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Query: pde 4
 1,625 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute myocardial dysfunction during cardiac surgery involves various pathophysiologic mechanisms such as reduction in myocardial contractility and an increase in afterload induced by peripheral vasoconstriction. In 30 consecutive patients undergoing coronary artery bypass grafting (CABG) and ten consecutive patients with aortic valve replacement (AVR), in whom therapy with catecholamines was expected to be necessary during and after weaning from cardiopulmonary bypass (CPB) on the basis of a retrospective study ("control" patients), 1.0 mg/kg of the phosphodiesterase (PDE) inhibitor enoximone was administered ten minutes prior to weaning from bypass (enoximone group). In eight CABG and four AVR patients weaning was possible without further pharmacologic support. Significantly less epinephrine was used in enoximone pretreated patients (8.8 +/- 3.0 micrograms/min) than in the control patients (21.4 +/- 4.4 micrograms/kg). The use of additional vasodilators was significantly less pronounced in these patients as well. Seven CABG and four AVR patients in the enoximone group needed additional vasoconstrictors (norepinephrine) to counteract marked, unwanted decrease in peripheral vascular resistance with a decrease in mean arterial pressure (MAP). Hemodynamic monitoring revealed a higher level in heart rate in the control patients with arrhythmia in seven of the CABG patients: MAP, right atrial pressure, cardiac index, and pulmonary capillary wedge pressure were without significant differences between the groups. Pulmonary artery pressure and TSR, however, increased more in the control group, indicating an increase in right and left ventricular afterload. The results of this study demonstrate that patients at risk of circulatory failure during or after weaning from CPB profit from pretreatment with PDE-III inhibitor enoximone due to a reduction in catecholamines and an improvement in hemodynamics.
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PMID:Efficacy of the phosphodiesterase inhibitor enoximone in complicated cardiac surgery. 214 12

A dissipative system is approximated by a nonlinear rate equation: Z congruent to K1Z - K2Z3 (K2 greater than 0), in which the right side is derived from -delta G/delta Z of Taylor's series of the thermodynamic potential given by Gibbs' function G(Tc, Pc) (Z) at about the critical point C(Tc, Pc) of the control variables (parameters) T and P. The stability or instability of the system is treated by the changes in the control parameters. In the case that T not equal to P not equal to 0 in the steady state, Z = 0, and T and P pass the point C, K1 becomes negative. By this change, the G function is convex at Z = 0 and each product is created rapidly with concentration or number of the molecules Z = ([K1]/K2)1/2. This dynamic theory is applied to enzyme cascades. Based on cyclic GMP (cGMP) hypothesis in visual transduction, the cascade hydrolysis of cGMP of vertebrates is analyzed by dividing it into two-step reaction cascades: The initial process is that metarhodopsin II catalyzes the exchange of GDP for GTP by transducin (Gtd) and that GTP-Gtd complex is hydrolyzed to GDP-Gtd complex. In the following cascade cGMP is hydrolyzed with amplification of phosphodiesterase (PDE) activated by the removal of the small inhibitory subunit. The quantity of the hydrolysis of cGMP is estimated as approximately 5 x 10(4-5) molecules per photolyzed rhodopsin semiempirically, and this coincides well with experiments.
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PMID:Chemical model of reaction cascades induced by activated enzymes or catalysts. Two-step cascades in visual transduction. 215 20

