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PubMed1992

[Myocardial infarction beyond the 48 first hours: treatment with calcium channel antagonists].

Calcium channel blocking agents prevent calcium entering cardiac and smooth muscle cells. With reduction of the blood pressure, heart rate and myocardial contractility, they reduce myocardial oxygen demand. By relieving spasm and coronary constriction, and dilating the collateral coronary vessels, they improve perfusion of the ischemic zones. The results in experimental infarction are contradictory: the reduction in the infarct size and ischaemia is not constant. In the Myocardial Infarction Study, a trial of lidoflazine in 1792 subjects followed up for an average of 5 years, there was no significant difference between the mortality rates of the two groups. In the Danish Verapamil Infarction Trial I, which included 436 subjects receiving 360 mg/day of verapamil or placebo, the 6 months mortality was less (NS) in the verapamil group (12.8%) than in the placebo group (13.9%) as was the reinfarction rate (7.8% versus 9.2%; NS). In the DAVIT II trial of 1775 subjects, treatment was introduced 9 +/- 2.7 days after admission. Mortality was lower (NS) in the verapamil group (11.1%) than in the placebo group (13.8%) and the recurrences were less common (p = 0.04) in the treatment group (11.0%) than with placebo (13.2%). The Secondary Prevention Reinfarction Israeli Nifedipine Trial is a comparison of Nifedipine 30 mg/day and placebo introduced 7-21 days after infarction in 2276 subjects. After 10 months, the mortality and reinfarction rate were similar in both groups, as in the SPRINT II trial (60 mg/day of nifedipine or placebo) at 6 months. In the Multicenter Diltiazem Postinfarction Trial of 2466 patients, Diltiazem 240 mg/day or placebo was administered 3 to 15 days after infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2003

Management of calcium channel antagonist overdose.

Calcium channel antagonists are used primarily for the treatment of hypertension and tachyarrhythmias. Overdose of calcium channel antagonists can be lethal. Calcium channel antagonists act at the L-type calcium channels primarily in cardiac and vascular smooth muscle preventing calcium influx into cells with resultant decreases in vascular tone and cardiac inotropy and chronotropy. The L-type calcium channel is a complex structure and is thus affected by a large number of structurally diverse antagonists. In the setting of overdose, patients may experience vasodilatation and bradycardia leading to a shock state. Patients may also be hyperglycaemic and acidotic due to the blockade of L-type calcium channels in the pancreatic islet cells that affect insulin secretion. Aggressive therapy is warranted in the setting of toxicity. Gut decontamination with charcoal, or whole bowel irrigation or multiple-dose charcoal in the setting of extended-release products is indicated. Specific antidotes include calcium salts, glucagon and insulin. Calcium salts may be given in bolus doses or may be employed as a continuous infusion. Care should be exercised to avoid the administration of calcium in the setting of concomitant digoxin toxicity. Insulin administration has been used effectively to increase cardiac inotropy and survival. The likely mechanism involves a shift to carbohydrate metabolism in the setting of decreased availability of carbohydrates due to decreased insulin secretion secondary to blockade of calcium channels in pancreatic islet cells. Glucose should be administered as well to maintain euglycaemia. Supportive care including the use of phosphodiesterase inhibitors, adrenergic agents, cardiac pacing, balloon pump or extracorporeal bypass is frequently indicated if antidotal therapy is not effective. Careful evaluation of asymptomatic patients, including and electrocardiogram and a period of observation, is indicated. Patients ingesting a nonsustained-release product should be observed in a monitored setting for 12 hours, while those who ingest a sustained-release preparation should be observed for no less than 24 hours. Charcoal should be given to the asymptomatic patient with a history of calcium channel antagonist overdose.

Algorithms↗

PubMed1986

Mechanisms of action and differences in calcium channel blockers.

