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PubMed1990

Multiple conductance levels of the dihydropyridine-sensitive calcium channel in GH3 cells.

Calcium channels in GH3 cells exhibit at least five conductance levels when examined in cell-attached or outside-out patches. These channels resemble the high threshold Ca2+ current in their range of activation and inactivation, and in their sensitivity to dihydropyridines (DHP). Mean open times for the five levels were brief (less than 1 msec) in control solutions but increased in the presence of BAY K 8644. In 100 mM Ba2+ and BAY K 8644, the five predominant slope conductances were 8-9, 12-13, 16-18, 23-24, and 28 pS. The present study is the first report of multiple levels of the DHP-sensitive Ca2+ channel occurring with high frequency in native membranes. The range of conductance levels that we observed encompasses the range of conductances found for two other different types of Ca2+ channels and indicates that unit conductance should be used with caution as a distinguishing characteristic for identification of different channel types.

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

PubMed1987

Cocaine-calcium channel antagonist interactions.

Diltiazem, a benzothiazepine calcium channel antagonist, was given to six healthy men as a single 60 mg oral dose 120 min before IV injection of cocaine (0.2 mg/kg) in a double-blind, placebo-controlled, two-session study. Diltiazem alone produced no significant effects. Cocaine increased blood pressure, heart rate, pupil size and subjective "high" ratings, and decreased skin temperature. Diltiazem pretreatment diminished the cocaine effect on skin temperature, but did not otherwise alter the response to cocaine. Calcium channel antagonists diminish the effects of cocaine in vitro and in animals. Dosage considerations may be critical because of the differential sensitivity of various tissues to calcium channel antagonists.

Adult↗

PubMed1993

Potentiation of antinociceptive effects of morphine by calcium-channel blockers at the level of the spinal cord.

BACKGROUND: Opioids inhibit voltage-dependent calcium-channel conductance, which is essential for the nervous system to be able to signal a painful event. Accordingly, interference with calcium-channel conductance may enhance opioid analgesia. The current study was designed to investigate the effects of calcium-channel blocking drugs on the antinociception of morphine at the level of the spinal cord. METHODS: Rats were chronically implanted with catheters in the lumbar intrathecal space. Tail-flick test was used to assess thermal nociception. Intrathecally administered drugs were morphine, calcium-channel blockers (verapamil, diltiazem, and nicardipine), or a combination of morphine and calcium-channel blocker. RESULTS: Intrathecal administration of morphine produced a significant dose-dependent antinociception in the tail-flick test. In contrast, intrathecal administration of calcium-channel blockers, verapamil, diltiazem, and nicardipine, did not show any antinociception at the employed doses. However, when intrathecally administered calcium-channel blockers, verapamil (50 micrograms), diltiazem (100 micrograms), or nicardipine (20 micrograms), were combined with ineffective (0.25, 0.5, 1, or 2 micrograms) or moderately effective (5 micrograms) doses of intrathecally administered morphine, significant antinociception was produced. These interactions were synergistic. There were no significant changes in MAP or HR after the intrathecal administration of 200 micrograms verapamil or 2 micrograms morphine combined with 50 micrograms verapamil. CONCLUSIONS: The authors interpreted these results to indicate that calcium-channel blocking drugs synergistically potentiate the analgesic effects of morphine at the level of the spinal cord. Before these results can be translated into clinical use, however, adequate toxicity studies must be conducted to examine the effect of the perispinal administration of calcium-channel blocking drugs on spinal cord function.

Animals↗

PubMed1992

Effects of endothelin and calcium channel blockers on membrane voltage and intracellular calcium in cultured bovine trabecular meshwork cells.

The membrane voltage was measured in cultured bovine trabecular meshwork cells. External barium (Ba2+; 10 mM) evoked repetitive overshooting action potentials which were reversibly inhibited by 10(-6) M nifedipine but insensitive to tetrodotoxin (10(-5) M). In contrast, no action potentials could be induced in bovine corneal endothelial cells. The vasoactive peptide endothelin (10(-9)-10(-6) M) induced dose-dependent depolarizations. The intracellular calcium concentration measured by the fura-2 method increased after endothelin application. An initial peak was followed by a sustained plateau. The effect of endothelin on the membrane potential and intracellular calcium value is typical for smooth muscle cells showing a contractile response to the peptide. Recent studies have shown the contractility of bovine trabecular meshwork. We conclude that calcium-channel antagonists and endothelin may alter the aqueous humour outflow through the trabecular meshwork.

