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 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enoximone, a phosphodiesterase inhibitor, is a potent inotropic vasodilator agent that causes a marked improvement in systemic hemodynamics in patients with severe chronic congestive heart failure. Cardiac index, stroke volume index and stroke work index increase, and there is a significant decrease in pulmonary capillary wedge pressure. Left ventricular dP/dt increases, despite a decrease in arterial pressure and systemic vascular resistance and without any significant change in heart rate, indicating a positive inotropic effect. A marked decrease in systemic vascular resistance indicates that decreased left ventricular outflow resistance resulting from peripheral vasodilation also contributes to improvement in left ventricular function. In some patients, left ventricular end-diastolic volume increases despite a marked decrease in pulmonary capillary wedge pressure, suggesting an improvement in apparent left ventricular compliance, which may also be contributory to improved left ventricular function.
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PMID:Potential mechanisms of improved left ventricular function with enoximone in severe congestive heart failure. 295 66

Twelve patients with congestive heart failure underwent a double-blind, placebo-controlled study for the purpose of examining the central and regional hemodynamic effects of first-dose (1 and 2 mg/kg) oral enoximone, a new phosphodiesterase III inhibitor. Enoximone augmented cardiac output, generally through a positive chronotropic response. Indices of left ventricular contractility, specifically stroke volume, delta P/delta t, fractional shortening rate, and the duration of the preejection period, were only modestly enhanced by enoximone. At 2 mg/kg, systemic vascular resistance fell below baseline values without affecting systemic blood pressure; these parameters were not altered by the 1 mg/kg dose. Both pulmonary artery pressure and pulmonary vascular resistance dropped below baseline and below placebo control for the 2 mg/kg dose. Enoximone at 2 mg/kg lowered right and left heart filling pressures below baseline. Examination of regional hemodynamic responses to both doses demonstrated a reduction in limb vascular resistance and an increase in limb blood flow proportional to the concomitant increase in cardiac output. Renal and hepatic-splanchnic blood flow and vascular resistances were not altered by enoximone. First-dose oral enoximone (1 and 2 mg/kg) alters hemodynamics in heart failure by predominant vasodilatation, particularly of limb-musculoskeletal and pulmonary vascular beds, some positive chronotropism, and modest positive inotropism.
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PMID:Central and regional hemodynamic effects of oral enoximone in congestive heart failure: a double-blind, placebo-controlled study. 296 46

Thirteen patients in severe cardiogenic shock, persisting despite the use of adrenergic agents, were treated with enoximone, a recently available phosphodiesterase inhibitor. Cardiogenic shock was characterized by low cardiac output (less than 2.5 liter.min-1.m-2), elevated pulmonary artery balloon-occluded pressure (greater than or equal to 15 mm Hg), decreased urine output (less than 20 ml.hour-1) and increased blood lactate (greater than or equal to 2.0 mEq.liter-1). Ten patients were mechanically ventilated. A short-term intravenous infusion of 0.5 mg.kg-1 in 20 minutes of enoximone resulted in significant increases in cardiac index (from 1.8 +/- 0.3 to 2.9 +/- 0.3 liter.min-1.m-2, p less than 0.001) and stroke index (from 17.8 +/- 3.3 to 21.9 +/- 5.1 ml.m-2, p less than 0.001) and significant decrease in pulmonary artery balloon-occluded pressure (from 21.7 +/- 5.8 to 19.8 +/- 6.0 mm Hg, p less than 0.01) without a consistent change in mean arterial pressure (from 79 +/- 8 to 76 +/- 9 mm Hg, difference not significant). Enoximone administration decreased arterial oxygen tension (from 108 +/- 42 to 94 +/- 36 mm Hg, p less than 0.01) and increased venous admixture (from 12.8 +/- 6.5 to 16.0 +/- 8.0%, p less than 0.01). In 8 patients, a second infusion of 0.5 mg.kg-1 immediately thereafter amplified these changes. All patients but one survived the episode of cardiogenic shock and 5 patients left the hospital alive. These results indicate that the addition of enoximone to adrenergic agents in the treatment of cardiogenic shock can markedly increase cardiac output and stroke volume without substantial effects on arterial pressure.
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PMID:Administration of enoximone in cardiogenic shock. 297 Jul 77