Calcium ion (Ca++) serves an important role as an activation messenger; it initiates or regulates key cellular processes including contraction in the heart and vascular smooth muscle. Ca++ acts as both an electrical and a chemical signal. Upon entering the cell, the positively charged Ca++ carries an inward (depolarizing) current that contributes to pacemaker activity in the sinoatrial node and to atrioventricular conduction. Ca++ also binds to anionic surfaces of cell membranes and to anionic groups of both extracellular and intracellular proteins. The intracellular calcium-binding proteins include troponin and calmodulin, which when bound to Ca++ initiate contraction in cardiac and smooth muscles, respectively. Calcium channel blockers inhibit the entry of calcium into the cell, and thus prevent calcium from gaining access to the high-affinity, intracellular calcium-binding proteins. Verapamil and diltiazem decrease myocardial contractility and inhibit smooth muscle tone, while the dihydropyridines are mainly vasodilators. All of these drugs can play an important role in the treatment of hypertension.

Calcium↗

PubMed1999

Combination of calcium channel blockers and beta-blockers for patients with exercise-induced angina pectoris: beneficial effect of calcium channel blockers largely determined by their effect on heart rate.

The combination of calcium channel blockers and beta-blockers is more effective for the treatment of exercise-induced angina pectoris than beta-blocker monotherapy. As ischemia in exercise-induced angina is essentially preceded by an increase in heart rate, calcium channel blockers with a negative chronotropic property may perform better for this purpose than nonchronotropic compounds. A 335-patient, 10-week, double-blind, parallel-group comparison of amlodipine 5 mg and 10 mg, diltiazem 200 mg and 300 mg, and mibefradil 50 mg and 100 mg treatment added to baseline beta-blocker treatment was performed. Exercise testing (ETT) was performed by bicycle ergometry. All of the calcium channels blockers significantly delayed the onset of 1 mm ST-segment depression on ETT (p < 0.001 for any treatment vs. baseline). In addition, mibefradil, in both low- and high-dose treatments, produced the largest delays (low dose: different from diltiazem and amlodipine by 24.1 and 29.8 seconds, respectively, p < 0.003 and < 0.001; high dose: different from diltiazem and amlodipine by 33.7 and 37.0 seconds, respectively, p < 0.001 and < 0.001). A stepwise logistic regression analysis revealed that this beneficial effect of calcium channel blockers was largely dependent on their effect on heart rate. Serious symptoms of dizziness likewise occurred significantly more frequently on mibefradil (p < 0.05 vs. diltiazem) and urged no fewer than 19 patients on mibefradil to withdraw from the trial. The authors conclude that calcium channel blockers with a negative chronotropic property provide a better delay of ischemia in patients with exercise-induced angina, but the concomitant risk of intolerable dizziness may reduce this benefit.

Adolescent↗

PubMed1999

Dissection of the calcium channel domains responsible for modulation of neuronal voltage-dependent calcium channels by G proteins.

The molecular determinants for G-protein regulation of neuronal calcium channels remain controversial. We have generated a series of alpha 1B/alpha 1E chimeric channels, since rat brain alpha 1E (rbEII), unlike human alpha 1E, showed no G-protein modulation. The study, carried out in parallel using D2 receptor modulation of calcium currents in Xenopus oocytes of G beta gamma modulation of calcium currents in COS-7 cells, consistently showed an essential role for domain I (from the N terminus to the end of the I-II loop) of the alpha 1B Ca2+ channel in G-protein regulation, with no additional effect of the C terminal of alpha 1B. The I-II loop alone of alpha 1B, or the I-II loop together with the C-terminal tail, was insufficient to confer G-protein modulation of alpha 1E (rbEII). We have further observed that the alpha 1E clone rbEII is truncated at the N-terminus compared to other alpha 1 subunits, and we isolated a PCR product from rat brain equivalent to a longer N-terminal isoform. The long N-terminal alpha 1E, unlike the short form, showed G-protein modulation. Furthermore, the equivalent truncation of alpha 1B (delta N1-55) abolished G-protein modulation of alpha 1B. Thus, we propose that the N terminus of alpha 1B and alpha 1E calcium channels contains essential molecular determinants for membrane-delimited G-protein inhibition, and that other regions, including the I-II loop and the C terminus, do not play a conclusive role alone.

