Calcium channel blockers prevent stress-induced ulcers in rats.

Gastric mucosal damage induced by cold and restraint stress caused increase in gastric lipid peroxidation (LP) and decrease in gastric glutathione levels. Two calcium-channel blockers, verapamil and nicardipine, prevented stress-induced increase in gastric LP, as well as ulcer formation. Both calcium-channel blockers protected against stress-induced ulcers, and inhibition of LP may be among their mechanisms of action.     

Calcium channel inhibitors prevent apomorphine- and oxytocin-induced penile erection and yawning in male rats

The effect of i.p. injection of the calcium channel inhibitors, verapamil, flunarizine, nifedipine, nimodipine and nicardipine, on penile erection and yawning induced by the dopamine agonist, apomorphine, or by oxytocin was studied in male rats. The five compounds antagonized in a dose-dependent manner the behavioral responses induced either by apomorphine or oxytocin. Nimodipine and nicardipine were found to be the most potent, being active in doses between 5 and 20 mg/kg, while nifedipine, verapamil and flunarizine were active in doses higher than 15 mg/kg. The results suggest that calcium is involved in the expression of the above-mentioned behavioural responses.     

Calcium channel antagonists suppress nicotine-induced place preference and locomotor sensitization in rodents

The influence of calcium channel antagonists on the behavioral sensitization to nicotine-induced hyperlocomotion and place preference was investigated. Locomotor sensitization in mice was produced by injecting nicotine (0.5 mg/kg, i.p.) for 5 consecutive days before placement in an apparatus in which locomotor activity was evaluated for 1 h. One week later, activity of mice was recorded after challenge with the same dose of nicotine. The L-type voltage-dependent calcium channel antagonists: nimodipine (5, 10 and 20 mg/kg, i.p.), verapamil (5, 10 and 20 mg/kg, i.p.) and diltiazem (5, 10 and 20 mg/kg, i.p.) were injected 15 min before each injection of nicotine (induction of sensitization) or acutely 15 min before a challenge nicotine injection (expression of sensitization). It was shown that the calcium channel blockers attenuated both the induction and expression of nicotine-induced locomotor sensitization in a dose-dependent manner. In the place preference paradigm, nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.5 mg/kg, i.p., 4 drug sessions). Pretreatment with nimodipine (10 mg/kg, i.p.), verapamil (10 mg/kg, i.p.) and diltiazem (10 mg/kg, i.p.) blocked nicotine-induced place conditioning. These results suggest the common calcium-dependent mechanisms of nicotine-induced behavioral sensitization and place preference.     

Effects of calcium channel inhibitors on the hypothermic response to oxotremorine in normo and hypercholinergic rats.

The Flinders Sensitive Line of rats (FSL) has been selectively bred to have increased sensitivity to cholinergic drugs. Typically, these rats react with twice as great a hypothermic effect to muscarinic agonists such as oxotremorine, as do similarly bred Flinders Resistant Line rats (FRL). We compared the effects of three chemically different calcium channel inhibitors (diltiazem, nicardipine and verapamil) on the hypothermia induced in FRL and FSL rats by oxotremorine (0.2 mg kg-1 s.c.). Each drug was injected i.p. in a dose of 20 mumol kg-1 30 min before oxotremorine. Methylatropine (2 mg kg-1 s.c.) was administered 15 min before oxotremorine to block the peripheral effects of the agonist. The hypothermic effect of oxotremorine in FSL rats was antagonized by nicardipine and diltiazem. In contrast, verapamil failed to influence the hypothermic response in FSL rats. Verapamil significantly (P less than 0.05) augmented oxotremorine hypothermia in FRL rats. Diltiazem and nicardipine were without effect on oxotremorine-induced hypothermia in FRL rats. There were no significant changes in temperature in separate groups of FRL and FSL rats treated with calcium channel inhibitors alone.     

New hydroxyethylamine HIV protease inhibitors that suppress viral replication.