Milrinone is a bipyridine derivative of amrinone, with approximately 10 to 75 times greater positive inotropic potency, and separate direct vasodilatory properties. As with amrinone, the relative importance of these properties to treatment of congestive heart failure still remain controversial. The mode of action of milrinone appears to be due in part to selective inhibition of a specific cardiac phosphodiesterase with a subsequent increase in intracellular cyclic adenosine monophosphate and alteration in intracellular and extracellular calcium transport. Clinical experience has involved both short and long term treatment of a limited number of patients with moderate to severe congestive heart failure refractory to conventional therapy. Milrinone has usually been administered as intravenous bolus doses (12.5 to 75 micrograms/kg) and/or continuous intravenous infusion (0.5 microgram/kg/min), or orally (30 to 40 mg/day in divided doses). Milrinone rapidly improves cardiac performance by enhancing myocardial contractility, and by decreasing systemic vascular resistance (afterload), left ventricular filling pressure (preload), and pulmonary arterial pressure. Exercise performance improvement occurs with enhancement of left ventricular performance but without a significant increase in myocardial oxygen consumption or significant decrease in mean arterial pressure. Milrinone has been compared with dobutamine, nitroprusside and captopril in preliminary short term studies in patients with severe congestive heart failure. Milrinone significantly increased stroke work index and decreased left ventricular filling pressure compared to nitroprusside. When compared with dobutamine, both drugs improved cardiac index (to a similar degree), but milrinone significantly reduced right atrial pressure, pulmonary capillary wedge pressure and left ventricular end-diastolic pressure. One small study suggests that short term effects of intravenous milrinone may be superior to those of oral captopril, and it appears that the addition of captopril to milrinone therapy may produce a synergistic haemodynamic effect. Preliminary long term studies suggest that tolerance to the haemodynamic effects of milrinone does not occur, and that the drug is well tolerated and without the thrombocytopenic effects, fever and gastrointestinal complications observed with amrinone. However, it has not been demonstrated that milrinone improves the prognosis of the disease or the overall mortality and its propensity to produce arrhythmias has not been fully agreed upon.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Milrinone. A preliminary review of its pharmacological properties and therapeutic use. 305 25

This study explored the hemodynamic effects of amrinone, a phosphodiesterase inhibitor, in association with intravenous fluids, in the treatment of endotoxin shock. Mongrel dogs were anesthetized with pentobarbital and mechanically ventilated with room air. Treatment was started 30 min after slow intravenous administration of 3 mg/kg of E. coli endotoxin. In the first part of the study, ten dogs were resuscitated for 30 min with intravenous saline alone (10 ml/kg) and for the next 3 h by saline (10 ml/kg/h) and amrinone 40 micrograms/kg/min. During this latter period, arterial pressure remained stable while cardiac output significantly increased from 3.1 +/- 0.5 to 5.2 +/- 0.7 l/min (P less than 0.01), and oxygen delivery increased from 616 +/- 92 to 983 +/- 156 ml/min (P less than 0.01). Comparison with control animals revealed that amrinone infusion prevented the decrease in left ventricular stroke work and markedly increased oxygen delivery. In the second part of the study, 18 dogs were treated by saline infusion titrated to maintain pulmonary artery balloon-occluded pressure at baseline level. In ten dogs, amrinone was added 60 min after endotoxin administration at a dose of 40 micrograms/kg/min. Total amount of fluids infused averaged 87 +/- 14 ml in the amrinone-treated dogs and 64 +/- 15 ml in the control dogs (differences nonsignificant). Oxygen delivery and oxygen consumption increased significantly in the amrinone-treated dogs (from 541 +/- 36 to 1063 +/- 176 ml/min, P less than 0.01, and from 145 +/- 23 to 202 +/- 38 ml/min, P less than 0.01, respectively) but not in the control dogs. The amrinone-treated dogs had lower PaO2 and higher venous admixture than the control dogs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Amrinone administration in endotoxin shock. 329 77

The hemodynamic effects of CI-914, a phosphodiesterase inhibitor, were studied in 12 patients with left ventricular (LV) dysfunction who were undergoing diagnostic cardiac catheterization. CI-914 was infused intravenously at a rate of 0.8 to 7.0 micrograms/kg/min for 30 to 60 minutes; hemodynamic values were measured every 10 minutes. No effect was seen in the patient receiving 0.8 microgram/kg/min. At infusion rates of 1.2 to 2.4 micrograms/kg/min, cardiac index increased by 14% (p less than 0.025). At infusion rates of 4.5 to 7.0 micrograms/kg/min, cardiac index increased by 21% (n = 8, difference not significant [NS]). Among 4 patients (group B) with an initial pulmonary artery wedge pressure greater than 20 mm Hg and cardiac index less than 2.5 liters/min/m2, cardiac index increased by 50% (p less than 0.001); it did not change among the 4 patients with an initial pulmonary artery wedge pressure of less than 20 mm Hg and cardiac index of more than 2.5 liters/min/m2 (group A). Although systemic vascular resistance decreased in all 8 patients by 26% (p less than 0.01), the reduction was greater in group B (33%, p less than 0.01) than in group A (16%, NS). Peak +dP/dt increased in all 8 patients by 13% (p less than 0.01). Mean stroke work index increased from 29 +/- 15 to 34 +/- 13 g-m/m2; the double product fell from 101 +/- 31 to 91 +/- 23 (NS). In all 12 patients, a linear correlation between peak venous blood concentration and peak effect on cardiac index, systemic vascular resistance and pulmonary artery wedge pressure was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of CI-914 in congestive heart failure due to coronary artery disease or idiopathic cardiomyopathy. 375 29