Amino Acid Sequence↗

PubMed1985

Basic cellular mechanisms of action of the calcium-channel blockers.

Calcium-channel blockers inhibit the entry of calcium ion (Ca++) into excitable cells, including those of coronary and peripheral arterial smooth muscle and the heart. The ability of these drugs to block Ca++ entry into cells inhibits the essential role of this cation as an intracellular messenger. The effects of calcium-channel blockers on the heart include a negative inotropic effect on the working myocardial cells of the atria and ventricles. Because the up-stroke of the action potential in these regions of the heart, and in the rapidly conducting cells of the His-Purkinje system, is due to a fast, sodium-dependent ionic current, calcium-channel blockers do not inhibit conduction in these cells. In the sinoatrial and atrioventricular (AV) nodes, on the other hand, depolarization is due primarily to a Ca++-dependent slow inward current; as a result, the calcium-channel blockers inhibit the sinus pacemaker and AV conduction. Because our knowledge of the molecular structure of the calcium channels in the heart and smooth muscle is rudimentary, little is known of the molecular mechanisms by which calcium-channel blockers inhibit Ca++ entry across the sarcolemmal membranes in these cells. It is apparent, however, that the actions of different members of this class of drugs on the sarcolemma are not the same. Indirect evidence indicates that some members of this class of drugs may interact with hydrophobic regions of the proteins that make up, or regulate, the calcium channels in the plasma membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium↗

PubMed1999

Regulation of cell movement is mediated by stretch-activated calcium channels.

Intracellular calcium regulates many of the molecular processes that are essential for cell movement. It is required for the production of actomyosin-based contractile forces, the regulation of the structure and dynamics of the actin cytoskeletons, and the formation and disassembly of cell-substratum adhesions. Calcium also serves as a second messenger in many biochemical signal-transduction pathways. However, despite the pivotal role of calcium in motile processes, it is not clear how calcium regulates overall cell movement. Here we show that transient increases in intracellular calcium, [Ca2+]i, during the locomotion of fish epithelial keratocytes, occur more frequently in cells that become temporarily 'stuck' to the substratum or when subjected to mechanical stretching. We find that calcium transients arise from the activation of stretch-activated calcium channels, which triggers an influx of extracellular calcium. In addition, the subsequent increase in [Ca2+]i is involved in detachment of the rear cell margin. Thus, we have defined a mechanism by which cells can detect and transduce mechanical forces into biochemical signals that can modulate locomotion.

Animals↗

PubMed1988

Photoaffinity-labelling of the calcium-channel-associated 1,4-dihydropyridine and phenylalkylamine receptor in guinea-pig hippocampus. A 195 kDa polypeptide carries both drug receptors and has similarities to the alpha 1 subunit of the purified skeletal-muscle calcium channel.

