Dihydropyridine Ca2+ entry blockers selectively inhibit peak I cAMP phosphodiesterase

Norman, Jon; Ansell, Justin; Phillipps, Mildred A.

doi:10.1016/0014-2999(83)90036-5

Cited by 53 publications

(10 citation statements)

References 17 publications

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“…6). Therefore, as several authors reported re cently [Norman et al, 1983;Thayer and Faith last, 1983;Luchowski et al. 1984;I 'an Ingewen et al, 1984] the role of the nitrendi pine-calmodulin interaction may be insignif icant in the Ca2+-blocking mechanism in ex citable tissues.…”

Section: Discussionmentioning

confidence: 99%

Nitrendipine, Nifedipine and Verapamil Inhibit the in vitro Formation of Irreversibly Sickled Cells

Horiuchi

et al. 1986

Pharmacology

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Nitrendipine, nifedipine and verapamil inhibit the in vitro formation of irreversibly sickled cells. Using a method of forming both dehydrated cells and irreversibly sickled cells in vitro by repeated cycles of sickling and unsickling, the effects of several drugs in inhibiting the formation of these cells were studied. Drugs known as Ca²⁺ channel antagonists, such as nitrendipine, nifedipine and verapamil were found to inhibit these reactions. Other types of calcium channel blockers, such as lanthanum and zinc, did not inhibit the formation of these cells. The potency of drugs to inhibit irreversibly sickled cell formation was related to the potency of inhibition of calmodulin-activated phosphodiesterase.

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Section: Discussionmentioning

confidence: 99%

Nitrendipine, Nifedipine and Verapamil Inhibit the in vitro Formation of Irreversibly Sickled Cells

Horiuchi

et al. 1986

Pharmacology

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“…This has been reported on phosphodiesterase prepared from bovine heart [32,33] as well as on rabbit platelets [34], These latter authors found for N if and approximate IC50 value of 800 pmol/l for in vitro rabbit ADP-induced platelet aggrega tion. This could certainly be explained by methodological differences.…”

Section: Discussionmentioning

confidence: 71%

Comparative Inhibitory Effects of Dihydropyridines on Platelet Aggregation, Calcium Uptake and Cyclic AMP Concentration

Blache

Ojeda

1992

Pharmacology

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We studied the in vitro effects of several calcium channel blockers from the dihydropyridine (DHP) family on platelet aggregation and endogenous serotonin secretion, calcium uptake and cyclic AMP (cAMP) concentration using washed rat platelets. We found that, after 1 min incubation, nifedipine (Nil), nitrendipine (Nit) and nisoldipine (Nis) inhibited the thrombin-induced platelet aggregation and serotonin secretion with IC50 of about 140, 5 and 2 μmol/l, respectively. Nis and Nit are thus much more active than Nif. We also found that the thrombin-induced Ca²⁺ uptake amounted to 2,600 ± 326 pmol Ca²⁺/10⁹ platelets in control conditions. In the presence of 10 μmol/l of the DHP, this uptake was decreased by 19, 49 or 77 %, with Nif, Nit or Nis, respectively. Compound BAY K 8644 (BK) with known agonistic properties on the calcium channel had inhibitory effects on the studied parameters. These compounds were in the order of Nif < BK < Nit < Nis. When added to previously aggregated platelets, Nit caused them to deaggregate. These results seem to be similar to those obtained with cAMP analogues or adenylate cyclase activators. The platelet resting cAMP concentration was therefore measured in the presence of the DHP. A nonsignificant increase was found with 20 μmol/l Nif whereas significant increases of 20 and 68 % as compared with controls were obtained with 20 μmol/l Nit and Nis, respectively. Partition studies between platelets and plasma lipoproteins indicated that the effects might be related to the lipophilicity of the compounds. These data suggest that these agents work on platelet activity by multiple effects located intracellularly or at the membrane level. We propose that these effects could work in combination to explain the in vivo potency of these agents in the treatment of cardiovascular disorders.

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“…nicardipine. The potent inhibitory action of nifedipine on calmodulin-sensitive PDE has recently been reported but not of diltiazem and verapamil Norman et al 1983). In addition Skolnick and Daly (1976) reported that clonidine can potentiate the effect of a-adrenoceptor or /3-adrenoceptor mediated elevation in adenylate cyclase activity in the cerebral cortex.…”

Section: Discussionmentioning

confidence: 99%

The mechanism of centrally mediated cardiovascular actions of the three structurally different calcium antagonists, verapamil, diltiazem and nicardipine, in rats.

Imai

Abe

Sasaki

et al. 1987

Tohoku J. Exp. Med.

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Centrally mediated cardiovascular effects of the three structurally different calcium antagonists (Ca-antagonists), i.e., verapamil, diltiazem and nicardipine, were studied in rats. In conscious rats, when administered intracerebroventricularly (icy. ) in doses of 0.3, 1 and 3,ug/kg/min for 30 min, all the three Ca-antagonists induced dose-dependent increases in mean arterial pressure (MAP) and pulse rate (PR), whereas nicardipine administered intravenously (iv.) caused a decrease in MAP and an increase in PR. In anesthetized rats all the three Ca-antagonists in a dose of 3 ,u g/kg/min for 60 min i.c.v, significantly potentiated the hypotensive and bradycardic effects of icy. clonidine. Nicardipine, in a dose of 0.3 1cg/kg/min for 60 min icy., attenuated the hypotensive and bradycardic effects of icy. clonidine or B-HT 920, an a2-adrenoceptor agonist, in anesthetized rats, whereas it did not modify the cardiovascular effect of icy. angiotensin II or y-aminobutylic acid in conscious rats. Nicardipine, in a dose of 0.3 1ug/kg/min for 60 mm iv., did not modulate the hypotensive and bradycardic effects of icy. clonidine. 3-Isobutyl-lmethylxanthine (IBMX), a cyclic AMP phosphodiesterase inhibitor, in a dose of 3 ,ug/kg/min for 60 min icy., also attenuated the hypotensive and bradycardic effects of icy. clonidine. Potentiation by the three icy. Ca-antagonists of the hypotensive and bradycardic effects of clonidine would be explainable if their inhibitory effect on Ca-influx is exerted at presynaptic nerve terminals but not at postsynaptic. The mechanisms of the cardiovascular effect of icy. Ca-antagonists still remain to be elucidated but may be independent of a central a2-adrenoceptor mechanism. Dihydropyridine Ca-antagonists like nicardipine are also potent inhibitor of cyclic AMP phosphodiesterase. Since IBMX mimicked the effect of nicardipine, the effect of a low dose of icy. nicardipine in attenuating the hypotensive and bradycardic effects of icy. clonidine may be mediated by inhibition of cyclic AMP phosphodiesterase in the central nervous system. clonidine ; IBMX ; central nervous system ; blood pressure ; pulse rate

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Dihydropyridine Ca2+ entry blockers selectively inhibit peak I cAMP phosphodiesterase

Cited by 53 publications

References 17 publications

Nitrendipine, Nifedipine and Verapamil Inhibit the in vitro Formation of Irreversibly Sickled Cells

Nitrendipine, Nifedipine and Verapamil Inhibit the in vitro Formation of Irreversibly Sickled Cells

Comparative Inhibitory Effects of Dihydropyridines on Platelet Aggregation, Calcium Uptake and Cyclic AMP Concentration

The mechanism of centrally mediated cardiovascular actions of the three structurally different calcium antagonists, verapamil, diltiazem and nicardipine, in rats.

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