Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conventional pharmacologic therapy for the management of congestive heart failure includes inotropic, vasodilator, and diuretic agents. Phosphodiesterase inhibitors are a new class of inotropic agent that possesses both inotropic and vasodilating capability. Currently, only one of these agents, amrinone (Inocor), has been approved for clinical use in the United States. Nursing management of the patient receiving amrinone requires knowledge of the appropriate vehicle for administration, the recommended dose, and adverse reactions. A thorough understanding of the hemodynamic alterations in CHF, as well as the effect of amrinone on these hemodynamic parameters, is an essential component of nursing care. Amrinone is only available for intravenous administration. Clinical trials, involving several investigational phosphodiesterase inhibitors, are being conducted. These drugs are being administered orally and intravenously. The goal of research is to develop a potent positive inotrope that will be available for both oral and intravenous administration. The focus of current research involving phosphodiesterase inhibitors includes studying the effect of these agents on myocardial ischemia as well as the mortality and morbidity of CHF. Additional knowledge regarding these and other issues is needed before the new inotropes can become a routine component of the pharmacological armamentarium for treatment of CHF.
...
PMID:Cardiac drugs: new inotropes. 281 83

MCI-154 is a new positive inotropic agent with vasodilating property. Experiments were carried out in the canine isolated right ventricular muscle in order to elucidate whether or not cyclic AMP is involved in the positive inotropic effect (PIE) of MCI-154. MCI-154 (10(-7) to 10(-4) M) produced a concentration-dependent PIE amounting to 75% of the maximal effect of isoproterenol. MCI-154 did not affect the time to peak tension and had a tendency to shorten the relaxation time and total duration of contraction. Pindolol, reserpine-pretreatment or tetrodotoxin did not modify the PIE of MCI-154. MCI-154 increased the cyclic AMP levels only at 3 X 10(-4) M, whereas CI-914, of which chemical structure is similar to that of MCI-154, elevated definitely the cyclic AMP at the lower concentrations (10(-5) to 10(-4) M). Carbachol at a concentration known to decrease markedly the PIE of amrinone, milrinone and papaverine, did not affect the PIE of MCI-154. MCI-154 inhibited the activity of a crude phosphodiesterase (PDE) from the canine ventricular muscle and it enhanced the PIE of isoproterenol, which implied the involvement of cyclic AMP. However, the maximal inhibition of PDE by MCI-154 remained less than 18%. Amrinone, milrinone and papaverine inhibited more potently the PDE activity than MCI-154. These results suggest that the elevation of cyclic AMP levels is only partially involved in the PIE of MCI-154 in the canine right ventricular muscle, and that MCI-154 may have novel mechanisms of action different from those of amrinone, milrinone and CI-914 that are largely cyclic AMP-dependent.
...
PMID:Does the positive inotropic action of a novel cardiotonic agent, MCI-154, involve mechanisms other than cyclic AMP? 282 54

The aim of inotropic therapy is to increase the force of myocardial fibre shortening by improving the availability of calcium to the contractile proteins. Digitalis remains the most widely used drug, but its positive inotropic effects are weak and the therapeutic index is low. Dobutamine is the most useful catecholamine because the most cardioselective and it induces the least increase in myocardial oxygen consumption. There are three groups of new inotropic agents: sympathomimetics: pirbuterol and prenalterol are effective in the short term but tolerance is usually observed within a few weeks. Salbutamol and terbutaline have only been assessed in acute studies, phosphodiesterase inhibitors (MDL 17043, MDL 19025) are powerful inotropic agents in the short and medium term. ARL 115 has mainly been studied by parenteral administration, Amrinone has a largely unknown mode of action, but is a very effective positive inotropic drug; its side-effects limit it as age. However, its derivative, milrinone, seems to be more inotropic and less toxic. The new inotropic drugs currently under assessment are active in the short term but their long-term efficacy and side-effects are still little known. The ideal inotropic agent remains to be discovered.
...
PMID:[Positive inotropic agents. Generalities and classification]. 286 22