Animals↗

PubMed1997

Use of calcium channel blockers and breast carcinoma risk in postmenopausal women.

BACKGROUND: The use of calcium channel blockers in an elderly population recently was reported to be associated with the incidence of cancer. The Cardiovascular Health Study, a multisite observational cohort study, provided the opportunity to investigate the epidemiologic association between the use of calcium channel blockers and breast carcinoma risk in 3198 women age > or = 65 years. METHODS: Standard questionnaires and clinical procedures were administered at four study sites annually from 1989-1990 to 1993-1994. Drug usage was assessed by a medication inventory and hospitalizations for 75 incident invasive breast carcinoma cases were identified using International Classification of Diseases-9 Clinical Modification codes. Time-dependent Cox proportional hazards regression models were used to assess associations between incident breast carcinoma and the use of specific antihypertensive medication including calcium channel blockers. RESULTS: In adjusted Cox proportional hazards models, an elevated risk of breast carcinoma was associated with use of calcium channel blockers (hazard ratio [HR]: 2.57; 95% confidence interval [CI], 1.47-4.49). This association persisted when the comparison group was users of other antihypertensive medication. No associations between the use of other antihypertensive medication with incident breast carcinoma were found. Associations were enhanced by assessment of high dose at baseline (HR: 4.42; 95% CI, 1.37-14.27) and when calcium channel blockers were combined with estrogen use (HR: 4.48; 95% CI, 1.58-12.75). The association was found to be strongest for the use of estrogens with immediate release calcium channel blockers (HR: 8.48; 95% CI, 2.99-24.08). CONCLUSIONS: Although the number of cases was limited in this observational study, associations found between the use of calcium channel blockers and incident invasive breast carcinoma warrant further investigation. Site specific carcinomas should be included as an outcome of ongoing and planned long term clinical trials using calcium channel blockers.

Age Factors↗

PubMed2003

Calcium-channel blockers and end-stage renal disease: pharmacokinetic and pharmacodynamic considerations.

PURPOSE OF REVIEW: To characterize the pharmacokinetics and pharmacodynamics of the different calcium-channel blockers. RECENT FINDINGS: Calcium-channel blockers have been in use for some time in the end-stage renal disease population. Their primary use has been as antihypertensive and antianginal therapies. In this regard, they are effective agents. Recently, it has been noted that dialysis-related hypotension occurs less frequently in calcium-channel blocker treated patients. Also, access patency and overall patient survival are improved with calcium-channel blocker therapy. SUMMARY: Calcium-channel blockers are useful agents for the control of hypertension in end-stage renal disease patients and appear to favorably influence survival in this population. Calcium-channel blockers are not dialyzable and their pharmacokinetics do not substantially change with renal failure therefore they do not require dose adjustment based on level of renal function. Too few studies exist to determine if individual calcium-channel blockers differ in their effects. Prospective, randomized, controlled clinical trials are needed in the end-stage renal disease population to better understand the role of calcium-channel blockers in the excess cardiovascular disease burden of this population.

Biological Availability↗

PubMed2003

Novel vascular biology of third-generation L-type calcium channel antagonists: ancillary actions of amlodipine.

Calcium channel blockers (CCBs) were developed as vasodilators, and their use in cardiovascular disease treatment remains largely based on that mechanism of action. More recently, with the evolution of second- and third-generation CCBs, pleiotropic effects have been observed, and at least some of CCBs' benefit is attributable to these mechanisms. Understanding these effects has contributed greatly to elucidating disease mechanisms and the rationale for CCB use. Furthermore, this knowledge might clarify why drugs are useful in some disease states, such as atherosclerosis, but not in others, such as heart failure. Although numerous drugs used in the treatment of vascular disease, including statins and angiotensin-converting-enzyme inhibitors, have well-described pleiotropic effects universally accepted to contribute to their benefit, little attention has been paid to CCBs' potentially similar effects. Accumulating evidence that at least 1 CCB, amlodipine, has pharmacologic actions distinct from L-type calcium channel blockade prompted us to investigate the pleiotropic actions of amlodipine and CCBs in general. There are several areas of research; foci here are (1) the physicochemical properties of amlodipine and its interaction with cholesterol and oxidants; (2) the mechanism by which amlodipine regulates NO production and implications; and (3) amlodipine's role in controlling smooth muscle cell proliferation and matrix formation.

Amlodipine↗

PubMed2001

Effects of calcium channel antagonists on the corpora allata of adult male loreyi leafworm Mythimna loreyi: juvenile hormone acids release and intracellular calcium level.

