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

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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 available literature on the evaluation of diastolic function, the importance of diastolic dysfunction in congestive heart failure (CHF), and the effects of therapeutic agents on diastolic dysfunction are summarized. The normal cardiac cycle consists of two components: systole (contraction; ventricular emptying) and diastole (dilation; ventricular filling). Recent studies have shown that 30-40% of patients with CHF have normal systolic function; the majority of these patients have diastolic dysfunction as the underlying disorder. As a result, the role of diastolic dysfunction in CHF is currently an area of interest for researchers. The two primary causes of diastolic dysfunction are left ventricular hypertrophy and ischemic heart disease. Patients with CHF caused by diastolic dysfunction and patients with CHF caused by systolic dysfunction have nearly identical clinical presentations. Therapy with diuretics, vasodilators, angiotensin-converting-enzyme inhibitors, beta-agonists, the partial beta-agonist xamoterol, phosphodiesterase III inhibitors, or calcium-channel blockers may be beneficial in patients with diastolic dysfunction. Therapy with digitalis glycosides would be of no benefit, and could theoretically be detrimental, in patients with predominant diastolic dysfunction. Available data indicate that beta blockers have neither an important beneficial effect nor an important detrimental effect on diastolic function. Continued studies into diastolic dysfunction and the diastolic properties of agents that are used in the treatment of CHF should enhance the understanding of this clinical syndrome and the drugs used to treat it.
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PMID:Diastolic dysfunction in congestive heart failure. 179 21

In heart failure, many alterations occur in the ventricle as a whole, as well as in the myocardial cell. In the first part of this review we report on the macroscopic structure of the left ventricle by analysing the relation between left ventricular dilatation and left ventricular hypertrophy in terms of ventricular wall stress. Peak systolic stress in dilated ventricles of patients with compensated heart failure does not differ from values obtained in normal ventricles, whereas the systolic stress-time integral is increased by more than 40%. The stress-time integral is a major determinant of myocardial oxygen consumption, and its reduction by peripheral vasodilation leads to a proportional decrease in left ventricular oxygen consumption. In contrast, the phosphodiesterase inhibitor, enoximone, decreases the stress-time integral without a proportional decrease in myocardial oxygen consumption, due to the competition between positive inotropic effect with increased oxygen consumption and a vasodilating effect with decreased oxygen consumption. Beta-1 adrenoceptor agonists increase myocardial oxygen consumption. In the second part of this review we report on the functional alterations of the following subcellular and molecular structures in the failing myocardium: (1) adrenoceptors and G-proteins; (2) sarcoplasmic reticulum with an altered force-frequency relationship; (3) the acto-myosin system with decreased velocity of shortening and increased economy of force generation. On the basis of these alterations, a disadvantageous chain of events develops in the failing myocardial cell.
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PMID:The heart in heart failure. Ventricular and myocardial alterations. 183 95

Left ventricular hypertrophy (LVH) produced by aortic valve plication leads to increased myocardial cyclic GMP. We tested whether this was a result of increased soluble guanylate cyclase activity or nitric oxide (NO) synthase and its functional consequences. We used the nitric oxide donor 3-morpholino-sydnonimine (SIN-1) or the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME) in 12 control and 12 LVH anesthetized open-chest mongrel dogs. L-NAME (6 mg/kg) or SIN-1 (1 microgram/kg per min) was infused into the left anterior descending coronary artery and regional segment work and cyclic GMP levels were determined. In vitro myocardial guanylate cyclase sensitivity (0.43 +/- 0.04 to 0.28 +/- 0.04 mM [EC50]) and maximal activity (10.1 +/- 2.9 to 25.5 +/- 6.5 pmol/mg protein per min) were significantly increased in LVH as compared with control animals in response to nitroprusside stimulation, but cyclic GMP-phosphodiesterase activity was similar. In LVH dogs, basal cyclic GMP was significantly elevated in vivo when compared with controls. Treatment of dogs with SIN-1 resulted in a significant increase in cyclic GMP in control (1.09 +/- 0.12 to 1.48 +/- 0.19 pmol/gram) and a greater increase in the LVH group (1.78 +/- 0.16 to 3.58 +/- 0.71 pmol/g). L-NAME had no effect on myocardial cyclic GMP levels in control or LVH dogs. Segment work decreased in the control group after SIN-1 (1,573 +/- 290 to 855 +/- 211 grams x mm/min). LVH dogs showed no decrement in work as a result of treatment with SIN-1. L-NAME did not cause significant changes in myocardial cyclic GMP, O2 consumption, or work in either control or LVH dogs, but vascular effects were evident. SIN-1 increased cyclic GMP, and with greater effect on LVH; however, this resulted in a decrement in function only in the control group. The greater increased cyclic GMP in LVH dogs is not related to increased NO production, but is related to significantly higher sensitivity and maximal activity of soluble myocardial guanylate cyclase.
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PMID:Increased guanylate cyclase activity is associated with an increase in cyclic guanosine 3',5'-monophosphate in left ventricular hypertrophy. 869 76

