Inhibition of cyclic amp phosphodiesterase by 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(N-benzyl-N-methylamino)] ethyl ester 5-methyl ester hydrochloride (YC-93), a potent vasodilator

Sakamoto, Nobuo; Terai, Michio; Takenaka, Toichi; Maeno, Hiroo

doi:10.1016/0006-2952(78)90462-8

Cited by 83 publications

(20 citation statements)

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“…3j). These compounds lead to an increase in cellular cAMP levels by targeting different enzymes involved in cAMP production, which culminates in the activation of PKA, a negative regulator of the Hh pathway [36,38]. The synergistic effect that we observed suggests that both compounds are active in our system yet neither one alone is effective in inhibiting Hh signaling.…”

Section: E F Gmentioning

confidence: 82%

In vivo analysis of compound activity and mechanism of action using epistasis in Drosophila

2010

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The recent establishment of high-throughput methods for culturing Drosophila provided a unique ability to screen compound libraries against complex disease phenotypes in the context of whole animals. However, as compound studies in Drosophila have been limited so far, the degree of conservation of compound activity between Drosophila and vertebrates or the effectiveness of feeding as a compound delivery system is not well known. Our comprehensive in vivo analysis of 27 small molecules targeting seven signaling pathways in Drosophila revealed a high degree of conservation of compound activity between Drosophila and vertebrates. We also investigated the mechanism of action of AY9944, one of the Hh pathway antagonists that we identified in our compound feeding experiments. Our epistasis analysis of AY9944 provided novel insights into AY9944's mechanism of action and revealed a novel role for cholesterol transport in Hh signal transduction.

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Section: E F Gmentioning

confidence: 82%

In vivo analysis of compound activity and mechanism of action using epistasis in Drosophila

2010

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“…In this respect the low dose of nicardipine was of particular interest. Here, it should be recalled that nicardipine is not only a Ca-antagonist but also a potent inhibitor of cyclic AMP phosphodiastase (PDE) (Sakamoto et al 1978 ;Nishikori et al 1981). The involvement of PDE inhibition in the action of nicardipine has been demonstrated in rat uterine smooth muscle : When oxytocin-contracted uterine smooth muscle is relaxed by nicardipine, there is an increase in intracellular level of cyclic AMP (Nishikori et al 1981).…”

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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“…with IC50s in the micromolar range. However, non-dihydropyridine cal cium channel blockers could not bring about any mod ification in these enzyme activities (11,12). From the results in Fig.…”

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confidence: 91%

Effects of Nifedipine and Nicardipine on Glucagon-Stimulated Gluconeogenesis in Primary Cultures of Rat Hepatocytes.

Ogihara

1992

Jpn.J.Pharmacol

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ABSTRACT-The effects of nifedipine and nicardipine on glucagon-stimulated gluconeogenesis from lactate were examined in primary cultures of rat hepatocytes. Nifedipine and nicardipine (10-v 10-5 M) significantly potentiated the glucagon-stimulated gluconeogenesis from lactate by increasing intra cellular cAMP levels. In contrast, diltiazem and verapamil did not potentiate the glucagon-stimulated gluconeogenesis. 1-Methyl-3-isobutylxanthine and papaverine also potentiated the glucagon-stimulated gluconeogenesis from lactate. On the basis of these results, possible mechanisms by which nifedipine and nicardipine potentiate the glucagon-stimulated gluconeogenesis will be discussed.Keywords: Nifedipine, Gluconeogenesis, Primary cultures of rat hepatocytesCalcium channel blockers such as nifedipine, nicardi pine and a number of related agents have been widely used in the management of hypertension and related cardiovascular disease. Although mechanisms of action of these agents on the cardiovascular system have been extensively studied in vitro and in vivo, there have only been a few reports about the effects of these calcium channel blockers on the regulation of glucose metabo lism. Previous studies have shown that dihydropyridine cal cium channel blockers, nifedipine and nicardipine, pro duce mild hyperglycemia in 20 hr-starved streptozot ocin-diabetic rats in vivo (1). Since plasma glucose levels are dependent on both hepatic glucose produc tion (glycogenolysis and gluconeogenesis) and periph eral glucose utilization, the mechanism of action of these agents may be related to the stimulation of he patic glucose production and/or the peripheral glucose utilization (2).However, in vivo experimental systems have some limitations, for instance that the results are affected by the indirect effects of many endogenous factors (1). Compared to the whole animal, an in vitro system has the advantage that endogenous hormones and other effectors do not influence the process being studied and various hormonal conditions can be tested in one single cell preparation. In addition, high levels of glucagon and catecholamines that may occur in diabetes in vivo increase glucose production by the liver. In the present study, the author examined whether these calcium channel blockers affect the glucagon-stimulated gluco neogenesis in primary cultures of rat hepatocytes.Liver parenchymal cells were isolated from male Wistar rats weighing 200 250 g by a modification of the procedure of Berry and Friend, which is described in detail elsewhere (3). In brief, the liver was first per fused via the portal vein with a calcium-free Hanks 10 mM Hepes buffer (pH 7.4) at 37°C and at a flow rate of 30 ml/min for 10 min. The second step was per formed with the same buffer containing 0.025% colla genase and 0.075% CaCl2 at the same flow rate. At the end of the perfusion, the cells were dispersed in calcium-free Hanks' solution. They were washed three times by slow centrifugation (50 g) for 1 min to remove cell debris, damaged cells and non-parenchymal ...

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Inhibition of cyclic amp phosphodiesterase by 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(N-benzyl-N-methylamino)] ethyl ester 5-methyl ester hydrochloride (YC-93), a potent vasodilator

Cited by 83 publications

References 13 publications

In vivo analysis of compound activity and mechanism of action using epistasis in Drosophila

In vivo analysis of compound activity and mechanism of action using epistasis in Drosophila

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

Effects of Nifedipine and Nicardipine on Glucagon-Stimulated Gluconeogenesis in Primary Cultures of Rat Hepatocytes.

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