase inhibitors is greatly reduced compared to healthy controls. This cannot be explained by an impaired sensitivity of the PDEs because the PDEs were similarly inhibited by PDE inhibitors in both healthy and diseased hearts. However, because the reduced positive inotropic effect is accompanied by a reduced increase in cellular cAMP concentration, an impaired formation of cAMP by the adenylate cyclase is probably involved. The impaired adenylate cyclase activity can result from an increased inhibitory GTP-binding protein (Gi-protein) recently observed in failing hearts.
J Cardiovasc Pharmacol 1989
PMID:Phosphodiesterase inhibition and positive inotropic effects. 247 97

Enoximone is a selective inhibitor of a low Km, cyclic AMP-specific type of phosphodiesterase (PDE III). In guinea pig and chicken atria, enoximone (0.1-100 mumol/L) caused a weak increase in the force of contraction. The heart rate was slightly enhanced or was unchanged (chicken). Enoximone (30 mumol/L) also failed to shift the concentration-response curves for the positive inotropic and chronotropic effects of norepinephrine in guinea pig atria. Under almost the same conditions, enoximone and the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) markedly potentiated the forskolin-induced mobilization of choline from phospholipids. The concentrations of IBMX (100 mumol/L) and of enoximone (50 mumol/L) used were equieffective and did not enhance choline mobilization by themselves. Cardioinhibition caused by acetylcholine was unaffected by enoximone. In perfused guinea pig hearts, the release of [3H]norepinephrine evoked by field stimulation (5 Hz) was increased by 50 mumol/L enoximone both in the absence and presence of cocaine plus corticosterone. In contrast, enoximone failed to alter the release of acetylcholine in chicken hearts at rest and during field stimulation (5 Hz), which directly depolarizes the intrinsic post-ganglionic nerves. Similar results were obtained in guinea pig hearts using [3H]acetylcholine. In contrast, when the release of labeled or unlabeled acetylcholine was evoked by (preganglionic) vagal stimulation, enoximone (30 and 50 mumol/L) and IBMX (50 mumol/L) reduced the release in both species. Taken together, enoximone and IBMX apparently reduced ganglionic transmission. The results further indicate functional compartmentalization of PDE III in guinea pig myocardial cells. PDE III appears to be involved in the regulation of myocardial choline-phospholipid hydrolysis and of norepinephrine release.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1989
PMID:Effects of the phosphodiesterase inhibitor enoximone on the autonomic innervation of the isolated heart. 248 Apr 84

Enoximone belongs to a new class of inotropic drugs that are not related either to digitalis or to catecholamines. It acts primarily through selective inhibition of phosphodiesterase III (PDE-III) and has additional vasodilating properties. Hemodynamic effects of intravenously administered enoximone (0.5 mg/kg) were investigated in patients undergoing aortocoronary bypass grafting before and during anesthesia as well as during extracorporeal circulation (ECC). Patients who were impossible to be weaned off ECC without pharmacological support were investigated also. A significant increase in cardiac index and dp/dtmax, a decrease in pulmonary capillary pressure, and a small decrease in mean arterial pressure were the major hemodynamic effects. Heart rate was not changed and no signs of arrhythmia were seen during the entire investigation period. Interactions with the anesthetics used could not be observed in this study. In patients with impaired myocardial performance during weaning from ECC, enoximone seems to be helpful in stabilizing cardiac output and decreasing filling pressure. The mechanism for improvement appears to be enhanced contractility due to its positive inotropic effects, as well as a decrease in left ventricular outflow resistance resulting from peripheral vasodilation.
J Cardiovasc Pharmacol 1989
PMID:Hemodynamic effects of enoximone in cardiac surgery patients. 248 Apr 86

Cardiac failure is treated with increasing success by phosphodiesterase-III (PDE-III) inhibitors such as amrinone, milrinone, and enoximone. While relatively pure positive inotropic substances (e.g., dopamine and dobutamine) are limited by tolerance development and MVO2 increase, the efficacy of PDE inhibitors is maintained by avoiding catecholamine and beta-receptors. They have positive inotropic, positive lusitropic, and vasodilatatory properties; myocardial oxygen consumption remains unaltered. PDE-III inhibitors act by selectively inhibiting PDE-III, leading to an increased cAMP concentration in myocardial and smooth muscle cells. In contrast, forskolin increases intracellular cAMP by activation of adenylate cyclase. It could be shown that parenteral administration of the PDE inhibitors sulmazole, amrinone, and enoximone resulted in preload and afterload reduction due to vasodilation with concomitant decrease of peripheral and pulmonary vascular resistance; they also led to elevated cardiac output and ejection fraction as well as a significant increase in dp/dtmax, while left ventricular filling pressures were markedly lowered. Pulmonary pressure values fell significantly, whereas heart rate and myocardial oxygen consumption showed no clinically relevant alterations. In patients with angiographically documented coronary artery disease, the anti-ischemic efficacy of enoximone could be proven both during exercise and stress pacing. The decrease of the pathologically elevated pulmonary pressures during ischemia was accompanied by reduced ST-segment depression following enoximone without changing MVO2 significantly. First tests after intracoronary application of enoximone confirmed its direct myocardial efficacy, indicating its positive inotropic and lusitropic properties. Thus, patients in cardiac failure have useful therapeutic alternatives at their disposal when taking PDE inhibitors. The anti-ischemic properties of these drugs need further evaluation.
J Cardiovasc Pharmacol 1989
PMID:Present use of positive inotropic drugs in heart failure. 248 Apr 92

