Preliminary analysis of the discriminative stimuli induced by the calcium channel “agonist” BAY K 8644

Rats were trained in a drug discrimination paradigm to press one of two levers for food reward after injection of the racemic dihydropyridine (DHP) Ca²⁺ -channel activator BAY K 8644 (2.5 mg/kg) and to press the other after vehicle injection. The discrimination was reliably attained in an average of 48 sessions. Thereafter, tests with various doses of BAY K 8544 yielded a dose-dependent selection of the BAY K 8644 lever, with an ED₅₀ of 0.74 mg/kg. The (?)-enantiomer of BAY K 8644 generalized dose-dependently (ED₅₀ = 1.04 mg/kg), while the (+)-enantiomer showed no generalization up to 10 mg/kg. Furthermore, nifedipine pretreatment fully antagonized the BAY K 8644 stimulus. These data indicate that BAY K 8644 produces physiological effects that can readily serve as discriminative stimuli in rats. The results also support the mediation of the BAY K 8644 stimulus through agonistic interaction with the calcium channel DHP receptor.     

Effects of dihydropyridine drugs on reversal by imipramine of helpless behavior in rats

The present study was undertaken in order to determine the effects of the dihydropyridine calcium channel blocker, nimodipine and the dihydropyridine calcium channel activator BAY k 8644, in the learned helplessness test in the rat. Nimodipine dose dependently (0.5-2 mg/kg per day) reversed the behavioral deficit induced by inescapable shocks. The reversal of helpless behavior by imipramine (32 mg/kg per day) was antagonized by BAY k 8644 (0.5 and 1 mg/kg per day), and the effects of imipramine 8 and 16 mg/kg per day) were potentiated by a subeffective dose (0.5 mg/kg per day) of nimodipine. These results suggest that central dihydropyridine binding sites may be specifically involved in the modulation of the imipramine reversal of helpless behavior and favor a physiological role for dihydropyridine binding sites in the brain.     

Activation of dihydropyridine receptors differentially regulates temperature responses in rat

Rats receiving the dihydropyridine Ca++ agonist BAY K8644 (0.1-3 mg/kg SC) displayed increasing loss of body temperature. At the highest dose tested (3 mg/kg) rats exhibited decreased motor activity, ataxia, increased vocalization upon handling and increased auditory sensitivity. Nimodipine (1 mg/kg SC) produced antagonism of this response when used as pretreatment at 15 and 30 minutes. The phenylalkylamine, verapamil (5 mg/kg) and the benzothiazepine diltiazem (10 mg/kg) did not alter BAY K8644-induced hypothermia. None of the three Ca++ channel antagonists produced changes in body temperature at the antagonist doses used. BAY K8644 (3 mg/kg SC) produced stimulation of Ca++/Mg++ ATPase activity by 31% in hypothalamus but not in cortex or cerebellum. This stimulation of enzyme activity was selectively prevented by nimodipine but not verapamil or diltiazem. No changes in enzyme activity were observed when Ca++ channel antagonists were used alone. These studies demonstrate that the Ca++ agonist BAY K8644 produces receptor mediated hypothermia which is dihydropyridine receptor dependent. Activation of Ca++ ATPase in the hypothalamus suggests that activation of dihydropyridine receptors may be coupled to Ca++ transport systems in this brain region and may reinforce the Ca++ set point theory of thermoregulation.     

The behavioral effects of the calcium agonist BAY K 8644 in the mouse: Antagonism by the calcium antagonist nifedipine

Summary Mice injected with the calcium agonist BAY K 8644 (2–4 mg/kg, i. p.) displayed profound behavioral changes including ataxia, decreased motor activity, Straub tail, arched back, limb clonus and tonus, and an increased sensitivity to auditory stimulation. BAY K 8644 significantly impaired rotorod performance in mice with an ED₅₀ of 0.8 mg/kg. The behavioral effects of BAY K 8644 were antagonized by nifedipine, but not by the non-dihydropyridine calcium channel antagonist verapamil or the -adrenoceptor antagonist prazosin. Further, the actions of BAY K 8644 were not mimicked by the -adrenoceptor agonist methoxamine at doses up to 4.5 mg/kg. These observations, coupled with the findings that BAY K 8644 is a potent, competitive inhibitor of [³H]nitrendipine binding to the dihydropyridine binding site in mouse brain (K _i=7.0×10^–9M), suggests that BAY K 8644 may produce its behavioral actions via an interaction with the DHP binding site, which has been linked to the control of calcium flux across membranes in peripheral tissues.     

