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

In this study, ligands from various chemical classes were investigated with respect to their relative affinities to calmodulin (CaM) and troponin C (TnC), using the fluorescent dye 3,3'-dipropylthiocarbocyanine iodide (diS-C3-5'). In parallel, functional tests were carried out determining the effects of the ligands on the CaM activated cyclic nucleotide phosphodiesterase (PDE) activity and the TnC mediated Ca-sensitivity of skinned myocardial fibres and cardiac myofibrils. The following results were obtained: 1) As a rule, most of the ligands tested had higher affinities to CaM than to TnC. 2) Even within one and the same pharmacological class (e.g. phenothiazines) the relative affinities for CaM and TnC varied considerably, trifluoperazine (TFP) or levomepromazine (LMP) showing low or no CaM specificity, methophenazine (MP) on the other hand being highly selective for CaM by a factor of more than 200. 3) In all cases tested, the functional tests were in good quantitative agreement with the binding data, showing inhibition of CaM stimulated PDE activity and Ca-sensitizing effects in concentrations corresponding well with the respective drug affinities to CaM and TnC, respectively. 4) It is concluded that a) interaction of ligands with TnC can lead to Ca-sensitization of the cardiac contractile system and a positive inotropic effect without a concomitant elevation of the intracellular level of activator Ca. This may result in a novel cardiotonic principle avoiding the common side effects of 'classical' positive inotropic agents due to Ca-overload. b) drug selectivity for TnC or CaM appears chemically achievable.
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PMID:Calmodulin and troponin C as targets for drug action. 244 86

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.
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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

1. A series of related methylxanthines were studied for their effects on the kinetics of decay of end-plate currents (e.p.c.s) and miniature end-plate currents (m.e.p.c.s) at motor end-plates of the frog. 2. Isobutyl methylxanthine (IBMX, 50 microM-3 mM) produced a concentration-dependent depression of the peak e.p.c. and m.e.p.c. amplitude and a change in the kinetics of e.p.c. and m.e.p.c. decay from the normal single-exponential to a double-exponential function. Drug effects of this nature are generally attributed to open-channel blockade. 3. After wash-out of IBMX, the decay of the e.p.c. or m.e.p.c. was restored to a single-exponential function but with a significantly prolonged time constant. 4. Caffeine or theophylline derivatives (0.1-4 mM), during exposure to drug, produced effects similar to those observed after the application of IBMX; namely a prolongation of the time course of e.p.c.s and m.e.p.c.s without changing the single-exponential nature of the function. 5. Computer simulations were made of the m.e.p.c.s in IBMX. The effects of IBMX could be fitted to the sequential model of channel block only if the prolonged time constant observed upon wash-out was used for the rate constant of channel closure. Independent calculations of the rate constant of channel closure during IBMX application were in agreement with those measured during wash-out. 6. The theophylline derivative 8-phenyltheophylline, a selective adenosine receptor blocker with minimal effects on phosphodiesterase (PDE), increased the time constant of e.p.c. decay in a manner similar to theophylline and caffeine. Non-xanthine PDE inhibitors, either had no effect on m.e.p.c. decay (papaverine) or decreased the time constant of decay (RO 20-1724). It is thus unlikely that PDE inhibition is responsible for the post-junctional effects of IBMX. 7. IBMX (50 microM-2 mM) increased quantal ACh release in the virtual absence of extracellular calcium and also increased the efficacy of adenosine derivatives in inhibiting ACh release. Adenosine (10-100 microM) or 2-chloroadenosine (1-10 microM) had no effect on the time constant of e.p.c. decay nor did these adenosine receptor agonists alter the post-junctional actions of IBMX. The effects of IBMX on end-plate channel kinetics are thus not due to the blockade of adenosine receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Independent control of channel closure and block of open channels by methylxanthines at acetylcholine receptors in frog. 245 Sep 93