This study identifies calcium-antagonist-receptor-carrying polypeptides of calcium channels in guinea-pig hippocampus membranes. The arylazide ligands (-)-[3H]azidopine and [N-methyl-3H]LU49888 [(-)-5-[(3-azidophenethyl) [N-methyl-3H]methylamino]-2-(3,4,5-trimethoxyphenyl-2- isopropylvaleronitrile] were used to selectively label 1,4-dihydropyridine and phenylalkylamine receptors respectively. In the absence of u.v. light, both ligands reversibly bound to a single class of high-affinity receptors with a calcium-channel-typical pharmacological profile. [N-methyl-3H]LU49888 bound to the extent of 849 +/- 188 fmol/mg of protein (mean +/- S.D., n = 3) with a dissociation constant (Kd) of 1.4 +/- 0.3 nM. Under identical assay conditions (-)-[3H]azidopine labelled to the extent of 562 +/- 132 fmol/mg of protein with a Kd of 0.096 +/- 0.024 nM. After u.v. irradiation of the [N-methyl-3H]LU49888- and (-)-[3H]azidopine-labelled membranes, both photo-affinity probes were found to be incorporated specifically into a 190-195 kDa band as shown by SDS/polyacrylamide-gel electrophoresis (SDS/PAGE). Photoincorporation occurred with a protection profile identical with that produced by reversible binding-inhibition. [N-methyl-3H]LU49888, but not (-)-[3H]-azidopine, specifically labelled an additional 265 kDa band. Both photolabelled bands had an identical electrophoretic mobility on SDS/PAGE, irrespective of pretreatment either with 10 mM-N-ethylmaleimide or 10 mM-dithiothreitol. The electrophoretic properties of the 195 kDa polypeptide and the lability of receptor-incorporated (-)-[3H]azidopine to nucleophilic agents resemble those of the previously described drug-receptor-carrying alpha 1 subunit of the purified skeletal-muscle calcium channel. The data suggest that this polypeptide carries both the high-affinity 1,4-dihydropyridine as well as the phenylalkylamine receptor of neuronal calcium channels in guinea-pig hippocampus and is a component of the L-type calcium channel.

Affinity Labels↗

PubMed1985

Comparative potencies of calcium channel antagonists and antischizophrenic drugs on central and peripheral calcium channel binding sites.

Dihydropyridines are potent agents on [3H]nitrendipine binding sites in heart and brain membranes. Like the phenylalkylamines, they are slightly more active on heart than on brain [3H]nitrendipine binding sites. On the other hand, the diphenylalkylamines, the diphenylpiperazines and the antischizophrenic drugs of the diphenylbutylpiperdine type are more potent on brain [3H]nitrendipine binding sites. The findings suggest tissue heterogeneity of [3H]nitrendipine binding sites and the possible development of diphenylbutylpiperidine-diphenylbutylpiperazine analogues that could selectively act on brain calcium channel antagonist binding sites.

Animals↗

PubMed1995

Single-channel properties of four calcium channel types in rat motoneurons.

Previous studies have demonstrated multiple components of whole-cell calcium currents in hypoglossal motoneurons (HMs); HMs possess a low-voltage-activated (LVA) current and three types of high-voltage-activated (HVA) calcium currents based on sensitivity to omega-Aga IVA, omega-Conotoxin GVIA (omega-CgTx) and dihydropyridine analogs (DHPs). In the present study, we recorded single-calcium channel activities from HMs using a cell-attached patch-clamp method and found four types of channels that could be discriminated based on kinetics, voltage dependency, DHP sensitivity, and single-channel conductances. The average single-channel conductances with 110 mM barium as a charge carrier were 7, 14, 20, and 28 pS. T-type channels had a single-channel conductance of 7 pS, activated at the most negative potentials for the calcium channels and inactivated during depolarization. L-type channels (DHP-sensitive channels) did not inactivate during depolarization and had a 28-pS single-channel conductance. Based on kinetics and sensitivity to holding potential, it is likely that the channels with conductances of 14 pS and 20 pS represent N-type and P-type channels, respectively. The N-type channel (14 pS) was sensitive to holding potential, showed modal gating, and inactivated during maintained depolarizations, whereas the P-type channel (20 pS) was rather insensitive to holding potential and did not inactivate during depolarization.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2006

Effects of voltage-gated calcium channel subunit genes on calcium influx in cultured C. elegans mechanosensory neurons.