Dihydropyridine calcium channel antagonists reduce immobility in the mouse behavioral despair test; antidepressants facilitate nifedipine action

The effect of the calcium channel antagonists nifedipine, nitrendipine, nimodipine, verapamil and diltiazem in the mouse behavioral despair test was investigated. The dihydropyridine calcium channel antagonists nifedipine, nitrendipine, nimodipine (0.1, 1, 10 mg/kg p.o.) but not the non-dihydropyridine compounds verapamil or diltiazem, dose dependently reduced immobility. Various antidepressant drugs (imipramine, mianserin, citalopram, (+)oxaprotiline) and (-)oxaprotiline in combination with nifedipine facilitated its effect.     

Opiate receptor mediated hyperthermic responses in rat following Ca++ channel antagonists

The effects of morphine sulfate on rectal temperature and on Ca++-stimulated Mg++ATPase activity in crude synaptosomal fraction (P2) of cortex, hypothalamus and cerebellum were investigated in rat. Morphine (3-15 mg/kg, SC) produced hyperthermia at 30-120 min after the drug administration. The Ca++/Mg++ ATPase activity in hypothalamus and cortex was decreased while there was no change in Mg++ ATPase activity. The enzyme activity in cerebellum was not affected. The opiate antagonist naloxone hydrochloride (5 mg/kg, SC) antagonized the effect of morphine on rectal temperature and Ca++/Mg++ ATPase activity. The effects of different calcium channel antagonists (nimodipine 1 mg/kg, verapamil 2.5 mg/kg and diltiazem 10 mg/kg, SC) on the changes induced by morphine were also investigated. These antagonists not only antagonized morphine hyperthermia, but also the inhibitory effect of morphine on Ca++/Mg++ ATPase activity in hypothalamus. The calcium channel agonist BAY K8644 (3 mg/kg, SC) produced hypothermia and also stimulation of Ca++/Mg++ ATPase activity in hypothalamus. Naloxone failed to alter these effects of BAY K8644. These studies demonstrate that Ca++ transport in hypothalamus, as indicated by Ca++/Mg++ ATPase activity, plays an important role in thermoregulation and thermoregulatory changes induced by opiates.     

Effects of calcium channel ligands on anaesthetic properties of ethanol in mice.

This study has examined the effect of two calcium channel antagonists--nifedipine, verapamil and a calcium channel agonist BAY K 8644 on duration of ethanol-induced anaesthetic activity measured as the loss of the righting reflex (LORR) in mice. Nifedipine (5 and 10 mg/kg, i.p.) and verapamil (10 and 20 mg/kg, i.p.) potentiated the acute general anaesthetic effect of ethanol (3.5 g/kg, i.p.). BAY K 8644 (2 mg/kg, i.p.) shortened the duration of ethanol-induced LORR. This action of BAY K 8644 was prevented by the pretreatment with nifedipine (2.5 mg/kg, i.p.) but not with verapamil (5 mg/kg, i.p.). Injections of both calcium channel blockers--nifedipine (2.5 mg/kg) and verapamil (5 mg/kg) did not influence the ethanol-induced hypnotic activity themselves. Our results suggest that the calcium ions are involved in the central depressant effects of acute ethanol administration at high doses. It can be supposed that the modification of the activity of voltage-dependent calcium channels plays an important role in the anaesthetic action of ethanol.     