Previously, we reported that amrinone increases isometric twitch force but relaxes K+-induced contracture in muscles from normal cat right ventricle. This study evaluated its effects on diseased cardiac tissue. Right-ventricular papillary muscles were obtained from cats with subacute right-ventricular failure (3-14 days after partial pulmonary-artery ligation) and studied in vitro during stimulation (0.5 Hz) and exposure to high-K+ Tyrode solution. Active isometric twitch force and rate of force development (dP/dt) were significantly lower in muscles from hearts with right-ventricular failure compared to control muscles. In addition, while time to peak force was not different, duration of the twitch was significantly longer. In contrast to its positive inotropic actions in control muscles, amrinone (5.3 X 10(-4) M) had no significant effects on twitch force and dP/dt in muscles from failed ventricles. Time to peak force was not changed by amrinone in either group, but unlike its action in control muscle, duration of the twitch was reduced in failed muscle. Amrinone reduced K+-contracture force similarly in both control and failed muscles. Isoproterenol (10(-6) M) significantly increased twitch force and dP/dt and reduced K+-contracture force in both muscle groups. Since amrinone appears to be a phosphodiesterase inhibitor, our data indicate that cyclic AMP (cAMP)-related relaxation processes, but not cAMP-related contractile processes, can be enhanced by phosphodiesterase inhibitors in experimental heart failure. Furthermore, amrinone's reduced positive inotropic effect in failed myocardium suggests that its improvement of ventricular function in patients reflects, in part, enhancement of relaxation.
...
PMID:Enhanced relaxation and reduced positive inotropic effects of amrinone in ventricular muscle from cats with subacute heart failure. Implications for drug therapy. 298 64

The bipyridine derivative amrinone is a specific phosphodiesterase III blocking agent. In vitro and in vivo studies show a dose-dependent increase in myocardial contractility induced by amrinone. In patients with congestive heart failure, the inotropic and vasodilator effects of amrinone contribute to cardiac improvement. When amrinone is used, the increase in myocardial oxygen consumption due to increased contractility is offset by the reductions in preload and afterload. In hearts with very high wall tension, myocardial oxygen consumption may even decrease with amrinone. Amrinone therapy is not accompanied by significant increases in heart rate. Tachyphylaxis has not been observed. The elimination half-life ranges between 2.5 and 3.5 h. A large quantity of amrinone is excreted unchanged, and therefore in cases of renal impairment the possibility of cumulation exists. The main adverse reaction of amrinone is a reversible thrombocytopenia induced by a dose-dependent decrease in platelet survival time. Therefore, frequent platelet counts are necessary when amrinone is administered. Numerous studies in patients with chronic congestive heart failure confirmed the beneficial hemodynamic effects of amrinone. Experience in the treatment of acute perioperative heart failure with amrinone are still limited, but the present results are encouraging; an additive effect of amrinone to catecholamines seems especially promising in the therapy of severe postoperative low-cardia-output syndrome.
...
PMID:[Amrinone (Wincoram)--a new positive inotropic and vasodilator agent]. 304 13

Clinical trials with new inotropic, non-adrenergic agents with vasodilating properties have open new perspectives for the treatment of acute and chronic heart failure. If their mechanism of action is not exactly known, they are likely to increase C.AMP by phosphodiesterase inhibition. A clear distinction has to be made concerning short- and long-term administration of these drugs. Amrinone (A) has been administered to 10 patients with low postoperative cardiac output as unique inotropic therapy and to 34 patients in severe cardiogenic shock, despite optimal treatment. In the latter group, A was added to the preliminary drugs. In both groups of patients, hemodynamics improved significantly, except in 4 patients in group II, who died. Except in one case with thrombocytopenia and one with supraventricular dysrhythmias, no serious side-effects were noted. No long-term treatment has been carried out in our institution. The literature has widely reported that the new inotropic drugs used in class III and IV patients, are likely to increase patient's well-being and exercise capacity, but not life expectancy.
...
PMID:New inotropic-vasodilating drugs in acute and chronic heart failure. 376 91