Voltage-gated calcium channels (VGCCs) serve as a critical link between electrical signaling and diverse cellular processes in neurons. We have exploited recent advances in genetically encoded calcium sensors and in culture techniques to investigate how the VGCC alpha1 subunit EGL-19 and alpha2/delta subunit UNC-36 affect the functional properties of C. elegans mechanosensory neurons. Using the protein-based optical indicator cameleon, we recorded calcium transients from cultured mechanosensory neurons in response to transient depolarization. We observed that in these cultured cells, calcium transients induced by extracellular potassium were significantly reduced by a reduction-of-function mutation in egl-19 and significantly reduced by L-type calcium channel inhibitors; thus, a main source of touch neuron calcium transients appeared to be influx of extracellular calcium through L-type channels. Transients did not depend directly on intracellular calcium stores, although a store-independent 2-APB and gadolinium-sensitive calcium flux was detected. The transients were also significantly reduced by mutations in unc-36, which encodes the main neuronal alpha2/delta subunit in C. elegans. Interestingly, while egl-19 mutations resulted in similar reductions in calcium influx at all stimulus strengths, unc-36 mutations preferentially affected responses to smaller depolarizations. These experiments suggest a central role for EGL-19 and UNC-36 in excitability and functional activity of the mechanosensory neurons.

Amino Acid Sequence↗

PubMed2001

The decompensated detrusor IV: experimental bladder outlet obstruction and its functional correlation to the expression of the ryanodine and voltage operated calcium channels.

PURPOSE: Calcium ion homeostasis has a significant role in smooth muscle function. Its regulation requires complex storage and release mechanisms via ion pumps and channels located within intracellular storage sites (sarcoplasmic reticulum) and at the plasma membrane. A prominent component of the sarcoplasmic reticulum is the ryanodine sensitive ion channel which releases calcium from the sarcoplasmic reticulum into the cytosol. At the level of the plasma membrane the voltage operated calcium channel (dihydropyridine sensitive) serves to allow an influx of extracellular calcium. Our prior studies have shown a loss of sarcoplasmic endoplasmic reticulum Ca++Mg++ATPase expression following outlet obstruction. In this study we correlate ryanodine and voltage operated calcium channel protein expression with bladder function following partial outlet obstruction. MATERIALS AND METHODS: Standardized partial bladder outlet obstructions were created in adult New Zealand white rabbits, which were divided into control, sham operated and obstructed groups. Muscle strip studies further subcategorized the obstructed group into compensated (force greater than 50% of control) and decompensated (force less than 50% of control) and were correlated with in vivo determinations of voiding frequency and voided volumes. Microsomal membrane protein fractions were prepared from the same bladder tissue and were used for Western blot analysis using specific monoclonal antibodies. RESULTS: Increased voiding frequency and decreased voided volumes correlated with the definitions of compensated and decompensated. The Western blots revealed a near disappearance of ryanodine expression in the decompensated group with minimal changes in the expression of the voltage operated calcium channel. CONCLUSIONS: Bladder performance as measured in vivo and in vitro after outlet obstruction is influenced in part by smooth muscle cell ability to maintain calcium homeostasis via the sarcoplasmic reticulum. Bladder decompensation is highly associated with a loss of sarcoplasmic reticulum function with lesser changes taking place in those calcium regulatory proteins at the plasma membrane.

Animals↗

PubMed1986

Exaggerated Dahl salt-sensitive kidney response to calcium channel agonist isomer of Bay k 8644, but not to calcium channel antagonist isomer of Bay k 8644.

We examined the influence of calcium channel agonist and antagonist optical isomers of BAY-K-8644 on the renal vascular resistance, glomerular filtration rate and sodium excretion of isolated perfused kidneys from Dahl salt-sensitive (DS) and salt-resistance (DR) rats previously stabilized on high- and low-NaCl regimens. The agonist isomer affected these parameters at a lower concentration and to a greater degree in the high-salt DS rat kidneys than in the other three groups. The antagonist isomer also reversed agonist-induced changes to the greatest degree in the high-salt DS rat kidneys. However, the low-salt DS and high-salt DR rat kidneys appeared to be slightly more reactive to these isomers than the low-salt DR rat kidneys, suggesting that hereditary predisposition and dietary NaCl may contribute independently to renal responsiveness to calcium channel-active agents.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1988

Differential effects of calcium channel blockade and intracellular calcium antagonism on endothelium-dependent responses of the rat aorta to drugs.