Cyclic nucleotide phosphodiesterases (PDEs) from canine trachealis were characterized with respect to their kinetic properties, sensitivity to selective inhibitors, and subcellular distribution. Extracts from whole tissue homogenates were applied to DEAE-Sepharose anion exchange columns and eluted with a linear sodium acetate gradient. Three major peaks of PDE activity were resolved. The first (PDE I), which eluted at 0.2 M sodium acetate, was applied to a calmodulin (CaM)-Sepharose affinity column and resolved into CaM-insensitive and CaM-sensitive PDEs. The CaM-insensitive isozyme (PDE Ia) had apparent Km values of 135 microM (cAMP) and 4 microM (cGMP) and was potently inhibited by zaprinast (Ki = 0.1 microM). The CaM-sensitive isozyme (PDE Ic) had apparent Km values of 1 microM (cAMP) and 2 microM (cGMP) and was inhibited by zaprinast with an apparent Ki of 35 microM. The second peak of activity (PDE II) from the anion exchange column eluted at 0.3 M sodium acetate and had apparent Km values of 93 microM (cAMP) and 60 microM (cGMP). The enzyme displayed positive cooperativity with respect to the hydrolysis of cAMP (nH = 1.7). Low concentrations of cGMP (0.1-1 microM) reduced cooperativity (nH = 1.1) and increased the hydrolysis of 1 microM cAMP. The third peak of activity from the anion exchange column eluted at 0.6 M sodium acetate and displayed anomalous kinetics that suggested the presence of two isozymes. This was supported by the observation that enzyme activity was only partially inhibited by SK&F 94120 or Ro 20-1724 but was abolished by the combination of the two PDE inhibitors. Subsequent studies confirmed the existence of two isozymes. The first, PDE III, had apparent Km values of 0.3 microM (cAMP) and 8 microM (cGMP) and was inhibited by cGMP (IC50 = 0.1 microM), SK&F 94120 (Ki = 7.8 microM), and SK&F 94836 (Ki = 0.4 microM). The second, PDE IV, had apparent Km values of 4 microM (cAMP) and 40 microM (cGMP) and was inhibited by Ro 20-1724 (Ki = 5.2 microM) and rolipram (Ki = 0.5 microM) but not by cGMP. Assessment of the 100,000 x g soluble and particulate PDE activity revealed that all five isozymes were present in the soluble fraction, but only four isozymes (PDEs Ia, Ic, III, and IV) were present in the particulate fraction. These results indicate that five distinct PDE isozyme exist in canine trachealis and that these isozymes differ in their kinetic characteristics, sensitivity to activators and inhibitors, and subcellular distribution.
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PMID:Characterization and selective inhibition of cyclic nucleotide phosphodiesterase isozymes in canine tracheal smooth muscle. 215 70

1. The effects of siguazodan (SK&F 94836) a selective phosphodiesterase (PDE) inhibitor with inotropic and vasodilator activity, were studied on human platelets. 2. Siguazodan selectively inhibited the major cyclic AMP-hydrolysing PDE in human platelet supernatants. The inhibited enzyme has been variously termed cyclic GMP-inhibited PDE or PDE-III. 3. In platelet-rich plasma (PRP), siguazodan inhibited U46619-induced aggregation more potently than that induced by ADP and collagen. Treatment of the PRP with aspirin had no effect on the potency of siguazodan. 4. In washed platelets, siguazodan increased cyclic AMP levels and reduced cytoplasmic free calcium [( Ca2+]i). ADP decreased the ability of siguazodan to raise cyclic AMP and this may explain its lower potency in inhibiting responses to ADP. 5. Siguazodan has anti-platelet actions over the same concentration range that it is an inotrope and vasodilator.
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PMID:The effects of siguazodan, a selective phosphodiesterase inhibitor, on human platelet function. 215 47

To evaluate the role of domain I of calmodulin (CaM) in the activation of target enzymes, a series of CaM mutants was constructed in which domain I (49 amino acids) was substantially deleted, or was exchanged with the homologous region (58 amino acids) of cardiac troponin C (cTnC). The proteins are 1) aM, a mutant CaM in which domain I has been deleted; 2) TaM, first domain of cTnC, last three domains of CaM; 3) TaM-BMI, same as TaM, except the nonfunctional first Ca2(+)-binding domain has been restored by mutagenesis; 4) CaT, first domain of CaM, last three domains of cTnC. These proteins were evaluated for Ca2+ binding properties and as activators of three CaM target enzymes, CaM-dependent phosphodiesterase (PDE), smooth muscle myosin light chain kinase (MLCK), and CaM-dependent multifunctional protein kinase (CaM kinase II). The chimeric proteins containing four domains bound Ca2+ in the manner expected from the number and nature of EF hands. In contrast, aM bound only two Ca2+, suggesting that deletion of domain I may have disrupted binding in one of the remaining three domains, and did not activate the three enzymes. The kinetics of activation of PDE by CaM, TaM, and TaM-BMI were identical. Although cTnC and CaT could maximally activate PDE, the Kact for these mutants were greater than 2000 times than for CaM. All mutated proteins except CaT were poor activators of CaM kinase II and this protein activated the kinase to 65% that of CaM, with a nearly identical Kact. CaT and TaM, were poor agonists of MLCK. Activation of Ca2(+)-binding site I in TaM (TaM-BMI), completely prevented activation of MLCK. In addition, TaM-BMI was a potent competitive inhibitor of MLCK activation by CaM (Ki = 66 nM). We conclude 1) a domain I is necessary to activate these target enzymes, and the substitution of the corresponding region of cTnC into CaM leads to differential effects; 2) an active first Ca2(+)-binding site is not essential for activation of PDE and the primary sequence of the first domain of CaM need not be highly conserved; 3) for CaM kinase II, determinants in the first domain are critical whereas more flexibility exists for the remaining three domains; 4) since TaM-BMI acts as a potent competitive inhibitor of MLCK binding of CaM to a target enzyme and activation can be dissociable events.
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PMID:Chimeric calmodulin-cardiac troponin C proteins differentially activate calmodulin target enzymes. 216 Sep 66

