PCA 50941, a novel Ca2+ channel agonist

Priego, Julián; Gonzáles-Morales, María Antonia; Cillero, F. J.; Villarroya, Mércedes; Sunkel, Carlos; Casa-Juana, Miguel Fau de; López, Manuela G.; Artalejo, Cristina R.; Pascual, Ricardo de; Garcı́a, Antonio G.

doi:10.1016/0014-2999(93)90163-c

Cited by 7 publications

(3 citation statements)

References 13 publications

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“…However, there are other calcium channel agonists that cause little vasoconstriction and cardiac inotropic effects. For instance, we synthesized a 1,4-dihydropiridine derivative named PCA50941 (50) that caused little coronary vasoconstriction and cardiac inotropic effect compared with BAY K 8644 (37). Furthermore, PCA50941 activated adrenal medullary catecholamine release (30); whereas BAY K 8644 reduced coronary blood flow, augmented arterial pressure, left ventricular pressure, and dP/dt, PCA50941 did not change these parameters (14).…”

Section: Discussionmentioning

confidence: 98%

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Differences in the quantal release of catecholamines in chromaffin cells of rat embryos and their mothers

Fernández-Morales

Cortés-Gil²,

Garcı́a³

et al. 2009

American Journal of Physiology-Cell Physiology

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Studies on the bulk catecholamine release from fetal and neonatal rat adrenals, adrenal slices, or isolated chromaffin cells stimulated with high K(+), hypoxia, hypercapnia, or acidosis are available. However, a study analyzing the kinetics of quantal secretion is lacking. We report here such a study in which we compare the quantal release of catecholamines from immature rat embryo chromaffin cells (ECCs) and their mothers' (MCCs). Cell challenging with a strong depolarizing stimulus (75 mM K(+)) caused spike bursts having the following characteristics. ECCs released more multispike events and wave envelopes than MCCs. This, together with narrower single-spike events, a faster decay, and a threefold smaller quantal size suggest a faster secretory machinery in ECCs. Furthermore, with a milder stimulus (25 mM K(+)) enhanced Ca(2+) entry by L-type Ca(2+) channel activator BAY K 8644 did not change the kinetic parameters of single spikes in ECCs; in contrast, augmentation of Ca(2+) entry increased spike amplitude and width, quantal size, and decay time in MCCs. This suggests that in mature MCCs, the last exocytotic steps are more tightly regulated than in immature ECCs. Finally, we found that quantal secretion was fully controlled by L-type voltage-dependent Ca(2+) channels (VDCCs) in ECCs, whereas both L- and non-L VDCCs (N and PQ) contributed equally to secretion control in MCCs. Our results have the following physiological, pharmacological, and clinical relevance: 1) they may help to better understand the regulation of adrenal catecholamine release in response to stress during fetal life and delivery; 2) if clinically used, L-type Ca(2+) channel blockers may augment the incidence of sudden infant death syndrome (SIDS); and 3) so-called Ca(2+) promotors or activators of Ca(2+) entry through L-type VDCCs may be useful to secure a healthy catecholamine surge upon violent stress during fetal life, at birth, or to prevent the SIDS in neonates at risk.

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Section: Discussionmentioning

confidence: 98%

“…Adrenal glands were then removed from the embryos, fat-trimmed, and introduced in 1 ml of an enzymatic solution of identical composition to the one described by Sorensen et al (37). Papain (15-20 U/ml) was added for tissue digestion.…”

Section: Methodsmentioning

confidence: 99%

Differences in the quantal release of catecholamines in chromaffin cells of rat embryos and their mothers

Fernández-Morales

Cortés-Gil²,

Garcı́a³

et al. 2009

American Journal of Physiology-Cell Physiology

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“…These tissues are highly sensitive to small increases of Ca 2+ entry under conditions of mild K + depolarization [92,93]. These tissues are highly sensitive to small increases of Ca 2+ entry under conditions of mild K + depolarization [92,93].…”

Section: Neuroprotective Profile Of the 4-phenyl-18-naphthyridine 30mentioning

confidence: 99%

1,8-Naphthyridine derivatives as Cholinesterases Inhibitors and Cell Ca2+ Regulators, a Multitarget Strategy for Alzheimer's Disease

Egea¹,

Rı́os²

2011

CTMC

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The synthesis and the pharmacological evaluation of 1,8-naphthyridine derivatives and related compounds as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as voltage-dependant Ca(2+) channels (VDCC) modulators of are summarized. These compounds are closely related to the anticholinesterasic tacrine and the well-known Ca(2+)-antagonists 1,4-dihydropyridines. They were obtained from polyfunctionalized 2-amino-3-cyanoheterocycles via Friedlander-type reaction with selected cycloalkanones. Most of the compounds showed moderate inhibitory activity of cholinesterases, with selectivity to the AChE inhibition, and blocked Ca(2+) channels, preferentially the L-subtype, when a 4-aryl-1,4-DHP-like moiety were present in its chemical structure. Taking into account that the regulation of Ca(2+) entry to cells has been described to play a key role in cell death/survival processes, some of them were studied as cytoprotective agentes against different toxic stimuli. Specifically, the 1,8-naphthyridine derivative 30 was described to exert a tiny positive effect on Ca(2+) entry to cells, as single cell, isolated organ, and (45)Ca(2+) uptake experiments showed. This slight "Ca(2+)-promoter" behavior was related to its cytoprotective effect against several toxic stimuli, as Ca(2+)-chelating and antiapoptotic protein Bcl-2 was overexpressed in bovine chromaffin cells preincubated with 30. In fact, the relationship between small elevations of [Ca(2+)](c) and neuroprotection has been deeply studied by our group and others, concluding that a huge blockade of Ca(2+) entry does not have to generate neuroprotection, but the precise regulation, up or down, of such [Ca(2+)] concentrations.

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Pharmacology of Cav1 (L-Type) Channels

Triggle

2004

Calcium Channel Pharmacology

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PCA 50941, a novel Ca2+ channel agonist

Cited by 7 publications

References 13 publications

Differences in the quantal release of catecholamines in chromaffin cells of rat embryos and their mothers

Differences in the quantal release of catecholamines in chromaffin cells of rat embryos and their mothers

1,8-Naphthyridine derivatives as Cholinesterases Inhibitors and Cell Ca2+ Regulators, a Multitarget Strategy for Alzheimer's Disease

Pharmacology of Cav1 (L-Type) Channels

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