It has been suggested that amrinone and AR-L57 enhance cardiac contractility either by inhibiting phosphodiesterase activity or altering Ca++ homeostasis. Because these novel agents are potentially useful in the management of heart failure, it was of interest to more clearly define their mechanism(s) of action. Amrinone and AR-L57 caused concentration-dependent increases in the contractile states of either perfused guinea-pig hearts or cultured rat cardiomyocytes. To determine whether these actions might result from an increase in sarcolemmal Ca++ movement, the effects of these agents on Ca++ accumulation were studied in a simple system, dog erythrocytes. Both agents promoted erythrocyte Ca++ accumulation in time and concentration-dependent manners, effects that resulted primarily from increased Ca++ entry. However, because these effects were not measurable at inotropic drug concentrations and were apparent only after a 30-min incubation, they did not provide an explanation for the inotropic effects of these agents. Amrinone and AR-L57 inhibited dog heart phosphodiesterase activity (isozyme III) with EC50 values of 23 and 420 microM, respectively; however, only the inotropic responses to amrinone were attenuated by the muscarinic agonist, carbachol, thereby implying a cAMP (cyclic AMP)-dependent mechanism. In cultured ventricular cells, concentrations of amrinone (2 X 10(-4) M) and AR-L57 (3 X 10(-5) M) that caused maximal inotropic responses were associated with the activation of glycogen phosphorylase, but neither drug significantly increased the activation state of cAMP-dependent protein kinase. To further probe the effects of these drugs on intracellular cAMP and Ca++ metabolism, their effects on protein phosphorylation were studied.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Molecular basis for the cardiovascular activities of amrinone and AR-L57. 608 73

Amrinone is a new noncatechol, nonglycoside agent with cardiotonic and vasodilator properties. This paper examines the effects of amrinone in the toad urinary bladder, a tissue whose function may be altered by many factors which also change cardiovascular activity. Amrinone enhanced the effect of vasopressin and cyclic AMP on water and urea permeabilities, as well as the effect of vasopressin on sodium transport. Consistent with these actions, amrinone inhibited cyclic AMP phosphodiesterase activity in epithelial homogenates and increased both cyclic AMP content and the protein kinase activity ratio measured in intact epithelial cells. The inhibitory effect of amrinone on phosphodiesterase may be relevant to its cardiostimulatory and vasodilator activities.
...
PMID:The effects of amrinone on transport and cyclic AMP metabolism in toad urinary bladder. 625 81

The relaxing effect of Amrinone, an inotropic and vasodilating agent, was investigated on the isolated guinea pig tracheal smooth muscle in comparison and in association with Aminophylline. Amrinone (pD2 = 5.02 +/- 0.07) resulted more active than Aminophylline (pD2 = 4.25 +/- 0.08) in relaxing the isolated guinea pig trachea. The interaction curves of the two drugs showed the pattern typical for "competitive synergism", thus suggesting that Amrinone may act on tracheal muscle through inhibition of phosphodiesterase.
...
PMID:Amrinone relaxing effect on the isolated guinea pig trachea and its interaction with aminophylline. 686 73

The direct and interactive effects of phosphodiesterase inhibition (PDEI) and beta-adrenergic receptor (beta AR) stimulation on isolated myocyte contractile function were examined after hypothermic, hyperkalemic, cardioplegic arrest (HHCA) and under normothermic conditions. Left ventricular (LV) myocytes were isolated from porcine hearts and myocyte contractile function was measured under normothermic conditions (37 degrees C in standard media) and after HHCA (2 h at 4 degrees C in Ringer's solution with 24 mEq KCl) with subsequent rewarming. Myocytes were then randomly assigned to treatment with the beta AR agonist isoproterenol (25 nM), the phosphodiesterase inhibitor amrinone (50 microM), or a combination of these compounds and contractile function measurements repeated. Baseline myocyte contractile function was reduced by 32% after HHCA. Isoproternol alone increased myocyte contractile function more than 100% under both normothermic conditions and after HHCA, whereas amrinone alone significantly (60%) improved myocyte contractile function only after HHCA. Amrinone preincubation followed by isoproterenol improved contractile function after HHCA to a greater extent than all other treatment protocols. In contrast, combination treatment under normothermic conditions did not augment myocyte contractile function relative to isoproterenol alone. These findings suggest that amrinone has differential effects on contractile processes. Moreover, the marked improvement of contractile function after HHCA with PDEI pretreatment followed by beta AR stimulation may have implications in treatment strategies for improving myocardial function after cardiopulmonary bypass and provide insight into contractile dysfunction after HHCA.
...
PMID:The direct and interactive effects of phosphodiesterase inhibition and beta-adrenergic stimulation on myocyte contractile function after hypothermic cardioplegic arrest. 748 79


<< Previous 1 2 3 4 5 6 7 Next >>

---