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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pial arterioles of living mice anesthetized with urethane were monitored by television microscopy. I tested the existence of an adenylate cyclase-cyclic adenosine monophosphate (cAMP) system for dilating the arterioles by topically applying the following drugs: cAMP (10(-3) M), its more potent analogue dibutyryl cAMP (10(-3) and 10(-4) M), and forskolin (10(-6) M). Forskolin activates endogenous adenylate cyclase, which leads to increases in endogenous cAMP. Each drug was applied for 30 seconds; all three produced dilation. I then applied either cAMP or forskolin in the presence or absence of 10(-4) M isobutylmethylxanthine (IMX), an inhibitor of endogenous phosphodiesterase, which destroys cAMP. The presence of IMX significantly potentiated the dilation produced by exogenous cAMP and forskolin. These data indicate that cerebral surface arterioles of mice respond to cAMP with dilation and contain the enzymes for producing and inactivating this dilator. The existence of an adenylate cyclase-cAMP dilating mechanism in pial arterioles does not rule out the simultaneous existence of other dilating mechanisms.
Stroke 1988 Jul
PMID:In vivo evidence that an adenylate cyclase-cAMP system dilates cerebral arterioles in mice. 253 12

Enoximone, a relatively new type III phosphodiesterase (PDE III) inhibitor with combined positive inotropic and vasodilating properties, was used as a pharmacological bridge to heart transplantation in a patient with severe dilatative cardiomyopathy (ejection fraction 11-13%), who developed cardiogenic shock refractory to conventional therapy with catecholamines and vasodilators. Enoximone led to an 88% increase in cardiac index (from 1.6 to 3.0 l/min.m2). Despite a noticeable rise in heart rate, stroke index increased by 57%. Systemic vascular resistance decreased by 48% without any relevant change in mean arterial pressure. Cardiac filling pressures remained high. Oxygen transport doubled and oxygen extraction ratio decreased by 10%. Apart from a decrease in arterial oxygen tension (from 15.8 to 12.8 kPa [119 to 96 mm Hg]), no other side effects were noted. Withdrawal of catecholamine therapy did not cause any relevant haemodynamic changes. Although complications arose from an uncontrolled septic state, orthotopic heart transplantation was performed with success 74 hours after initiation of enoximone therapy. As the PDE III inhibitor enoximone exerts its potent inotropic and vasodilating effects without requiring adrenergic receptor activation, it may be used as an alternative to mechanical support in patients who develop cardiogenic shock resistant to catecholamines while awaiting heart transplantation.
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PMID:[Enoximone as an alternative to mechanical circulatory support prior to heart transplantation]. 252 33

In the first part of this presentation, data is reported on the hemodynamic effects of forskolin given to patients with dilated cardiomyopathy in a concentration of 3 micrograms/kg/min and 4 micrograms/kg/min. At the lower dosage, forskolin had no effect on dP/dtmax, cardiac index, ejection fraction, or myocardial oxygen consumption. With small dosages of dobutamine, however, an increase of all four parameters has been observed in the same group of patients. Systemic vascular resistance and left ventricular enddiastolic pressure fell with forskolin given at the lower concentration. Forskolin administered at a dosage of 4 micrograms/kg/min induced an increase in dP/dtmax by 19% and a 16% rise in heart rate. However, these changes were associated with symptomatic flush syndromes. Therefore, forskolin may serve as a vasodilating substance in lower concentrations, but cannot be used as a positive inotropic compound because of the subjective symptoms. In the second part, a study is reported in which an anti-ischemic effect of the phosphodiesterase inhibitor enoximone was observed in patients with proven significant coronary heart disease. With respect to the hemodynamic parameters, the most striking findings were the decreases in left ventricular enddiastolic pressure and systemic vascular resistance. Furthermore, when left ventricular stroke work index was plotted as a function of the left ventricular enddiastolic pressure, enoximone shifted the left ventricular function curve to the left. Therefore, the anti-ischemic effect of enoximone may not only be due to a reduction in preload and afterload but may rather reflect an effect on diastolic compliance. Studies with intracoronary injections of enoximone and animal experiments support this hypothesis.
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PMID:Cardiovascular effects of forskolin and phosphodiesterase-III inhibitors. 253 Sep 74

The direct negative inotropic actions of calcium channel blockers limit the use of these otherwise effective systemic and coronary vasodilators in patients with heart failure. We studied the effects of amrinone pretreatment on the dose--hemodynamic response curve of diltiazem in order to test the hypothesis that amrinone might potentiate diltiazem's positive effects in anesthetized dogs. The control group (no pretreatment, n = 6) had a typical dose-related response to diltiazem (50, 100, and 150 micrograms/kg): coronary and systemic vasodilation, increased stroke volume, and no change in myocardial work and power. Amrinone pretreatment of the study group (n = 7) altered the hemodynamic response, thus maximal systemic vasodilation and stroke volume increase at a lower diltiazem dose, a 15 to 35% increase in myocardial work and power, and more profound coronary vasodilation. We propose that amrinone, by inhibiting phosphodiesterase, potentiates diltiazem vasodilation and reflexly secreted catecholamines' actions on the heart. This positive interaction may permit effective use of lower doses of diltiazem, thus circumventing its dose-limiting direct negative effects while still profitting from beneficial peripheral, reflex, and coronary actions.
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PMID:Positive hemodynamic interaction between amrinone and diltiazem in anesthetized dogs. 259 32