The actions of many vasoactive drugs are mediated through, or modified by, the endothelium-derived relaxing (EDRF) and constricting (EDCF) factors. While EDRF appears to be nitric oxide, EDCF is a peptide or cyclooxygenase product. Using verapamil (a calcium channel blocker), propyl methylenedioxyindene (pr-MDI; an intracellular calcium antagonist), and sodium nitroprusside (which liberates nitric oxide from its molecular structure) as EDRF-independent pharmacological probes in rat aortic rings with and without endothelium, we attempted to provide additional insight into the role of extracellular [( Ca]o) and intracellular [( Ca]i) calcium in EDRF and EDCF release and action, and to explain some mechanisms underlying the modulatory effects of these endothelial factors on the actions of vasoactive drugs. The findings suggest that (1) the [Ca]o required for evoked EDRF release does not enter endothelial cells through verapamil-sensitive calcium channels; (2) mobilization of endoplasmic reticular [Ca]i by [Ca]o entering the endothelial cell may be the trigger for evoked EDRF release; (3) spontaneous release of EDRF appears to depend more on mobilization of [Ca]i than on influx of [Ca]o; (4) the action of EDRF on smooth muscle either does not require Ca or does not involve the mobilization of [Ca]i by [Ca]o; (5) Both EDRF and EDCF can modulate the actions of vasoactive drugs; (6) the EDCF of the rat aorta is not a cyclooxygenase product, and (7) the action of EDCF on vascular smooth muscle, and possibly its release from endothelial cells, are Ca-dependent.

Acetylcholine↗

PubMed1992

GM1-ganglioside regulation of EGF-induced gastric mucosal calcium channel activation.

1. Calcium channels, isolated from gastric epithelial cell membranes when reconstituted into phosphatidylcholine vesicles exhibited active 45Ca2+ uptake as evidenced by a dose dependent response to calcium channel activator, BAY K8644, and antagonist, PN200-110. 2. The channels on epidermal growth factor (EGF) binding in the presence of ATP showed an increase in tyrosine phosphorylation of 55 and 170 kDa calcium channel proteins. Such phosphorylated channels following reconstitution into the vesicles displayed a 48% greater 45Ca2+ uptake than that of the controls. 3. The binding of EGF to calcium channel protein was inhibited by GM1-ganglioside reaching maximum inhibition of 65% at 40 nM GM1. In contrast, calcium channel antagonist, PN200-110, had no effect on EGF binding. 4. The EGF-stimulated calcium channel protein phosphorylation was inhibited by GM1. This inhibitory effect was mainly reflected in the decrease of tyrosine phosphorylation of 55 and 170 kDa proteins. 5. The results suggest the participation of GM1-ganglioside in the regulation of EGF-stimulated gastric mucosal calcium channel activation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1985

Effects of 1,25(OH)2D3 and calcium channel blockers on cecal calcium transport in the rat.

To determine whether calcium transport across rat cecum is vitamin D dependent, we measured in vitro bidirectional calcium fluxes under short-circuited conditions across cecum from rats that were vitamin D deficient, vitamin D replete, or vitamin D deficient or vitamin D replete and injected with either 10, 25, or 75 ng of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] daily for 4 days before study. Vitamin D deficiency decreased net calcium absorption (Jnet) by reducing the mucosal-to-serosal absorptive flux (Jm----s) from 168 +/- 18 to 33 +/- 5 nmol X cm-2 X h-1 (mean +/- SE, P less than 0.0001). Twenty-five nanograms of 1,25(OH)2D3 raised Jm----s to 124 +/- 17 nmol X cm-2 X h-1, not different from values in vitamin D-replete rats. Although active calcium absorption by cecum appears to respond to vitamin D, calcium Jm----s is near maximal under normal conditions, and further stimulation follows only pharmacological doses of 1,25(OH)2D3. The in vitro addition of the calcium channel blocker verapamil (5 X 10(-5) M) to the mucosal side of cecum from vitamin D-replete rats reduced calcium Jm----s, but lower concentrations of verapamil or nitrendipine (10(-5) to 10(-9) M) did not reduce calcium Jm----s. The lack of inhibition by low concentrations of channel blockers suggest that the plasma membrane channels for calcium translocation across intestinal epithelium may not be analogous to voltage-dependent calcium channels in excitable tissue. The inhibition of cecal calcium transport that was blocked by high concentrations of verapamil may represent a nonspecific effect of the agent.