1. The effects of adibendan (BM 14.478; 7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f] benzimidazole-6-one) on force of contraction and beating frequency were analysed in guinea-pig electrically driven papillary muscles and spontaneously beating right auricles, respectively. The effects of 3-isobutyl-1-methylxanthine (IBMX) and milrinone were studied for comparison. 2. Adibendan exerted a concentration-dependent (0.03-300 mumol/l) positive inotropic effect in papillary muscles (EC50 = 1.3 mumol/l) which was only partially reversible. The efficiency of adibendan was less than that of milrinone, but adibendan was about two orders of magnitude more potent and had only slight positive chronotropic effects (113% of pre-drug values) at most. Milrinone increased the frequency of beating maximally to 140% of pre-drug values. The positive inotropic effect of adibendan is probably at least partially mediated by cAMP since carbachol reduced the increase in force of contraction by about 75%. 3. To elucidate the mechanism of action of adibendan we investigated its effects on phosphodiesterase I-III and adenylate cyclase activity in isolated preparations from guinea-pig hearts. 4. Adibendan selectively inhibited phosphodiesterase III (PDE III) activity concentration-dependently (IC50 = 2.0 mumol/l). The IC50 values for the inhibition of PDE I or II were more than 60-fold higher. Since adibendan did not affect adenylate cyclase activity a stimulation of the cAMP synthesis as a mechanism of action can be ruled out. 5. The results provide evidence that the positive inotropic action of adibendan is at least in part due to an inhibition of cAMP-PDE III.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of action and cardiotonic activity of a new phosphodiesterase inhibitor, the benzimidazole derivative adibendan (BM 14.478), in guinea-pig hearts. 245 16

The effect on cyclic AMP levels and bone resorption by two methylxanthine cyclic AMP phosphodiesterase (PDE) inhibitors, isobutyl-methylxanthine (IBMX) and theophylline, and two non-xanthine PDE inhibitors, Ro 20-1724 and rolipram, was studied in cultured mouse calvarial bones. Cyclic AMP accumulation in calvarial bones increased when Ro 20-1724 (0.1 mmol/l) or rolipram (30 mumol/l) was present in culture medium in 2 h incubations, and when IBMX (0.3 mmol/l) or theophylline (3 mmol/l) was present in 4 h incubations. The cyclic AMP response to PDE-inhibitors could be completely abolished by the cyclooxygenase-inhibitor indomethacin (1 mumol/l). In 120 h cultures, IBMX, theophylline, Ro 20-1724 and rolipram stimulated the release of 45Ca from calvarial bones prelabelled in vivo with 45Ca. This stimulatory effect could not be seen when the endogenous production of prostaglandins was reduced by adding indomethacin (1 mumol/l), hydrocortisone (1 mumol/l) or meclofenamic acid (1 mumol/l) to culture medium. These concentrations of indomethacin, hydrocortisone and meclofenamic acid did not reduce PTH- (10 nmol/l) or choleratoxin-stimulated (0.1 micrograms/ml) 45Ca release from mouse calvarial bones cultured for 120 h. The stimulation of 45Ca release in long-term cultures by the PDE inhibitors could be demonstrated in the presence of indomethacin, provided adenylate cyclase was stimulated by forskolin (1-10 nmol/l). The stimulatory effect of 1 alpha (OH)D3 on 45Ca release could not be potentiated by the PDE-inhibitor rolipram. These results suggest that basal adenylate cyclase activity in cultured murine calvaria is very low and that therefore PDE inhibitors are inactive unless a stimulator of adenylate cyclase is present. The adenylate cyclase stimulator may be an endogenous autacoid such as a prostaglandin.
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PMID:Delayed stimulation of bone resorption in vitro by phosphodiesterase inhibitors requires the presence of adenylate cyclase stimulation. 246 48

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.
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PMID:Cardiovascular properties of MS-857, a new and potent cardiotonic agent, on normal and failing hearts. 246 58