Heart failure remains a major therapeutic problem with a poor prognosis despite therapy with digitalis, diuretics and vasodilator drugs. Because impaired myocardial contractility is a principal feature of persistent heart failure, the development of phosphodiesterase inhibitors, e.g. milrinone, has presented important therapeutic possibilities. Milrinone exerts both positive inotropic and vasodilator activity, and improves systemic haemodynamics by increasing left ventricular stroke volume and decreasing left ventricular filling pressure and systemic vascular resistance. In addition to improving systolic pump function, milrinone has also been shown to improve impaired diastolic relaxation of the failing heart. Importantly, treatment with milrinone does not significantly increase myocardial oxygen consumption. In moderate to severe heart failure (NYHA class III and IV), intravenous and oral milrinone have been shown not only to produce acute haemodynamic improvement but also to relieve the associated symptom of breathlessness, with improvement in quality-of-life indices. In placebo-controlled, double-blind studies oral milrinone has enhanced exercise tolerance and increased total body oxygen consumption in mild (class II), moderate and severe heart failure. There is no evidence of a substantial pro-arrhythmic effect or other significant non-cardiovascular side-effects associated with the use of milrinone. The possibility of improved survival, which is still the ultimate goal of therapy with phosphodiesterase inhibitors, remains to the studied. Similarly, the role of these agents in the management of mild heart failure, alone or in addition to therapy with diuretics and angiotensin-converting enzyme (ACE) inhibitors, warrants further evaluation.
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PMID:Therapeutic achievements of phosphodiesterase inhibitors and the future. 268 Apr 98

We evaluated the effects of cilostazol, a selective inhibitor of cyclic adenosine monophosphate phosphodiesterase, on the pial vessels of adult cats subjected to endothelial damage followed by middle cerebral artery occlusion. Six cats were treated with cilostazol and four with 30% N,N-dimethylformamide in 70% saline (solvent). The brain surface was irradiated with ultraviolet rays through a cranial window for 3 minutes to selectively damage the endothelium of the pial vessels in both groups. Beginning 32 minutes after termination of the irradiation, the middle cerebral artery was occluded for 30 minutes. Thirty minutes before occlusion, intravenous infusion of 30 micrograms/kg/min cilostazol or 0.1 ml/kg/min solvent was begun and continued until the end of the study. Before occlusion, the infusion of cilostazol induced a significant (p less than 0.05) dilatation while the infusion of solvent produced no significant changes in the diameter of the pial arteries. The pial veins of solvent-treated cats showed significant (p less than 0.05) constriction during occlusion, whereas cilostazol-treated cats exhibited only mild constriction of the pial veins. The formation of platelet thrombi after occlusion was significantly (p less than 0.05) inhibited in the pial veins of cilostazol-treated compared with solvent-treated cats. Similarly, the microcirculation of the pial veins was effectively restored after reopening of the middle cerebral artery in cilostazol-treated compared with solvent-treated cats. Our data suggest that cilostazol is an effective antithrombotic agent as well as a potent vasodilator acting on vascular smooth muscle.
Stroke 1989 May
PMID:Effects of a selective inhibitor of cyclic AMP phosphodiesterase on the pial microcirculation in feline cerebral ischemia. 271 8

UDCG-115 is a new cardiotonic agent which in vitro increases the sensitivity of the contractile proteins to calcium ions, inhibits the activity of phosphodiesterase, and prolongs the duration of the action potential. The influence of UDCG-115 (i.v.) on hemodynamics and myocardial energetics was investigated in patients with idiopathic dilated cardiomyopathy (NYHA II-III) and compared to the effects of the pure vasodilator nitroprusside. UDCG-115 increased cardiac index from 3.2 +/- 0.4 to 4.2 +/- 0.8 l/min/m2 (p less than 0.01) and decreased left ventricular end-diastolic wall stress (preload) from 52 +/- 21 to 28 +/- 18 10(3) dyn/cm2 (p less than 0.01) and end-systolic wall stress (afterload) from 201 +/- 61 to 129 +/- 43 10(3) dyn/cm2 (p less than 0.01) compared to control conditions. Compared to nitroprusside, for a similar decrease in preload and afterload. UDCG-115 increased cardiac index by 40% (p less than 0.01), stroke volume index by 37% (p less than 0.01) and maximum rate of left ventricular pressure rise by 23% (p less than 0.05). Heart rate did not significantly change with either drug. Myocardial oxygen consumption per beat decreased by 33% (p less than 0.05) with UDCG-115 and by 30% (p less than 0.01) with nitroprusside. With both drugs, the decrease of myocardial oxygen consumption correlated significantly with the decrease of left ventricular systolic stress-time integral. The slopes of the respective linear regression lines were not significantly different. Thus, UDCG-115 given intravenously in patients with idiopathic dilated cardiomyopathy and moderate congestive heart failure exhibits significant inotropic and vasodilating properties. The systemic hemodynamic actions are associated with favorable effects on myocardial energetics.
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PMID:Influence of the calcium-sensitizer UDCG-115 on hemodynamics and myocardial energetics in patients with idiopathic dilated cardiomyopathy. Comparison with nitroprusside. 281 56