The effects of Ca2+ antagonists (nicardipine, felodipine, nitrenedipine, isradipine, niphedipine, darodipine and riodipine) and Ca2+ agonists (BAY K8644 and CGP 28392), 1.4-dihydropyridine derivatives (1.2-DHP), on the calmodulin (CM)-dependent activation of cyclic nuxleotide phosphodiesterase (PDE) were studied. Both the blockers and activators of slow potential-dependent Ca2+ channels induced a un-competitive inhibition of the CM-dependent PDE activity. 1.4-DHP was found to replace the fluorescent probe, diS-C3-(5), from the Ca2(+)-dependent calmodulin-dye complex (K0.5 = 4-60 microM) but at concentrations below 100 microM had no effect on the Ca2(+)-dependent troponin C-dye complex. Darodipine (100 microM) did not interact with the proteins. The 1.4-DHP interaction with CM did not interfere with PDE activation. It is concluded that 1.4-DHP may affect Ca2+ dependent processes not only at the levels of activation or blocking of Ca2+ channels, but also through regulation of Ca2(+)-CM dependent enzymes.
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PMID:[Interaction of calcium agonists and antagonists with Ca-binding proteins and their effect on cyclic nucleotide phosphodiesterase]. 216 22

The characteristics of the binding of the 1,4-dihydropyridine Ca2+ antagonist, 2-nitratopropyl 3-nitratopropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine 3,5-dicarboxylate (CD-349), to calmodulin (CaM) and the effect of CD-349 on the Ca2+/CaM-dependent enzyme, cyclic GMP (cGMP) phosphodiesterase (PDE), were investigated. CD-349 showed a Ca2(+)-dependent binding to CaM, in equilibrium column binding studies. CD-349 inhibited the [3H]CD-349 binding to CaM, at a concentration producing a 50% inhibition (IC50) of 2.4 microM, whereas the CaM antagonist, trifluoperazine hydrochloride (TFP), stimulated the [3H]CD-349 binding to CaM. Scatchard plot analysis of the binding of CD-349 to CaM revealed that the apparent dissociation constant (Kapp) of CD-349 was 2.1 microM and the maximal number of binding sites (Bmax) of CD-349 was 1.0 nmol/nmol CaM. In the presence of TFP, the Kapp and Bmax values of CD-349 binding to CaM were changed to 1.1 microM and 1.5 nmol/nmol CaM respectively. Although the CaM antagonists, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7) and TFP, decreased and increased, respectively, the fluorescence intensity caused by 2-p-toluidinylnaphthalene-6-sulfonic acid (TNS)-CaM binding, CD-349 only slightly decreased the fluorescence of TNS bound CaM. CD-349 inhibited both basal and Ca2+/CaM-activated cGMP PDE activity. However, CaM did not competitively antagonize the CD-349-induced inhibition of the Ca2+/CaM-activated PDE activity. In addition, the kinetic study showed that CD-349 inhibited both basal and Ca2+/CaM-activated cGMP PDE activity, competitively with cGMP, with almost the same inhibition constant (Ki). These results suggest that CD-349 binds to CaM, with Ca2+ dependency, at sites differing from those which bind to the CaM antagonist. The inhibitory activity of CD-349 on Ca2+/CaM-dependent PDE does not seem to be due to a CaM antagonistic action.
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PMID:Interaction of the dihydropyridine calcium antagonist, CD-349, with calmodulin. 216 84