Understanding the mechanism of action and the pharmacokinetic properties of vasodilatory drugs facilitates optimal use in clinical practice. It should be kept in mind that a drug belongs to a class but is a distinct entity, sometimes derived from a prototype to achieve a specific effect. The most common pharmacokinetic drug improvement is the development of a drug with a half-life sufficiently long to allow an adequate once-daily dosage. Developing a controlled release preparation can increase the apparent half-life of a drug. Altering the molecular structure may also increase the half-life of a prototype drug. Another desirable improvement is increasing the specificity of a drug, which may result in fewer adverse effects, or more efficacy at the target site. This is especially important for vasodilatory drugs which may be administered over decades for the treatment of hypertension, which usually does not interfere with subjective well-being. Compliance is greatly increased with once-daily dosing. Vasodilatory agents cause relaxation by either a decrease in cytoplasmic calcium, an increase in nitric oxide (NO) or by inhibiting myosin light chain kinase. They are divided into 9 classes: calcium antagonists, potassium channel openers, ACE inhibitors, angiotensin-II receptor antagonists, alpha-adrenergic and imidazole receptor antagonists, beta 1-adrenergic agonist, phosphodiesterase inhibitors, eicosanoids and NO donors. Despite chemical differences, the pharmacokinetic properties of calcium antagonists are similar. Absorption from the gastrointestinal tract is high, with all substances undergoing considerable first-pass metabolism by the liver, resulting in low bioavailability and pronounced individual variation in pharmacokinetics. Renal impairment has little effect on pharmacokinetics since renal elimination of these agents is minimal. Except for the newer drugs of the dihydropyridine type, amlodipine, felodipine, isradipine, nilvadipine, nisoldipine and nitrendipine, the half-life of calcium antagonists is short. Maintaining an effective drug concentration for the remainder of these agents requires multiple daily dosing, in some cases even with controlled release formulations. However, a coat-core preparation of nifedipine has been developed to allow once-daily administration. Adverse effects are directly correlated to the potency of the individual calcium antagonists. Treatment with the potassium channel opener minoxidil is reserved for patients with moderately severe to severe hypertension which is refractory to other treatment. Diazoxide and hydralazine are chiefly used to treat severe hypertensive emergencies, primary pulmonary and malignant hypertension and in severe preeclampsia. ACE inhibitors prevent conversion of angiotensin-I to angiotensin-II and are most effective when renin production is increased. Since ACE is identical to kininase-II, which inactivates the potent endogenous vasodilator bradykinin, ACE inhibition causes a reduction in bradykinin degradation. ACE inhibitors exert cardioprotective and cardioreparative effects by preventing and reversing cardiac fibrosis and ventricular hypertrophy in animal models. The predominant elimination pathway of most ACE inhibitors is via renal excretion. Therefore, renal impairment is associated with reduced elimination and a dosage reduction of 25 to 50% is recommended in patients with moderate to severe renal impairment. Separating angiotensin-II inhibition from bradykinin potentiation has been the goal in developing angiotensin-II receptor antagonists. The incidence of adverse effects of such an agent, losartan, is comparable to that encountered with placebo treatment, and the troublesome cough associated with ACE inhibitors is absent.
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PMID:Clinical pharmacokinetics of vasodilators. Part I. 964 8