The synthesis of analogues of AcSerLeuAsn[Phe-HEA-Pro]IleValOMe (1, JG-365; where HEA stands for the hydroxyethylamine unit 2), a tight-binding inhibitor of HIVP, are reported. Systematic modification of the P3 and P3' regions of the inhibitors has led to smaller HIVP inhibitors that inhibit viral replication in HIV-infected and SIV-infected cell cultures. Six aliphatic and/or aromatic derivatives were prepared by replacing residues in the P3 regions of BocLeuAsn[Phe-HEA-Pro]IleValOMe. Aromatic side chains at P3 gave better inhibitors than aliphatic side chains. The better inhibitors in this series contained a beta-naphthylalanine or a biphenyl unit at P3. A second series of HIVP inhibitors were obtained by converting the P3 group into acyl groups. CbzAsn[Phe-HEA-Pro]IlePheOMe and Qua-Asn-[Phe-HEA-Pro]-Ile-Phe-OMe (where Qua = quinolin-2-ylcarbonyl) are potent HIVP inhibitors with Ki values equal to 1.0 and 0.1 nM, respectively. The inhibition constants were determined by using the continuous fluorometric assay developed by Toth and Marshall. The activities of the protease inhibitors for inhibition of SIV replication were determined in vitro using CEM x 174 cells. Inhibition of HIV infection was determined essentially as reported by Pauwels and co-workers. The anti-HIV assay was carried out in culture using CEM cells (a CD4+ lymphocyte line) infected with virus strain HTLV-IIIb with a multiplicity of infection of 0.1. Several analogues inhibited the cytopathic effect at concentrations of 0.1-0.8 microgram/mL. These results establish that good inhibitors of HIV protease that inhibit viral replication in infected lymphocytes in in vitro cell assays can be obtained from JG-365 when the AcSerLeu unit is replaced by aromatic acyl derivatives.     

Calcium channel blocker-like action of reserpine in smooth muscle.

The effect of reserpine on vascular and intestinal smooth muscles was examined. In these muscles, reserpine inhibited the high K(+)-induced contraction, and this inhibitory effect was antagonized by the increase in external Ca2+ concentration and also by a Ca2+ channel activator, Bay k8644. In rabbit aorta, increases in cytosolic Ca2+ level and muscle tension due to high K+ were inhibited in parallel by reserpine. These results suggest that reserpine inhibits L-type Ca2+ channels to inhibit smooth muscle contraction.     

Calcium channel blockers in cerebral ischaemia

Ischaemic stroke usually results from the obstruction of a major cerebral vessel which leads to a decrease in cerebral blood flow, and a subsequent reduction in ATP. This energy loss leads to impaired cellular function due to reduced ATP-dependent processes and a disruption in ionic gradients across membranes. Under these conditions, there is a significant efflux of K+ from cells producing cellular depolarisation and the movement of extracellular calcium into cells through calcium channels. It is this increase in intracellular calcium that leads to the 'calcium toxicity' that has been associated with cerebral ischaemia. Increased intracellular calcium triggers the break-down of phospholipids, proteins and nucleic acids. This is activated by calcium-dependent phospholipases, proteases and endonucleases, and contributes to structural and functional damage of the cell membrane, which compromises cell function and facilitates cell death. Calcium channel blockers are used routinely to treat cardiovascular disease and hypertension. Although some experimental studies over the last decade suggest efficacy/benefit in the treatment of experimental ischaemic stroke, clinical data do not bear this out. This article discusses the role of voltage-operated calcium channel blockers in stroke, and reviews much of the available experimental and clinical data.     

Calcium valproate-induced uterine adenocarcinomas in Wistar rats.

Calcium valproate is an anticonvulsant agent with pharmacokinetic properties similar to sodium valproate and valproic acid. Potential carcinogenesis of calcium valproate was evaluated in B6C3F1 mice and Wistar rats given 125, 250 and 500 mg/kg in the diet for 104 weeks. Survival in treated rats increased in a dose-related pattern despite a tumorigenic response in females. Adenocarcinomas of the uterus and cervix were increased in treated rats when compared to controls. The incidence of uterine neoplasia was 8, 20, 14 and 32% in the control, 125, 250 and 500 mg/kg groups, respectively. Neoplasia in treated rats were detected against a higher than expected background of adenocarcinomas in concurrent controls, since 8% incidence in controls was substantially above the laboratory historical database value of 0.6%. Tumors varied from epithelial masses confined to the endometrium, to transmural, highly desmoplastic neoplasms that invaded the serosa lining and the peritoneal cavity. These tumors metastasized in treated rats but not in controls. The statistically significant (P less than 0.01) increase in uterine adenocarcinomas found in females given 500 mg/kg of calcium valproate contrasts the absence of this tumor type in a previous rat carcinogenicity bioassay with valproic acid. Subcutaneous fibrosarcomas were significantly increased in valproic acid-treated males, but no uterine tumors were reported in females. It is puzzling that a true carcinogenic potential would be expressed by markedly different target organs as obtained with the acid and calcium salt of this moiety.     