1. The pharmacological and biochemical effects of a novel cardiotonic agent, Org10325 have been studied in isolated cardiac and vascular tissue preparations. 2. Org10325 produced concentration-dependent (0.15-4.8 mM) positive inotropic, positive chronotropic and vascular relaxant responses in rabbit isolated papillary, atrial and aortic preparations, respectively. The maximal chronotropic effect (45%) was significantly less than the isoprenaline maximum. The inotropic effects of Org10325 were not modified by alpha- or beta-adrenoceptor blockade or by pretreatment with reserpine. Org10325 was at least 23 times more potent at relaxing aortic strips pre-contracted with phenylephrine than with KCl. 3. Org10325 (74 microM) potentiated (10-14 fold) the positive inotropic effects of isoprenaline in rabbit isolated papillary muscles. Carbachol inhibited the positive inotropic effect of Org10325. Both the positive inotropic and vasorelaxant effects of Org10325 were accompanied by increases in cyclic AMP but not cyclic GMP. 4. In rat perfused heart preparation Org10325 increased phosphorylase a, cyclic AMP-dependent protein kinase activities and stimulated phosphorylation of contractile proteins (troponin-I and C-protein). 5. Org10325 selectively inhibited the cyclic AMP hydrolytic activity of cyclic AMP high affinity cyclic nucleotide phosphodiesterase (PDE) isoenzymes, PDE III (IC50 65 microM) and PDE IV (IC50 71 microM), from rabbit cardiac ventricle. Weak inhibition (IC50 greater than 250 microM) of PDE I and PDE II was observed. 6. The results show that the cardiac and vascular effects of Org10325 are mediated by an increase in cellular cyclic AMP due to inhibition of PDE III and PDE IV activities. However, in contrast to other PDE-inhibitors OrglO325 produced a marked increase in relaxation time of isolated papillary muscle suggesting the involvement of additional cyclic AMP-independent mechanisms of action.
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PMID:Pharmacological and biochemical effects of the cardiotonic agent Org10325 in isolated cardiac and vascular tissue preparations. 216 38

The purpose of this study is to clarify the pharmacological effects of E-1020 a new cAMP-specific phosphodiesterase (PDE) inhibitor, on cAMP or cytosolic free calcium (Ca) of cultured vascular smooth muscle cells (VSMC). VSMC were separated from the thoracic aorta of 2- to 3-month-old Wistar Kyoto rats (WKY). cAMP was measured by using the 125I-cAMP radioimmunoassay kit. The cytosolic free Ca of VSMC was measured by using the fluorescence Ca indicator, Fura-2/acetoxymethyl ester (Fura-2/AM). As a result, E-1020 increased the cAMP of VSMC in a dose-dependent manner, and about two fold increase in cAMP was observed by 10(-4) M E-1020. E-1020 decreased the cytosolic free concentration of Ca in a dose-dependent manner, and a significant decrease in cytosolic free Ca was observed by greater than 10(-6) M E-1020. These effects of E-1020 on cAMP and cytosolic free Ca were enhanced in the presence of low concentration (10(-8) M) of DL-noradrenaline. That is, a more prominent decrease in cytosolic free Ca than that of E-1020 alone was observed. Our results show that E-1020 decreases cytosolic free Ca of VSMC in parallel with increase in cAMP, and thereby suggest a potential vasodilating activity in vivo.
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PMID:Effects of E-1020, a new cyclic AMP-specific phosphodiesterase inhibitor, on cyclic AMP and cytosolic free calcium of cultured vascular smooth muscle cells. 217 82

Rolipram (4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone) represents a new class of specific low Km cAMP phosphodiesterase (PDE) inhibitors. This compound enhances basal, hormone- and forskolin-elicited cAMP accumulation in prolactin (PRL) producing rat pituitary adenoma (GH4C1) cells in culture (ED50 = 5.10(-8) M). This effect is due to a selective inhibition of the low Km cAMP PDE (type III), since neither basal nor hormone-stimulated adenylate cyclase (AC) nor the Ca2+/calmodulin-dependent PDE were affected by rolipram. The drug enhanced vasoactive intestinal polypeptide (VIP)-stimulated PRL-secretion, while thyroliberin (TRH)- and 12-0-tetradecanoyl phorbol-13-acetate (TPA)-elicited PRL egress were slightly reduced indicating a cAMP-mediated reduction of protein kinase C (PK-C) mediated PRL release. Interestingly, inhibition of PRL secretion by somatostatin (SRIH) was completely suppressed suggesting cAMP-mediated inactivation of some GTP-binding protein(s) of the alpha i family (G alpha i2 or Gk). Rolipram did not affect phosphoinositide metabolism (i.e. IP3 accumulation), neither acutely nor after long term administration. Rolipram, like the cAMP PDE inhibitor Ro 20-1724, did not influence AC and PDE I, but dose-dependently inhibited PDE III activity. Long term incubation of GH4C1 cells with rolipram in the presence of noradrenaline (NA) exerted a marginal decrease of beta-receptor number, AC activation and cAMP accumulation, while Ro 20-1724 brought about a marked down-regulation and desensitization of the AC complex. In summary, rolipram selectively interacts with PDE III in rat pituitary adenoma cells in culture and does not result in beta-adrenoceptor AC downregulation. These features are not shared by the other drugs tested.
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PMID:The pharmacodynamic action of the cyclic AMP phosphodiesterase inhibitor rolipram on prolactin producing rat pituitary adenoma (GH4C1) cells. 217 76


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