The peak hemodynamic effect and hormonal response of the phosphodiesterase inhibitor enoximone (MDL 17,043) were compared with those of dobutamine in 10 patients with severe congestive heart failure. Both agents significantly (p less than 0.05) increased cardiac index, stroke volume index and heart rate. Enoximone tended to decrease mean systemic arterial and pulmonary artery wedge pressures (0.05 less than p less than 0.1), whereas dobutamine did not. Both agents decreased systemic vascular resistance (p less than 0.05). The increase in heart rate was greater with dobutamine than with enoximone (p less than 0.05). Plasma renin activity increased significantly with dobutamine (from 11.3 +/- 13.5 to 17.8 +/- 15.0 ng/ml/hour, p less than 0.01) and with enoximone (from 13.6 +/- 18.3 to 16.6 +/- 18.8 ng/ml/hour, 0.05 less than p less than 0.1). Dobutamine suppressed plasma norepinephrine level (p less than 0.05) and enoximone did not. Neither agent affected the plasma vasopressin level. These data demonstrate a similar acute hemodynamic and hormonal profile for both enoximone and dobutamine. Further, dobutamine, like other beta agonists, provokes renin secretion and may do so to a greater extent than enoximone.
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PMID:Comparative hemodynamic and hormonal response of enoximone and dobutamine in severe congestive heart failure. 294 27

The hemodynamic and myocardial energetic changes due to pulsus alternans were investigated by left and right heart catheterization and by oxygen consumption measurements in three patients with dilative cardiomyopathy. In all three patients, pulsus alternans developed after intravenous administration of the phosphodiesterase inhibitor enoximone. Following enoximone (Patients 1/2/3), left ventricular peak systolic pressure was reduced, in the respective patients, from 100/103/115 mmHg (normal beat) to 91/96/94 mmHg (strong beat) and further to 59/80/85 mmHg (weak beat); left ventricular end-diastolic pressure was reduced from 24/23/22 mmHg (normal beat) to 5/10/6 mmHg (strong beat) and further to 3/7/4 mmHg (weak beat). Cardiac output increased by an average of 16%. Heart rate increased by an average of 12%. Stroke work (during pulsus alternans mean between strong and weak beats) did not change (less than 5%) in any of the three patients. Arterial-coronary-sinus oxygen content difference decreased by 5%/13%/22, respectively. Myocardial oxygen consumption per beat decreased in Patient 1 by 8%, in Patient 2 by 8% and remained unchanged in Patient 3. It is concluded that pulsus alternans occurred in consequence of alternating systolic performance. The alternation in systolic performance most probably resulted from a disturbance in excitation-contraction coupling induced by enoximone. The pronounced reduction of left ventricular preload following administration of enoximone may have augmented further the differences between the strong and the weak beat. A disturbance in myocardial oxygen metabolism was ruled out as the cause of pulsus alternans in these patients.
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PMID:Hemodynamics and myocardial oxygen metabolism of pulsus alternans in patients with dilative cardiomyopathy. 295 30

In patients with chronic cardiac failure, improvement in ventricular function is observed after the administration of enoximone, a phosphodiesterase inhibitor with inotropic and vasodilator properties. The relative contributions of positive inotropy and vasodilation to the improvement in pump performance, however, remain uncertain. Therefore, findings from a series of dog experiments designed to resolve this issue are reviewed. Also, our current understanding of the physiologic response to enoximone in patients with cardiac failure, including the responses of myocardial oxygen consumption and efficiency, are considered. It is concluded that, enoximone produces a substantial (66 +/- 2% in dogs) increase in contractility, a relatively minor increase in heart rate (0 to 12%) and a decrease in systemic vascular resistance (-28 to -49%). These are the ranges of average responses based on review of published findings. These physiologic responses lead to an improvement in the pumping function of the failing heart; cardiac output (23 to 83%) and stroke work index (17 to 88%) are increased, and pulmonary capillary wedge pressure (-19 to -59%) and right atrial pressure (-29 to -60%) are decreased. The influence of enoximone on myocardial oxygen consumption is less consistent (-18 to +33%). Nevertheless, enoximone improves the efficiency of the failing heart.
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PMID:Physiologic response to the inotropic and vasodilator properties of enoximone. 295 62


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