Calcium antagonists isradipine and nimodipine suppress cocaine and morphine intravenous self-administration in drug-naive mice.

The effect of isradipine and nimodipine, two dihydropyridine calcium antagonists, on intravenous self-administration of cocaine and morphine in naive mice has been investigated. When morphine or cocaine injections were made contingent upon nose-poke response by naive mice, they increased their rate of nose-poking with respect to animals receiving contingent saline injections or yoked control animals, receiving noncontingent cocaine or morphine injections. Pretreatment of mice with isradipine (1.0-3.0 mg/kg, SC) or nimodipine (5-20 mg/kg, SC) inhibited in a dose-related manner self-administration both of cocaine and morphine contingent upon a nose-poke response. The ED50 of isradipine against cocaine and morphine self-administration was 1.7 and 2.1 mg/kg, respectively. The relative values for nimodipine were 14.5 and 11.4 mg/kg, respectively. These data suggest that nimodipine and, especially, isradipine suppress the reinforcing properties of morphine and cocaine and may be an effective pharmacotherapy for treatment of cocaine and heroin abuse.     

Attenuation of morphine withdrawal syndrome by macromolecular synthesis inhibitors in rats

Attenuation of the morphine withdrawal syndrome by the combination treatment of morphine and protein/nucleic acid synthesis inhibitors was investigated in rats. Groups of rats were treated twice daily with gradually increasing doses of morphine (4–28 mg/kg) in combination with a protein/nucleic acid synthesis inhibitor (actinomycin D, chloramphenicol, cycloheximide, cytarabine, or tetracycline) for 14 days. Withdrawal was precipitated by naloxone on day 15 and the withdrawal manifestations were scored on a weighted basis for mild, moderate, and severe signs. The mild withdrawal signs were significantly decreased by cytarabine and tetracyline whereas the other combination-treated groups were only slightly decreased. The moderate and serve withdrawal signs for all combination-treated groups were significantly suppressed compared to the morphine-treated group. Therefore, attenuation of the morphine withdrawal syndrome by these protein/nucleic acid synthesis inhibitors supports an involvement of macromolecules in the development of physical dependence.     

Calcium channel blockers in the spectrum of antihypertensive agents

Calcium channel blockers (CCBs) are widely used in the treatment of hypertension. Through blood pressure reduction, and possibly other mechanisms such as antioxidative effects, they may play a role in diminishing the risk for a variety of cardiovascular outcomes. The combination of CCBs with other newer antihypertensive agents such, as ACE inhibitors and angiotensin receptor blockers, may provide complementary effects on risk reduction in cardiovascular adverse events and renal disease. Although the efficacy of CCBs as antihypertensive agents has been adequately demonstrated, there have been concerns regarding the use of short acting dihydropyridines after acute myocardial infarction. There have also been questions about the role of CCBs with regards to other antihypertensive agents in renal disease. For example, differential effects of dihydropyridine and non-dihydropyridine CCBs may affect progression of renal disease and risk for diabetes. Certain precautions involving drug interactions are needed because of the effects of CCBs on the CYP450 enzyme systems.     