This study was designed to test whether increased inotropy caused by raising intracellular cAMP would add to the positive inotropy caused by reducing cGMP and whether this relationship was affected by experimental hypertrophy. We used open chest anesthetized dogs with left ventricular hypertrophy (LVH) induced by valvular aortic stenosis and age matched controls (CON). Hearts were instrumented to measure local segment shortening, force, and regional work. Milrinone (MIL), a selective cyclic AMP-phosphodiesterase inhibitor, and methylene blue (MB), a guanylate cyclase inhibitor, were used to alter cAMP and cGMP levels. Ten CON and 11 LVH animals were randomly assigned to receive first either MIL (1 microg/kg/min) or MB (2 mg/kg/min) intracoronary (i.c.) infusion. After 10 min, simultaneous i.c. infusion of the other agent was begun. MIL increased regional minute work (g x mm/min) in both CON (1311 +/- 207 to 2072 +/- 285) and LVH (1052 +/- 136 to 1371 +/- 351) hearts. MB did not increase work significantly, but did increase contractile force. MIL + MB increased work from baseline; however, the combination did not increase work more than either agent alone (1961 +/- 510 CON; 1390 +/- 285 LVH). Myocardial cAMP levels (pmol/g) were significantly increased by MIL in both CON (329 +/- 53 to 437 +/- 13) and LVH hearts (351 +/- 67 to 538 +/- 32), and the addition of MB further raised cAMP (879 +/- 115 CON; 741 +/- 96 LVH). MB resulted in decreased myocardial cGMP (pmol/g) (3.20 +/- 0.61 to 2.16 +/- 0.92 CON; 5.21 +/- 1.15 to 2.46 +/- 0.56 LVH), while MIL increased cGMP (3.20 +/- 0.61 to 6.24 +/- 1.79 CON; 5.21 +/- 1.15 to 6.53 +/- 0.41 LVH). Both MIL and MB caused increases in O2 consumption, with MIL + MB together increasing O2 consumption further. The current findings demonstrate a potentiation of cAMP production in the presence of MIL + MB above either agent alone, but this did not lead to potentiation of positive functional effects. High levels of cGMP caused by milrinone may have limited the positive functional effects of cAMP.
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PMID:Positive functional effects of milrinone and methylene blue are not additive in control and hypertrophic canine hearts. 969 27

We investigated the effects of long-term treatment with a selective phosphodiesterase 5 inhibitor E4010, 4-(3-chloro-4methoxybenzyl)amino-1-(4-hydroxypiperidino)-6-phth alazin ecarbonitrile monohydrochloride, on the survival rate of rats with pulmonary hypertension induced by monocrotaline (MCT). After an s.c. injection of 40 mg/kg MCT (day 0), male Wistar rats of 4 weeks of age were divided into four groups. Vehicle-treated rats (control, n = 8) and MCT-treated rats (n = 32) were fed a commercial diet. E4010-treated rats were given a commercial diet containing 0.01% (E4010 0.01%, n = 32) and 0.1% (E4010 0.1%, n = 32) of E4010, respectively. At day 23, all rats in the control group and 28.1% of those in the MCT group (P <.01 versus control) were alive. Although the survival rate of E4010 0.01%-treated rats was not improved (50%) compared with MCT, those at 0.1% showed a significant difference (84. 4%, P <.01 versus MCT). For MCT rats (n = 9), right ventricle weight and the levels of plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cGMP, and cyclic AMP were higher compared with control (n = 8). In E4010 0.1%-treated rats (n = 27), the right ventricular hypertrophy was suppressed, and the increase in plasma cGMP level was amplified compared with MCT without any effects on plasma ANP, BNP, and cyclic AMP levels. Accordingly, we consider that the mechanism of action of E4010 may be related to the decreased pulmonary arterial pressure caused by the augmentation of pulmonary arterial relaxation through an ANP and/or BNP-cGMP system. These results suggest that E4010 will be useful for the treatment of pulmonary hypertension.
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PMID:Improvement of mortality by long-term E4010 treatment in monocrotaline-induced pulmonary hypertensive rats. 1041 87