Yawning induced by apomorphine,physostigmine or pilocarpine is potentiated by dihydropyridine calcium channel blockers

Previous studies have shown that dihydropyridine (DHP) calcium channel blockers can potentiate yawning induced by apomorphine in rats. The present study was undertaken to examine whether or not this interaction was seen with other compounds that induce yawning or if it represented a specific interaction with dopaminergic mechanisms. Yawning induced by apomorphine (40 µg/kg SC), physostigmine (50 µg/kg SC) or pilocarpine (1 mg/kg SC) was dose-dependently potentiated by the DHP calcium channel blocker nifedipine (1.25–10 mg/kg IP). Nimodipine (1.25–5 mg/kg IP) and nitrendipine (1.25–5 mg/kg IP) also significantly increased the yawning response. The DHP calcium channel blockers alone induced only a low incidence of yawning. The effects of nifedipine on physostigmine-induced yawning were reversed by the DHP calcium channel activator BAY K 8644 which also inhibited yawning induced by physostigmine (100 µg/kg SC) and pilocarpine (2 mg/kg SC). In contrast to the DHP compounds, diltiazem (2.5–10 mg/kg IP) and verapamil (2.5–10 mg/kg IP) failed to potentiate yawning. Sulpiride (10 mg/kg SC) antagonised the nifedipine potentiation of apomorphine-induced yawning but not that of physostigmine-induced yawning; atropine (2.5 mg/kg SC) antagonised both effects. These results support the hypothesis that this effect of dihydropyridine compounds is not dependent on, nor mediated through, dopaminergic mechanisms.     

Calcium channel modulation: ability to inhibit or promote calcium influx resides in the same dihydropyridine molecule

BAY K 8644, a dihydropyridine of the nifedipine type, was shown to increase coronary resistance and to enhance myocardial contractility (Schramm et al., Nature 1983;303:535-7), in contrast to the well-known vasodilating and negative inotropic effects of the "classical" calcium channel blockers. In the isolated perfused guinea pig heart at high concentrations (greater than 3 microM), however, the coronary constricting and positive inotropic effects of BAY K 8644 progressively reverse until the drug has a negative inotropic effect and decreases coronary resistance, thus mimicking the effects of the "classical" calcium antagonists. On the other hand, in the same experimental model, calcium antagonists like nifedipine, nitrendipine, and nicardipine are shown to exert a small but definite positive inotropic effect at low concentrations, indicating a calcium agonistic action at those concentrations. To explain the pharmacological effects of BAY K 8644 and the calcium channel blockers of the dihydropyridine type, a model is proposed that suggests the existence of two dihydropyridine binding sites per channel. According to this model, it depends on the chemical structure of the respective dihydropyridine whether, after occupation of the first site, which increases the calcium influx through the channel, the occupation of the second site is unimpaired, turning the channel to one with low calcium permeability; or whether occupation of the second site is hindered, leaving the channel in the high conductance state.     

Calcium agonists and antagonists of the dihydropyridine type: Antinociceptive effects,interference with opiate-μ-receptor agonists and neuropharmacological actions in rodents