Calcium channel blockers in the spectrum of antihypertensive agents

Calcium channel blockers (CCBs) are widely used in the treatment of hypertension. Through blood pressure reduction, and possibly other mechanisms such as antioxidative effects, they may play a role in diminishing the risk for a variety of cardiovascular outcomes. The combination of CCBs with other newer antihypertensive agents such, as ACE inhibitors and angiotensin receptor blockers, may provide complementary effects on risk reduction in cardiovascular adverse events and renal disease. Although the efficacy of CCBs as antihypertensive agents has been adequately demonstrated, there have been concerns regarding the use of short acting dihydropyridines after acute myocardial infarction. There have also been questions about the role of CCBs with regards to other antihypertensive agents in renal disease. For example, differential effects of dihydropyridine and non-dihydropyridine CCBs may affect progression of renal disease and risk for diabetes. Certain precautions involving drug interactions are needed because of the effects of CCBs on the CYP450 enzyme systems.     

Calcium channel blockade in experimental aminoglycoside nephrotoxicity

Calcium channel blocker therapy has proved protective in certain models of ischemic-induced acute renal failure. This effect may be related to the prevention of calcium influx into injured cells or by the vasodilatory effects of verapamil that may result in an improvement in renal blood flow. In the current study, the effect of verapamil treatment on the development of renal insufficiency and renal tissue calcium accumulation following aminoglycoside administration was investigated. The degree of functional damage and cortical tissue calcium accumulation after six or nine days of gentamicin administration (120 mg/kg body weight/day) was not significantly different in rats whose drinking water contained verapamil (10 mg/100 cc) than corresponding values in control animals. The tissue calcium accumulation correlated with the degree of reduction of creatinine clearance and probably reflects the extent of lethal tubular cell injury.     

Calcium channel blocker-like action of 1,9-dideoxyforskolin in vascular smooth muscle.

The inhibitory effect of 1,9-dideoxyforskolin (DFK) on the contraction of rat aorta was compared with that of forskolin. DFK inhibited the contraction induced by high K+ more strongly than that induced by norepinephrine, whereas forskolin more strongly inhibited the norepinephrine-induced contraction. The inhibitory effect of DFK on high K(+)-induced contraction was antagonized by an increase in extracellular Ca2+ concentration. DFK inhibited the increase in cytosolic Ca2+ level and contraction in parallel whereas forskolin inhibited the contraction more strongly than the cytosolic Ca2+ level. These results suggest that DFK, but not forskolin, inhibits vascular smooth muscle contraction by a Ca2+ channel blocker-like action.     

Effectiveness of lofexidine in blocking morphine-withdrawal signs in the rat

Discontinuation of chronic morphine infusion in rats 3esulted in the reliable occurrence of withdrawal body shakes. This sign of narcotic withdrawal was dose-dependently reduced by lofexidine (0.04–0.64 mg/kg) and clonidine (0.01–0.16 mg/kg). As with clonidine, the activity of lofexidine was not prevented by naloxone (5 mg/kg). In addition, diarrhea induced by naloxone (5 mg/kg) in morphine dependent rats was also prevented by lofexidine or clonidine pretreatment. These data suggest that lofexidine, like clonidine, may reduce the narcotic withdrawal syndrome in humans.     

Cholinergic agonists suppress play fighting in juvenile rats

Previous research has suggested that acetylcholine might activate play fighting in juvenile rats through its actions on central muscarinic receptors. To test this hypothesis we evaluated the effects on play fighting by the muscarinic agonists pilocarpine and arecoline given alone or in combination with the muscarinic antagonists scopolamine or methylscopolamine. Scopolamine, but not methylscopolamine which penetrates the brain poorly, suppressed play as indexed by frequency of pinning. Pilocarpine and arecoline also suppressed pinning at higher doses. Concurrent treatment with various agonist-antagonist dose combinations produced additive rather than counteractive effects. These data do not support the supposition that central muscarinic circuits are involved in the activation of play fighting.     

Intrathecal dynorphins suppress hindlimb electromyographic activity in rats

Intrathecal administration of dynorphin A-(1-17) produced suppression of hindlimb electromyographic activity in rats. This effect was seen also with the [D-Ala2]dynorphin (A-(1-17) analog. Intrathecal saline or the prototypical kappa opiate agonist, U50488, did not produce any change in electromyographic activity. These results, along with others, suggest that dynorphin or degradation fragment(s) of dynorphin, induces inhibition of ventral horn output and may possibly have toxic effects on ventral horn cells of the spinal cord.