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 ability of positive inotropic drugs to inhibit phosphodiesterase was assessed by observance of the potentiation of inotropic responses to the low intrinsic efficacy beta-adrenoceptor partial agonist prenalterol. Previous studies have shown that an increase in tissue stimulus response capability, as is produced for beta-adrenoceptors by blockade of phosphodiesterase, produces an increase in the maximal response to beta-adrenoceptor partial agonists. Using this principle, we tested cardiotonic drugs on normal and prenalterol-pretreated guinea pig left atria and compared the resulting inotropic responses statistically. Prenalterol pretreatment did not potentiate inotropic responses to methoxamine and CaCl2 and blocked (in accordance with beta-adrenoceptor occupation by a low-efficacy partial agonist) responses to norepinephrine (NE), tyramine, and to a certain extent ouabain. This latter finding was attributed to a low-level catecholamine-release by ouabain in this tissue. The inotropic responses to the phosphodiesterase inhibitors isobutylmethylxanthine (IBMX), theophylline, and enprophylline were greatly potentiated. Similarly, the responses to the cardiotonic drugs (known also to be inhibitors of phosphodiesterase) milrinone, amrinone, and fenoximone were potentiated. Positive inotropy to the cardiotonic drug sulmazole was not significantly potentiated by this procedure, indicating that in this tissue sulmazole may produce inotropic responses by other mechanisms as well. In general, this simple assay may be useful to detect blockade of cardiac phosphodiesterase concomitant with positive inotropy. Although a causal relationship between the PDE inhibition and positive inotropy may not be made from these data, knowledge of PDE blockade may still be useful in the assessment of inotropic mechanism and propensity for toxic side effects.
J Cardiovasc Pharmacol 1987 Dec
PMID:A method to assess concomitant cardiac phosphodiesterase inhibition and positive inotropy. 245 Feb 36

BM 14.478 (7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H pyrrolo[2,3-f]benz-imidazol-6-one) was investigated in several in vitro experiments to elucidate its positive inotropic and vasodilating efficacy and its mode of action. A direct positive inotropic action was achieved in papillary muscles (10(-6) to 5 X 10(-4) M) and electrically driven atria (10(-8) to 5 X 10(-4) M) from guinea pig hearts. The effect was not affected by propranolol, cimetidine, or tetrodotoxin, but diminished by carbachol. The effect of isoprenaline was amplified by threshold concentrations of BM 14.478 (10(-6) M). There was only a slight intrinsic chronotropic activity in spontaneously beating guinea pig atria. Atrial cyclic AMP (cAMP) was increased from 1.46 +/- 0.06 to 1.97 +/- 0.03 pmol/mg wet wt, at 3 X 10(-6) M. This might be due to an inhibition of cardiac phosphodiesterase(s) (PDE). IC50 of bovine PDE was 7.2 X 10(-5) M (5.4 X 10(-5) M to 9.7 X 10(-5) M). BM 14.478 shortened the duration of transmembrane action potential (90% repol.) by 8% and increased the Vmax of slow action potentials by 32% at 3 X 10(-4) M. In skinned porcine heart muscle fibers an increase in calcium-activated force up to 43 +/- 7% was observed (10(-7) to 10(-4) M). Rat aortas were relaxed by about 75% maximally (10(-7) to 10(-4) M). It is concluded that BM 14.478 is a potent inotropic drug which acts via an increase in myocardial cAMP content and in calcium sensitivity of contractile proteins.
J Cardiovasc Pharmacol 1988 Jan
PMID:In vitro investigations on a new positive inotropic and vasodilating agent (BM 14.478) that increases myocardial cyclic AMP content and myofibrillar calcium sensitivity. 245 Feb 61

alpha 1 Receptors have been investigated using a variety of experimental approaches. alpha 1-Receptor stimulation of phosphoinositide (PI) hydrolysis shows differences in agonist efficacy. The potency series and antagonists clearly suggest that alpha 1 receptors are coupled to phosphoinositide hydrolysis. This coupling appears to be mediated by a guanine nucleotide protein coupling the agonist-receptor complex to the phosphoinositide phosphodiesterase. However, certain alpha 1-agonists stimulate phosphoinositide hydrolysis only at very high concentrations that are not sensitive to prazosin antagonism. Other studies on alpha 1-receptor desensitization note discrepancies in coupling to phosphoinositide hydrolysis that are also found when comparing hypertensive (SHR) and normotensive (WKY) rats. Furthermore, molecular studies indicate that the apparent molecular weight of the alpha 1 receptors varies among tissues. These studies suggest heterogeneity in alpha 1 receptors and alpha 1-receptor-mediated responses. This heterogeneity is supported by studies on alpha 1-adrenergic-receptor-mediated decreases in angiotensin II receptors. The response to alpha 1 stimulation is opposite to that found with phorbol esters, which mimic the second messenger response to PI hydrolysis. Thus, these studies suggest that alpha 1-adrenergic receptors are coupled to multiple second messenger responses, one of which is phosphoinositide hydrolysis.
J Cardiovasc Pharmacol 1988
PMID:Alpha 1-adrenergic receptor stimulated responses. 245 24

