Enhancement of calcium influx in human platelets by CGP 28392, a novel dihydropyridine

1 Primary aggregate cultures of embryonic chick heart have been used to investigate the effects of calcium channel antagonists and facilitators on myocardial contractility. 2 The number of aggregates showing movement was inhibited in a concentration-dependent manner by calcium antagonists from different subgroups with negative log concentrations inhibiting movement in 50% of aggregates as follows: Class 1-nisoldipine (7.20); Class 2-verapamil (6.36), diltiazem (5.83); Class 3-lidoflazine (5.68), pimozide (6.25). 3 The effects of the dihydropyridine facilitators Bay K 8644 and CGP 28392 on aggregate beating were investigated by evaluating the interaction between calcium channel facilitators and antagonists from the three subgroups of calcium antagonists. Concentrations of antagonists that inhibited beating in 85% of aggregates were used. Both Bay K 8644 and CGP 28392 reversed nisoldipine-, diltiazem-or verapamil-induced inhibition of beating. 4 Bay K 8644 was approximately 10 times more potent than CGP 28392 in reversing nisoldipine-, diltiazem-or verapamil-induced inhibition of beating. 5 For each facilitator the concentrations causing 50% reversal of inhibition of aggregate beating against the three antagonists were similar. There was little evidence for differential modulation by verapamil or diltiazem of the action of the dihydropyridine facilitators. 6 Bay K 8644 did not reverse lidoflazine-or pimozide-induced inhibition of beating, indicating that these drugs may act at a site distinct from the dihydropyridine site on the calcium channel.

Section: Resultsmentioning

confidence: 99%

Effects of calcium channel antagonists and facilitators on beating of primary cultures of embryonic chick heart cells

Patmore¹,

Duncan²

1988

“…The dihydropyridine-type calcium channel activators described so far, such as the 3-nitro derivatives Bay K 8644 (Schramm et al, 1983a) and 202-791 (Hof et al, 1985), the lactone CGP 28392 (Erne et al, 1984), the 2-amino derivative H 160/51 (Beyer et al, 1985), and the amide YC-170 (Takenaka & Maeno, 1982) constitute a structurally heterogeneous group. Theoretical calculations (Mahmoudian & Richards, 1986) and comparisons between crystal structures of two of these agonists, Bay K 8644 and CGP 28392, with those of known antagonists, have led to proposals explaining the conformational differences between agonists and antagonists in terms of hydrogen bonding of the 1-NH group, ester group orientation and hydrophobic fit (Langs & Triggle, 1985).…”

Section: Discussionmentioning

confidence: 99%

RS 30026: a potent and effective calcium channel agonist

Patmore¹,

Duncan²,

Clarke³

et al. 1990

1 A series of dihydropyridine derivatives has been evaluated for calcium channel agonist activity using reversal of nisoldipine-induced inhibition of beating of aggregates of embryonic chick myocytes. This test appears to be specific for calcium channel agonists since isoprenaline and cardiac glycosides are inactive. 2 RS 30026 was the most potent of the series, was significantly more potent than CGP 28392 and of similar potency to Bay K 8644 (pEC50 = 7.45, 6.16 and 7.20, respectively 6 RS 30026 appears to be the most potent and effective calcium channel agonist described to date.

“…The first positive inotropic phase presumably relates to the ability of CGP to interact directly with sarcolemmal Ca2" channels and to stimulate Ca2+-entry into myocardial and other cells (Renaud et al, 1984;Erne et al, 1984;Brown et al, 1984;Hess et al, 1984;Thomas et al, 1985). In view of the conventional stimulatory action, the delayed negative inotropy of the Ca2" agonist seems paradoxical.…”

Section: Discussionmentioning

confidence: 99%

“…Calcium channel agonists belonging to the dihydropyridine family, represent a new type of cardioactive compound (Schramm et al, 1983;Erne et al, 1984;Schramm & Towart, 1985;Reuter et al, 1985). It has been demonstrated in several studies that dihydropyridine Ca2" channel activators (Bay K 8644, CGP28392, the (+)-isomer of 202-791) increase depolarization-induced uptake of45Ca2' and release of [3H]-noradrenaline, increase the V.. of the slow response action potential and enhance myocardial contractility and calcium current (Schramm et al, 1983;Erne et al, 1984;Thomas et al, 1984;1985;Renaud et al, 1984;Brown et al, 1984;Hess et al, 1984;Finet & Godfraind, 1985;Kongsamut et al, 1985;Dube et al, 1985;Schramm & Towart, 1985).…”

Section: Introductionmentioning

confidence: 99%

“…It has been demonstrated in several studies that dihydropyridine Ca2" channel activators (Bay K 8644, CGP28392, the (+)-isomer of 202-791) increase depolarization-induced uptake of45Ca2' and release of [3H]-noradrenaline, increase the V.. of the slow response action potential and enhance myocardial contractility and calcium current (Schramm et al, 1983;Erne et al, 1984;Thomas et al, 1984;1985;Renaud et al, 1984;Brown et al, 1984;Hess et al, 1984;Finet & Godfraind, 1985;Kongsamut et al, 1985;Dube et al, 1985;Schramm & Towart, 1985). The present experiments were undertaken to determine whether stimulation of transmembrane Ca2+-entry by the light-stable activator, CGP 28392 (CGP) (Truog et al, 1984) could affect the anomalous forcefrequency relationship in rat myocardium (Langer, 1978), since it is thought that the phenomenon may be causally related to the deficiency of transmembrane Ca2" influx in this species (Nawrath, 1980).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Biphasic inotropic effects of a Ca²⁺ channel activator CGP28392 in rat myocardium: possible relation to intracellular Ca²⁺ release

Kobrinsky¹,

Saxon²

1987

1 The inotropic effect of a Ca2+-entry stimulator, CGP28392, (CGP) was compared in rat and frog myocardium in a concentration-and time-dependent manner. 2 Frog preparations exhibited a persistent positive inotropic effect following prolonged treatment with CGP. 3 Compared to amphibian myocardium, rat ventricular muscle exhibited a biphasic time-dependent response to CGP: an initial increase in the twitch tension amplitude of 30% was changed to a reduction of 80% below the control level during prolonged exposure to CGP (stimulation frequency, 0.2 Hz). 4 Following prolonged incubation with CGP, the resting-state contraction was decreased and the negative force-frequency relation was converted into a positive one in rat muscle. 5 Since sarcoplasmic reticulum (SR) is the major source of Ca2" in a rested-state contraction, inhibition by CGP suggests an additional, intracellular action of the Ca2" channel activator on SRCa2' release in rat myocardium.