The calcium antagonist dihydropyridine derivative nimodipine and its enantiomers BAY N 5247, BAY N 5248, as well as BAY R 4407 (calcium antagonist (+)-enantiomer of the calcium agonist dihydropyridine BAY K 8644) do not exert antinociceptive effects in the rat as measured by the vocalization test in doses up to 100 g/kg IV, and in the mouse as measured by the hot plate test in oral doses up to 100 mg/kg. The calcium agonists BAY K 8644 and BAY R 5417 ((–)-enantiomer of BAY K 8644) are also ineffective in the rat vocalization test but BAY K 8644 increases reaction time in the hot plate test (mouse) dose-dependently (1–10 mg/kg PO). -Receptor agonist (fentanyl) antinociceptive effects are potentiated by simultaneous IV administration of the calcium antagonists, the (–)-enantiomer of nimodipine BAY N 5248 being the most potent. This applies for the rat (vocalization test) and the mouse (hot plate test). The influence on fentanyl antinociception in the rat of the calcium agonist BAY K 8644 and its (–)-enantiomer BAY R 5417 is biphasic: low doses attenuate, high doses potentiate fentanyl antinociception. In the mouse (hot plate test) antinociceptive effects of BAY K 8644 plus fentanyl are less than additive, indicating that the calcium agonist decreases fentanyl effects. The relative potency of calcium antagonists in potentiation of fentanyl antinociception correlates with their relative potency as calcium antagonists as measured by receptor binding studies, effects on vascular and cardiac muscle, and with their neuropharmacological actions (anticonvulsive effects, inhibition of balance and spontaneous motility as well as tranquilizing effects in the mouse). It is concluded that calcium antagonism potentiates -receptor agonist antinociceptive effects, whereas calcium agonism antagonizes -receptor agonist antinociception.Dedicated to Prof. Dr. H. Coper (Berlin) on the occasion of his 60th anniversary     

Effects of nifedipine, BAY K 8644, and pertussis toxin on pressor response to sarafotoxin-b in pithed rats.

The pressor actions of sarafotoxin-b (SRTX-b) were examined in pithed rats in the presence of the calcium channel antagonist nifedipine or the calcium channel activator BAY K 8644 intraarterially (i.a.) and also after pretreatment with pertussis toxin intravenously (i.v.). SRTX-b produced dose-dependent pressor effects in the pithed rat. The diastolic blood pressure (DBP) recorded in animals treated with the vehicle was 41 +/- 1 mm Hg; administration of BAY K 8644 0.1 or 0.3 mg/kg increased DBP pressure to 50 +/- 1 and 52 +/- 1 mm Hg, respectively, whereas nifedipine 0.1 or 0.3 mg/kg decreased DBP to 39 +/- 1 and 33 +/- 1 mm Hg, respectively. The actions of SRTX-b were significantly inhibited by nifedipine, whereas BAY K 8644 potentiated the pressor actions of SRTX-b. We observed that animals pretreated with pertussis toxin 25 or 50 micrograms/kg 3 days before we conducted the experiments had significantly lower DBP as compared with saline-treated animals. Treatment with pertussis toxin caused the DBP dose-response curve to SRTX-b to be displaced to the right. These results indicate that a nifedipine-sensitive (presumably extracellular) calcium pool is partly responsible for the pressor response induced by SRTX-b. They further suggest that in vascular smooth muscle, at least in some vascular beds, SRTX-b activates a pertussin toxin-sensitive G-protein that is coupled to a receptor-operated calcium or nonspecific cation channel.     

Ca2+ channel agonists enhance thyrotropin-releasing hormone-induced inositol phosphates and prolactin secretion.

The dihydropyridine Ca2+ channel activator BAY K 8644 (1 microM) stimulated basal prolactin secretion from perifused primary cultures of anterior pituitary cells and potentiated the stimulation of prolactin secretion by 1 microM thyrotropin-releasing hormone (TRH) 5-fold over 30 min. This potentiation was mimicked by other dihydropyridine agonists CGP 28392 and (+)-SDZ 202-791 and by (-)-BAY K 8644 (1 microM), but not by (+)-BAY K 8644. The Ca2+ channel antagonist nimodipine, at a concentration sufficient to block BAY K 8644-stimulated 45Ca2+ uptake in GH4C1 anterior pituitary tumor cells, decreased basal prolactin secretion and blocked the enhancement of basal and TRH-stimulated secretion by BAY K 8644. These results suggest that dihydropyridine agonists potentiate TRH-induced secretion through interaction with known stereospecific sites on Ca2+ channels. In GH4C1 cells, BAY K 8644 alone did not affect inositol polyphosphate accumulation, but potentiated TRH-stimulated accumulation of inositol 1,3,4-trisphosphate and inositol 1,3,4,5-tetrakisphosphate. Accumulation of the Ca(2+)-mobilizing isomer inositol 1,4,5-trisphosphate was not potentiated, suggesting that potentiation of TRH-stimulated hormone secretion by BAY K 8644 does not result from synergistic stimulation of phospholipase C, but may correlate with enhanced inositol trisphosphate-3-kinase activity.     