The biochemistry of platelets is surprisingly complex, and offers the opportunity for numerous platelet-aggregation inhibiting ("antiplatelet") drugs to interfere with different aspects of their metabolism and function. Thus, aspirin inhibits platelet aggregation by irreversibly inactivating cyclo-oxygenase, a key enzyme in platelet prostaglandin metabolism, while the other nonsteroidal anti-inflammatory drugs and sulphinpyrazone cause reversible and dose-dependent inhibition of the same enzyme. Dipyridamole can inhibit both platelet adhesion and aggregation by raising the platelet cyclic AMP level through phosphodiesterase inhibition. The use of aspirin, sulphinpyrazone, and dipyridamole as antithrombotic agents has now been extensively evaluated. In general, treatment with these drugs has been more likely to prevent arterial than venous thromboembolism, and aspirin or the combination of aspirin and dipyridamole has been more effective in this respect than has sulphinpyrazone. Recent evidence strongly suggests that aspirin reduces the risk of non-fatal myocardial infarction in patients with unstable angina, and that the administration of aspirin in combination with dipyridamole significantly improves graft patency after aortocoronary bypass. Aspirin also appears to reduce the likelihood of stroke or death in men with transient cerebral ischaemic attacks.
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PMID:Aspirin and other platelet-aggregation inhibiting drugs. 388 Aug 61

The biochemical mechanisms by which nitroso-vasodilators cause smooth muscle relaxation remain controversial. One theory states that the effects of nitroso-vasodilators are mediated by increased intracellular levels of cyclic GMP due to activation of guanylate cyclase. To test this hypothesis, the authors examined the effects of sodium nitroprusside (SNP) in anesthetized dogs with an without pretreatment with the phosphodiesterase inhibitor aminophylline. Aminophylline pretreatment resulted in a 2.8-fold potentiation of the hypotensive effects of a continuous infusion of SNP. Potentiation also was seen for the effects of SNP on stroke volume, heart rate, and plasma cyclic GMP levels. These results support the hypothesis that nitroso-vasodilators exert their effects via guanylate cyclase activation. The authors advise caution when vasodilator therapy with agents such as SNP, nitroglycerin, or hydralazine is instituted in patients receiving aminophylline and when aminophylline is either instituted or discontinued in patients on vasodilator therapy.
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PMID:Aminophylline potentiates sodium nitroprusside-induced hypotension in the dog. 609 2

Mechanisms of vascular hypertrophy induced by hypertension were studied in cultured aortic smooth muscle cells from spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) and compared with those from normotensive Wistar-Kyoto (WKY) rats. Fetal calf serum-stimulated ornithine decarboxylase (ODC) activity of cultured smooth muscle cells was greater in SHR and SHRSP than in WKY. Beta- but not alpha-adrenergic agonist stimulated ODC activity acutely in cultured smooth muscle cells from WKY, and isoprenaline-induced activation was blocked by the beta-blocker, propranolol, and enhanced by the phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine. These results indicate that cultured vascular smooth muscle cells from SHR and SHRSP are more prone to increase the protein synthesis than those from WKY through the trophic induction of ODC activity and that the regulation of ODC activity by catecholamines is mediated through beta-agonistic effect in cultured smooth muscle cells.
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PMID:Studies of hypertension-induced vascular hypertrophy in cultured smooth muscle cells from spontaneously hypertensive rats. 619 73

A series of new 2-(alkylthio)-5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines have been prepared as inhibitors of cAMP phosphodiesterase from various tissues. These derivatives were prepared via ring closure of various requisite 3-amino-1,2,4-triazole intermediates. 2-(Benzylthio)-5-methyl-7-(dimethylamino)-1,2,4-triazolo[1,5-a]pyrimidine (15a) is 6.3 times as potent as theophylline in inhibiting cAMP PDE isolated from rabbit heart. Treatment of dogs intravenously with 5 (mg/kg)/h of 15a gave a cardiac output increase of 69%, which was largely sustained for a 2-h period after administration of drug had ceased. There was no significant increase in heart rate upon administration of 15a. Related studies with 5,7-di-n-propyl-2-(benzylthio)-1,2,4-triazolo[1,5-a]pyrimidine (22a) in five dogs showed a 31.5% increase in cardiac output with an increase in stroke volume of 34.4% with no increase in heart rate. The specificity of action of these PDE inhibitors could be due to selective binding at a certain cAMP PDE site in the cardiovascular system. Several of these compounds are candidates for further studies with a view to clinical evaluation.
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PMID:2-(Alkylthio)-1,2,4-triazolo[1,5-a]pyrimidines as adenosine cyclic 3',5'-monophosphate phosphodiesterase inhibitors with potential as new cardiovascular agents. 627 46


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