The effects of voltage-dependent calcium channel (VDCC) antagonists and the non-specific calcium channel antagonists on both juvenile hormone acids (JHA) release and cytosolic free calcium concentration ([Ca2+]i) are investigated in the corpora allata (CA) of the adult males loreyi leafworm Mythimna loreyi. The VDCC antagonists used in this study are: the L-type antagonists diltiazem, nifedipine, and verapamil, the N-type antagonist omega-Conotoxin (CgTx) GVIA, the N- and P/Q-type antagonist omega-CgTx MVIIC, and the T-type antagonist amiloride. The non-specific calcium channel antagonists used in this study were cadmium (Cd2+), cobalt (Co2+), nickle (Ni2+), and lanthanum (La3+). The results show that both the DHPs-sensitive L-type antagonist nifedipine and the N-type antagonist omega-CgTx GVIA were able to inhibit JHA release, but only omega-CgTx GVIA was able to reduce the [Ca2+]i. Among the non-specific calcium channel antagonists, Cd2+ is the most potent in reducing JHA release but without obvious effect on the [Ca2+]i, La3+ significantly increases the [Ca2+]i but without effect on JHA release.

Animals↗

PubMed1999

Synthesis and biological activity of substituted bis-(4-hydroxyphenyl)methanes as N-type calcium channel blockers.

Voltage activated calcium channel (VACC) blockers have been demonstrated to have utility in the treatment of stroke and pain. A series of aminomethyl substituted phenol derivatives has been identified with good functional activity and selectivity for N-type VACC's over sodium and potassium channels. The methods of synthesis and preliminary pharmacology are discussed herein.

Calcium Channel Blockers↗

PubMed1998

The physiological and pharmacological significance of cardiovascular T-type, voltage-gated calcium channels.

An influx of calcium ions into cells, made possible by the opening of specific, voltage-gated channels, triggers muscular contraction and several other physiological processes. Two types of calcium channels, L-type and T-type, are found in the cardiovascular system. These two types of channels differ considerably in their electrical and chemical characteristics and in their distribution in tissue. The L-type calcium channel is responsible for normal myocardial contractility and for vascular smooth muscle contractility. In contrast, T-type calcium channels are not normally present in the adult myocardium, but are prominent in conducting and pacemaking cells. They are thought to help regulate vascular tone, signal conduction, cardiac pacemaking, and the secretion of certain intercellular transmitters. T-Type channels also seem to have an important role in normal growth processes and in the tissue remodeling that occurs in pathologic processes such as cardiac hypertrophy. Traditional calcium antagonists act on L-type channels. Mibefradil is a recently characterized calcium antagonist and the first that is selective for T-type calcium channels. This unique property may lead to major applications in cardiovascular medicine.

Animals↗

PubMed1989

Effect of calcium-channel blockers and salbutamol on the isolated mare uterus--interaction with the calcium agonist Bay K 8644.

The effects of nifedipine, verapamil and diltiazem were investigated in the isolated mare uterus in comparison with salbutamol. All the calcium-channel blockers and salbutamol inhibited the spontaneous, KC1- and electrically induced contractions; nifedipine and salbutamol were the most potent compounds. The calcium agonist Bay K 8644 (10(-8)-10(-6) mol/l) competitively antagonized the inhibitory effect of nifedipine (pA2 value = 8.54 +/- 0.06), whereas it was only slightly or totally ineffective against verapamil, diltiazem and salbutamol. These results indicate that calcium-channel blockers are potent inhibitors of mare uterine motility in vitro and emphasize the importance of Ca2+-related mechanisms in the control of uterine smooth-muscle contractility. Moreover, the validity of Bay K 8644 as a tool to distinguish classes of calcium-channel antagonists is confirmed.

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

PubMed1990

Renal vascular effects of calcium channel blockers in hypertension.

Recent evidence suggests that calcium channel blockers have specific effects on renal hemodynamics in patients with hypertension and may also slow the progression of chronic renal failure. When these agents are studied in vitro, their predominant effect is to reverse afferent arteriolar vasoconstriction induced by catecholamines or angiotensin II. Because efferent resistance may remain high, glomerular filtration rate rises while renal blood flow remains low. The effects in vivo are less consistent. In human hypertension, calcium channel blockers lower renal resistance and may raise both renal blood flow and glomerular filtration rate. In experimental models of chronic renal disease, calcium channel blockers slow the progression of renal damage; however, variable effects on renal hemodynamics have been found. Other factors implicated in the progression of renal damage, including compensatory renal hypertrophy, platelet aggregation, and calcium deposition, may also be favorably influenced by these agents. Recent studies suggest that calcium channel blockers may have similar protective effects in patients with hypertension and chronic renal disease.