1. The exponential decline of light-sensitive current seen after switch from Na+ to Li+ in the presence of Ca2+ probably depends on the activity of the phosphodiesterase (PDE) which hydrolyses cyclic GMP. 2. This probability is supported by experiments with suction electrodes which show that in toad and salamander rods the rate constant, b, of the exponential decline of current was increased at least 10-fold by moderate light intensities and decreased about 10-fold by 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of PDE. 3. The rate constant b is about 3 times more sensitive to weak lights or to IBMX than the membrane current. This may be explained by a feed-back involving calcium ions which tends to hold current constant, perhaps by calcium inhibition of guanylate cyclase. 4. The time course of b, which probably represents the changes in PDE activity, was measured by switching from Na+ to Li+ at various times after a flash. The results suggest that a moderate flash (140 Rh) increased b about 7 times in 0.5 s and that b then declined with a time constant of 1.5-2 s. 5. Extrapolated values of the parameter b suggest that strong flashes (5000-10,000 Rh) increased b from 1 s-1 in the dark to perhaps 60 s-1 and that b continued to increase with flash strength for several log units after the current had reached saturation. 6. The observations in 4 and 5 fit well with the idea that b is related to PDE activity and that changes in the latter are sufficient to account for the rising phase of the flash response. 7. After a flash the light-sensitive current recovers much more rapidly than the time constant b-1, a discrepancy which is explained if a light flash causes a delayed increase in guanylate cyclase activity. 8. The apparent delayed increase in cyclase activation is consistent with an inhibitory effect of [Ca2+]i which is reduced when calcium is pumped out during the plateau of the response. 9. Experiments in which pulses of IBMX were applied at different times during a flash response support the idea that a flash causes a delayed increase in the rate of supply of cyclic GMP. Quantitative analysis of these and other tests with IBMX gave rate constants similar to those obtained by the Na+----Li+ method.
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PMID:Control of light-sensitive current in salamander rods. 247 95

1. The mechanism by which acetylcholine (ACh), by stimulation of muscarinic receptors, acts to inhibit activation of the hyperpolarization-activated 'pacemaker' current, if was investigated in isolated rabbit sino-atrial (SA) node myocytes. 2. Intracellular loading with GTP gamma S, a non-hydrolysable analogue of GTP, did not impair the ACh action on if, but made it irreversible. On the other hand, the ACh action on if disappeared after a few minutes of cell loading with GDP beta S, a GDP analogue known to bind to G-proteins and prevent their receptor-stimulated action. Furthermore, incubation of cells in a solution containing pertussis toxin (PTX) led to abolition of the if response to ACh. These results indicate that the inhibitory effect of ACh on if is mediated by G-proteins activated by muscarinic receptors. 3. Intracellular loading with phosphodiesterase (PDE) increased the rate of if current run-down, but did not abolish the inhibitory action of ACh on if. 4. Extracellular perfusion with isobutylmethylxanthine (IBMX), a PDE inhibitor, increased if activation by shifting the current activation range to more positive voltages, as inferred by a three-pulse protocol analysis; in the presence of IBMX, the inhibition of if by ACh was not abolished. 5. The ACh-induced if depression persisted also in cells loaded with cyclic GMP. In these cells, as in those loaded with PDE, the if run-down was fast. 6. Oxotremorine, a muscarinic agonist coupled to adenylate cyclase but not to phosphoinositide turnover in cardiac cells, simulated ACh in its inhibitory action on if. The above results rule against the ACh action being mediated by PDE or by phosphoinositide turnover. 7. To investigate the possible involvement of cyclic AMP as a second messenger in the ACh action on if, we loaded cells with cyclic AMP and IBMX; under these conditions the action of ACh disappeared within a few minutes of whole-cell recording. 8. In cells where the slow inward Ca2+ current (isi) was measured together with if, ACh was seen to depress both currents. 9. In cells superfused with forskolin, the if amplitude on stepping to the half-activation voltage range was enhanced as a consequence of a depolarizing shift of the activation curve; ACh was not effective on if following stimulation by forskolin, but strongly depressed in the same cell the if current stimulated to a similar degree by isoprenaline.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Muscarinic control of the hyperpolarization-activated current (if) in rabbit sino-atrial node myocytes. 247 9