DPN 205-734 [5-(4-cyanophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-3-carbo nitrile] was investigated in vitro in Langendorff rabbit hearts, guinea pig and rabbit papillary muscles, and rat myocardium and in vivo in anesthetized and unanesthetized dogs, pithed open-chest cats, anesthetized rats, and cardiomyopathic hamsters. In vitro, this substance caused a concentration-dependent positive inotropic effect. Left ventricular dP/dtmax was increased in anesthetized dogs after intravenous injection of 0.02 and 0.2 mg/kg (35 +/- 10 and 130 +/- 13%, respectively) and in unanesthetized dogs after oral doses of 0.05-0.5 mg/kg (15 +/- 2 to 71 +/- 14%). DPN 205-734 lowered blood pressure and total peripheral resistance in several experimental models, indicating an afterload-reducing effect. It induced moderate tachycardia. The positive inotropic effect is not explainable by beta-stimulation as shown in pithed open-chest cats pretreated with propranolol. A phosphodiesterase-inhibiting activity (IC50 = 35.5 microM), measured in rat myocardium, may be primarily responsible for the positive inotropic action. In guinea pig papillary muscles partially depolarized with 22 mM K+, DPN 205-734 in a concentration of 1 microM restored slow action potentials, which were then blocked by carbachol. These actions can be explained by the increase in cardiac cyclic AMP level due to a phosphodiesterase-inhibiting effect. In rabbit papillary muscles the positive inotropic effect of DPN 205-734 (100 microM) was only moderately inhibited by carbachol (3 microM), suggesting an additional mechanism.
J Cardiovasc Pharmacol 1988 Oct
PMID:Pharmacological actions of DPN 205-734, a novel cardiotonic agent. 246 46

The number of cardiac beta-adrenoceptors and the positive inotropic effect of isoprenaline and milrinone were measured in cardiac membranes and isolated, electrically driven muscle strips from nonfailing donor hearts and from patients with mitral valve disease (NYHA II-III), ischemic heart disease, and dilated cardiomyopathy (NYHA IV). In nonfailing hearts, the number of beta-adrenoceptors were 41.5 fmol/mg protein (mean, n = 3). In ischemic heart disease and NYHA II-III, there was a loss of cardiac beta-adrenoceptors (22.1 fmol/mg protein, mean, n = 3; 23.2 +/- 2.7 fmol/mg protein, n = 30), respectively. In NYHA IV, there was a pronounced reduction of the number of cardiac beta-adrenoceptors to 12.1 +/- 1.5 fmol/mg protein (n = 15). The Kd value did not differ in either group. Correspondingly, the positive inotropic effect of isoprenaline was more pronounced in nonfailing myocardium, reduced in NYHA II-III and ischemic heart disease and almost blunted in NYHA IV. Similar results were observed with the phosphodiesterase inhibitor milrinone. A good correlation of the beta-adrenoceptor density to the maximal positive inotropic effect of isoprenaline and milrinone was observed. Neither the number of cardiac beta-adrenoceptors nor the positive inotropic effect of isoprenaline correlated with the age of the patients. We conclude that the number of cardiac beta-adrenoceptors and the positive inotropic effect of beta-adrenoceptor agonists are reduced in the failing human heart depending on the severity of heart failure. Furthermore, the positive inotropic effect of milrinone is also reduced and related to the reduction of beta-adrenoceptors. The lack of correlation with the age of the patients provides evidence for a predominant role of heart disease rather than aging in the reduction of beta-adrenoceptors and subsensitivity to cyclic AMP-increasing positive inotropic agents in the failing human heart.
J Cardiovasc Pharmacol 1988 Dec
PMID:Subsensitivity of the failing human heart to isoprenaline and milrinone is related to beta-adrenoceptor downregulation. 246 92