Calcium Channel Blockers↗

PubMed1992

Identification of two distinct proteins that are immunologically related to the alpha 1 subunit of the skeletal muscle dihydropyridine-sensitive calcium channel.

The alpha 1 subunit of the dihydropyridine-sensitive calcium channel is a protein which is critical for excitation-contraction coupling and L-type calcium current in skeletal muscle. Using antibodies generated against peptides from three regions of the deduced amino acid sequence of the alpha 1 subunit, we have identified two distinct proteins in rabbit skeletal muscle. Both proteins appeared to be recognized by antibodies against the amino (N) terminus of the alpha 1 subunit sequence. One protein was also recognized by antibodies against an internal (I) region of the predicted sequence but not by antibodies against the carboxyl (C) terminus. In contrast, the other protein was recognized by antibodies against the carboxyl terminus but not by the antibodies against the internal region. We have designated these proteins pNI and pNC based on their patterns of antibody recognition. No protein was detected which was recognized by all three antibodies. pNI is the protein commonly identified as the alpha 1 subunit of the dihydropyridine-sensitive calcium channel. Of note is that pNI, which apparently lacks sequences from the predicted carboxyl tail, is the protein present in preparations which we have previously demonstrated contain dihydropyridine-sensitive calcium channel activity. pNC is herein identified as a skeletal muscle protein that is immunologically related to the alpha 1 subunit of the dihydropyridine-sensitive calcium channel. Its function is unknown. In addition to their distinct patterns of antibody recognition, pNI and pNC were also distinguishable by several other properties. pNC migrated as a protein of approximately 160 kDa in 5% sodium dodecyl sulfate-polyacrylamide gels versus approximately 165 kDa for pNI. pNI was enriched in transverse tubule membranes, whereas pNC was found to be enriched in triad and junctional sarcoplasmic reticulum membrane fractions and was not found in transverse tubule membranes. Under conditions in which pNI bound to wheat germ agglutinin-Sepharose, pNC did not bind. The results demonstrate that there are two proteins in skeletal muscle which are immunologically related to the alpha 1 subunit of the dihydropyridine-sensitive calcium channel but which are distinguishable by several biochemical and immunological characteristics.

Amino Acid Sequence↗

PubMed1997

Identification of a 15-kDa cAMP-dependent protein kinase-anchoring protein associated with skeletal muscle L-type calcium channels.

Voltage-dependent potentiation of skeletal muscle L-type calcium channels requires phosphorylation by cAMP-dependent protein kinase (PKA) that is localized by binding to a cAMP-dependent protein kinase-anchoring protein (AKAP). L-type calcium channels purified from rabbit skeletal muscle contain an endogenous co-purifying protein kinase activity that phosphorylates the alpha1 and beta subunits of the channel. The co-purifying kinase also phosphorylates a known PKA peptide substrate, is stimulated by cAMP, and is inhibited by PKA inhibitor peptide-(5-24), indicating that it is PKA. PKA activity co-immunoprecipitates with the calcium channel, suggesting that the channel and the kinase are physically associated. Using biotinylated type II regulatory subunit of PKA (RII) as a probe, we have identified a 15-kDa RII-binding protein in purified calcium channel preparations, which we have designated AKAP-15. Anti-peptide antibodies directed against the alpha1 subunit of the calcium channel co-immunoprecipitate AKAP-15. Together, these findings demonstrate a physical link between PKA and the calcium channel and suggest that AKAP-15 may mediate their interaction.

Amino Acid Sequence↗

PubMed2006

Kinetics of internalization and degradation of N-type voltage-gated calcium channels: role of the alpha2/delta subunit.