The rationale of combining vasodilatation with positive inotropic intervention in the treatment of chronic heart failure has found a new implementation in the "inodilator" drugs. Inodilators are characterized by the properties of exerting positive inotropic effect and inducing systemic vasodilatation. The cellular mechanisms involved in the regulation of contractility of cardiac and vascular muscle and the pathophysiological events occurring in heart failure are briefly discussed, and the pharmacological profile as well as the therapeutic use of these drugs are reviewed. On the basis of the mechanism of action, two groups of inodilators are distinguished, the phosphodiesterase inhibitors and the dopaminergic agents. The increase of [cAMP]i induced by the phosphodiesterase inhibitors is responsible for their vasodilating effect and for the positive inotropic action, but many of them have in addition the ability to enhance the Ca2+ sensitivity of cardiac contractile proteins. The complex organization and the cardinal role of the catecholaminergic receptor system in the control of cardiovascular function and its contribution to the pathophysiological events occurring in heart failure are the rational basis of the therapeutic use of dopaminergic agents. These drugs, acting on DA, beta-, and alpha-receptors, exert not only positive inotropic and vasodilating effects, but also a diuretic action, and can reduce aldosterone and renin secretion, blunt an excessive sympathetic activity, and possibly promote the release of atrial natriuretic peptide. The multireceptor mechanism of dopamine-like drugs, which accounts for their favorable hemodynamic, neurohumoral, and diuretic effects, represents the most promising approach to inodilator therapy.
J Cardiovasc Pharmacol 1989
PMID:Present and future trends in research and clinical applications of inodilators. 248 38

Recent advances in our knowledge of heart failure have shown that both a central and a peripheral factor are involved in this syndrome. Therefore, the ideal drug should combine the properties of a positive inotropic agent with those of a peripheral vasodilator; many drugs recently introduced into clinical practice have been shown to present both of these features, and the term "inodilators" has been used to characterize them. Inodilators can be further classified on the basis of their mechanism of action, i.e., phosphodiesterase inhibitors, and sympathomimetic and dopaminergic drugs. Phosphodiesterase inhibitors include bipyridine, imidazolone, and benzimidazole derivatives, which present potent inotropic and vasodilatatory actions. Despite their favorable acute effects, long-term studies have often yielded controversial, and sometimes disappointing, results as their chronic administration seems often to be associated with untoward effects and, above all, a poor prognosis. Sympathomimetic agonists act by stimulation of beta-receptors, with a consequent increase of myocardial contractility and peripheral vasodilation. Differently from the parenteral drugs (e.g., dobutamine), the oral agents present many important shortcomings including central nervous system effects, increased myocardial oxygen consumption, tachyarrhythmias, and, above all, development of tolerance during chronic administration. Dopaminergic drugs possess a unique pharmacologic profile since they add to the adrenergic stimulation their selective action on dopaminergic receptors. Dopamine is still one of the most useful drugs for the treatment of acute heart failure; the two oral drugs that more closely resemble its actions are levodopa and ibopamine. The administration of levodopa to patients with heart failure can induce a significant hemodynamic improvement that is maintained during chronic therapy. Ibopamine has been widely shown to cause a significant hemodynamic improvement in patients with heart failure. Its effects can be ascribed to a moderate increase of myocardial contractility accompanied by peripheral and renal vasodilatatory actions. This drug can also counteract some of the neurohumoral mechanisms (e.g., sympathetic stimulation and aldosterone secretion) that are activated in heart failure. These features can explain the favorable results that have also been recently obtained after the chronic administration of ibopamine.
J Cardiovasc Pharmacol 1989
PMID:Clinical pharmacology of inodilators. 248 42

Intense efforts during the last decade to identify a useful positive inotropic agent to replace digitalis for the treatment of congestive heart failure have led to the discovery of several dozen potential substitutes, of which a number are currently undergoing clinical trials. In addition to producing a variety of new therapeutic entities, research in this area has also yielded valuable new information regarding the fundamental events that regulate calcium homeostasis and contractile function in the cardiac cell. For example, several of these new inotropic agents, including the calcium-channel stimulator BAY-k 8644, the sodium-channel stimulator DPI-201-186, and the sodium-calcium exchange inhibitor dichlorobenzamil, have provided considerable insight into the role of sodium and calcium in regulating contractility and the molecular events that mediate potential-dependent ion channels. Likewise, the discovery and development of agents like imazodan, amrinone, enoximone, and other selective type III phosphodiesterase inhibitors have provided new information regarding multiple molecular forms of cyclic nucleotide phosphodiesterase, compartmentation of cyclic AMP, and the importance of soluble vs. membrane-bound phosphodiesterases.
Cardiovasc Drugs Ther 1989 Mar
PMID:New mechanisms for positive inotropic agents: focus on the discovery and development of imazodan. 248 22


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