The cardiovascular properties of MS-857 [4-acetyl-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone ], a novel cardiotonic agent, were investigated in anesthetized and conscious dogs. MS-857 (1-100 micrograms/kg i.v.) produced a significant and dose-dependent increase in cardiac contractility with relatively small changes in heart rate and blood pressure. This indicates a sizable separation between positive inotropic and other effects of MS-857. Oral administration of MS-857 to conscious dogs (0.1-1 mg/kg) also produced a sustained increase in cardiac contractility in a dose-dependent manner. The total duration of action was longer than 7 h at a dose of 1 mg/kg p.o. There occurred no arrhythmias and no changes in animal behavior. After chronic oral administration, MS-857 completely retained its activities, indicating the lack of tachyphylaxis. In the acute heart failure models induced by either propranolol or pentobarbital, MS-857 reversed the cardiac depressant effects of these drugs. Moreover, MS-857 also significantly improved the pentobarbital-induced heart failure in the heart-lung preparation. MS-857 did not inhibit the Na+, K+-ATPase, but inhibited the phosphodiesterase (PDE) III selectively, both of which were prepared from the dog ventricular muscle. Thus, MS-857 can be characterized as a potent nonsympathomimetic, nonglycoside cardiotonic drug with a selective inhibitory activity on PDE III. The cardiovascular properties revealed by this study strongly suggest that MS-857 will exert a beneficial effect in the treatment of congestive heart failure.
J Cardiovasc Pharmacol 1988
PMID:Cardiovascular properties of MS-857, a new and potent cardiotonic agent, on normal and failing hearts. 246 58

Contractile dose-response relationships for amrinone, milrinone, piroximone, and sulmazole were compared in right ventricular papillary muscles isolated from adult and 14-16-day-old immature rabbits. These drugs were effective inotropic agents in immature myocardium as evidenced by substantial increases in the maximal rate of tension development. The rank order of maximum inotropic effect in the immature muscles was milrinone = sulmazole greater than piroximone greater than amrinone. Compared with adults, the relative magnitude of the inotropic response for each drug was greater in immature myocardium. Profiles of ventricular cytosolic cyclic nucleotide phosphodiesterase (PDE) activities resolved by anion exchange chromatography were similar for the two age groups. Immature myocardium was found to contain the Type IV (Peak III) high-affinity cAMP PDE that has been implicated in the mechanism of action of these drugs. Partially purified cytosolic Type IV PDE from immature and adult myocardium exhibited similar kinetic characteristics (cAMP Km = 0.9 microM; Vmax = 17 nmol/min/mg) and sensitivity to inhibition by cGMP. Except for piroximone, the inhibitory effect of each drug on cytosolic Type IV PDE activity from immature myocardium did not differ from the adult, as indexed by comparable concentrations required to inhibit activity by 50% (IC50) and Ki values (piroximone IC50 and Ki values were higher in the immature compared with the adult group). Thus, these studies demonstrated significant age-related differences in the contractile responses to amrinone, milrinone, piroximone, and sulmazole. These differences are not attributable to differences in myocardial cytosolic Type IV high-affinity cAMP PDE activity.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1989 Jan
PMID:Inotropic responses to cyclic nucleotide phosphodiesterase inhibitors in immature and adult rabbit myocardium. 246 26

The purpose of the present study was to examine the interrelationships among phosphodiesterase (PDE) isozyme inhibition, cAMP formation, activation of cAMP-dependent protein kinase (cAPK), and positive inotropy in isolated guinea pig cardiac muscle mediated by the cardiotonic/vasodilator agent, milrinone. Milrinone was a potent and selective inhibitor of the "low Km" cAMP PDE isozyme (peak III) isolated by diethylaminoethyl ether cellulose chromatography, with IC50 values of 0.7 microM for peak III PDE and 100 microM for peak I PDE. In isolated papillary muscles frozen at peak inotropic responses, positive and significant correlations were evident between isometric force development as a function of cAMP content (r = 0.72, p less than 0.05) or cAPK activity ratio, an index of activation of cAPK (r = 0.79, p less than 0.001), for concentrations of milrinone from 0.1-1000 microM. Similar correlations were evident in muscles frozen at peak inotropic responses for the beta-adrenoreceptor agonist isoproterenol (r = 0.96, p less than 0.001; r = 0.98, p less than 0.001, respectively), but not for ouabain or Bay K-8644. The temporal sequence of these events was also quantitated for concentrations of milrinone (100 microM) and isoproterenol (3 nM) that produced approximately a 100% increase in isometric force. Whereas early time interval of force development (30 s, 1 min, isoproterenol; 30 s milrinone) were not accompanied by significant increases in either cAMP content or cAPK activity ratio, peak increases in force development for both isoproterenol (2 min) and milrinone (1 min) were related to peak increases in cAPK activity ratios. In summary, these results show that significant increases in cAMP content or cAPK activation are correlated with positive inotropy in isolated guinea pig papillary muscles with milrinone. These correlations occur at concentrations of milrinone that inhibit cardiac PDE isozymes and are similar to the known cAMP-dependent cardiostimulant isoproterenol. These data support the hypothesis that selective PDE isozyme inhibition is a mechanism by which milrinone effects positive inotropy.
J Cardiovasc Pharmacol 1989 Apr
PMID:Phosphodiesterase isozyme inhibition, activation of the cAMP system, and positive inotropy mediated by milrinone in isolated guinea pig cardiac muscle. 247 Sep 89