The calcium channel agonist BAY k 8644 reduces ethanol intake and preference in alcohol-preferring AA rats

Applying a 12-h limited access, two-bottle choice procedure, antialcohol effects of the 1,4-dihydropyridine (DHP) L-type calcium (Ca²⁺) channel agonist BAY k 8644 were investigated in alcohol-preferring AA rats. In this Wistar line, selectively bred for a high 10% v/v ethanol (EtOH) preference in a free choice situation, effects on EtOH preference and intake, as well as on food and total fluid intake were evaluated for racemic BAY k 8644 (0.1–1 mg/kg IP; 0.25–2 mg/kg PO), its agonistic (?)-enantiomer (0.1–1 mg/kg IP and PO) and its antagonistic (+)-enantiomer (10–50 mg/kg IP and PO). Irrespective of route of application, BAY k 8644 was found to be effective in reducing both EtOH intake and preference (minimal effective dose: 0.5 mg/kg; maximum effect: approximately 60% of baseline levels). The (+)-enantiomer, acting as a low-potency Ca²⁺ channel antagonist, also reduced EtOH intake and preference, but the effects were not very selective as food intake was also substantially reduced. Moreover, the effects were only obtained at relatively high doses (50 mg/kg). The essential enantiomer involved in the antialcohol effects of BAY k 8644 seems to be the (?)-enantiomer, acting as a strong Ca²⁺ channel agonist. This latter compound was potent (minimal effective dose: 0.3 mg/kg), very effective in reducing EtOH intake (maximum effect: 29% of baseline level) and preference (26% of baseline) and apparently more selective. Although slightly decreasing over days, effects of (?)-BAY k 8644 on EtOH intake and preference were shown to remain after repeated treatment (10 successive days, 0.3 mg/kg IP). Interestingly, the acute antialcohol effects of (?)-BAY k 8644 (0.3–1 mg/kg IP) could not be antagonized with the DHP L-type Ca²⁺ channel antagonists nimodipine (0.01–1 mg/kg IP) and (?)-nimodipine (1–30 mg/kg IP). The present results suggest that a mechanism of action other than L-type Ca²⁺ channel agonism is involved in the antialcohol effects of (±)-and (?)-BAY k 8644. Alternatively, it is possible that the previously described antialcohol effects of DHP Ca²⁺ channel antagonists are not related to antagonistic activity at Ca²⁺ channels. Finally, it cannot be excluded that a mechanism unrelated to Ca²⁺ channels is responsible for the antialcohol effects of both DHP Ca²⁺ channel agonists and antagonists.     

The calcium channel agonist BAY k 8644 reduces ethanol intake and preference in alcohol-preferring AA rats