1. The aim of this study was to compare the effects of the non-selective phosphodiesterase (PDE) inhibitor, isobutylmethylxanthine (IBMX) and the selective PDE III inhibitor, milrinone, in a rabbit model of acute myocardial ischaemia. 2. Coronary artery occlusion caused changes in the ST-segment of the ECG and ectopic activity in all control rabbits. Ventricular fibrillation occurred in 10 out of 14 (71%) of these animals. Pretreatment with IBMX 100 micrograms kg-1 plus 10 micrograms kg-1 min-1, starting 10 min before coronary artery occlusion, reduced ischaemia-induced ST-segment changes and ventricular fibrillation occurred in only 10% of this group (n = 10). A similar dose of milrinone had no antiarrhythmic activity, whereas with a lower dose of milrinone, 30 micrograms kg-1 plus 3 micrograms kg-1 min-1 (n = 10), only 30% of rabbits fibrillated and ST-segment changes were attenuated. 3. Acute administration of both IBMX and milrinone reduced arterial blood pressure. With the higher dose of milrinone a significant effect was still present after 10 min of drug infusion. A greater hypotensive response to the higher dose of milrinone was observed in the rabbits which subsequently fibrillated during ischaemia. A marked tachycardia was also observed after administration of the higher dose of milrinone. 4. At the end of the experiment platelet aggregation was studied ex vivo. ADP-induced aggregation was reduced by pretreatment of the rabbits with milrinone but not IBMX. Both PDE inhibitors enhanced the ability of isoprenaline to inhibit ADP-induced platelet aggregation but milrinone was more effective, particularly at the higher dose. The results demonstrate that IBMX was antiarrhythmic but that this activity was not directly related to inhibition of platelet aggregation. Adverse haemodynamic effects may explain the failure of milrinone to have similar activity during myocardial ischaemia.
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PMID:Comparison of the effects of isobutylmethylxanthine and milrinone on ischaemia-induced arrhythmias and platelet aggregation in anaesthetized rabbits. 247 45

1. The mechanism by which M&B 22,948, MY-5445, vinpocetine and 1-methyl-3-isobutyl-8-(methylamino)xanthine (MIMAX), which have been described as selective cyclic GMP phosphodiesterase (PDE) inhibitors, relax rat aorta was investigated. 2. Three cyclic nucleotide PDEs were identified in the soluble fraction of rat aorta; a Ca2+-insensitive form exhibiting substrate selectivity for cyclic GMP (cGMP PDE), a Ca2+/calmodulin-stimulated form which also preferentially hydrolyzed cyclic GMP (Ca2+ PDE), and a form demonstrating substrate selectivity for cyclic AMP (cAMP PDE). 3. M&B 22,948 and MIMAX inhibited cGMP PDE (Ki = 0.16 microM and 0.43 microM, respectively) and Ca2+ PDE (Ki = 9.9 microM and 0.55 microM, respectively), but exhibited weak activity against cAMP PDE (Ki = 249 microM and 42 microM, respectively). MY-5445 selectivity inhibited cGMP PDE (Ki = 1.3 microM) and vinpocetine selectively inhibited Ca2+ PDE (Ki = 14 microM). 4. M&B 22,948 and MIMAX induced dose-dependent increases in the accumulation of cyclic GMP, but not cyclic AMP, in rat aorta pieces. These effects were greatly reduced by endothelial denudation and by methylene blue (5 microM) which blocks the actions of endothelium-derived relaxant factor. MY-5445 and vinpocetine had no effect on rat aorta cyclic GMP or cyclic AMP accumulation. 5. All four compounds caused dose-related relaxation of 5-hydroxytryptamine (10 microM) contracted, endothelium-intact rat aorta, the effects of M&B 22,948 and MIMAX being greatly reduced by methylene blue (5 microM). Methylene blue also caused 10 fold and 100 fold rightward shifts in the dose-response curves of MY-5445 and vinpocetine, respectively. 6. The results are consistent with the smooth muscle relaxant actions of M&B 22,948 and MIMAX, but not vinpocetine and MY-5445, being mediated through a mechanism involving inhibition of cyclic GMP hydrolysis.
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PMID:Role of selective cyclic GMP phosphodiesterase inhibition in the myorelaxant actions of M&B 22,948, MY-5445, vinpocetine and 1-methyl-3-isobutyl-8-(methylamino)xanthine. 248 Jan 68


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