The purpose of this study was to determine whether E-4010, a newly synthesized potent and selective orally active phosphodiesterase (PDE) 5 inhibitor, would prevent the development of chronic hypoxia-induced pulmonary hypertension in rats. In conscious, pulmonary hypertensive rats, a single oral administration of E-4010 (1.0 mg/kg) caused an acute, long-lasting reduction in mean pulmonary arterial pressure (PAP), with no significant effects on systemic arterial pressure, cardiac output, and heart rate. In rats that received food containing 0.01 or 0.1% E-4010 during the 3-wk exposure to hypoxia, mean PAP was significantly decreased (mean PAP 24.0 +/- 0.9, 16.2 +/- 0.8, and 12.8 +/- 0.5 mmHg in rats treated with 0, 0.01, and 0.1% E-4010-containing food, respectively), whereas mean systemic arterial pressure was unchanged and cardiac output was slightly increased compared with chronically hypoxic control rats. Right ventricular hypertrophy, medial wall thickness in pulmonary arteries corresponding to the respiratory and terminal bronchioles, and the degree of muscularization of more distal arteries were less severe in E-4010-treated rats. Long-term treatment with E-4010 caused an increase in cGMP levels in lung tissue and plasma but not in aortic tissue and no significant change in cAMP levels in either lung, aorta, or plasma. These results suggest that long-term oral treatment with E-4010 reduced the increase in PAP, right ventricular hypertrophy, and pulmonary arterial remodeling induced by exposure to chronic hypoxia, probably through increasing cGMP levels in the pulmonary vascular smooth muscle.
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PMID:E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats. 1044 15

1. Hypertension leads to ventricular hypertrophy and, eventually, to heart failure. The present study has investigated the functional consequences of deoxycorticosterone acetate (DOCA)-salt hypertension in rats by defining the inotropic, chronotropic and vascular responses to noradrenaline (NA; beta1-adrenoceptor agonist), forskolin (adenylate cyclase activator) and theophylline (phosphodiesterase inhibitor). 2. Administration of DOCA (25 mg, s.c., every 4th day) and excess salt (1% NaCl in drinking water) to uninephrectomized rats increased left ventricular wet weight by 35 and 71% after 4 and 8 weeks, respectively. Addition of KCl (0.4%) or CaCl2 (1%) in the drinking water for 4 weeks attenuated blood pressure increases, but not ventricular weight increases (46 and 28%, respectively). 3. Positive inotropic responses in papillary muscles from uninephrectomized rats to NA (-log EC50 6.73+/-0.38; n = 7), forskolin (-log EC50 6.15+/-0.31; n = 7) and CaCl2 (-log EC50 2.40+/-0.02; n = 14) were unchanged in hypertrophied left ventricles of DOCA and DOCA-CaCl2 rats, although maximal responses to NA were decreased in DOCA-KCI rats (1.2+/-0.6 mN, n = 8; DOCA-salt 2.9+/-0.5 mN, n = 6); theophylline was less potent in DOCA-salt rats. Positive chronotropic responses to NA, forskolin and theophylline in right atria and negative inotropic responses to carbachol in papillary muscles were unchanged. 4. Maximal vasoconstrictor responses to NA in thoracic aortic rings were reduced in DOCA-KCI rats to 2.4+/-0.9 mN (n = 5), but were increased in DOCA-CaCl2 rats to 26.6+/-2.2 mN (n = 7; DOCA-salt 7.8+/-2.2 mN, n = 9). Vasorelaxant responses to forskolin and theophylline were unchanged. 5. These results show that cardiac responses are only minimally affected during the development of DOCA-salt hypertension-induced hypertrophy, despite the reported decreases in adenylate cyclase activity, in these rats. This is in contrast with the decreased responses reported in other rat models of cardiac hypertrophy and in the failing human heart. Thus, hypertrophy in hearts of DOCA-salt hypertensive rats does not produce similar changes to the failing human heart.
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PMID:Cardiac and vascular responses in deoxycorticosterone acetate-salt hypertensive rats. 1077 23