The role of structural features of sulmazole, an imidazo(4,5-b)pyridine, in its inotropic action was examined by comparison with its reduced (4-methylthiophenyl) analog EMD 46512 and the corresponding imidazo(4,5-c)pyridine isomers isomazole and EMD 41000 on isolated guinea-pig papillary muscles and right atria and on Na,K-ATPase and phosphodiesterase III isolated from guinea-pig hearts. The pyridine nitrogen position in sulmazole was crucial for affinity to Na,K-ATPase (IC50 = 350 microM) because the imidazo(4,5-c)pyridines had little effect. Participation of Na,K-ATPase inhibition in sulmazole's inotropic effect (EC50 = 180 microM) was suggested by synergism with the Na channel activator germitrine. The methylsulfinyl oxygen at the phenyl ring decreased the affinity to Na,K-ATPase of sulmazole 40-fold: The reduced analog EMD 46512 was a potent inhibitor of Na,K-ATPase (IC50 = 8.5 microM) and a more potent inotropic agent (EC50 = 8.2 microM) that appeared to act predominantly through Na,K-ATPase inhibition. Micromolar through Na,K-ATPase inhibition. Micromolar IC50s for inhibition of phosphodiesterase III were 49 (sulmazole), 34 (EMD 46512), 18 (isomazole), and 13 (EMD 41000). Participation of this mechanism in the inotropic effect of sulmazole, isomazole, and EMD 41000, but not EMD 46512, was indicated by augmentation of slow action potentials, synergism with histamine, inhibition by carbachol, and (with the exception of EMD 41000) a positive chronotropic effect on the right atrium. Sulmazole appeared to combine the actions of its 4-methylthiophenyl analog EMD 46512 (an inhibitor of Na,K-ATPase) and of its imidazo(4,5-c)pyridine isomer isomazole (an inhibitor of phosphodiesterase III).
J Cardiovasc Pharmacol 1989 May
PMID:Imidazopyridines: roles of pyridine nitrogen position and methylsulfinyl oxygen for in vitro positive inotropic mechanism and chronotropic activity. 247 14

A cardiac phosphodiesterase (PDE) which specifically hydrolyzes cAMP and is inhibited by cyclic GMP has been suggested to be the site of action of new cardiotonic drugs. To investigate the effect of inhibitors, canine cyclic nucleotide PDEs were isolated from left ventricle and from sinoatrial node-enriched tissue, using identical techniques. Four PDE forms could be chromatographically resolved from each tissue, including a peak I PDE (calmodulin-activated phosphodiesterase, CaM-PDE), a peak II PDE (cyclic GMP-stimulated phosphodiesterase, CGS-PDE) and a peak III PDE (specific for cyclic AMP). The latter was further fractionated into two forms: One was inhibited by cyclic GMP and by the platelet antiaggregant AAL 05 (CGI-PDE), and the second was insensitive to cyclic GMP and was inhibited by rolipram (ROI-PDE). Reference PDE inhibitors, isobutyl-1-methylxanthine (IBMX) and papaverine, nonselectively inhibited the four forms isolated from the two tissues. Cardiotonic drugs (CI 930, LY 181512, piroximone, enoximone, and SK&F 94120) selectively inhibited CGI-PDE from ventricular tissue but were poorly active on both CGI-PDE and ROI-PDE from the sinoatrial-enriched fraction. In contrast, milrinone inhibited CGI-PDEs and ROI-PDEs from both ventricular and sinoatrial tissues. These results are in good agreement with pharmacologic data in the literature on the positive chronotropic and inotropic effects of the studied drugs in the dog. They provide a possible basis for the dissociation of these two properties of PDE inhibitors.
J Cardiovasc Pharmacol 1989 Aug
PMID:Differential sensitivity to cardiotonic drugs of cyclic AMP phosphodiesterases isolated from canine ventricular and sinoatrial-enriched tissues. 247 93


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