Applying a 12-h limited access, two-bottle choice procedure, antialcohol effects of the 1,4-dihydropyridine (DHP) L-type calcium (Ca²⁺) channel agonist BAY?k8644 were investigated in alcohol-preferring AA rats. In this Wistar line, selectively bred for a high 10% v/v ethanol (EtOH) preference in a free choice situation, effects on EtOH preference and intake, as well as on food and total fluid intake were evaluated for racemic BAY?k8644 (0.1–1?mg/kg IP; 0.25–2?mg/kg PO), its agonistic (?)-enantiomer (0.1–1?mg/kg IP and PO) and its antagonistic (+)-enantiomer (10–50?mg/kg IP and PO). Irrespective of route of application, BAY?k8644 was found to be effective in reducing both EtOH intake and preference (minimal effective dose: 0.5?mg/kg; maximum effect: approximately 60% of baseline levels). The (+)-enantiomer, acting as a low-potency Ca²⁺ channel antagonist, also reduced EtOH intake and preference, but the effects were not very selective as food intake was also substantially reduced. Moreover, the effects were only obtained at relatively high doses (50?mg/kg). The essential enantiomer involved in the antialcohol effects of BAY?k8644 seems to be the (?)-enantiomer, acting as a strong Ca²⁺ channel agonist. This latter compound was potent (minimal effective dose: 0.3?mg/kg), very effective in reducing EtOH intake (maximum effect: 29% of baseline level) and preference (26% of baseline) and apparently more selective. Although slightly decreasing over days, effects of (?)-BAY?k8644 on EtOH intake and preference were shown to remain after repeated treatment (10 successive days, 0.3?mg/kg IP). Interestingly, the acute antialcohol effects of (?)-BAY?k8644 (0.3–1?mg/kg IP) could not be antagonized with the DHP L-type Ca²⁺ channel antagonists nimodipine (0.01–1?mg/kg IP) and (?)-nimodipine (1–30?mg/kg IP). The present results suggest thata mechanism of action other than L-type Ca²⁺ channel agonism is involved in the antialcohol effects of (±)- and (?)-BAY?k8644. Alternatively, it is possible that the previously described antialcohol effects of DHP Ca²⁺ channel antagonists are not related to antagonistic activity at Ca²⁺ channels. Finally, it cannot be excluded that a mechanism unrelated to Ca²⁺ channels is responsible for the antialcohol effects of both DHP Ca²⁺ channel agonists and antagonists.     

Central and peripheral effects of the dihydropyridine calcium channel activator BAY K 8644 in the rat

Following intraperitoneal (i.p.) administration BAY K 8644 (0.5−4 mg/kg) induced an increase in blood pressure associated with bradycardia, increased tail-flick latency in response to radiant heat, decreased locomotion, induced muscle contraction, postural changes and also reduced reflex activity. Only the postural changes and reduced locomotion were seen after intracerebroventricular administration (5–20 μg/kg), suggesting that the other effects are mediated peripherally. All the above effects were antagonised by the calcium channel blocker nifedipine. BAY K 8644 (4 mg/kg i.p.) also significantly increased homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations in the cortex and striatum, an effect which could also be reversed by nifedipine. Apart from inducing hypotension and tachycardia, nifedipine alone had no effect on any of the above parameters. The analgesic-like activity of BAY K 8644 observed in the tail-flick test appears to be related to its vasoconstrictor effects as the peripherally acting vasodilator phenylephrine had similar analgesic activity. These results show that both central and peripheral dihydropyridine-sensitive calcium channels mediate the effects of BAY K 8644. Although a physiological role for the dihydropyridine-sensitive voltage-operated calcium channel in the CNS remains to be demonstrated, activation fo these channels can clearly have functional effects.     

Extracellular calcium dependence of the neurotensin-induced relaxation of intestinal smooth muscles: studies with calcium channel blockers and BAY K-8644

To investigate whether the neurotensin-induced relaxation of the rat duodenum and ileum is dependent on the external concentration of calcium, the effect of the neuropeptide was studied in isolated intestinal segments superfused with Tyrode solution containing no calcium, 1 or 2.5 mM Ca2+. The neurotensin-induced intestinal relaxation was reduced when the extracellular calcium concentration was lowered. In addition, the inhibitory effect of neurotensin was cancelled when the tissues were incubated in the presence of diltiazem, methoxyverapamil or nifedipine. BAY K-8644, a structural analog of nifedipine that functions as an agonist of the calcium channel, potentiated the neurotensin-induced smooth muscle relaxation. The facilitatory effect of BAY K-8644 was antagonized by nifedipine, indicating competition between the 2 dihydropyridines. Apamin, the K+ channel blocker, antagonized the neurotensin-induced visceral relaxation, displacing the concentration-response curve of the peptide to the right. Furthermore, apamin also blocked the effect of neurotensin when the neuropeptide was assayed in the presence of BAY K-8644. It is concluded that the smooth muscle relaxation induced by neurotensin is dependent on external calcium, suggesting that the activation of the neuropeptide receptor causes an influx of calcium which leads to the opening of K+ channels before smooth muscle relaxation is triggered.     