Animals↗

PubMed1988

Calcium channel blockade with verapamil. Effects on blood pressure, renal, and myocardial adrenergic, cholinergic, and calcium channel receptors in inbred Dahl hypertension-sensitive (S/JR) and hypertension-resistant (R/JR) rats.

Verapamil HCl was chronically administered to inbred Dahl S/JR and R/JR rats maintained on a diet containing 8.0% NaCl (w/w) and the effects on blood pressure (BP) and heart rate (HR) were investigated. Treatment over a 4-week period via implanted miniosmotic pumps attenuated but did not prevent the development of salt-induced hypertension (HT) in the S/JR rat. Elevated HR, possibly reflexive in origin, was observed in S/JR rats that received verapamil but not in similarly treated R/JR rats. Although verapamil retarded the development of HT in S/JR rats, BP rose to moderately hypertensive levels, and the ventricle/body weight ratio was elevated by the termination of the study. The effect of verapamil on the density and affinity of alpha 1-, alpha 2-, and beta-adrenergic, muscarinic cholinergic, and calcium channel receptors in renal and ventricular membranes was also assessed. The density of renal and ventricular alpha 1- and beta-adrenoceptors was not affected by chronic drug treatment. The density of renal alpha 2- and beta-adrenoceptors was greater in the S/JR strain than in the R/JR strain, regardless of the treatment. The density of muscarinic cholinergic and calcium channel receptors in the ventricle was not affected by the treatment. The results of this study suggest that the long-term antihypertensive effects of verapamil in the S/JR rat do not involve an alteration in the binding characteristics of adrenergic, cholinergic, or calcium channel receptor sites in ventricular and renal membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1999

Decreased (45)Ca(2)(+) uptake in P/Q-type calcium channels in homozygous lethargic (Cacnb4lh) mice is associated with increased beta3 and decreased beta4 calcium channel subunit mRNA expression.

The mutated gene in the lethargic (Cacnb4lh) mouse model of absence seizures encodes the beta4 subunit of voltage-gated calcium channels (VGCCs), leading to decreased mRNA expression of a beta4 subunit that is truncated and cannot bind to alpha1 subunits of VGCCs. In this study we accomplished two goals. First, we studied the functional consequence of altered VGCCs by examining the effects of a selective P/Q-type channel antagonist on KCl-induced (45)Ca(2)(+) uptake in brain synaptosomes from Cacnb4lh homozygotes and non-epileptic controls (designated by +/+). We found that depolarization-induced (45)Ca(2)(+) uptake was significantly reduced in the brains of Cacnb4lh homozygotes, and that the reduced uptake was completely accounted for by reduced function of P/Q-type calcium channel. Second, we examined VGCC subunit composition to determine if other subunits were altered in addition to the mutation affecting beta4 subunits in Cacnb4lh homozygotes; when alterations were found, we determined if they were regional or global. We used in situ hybridization histochemistry (ISHH) to analyze the neuro-anatomic distribution of beta4, beta1b, beta2, beta3, alpha1A, alpha1B, alpha1C, alpha1E, and alpha1G subunit mRNAs in brain sections from matched Cacnb4lh homozygotes and +/+ controls. Our results indicated that expression of beta4 subunit mRNA is globally reduced throughout the brains of Cacnb4lh homozygotes, in contrast to a small but significant global increase in the expression of beta3 subunit mRNA. There were no significant differences in expression of the other VGCC subunit mRNAs examined. Together, these findings indicate that a host of changes in VGCC subunit composition accompany reduced function of P/Q-type channels in homozygous lethargic mice.

Animals↗