We recently demonstrated that rapid ventricular pacing caused cardiac failure (Failure) in dogs with aortic stenosis-induced left ventricular hypertrophy (Hypertrophy) and isoproterenol caused no significant increases in function, O2 consumption and intracellular cyclic AMP level in the failing hypertrophied hearts. We tested the hypothesis that alterations in the beta1-adrenoceptor-signal transduction pathway would correlate with the reduced functional and metabolic responses to beta-adrenergic stimulation during the transition from the compensated hypertrophy to failure. Pressure overload-induced left ventricular hypertrophy was created using aortic valve plication in 10 dogs over a 6-month period. Five months after aortic valve plication, congestive heart failure was induced in 5 dogs by rapid ventricular pacing at 240 bpm for 4 weeks. The density of myocardial beta1-adrenoceptors (fmoles/mg membrane protein; fmoles/g wet tissue) was significantly reduced in the Failure dogs (176+/-19; 755+/-136) when compared to those of the Control (344+/-51; 1,551+/-203) and the Hypertrophy (298+/-33; 1,721+/-162) dogs. The receptor affinities were not significantly different among all groups. There was a small but significant decrease in the percentage of beta1-adrenoceptors of the failing hypertrophied hearts (62+/-3%) when compared to that of the hypertrophied hearts (77+/-5%). The basal myocardial adenylyl cyclase activity (pmoles/mg protein/min) was significantly lower in the Failure dogs (45+/-4) than in the Control (116+/-14) and Hypertrophy (86+/-6) dogs. The forskolin (0.1 mM)-stimulated adenylyl cyclase activity was also significantly lower in the Failure dogs (158+/-17) than in the Control dogs (296+/-35) and slightly lower than in the Hypertrophy dogs (215+/-10). There were no significant differences in low Km cyclic AMP-phosphodiesterase activities among all groups. We conclude that down regulation of beta1-adrenoceptors and reduced adenylyl cyclase activities contribute to the decreases in myocardial functions and beta-adrenergic responses in the failing hypertrophied hearts induced by rapid ventricular pacing.
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PMID:Down regulation of myocardial beta1-adrenoceptor signal transduction system in pacing-induced failure in dogs with aortic stenosis-induced left ventricular hypertrophy. 1082 23

In this study, we evaluated the effects of oral administration of DA-8159, a selective phosphodiesterase-5 inhibitor, on the development of pulmonary hypertension (PH) induced by monocrotaline (MCT). Rats were administered either MCT (60 mg/kg) or saline. MCT-treated rats were divided into three groups and received orally administered vehicle, or 1 mg/kg or 5 mg/kg of DA-8159, twice a day for twenty-one days. The MCT group demonstrated increased right ventricular weights, medial wall thickening in the pulmonary arteries, myocardial fibrosis and the level of plasma cyclic guanosine monophosphate (cGMP), along with decreased body weight gains. However, DA-8159 markedly and dose-dependently reduced the development of right ventricular hypertrophy and medial wall thickening. DA-8159 also amplified the increase in plasma cGMP level and significantly increased the level of lung cGMP, compared with the MCT group. Although the body weight gain was still lower from the saline-treated control group, DA-8159 demonstrated a significant increase in body weight gains, in both 1 mg/kg and 5 mg/kg groups, when compared with the MCT group. In myocardial morphology, MCT-induced myocardial fibrosis was markedly prevented by DA-8159. These results suggest that DA-8159 may be a useful oral treatment option for PH.
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PMID:DA-8159, a potent cGMP phosphodiesterase inhibitor, attenuates monocrotaline-induced pulmonary hypertension in rats. 1296 96


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