BAY k 8644, a calcium channel agonist, reverses hypotension in endotoxin-shocked rats

The hypotension and depressed myocardial function frequently observed in endotoxin-induced shock are difficult to overcome pharmacologically. In this paper we demonstrate that the calcium channel agonist BAY k 8644 potently elevates blood pressure in endotoxin-shocked rats. A one time dose as low as 10 μg/kg of BAY k 8644 significantly elevated mean arterial pressure (MAP) in endotoxin-treated hypotensive rats while having minimal effects in normal rats. The maximum BAY k-induced percentage increase in MAP was greater in endotoxin-treated rats when compared with saline-treated control (153% vs. 120% increase respectively). BAY k 8644 also caused a dose-dependent decrease in heart rate of 37% in endotoxin-treated rats and 39% in control rats (NS vs. control). No differences in the regulatory properties of [³H]nitrendipine binding sites were discerned comparing control and endotoxin-treated rats. Thus, the enhanced activity of BAY k 8644 in hypotensive rats was not due to augmented affinity for the cardiac dihydropyridine binding site. These results demonstrate that the use of calcium channel agonists might represent a unique pharmacologic approach in pathologic states characterized by hypotension and diminished cardiac function.     

Anticonvulsant profile of the dihydropyridine calcium channel antagonists, nitrendipine and nimodipine

The effects of the dihydropyridine calcium channel antagonists, nitrendipine and nimodipine, on convulsions produced by different mechanisms have been studied in rats. Nitrendipine and nimodipine significantly raised the thresholds to pentylenetetrazol for up to six hours after their injection. The calcium channel agonist, BAY K 8644, lowered the convulsion threshold to pentylenetetrazol and antagonised the effects of nitrendipine. In contrast, the severity of seizures produced by N-methyl-dl-aspartate (NMA) was increased by nitrendipine. BAY K 8644 also slightly increased the effects of NMA. Nimodipine and nitrendipine caused small, but significant, increases in the threshold pressures for the convulsions caused by raising the atmospheric pressure with helium gas. The compounds had no effect on strychnine convulsions. The conclusion is that the calcium channel antagonists are anticonvulsant against only certain types of convulsions, such as pentylenetetrazol and high pressure (and ethanol withdrawal, reported previously). Others may be increased, such as NMA seizures, or unaffected, such as strychnine-induced convulsions.     

Modulation of calcium ion influx by the 1,4-dihydropyridines nifedipine and BAY K 8644

We examined the effects of the new dihydropyridine calcium agonist BAY K 8644 on calcium influx and mechanical activity in rabbit aortic rings and compared them with those of the classical calcium antagonist nifedipine. The vasodilating effects of nifedipine and the vasoconstricting effects of BAY K 8644 can be explained by the calcium influx modulating activity of these two dihydropyridines. Only at the high concentration of 3 X 10(-6) mol/L BAY K 8644 is there a marked difference between increased calcium influx and reduced contraction.     

Bay K 8644 induces a reversible spasticity-like syndrome in rats

The dihydropyridine Bay K 8644 exerts a positive modulation of Ca²⁺ channels. Administration of Bay K 8644 3–5 mg/kg i.p. to rats induces within 15 min a severe spasticity syndrome consisting of stiff tail, arched back, stretching and twisting of forelimbs and hindlegs and backwards motility and rolling over. The syndrome was effectively antagonized by nifedipine 3–30 mg/kg but not by the other Ca²⁺ channel blockers flunarizine, diltiazem and verapamil. Diltiazem even enhanced the spasticity. Diazepam 10–30 mg/kg i.p. completely blocked the spasticity whereas the other muscle relaxants (−)-baclofen and the β-carboline ZK 93423 were completely inactive. These findings with Bay K 8644 suggest that spasticity may be caused by changed Ca²⁺ homeostasis.