The contribution of voltage-gated calcium channels to excitable cell function depends, critically, upon the mechanisms that control their expression at the cell surface. While co-assembly of the pore forming alpha(1) and auxiliary beta subunits enhances channel surface expression, the levels are still only 30-40% of those seen with the core alpha(1B)/beta(1b)/alpha(2)delta calcium channel complex. To rationalize this observation, it has been suggested that the alpha(2)/delta subunit might stabilize calcium channel expression at the cell surface. To test this notion, we have resolved the effect of the alpha(2)/delta subunit on the rates of binding, internalization and degradation of defined N-type calcium channel surface complexes expressed in HEK293 cells, through pulse-labeling with the selective, cell impermeable, radioligand [(125)I]-omega-CgTx. Through detailed kinetic and sensitivity analysis we show that alpha(1B)/beta(1b)/alpha(2)delta complexes are internalized slowly (k(int) 0.4/h), whereupon, most become degraded (k(deg) 0.02/h). In contrast, alpha(1B)/beta(1b) complexes are internalized more rapidly (k(int) 0.8/h), following which they are either quickly degraded (k(deg) 0.1/h) or are sequestered slowly (k(tra) 0.1/h) to a pool that is metabolically stable within the time-frame of our experiments (24h). In neither case did we find evidence for recycling via the cell surface. Thus, our data argue for a novel mechanism where complexes lacking an alpha(2)/delta subunit are cleared from the cell surface and are rapidly degraded or stored, possibly for further attempts at complexation as new alpha(2)/delta subunits become available. The slower rate of internalization of complexes containing the alpha(2)/delta subunit rationalizes the stabilizing effect this subunit has upon calcium channel surface expression and suggests a mechanism by which alpha(2)delta mutations may cause severe neurological deficits.

Animals↗

PubMed2006

Alternative splicing in the C-terminus of CaV2.2 controls expression and gating of N-type calcium channels.

N-type Ca(V)2.2 calcium channels localize to presynaptic nerve terminals of nociceptors where they control neurotransmitter release. Nociceptive neurons express a unique set of ion channels and receptors important for optimizing their role in transmission of noxious stimuli. Included among these is a structurally and functionally distinct N-type calcium channel splice isoform, Ca(V)2.2e[37a], expressed in a subset of nociceptors and with limited expression in other parts of the nervous system. Ca(V)2.2[e37a] arises from the mutually exclusive replacement of e37a for e37b in the C-terminus of Ca(V)2.2 mRNA. N-type current densities in nociceptors that express a combination of Ca(V)2.2e[37a] and Ca(V)2.2e[37b] mRNAs are significantly larger compared to cells that express only Ca(V)2.2e[37b]. Here we show that e37a supports increased expression of functional N-type channels and an increase in channel open time as compared to Ca(V)2.2 channels that contain e37b. To understand how e37a affects N-type currents we compared macroscopic and single-channel ionic currents as well as gating currents in tsA201 cells expressing Ca(V)2.2e[37a] and Ca(V)2.2e[37b]. When activated, Ca(V)2.2e[37a] channels remain open for longer and are expressed at higher density than Ca(V)2.2e[37b] channels. These unique features of the Ca(V)2.2e[37a] isoform combine to augment substantially the amount of calcium that enters cells in response to action potentials. Our studies of the e37a/e37b splice site reveal a multifunctional domain in the C-terminus of Ca(V)2.2 that regulates the overall activity of N-type calcium channels in nociceptors.

Action Potentials↗

PubMed1993

[Molecular structure and functional sites of the cardiac calcium channels].

Voltage gated L-type and T-type calcium channels are electrophysiologically characterized in the cardiac tissues. L-Type calcium channels are abundant in skeletal muscle and results from molecular studies have stimulated researches on the cardiac counterpart. This paper briefly reviews the recent progress in molecular constituents and functional sites of the cardiac calcium channel. The channel is composed of five subunits, alpha 1, alpha 2, beta, gamma, and delta, at least, but heterogeneous existence of alpha 1, beta, and gamma is also observed. The 1,4-dihydropyridine binding site has been identified in the skeletal muscle and cardiac calcium channels by photoaffinity labeling. Their sites are compared in the primary structures. PKA modulation of the cardiac channel is also discussed with the respect to phosphorylation site.

Amino Acid Sequence↗

PubMed1989

Inhibitory effects of calcium channel blockers on intestinal motility in the dog.

Calcium channel blockers are now widely used for the treatment of cardiovascular disorders. However, data concerning their effects on intestinal motility in vivo are still rather fragmentary. Therefore, we evaluated the effects of three prototype calcium channel blockers (nifedipine, verapamil and diltiazem) on intestinal motility in five fasting, conscious dogs fitted with electrodes and strain-gauges along the small bowel. The myoelectric data were analyzed by a recently developed and validated computer program which allows accurate monitoring of intestinal spike activity. The mechanical data were analyzed by calculating a motility index. After recording of at least two migrating motor complexes (control), an i.v. infusion of one of the following calcium channel blockers was maintained for 3 h: 0.29 or 0.87 mumol/kg per h nifedipine, 1.02 or 2.04 mumol/kg per h verapamil and 1.11 or 2.22 mumol/kg per h diltiazem. Nifedipine 0.29 mumol/kg per h significantly reduced (P less than 0.05) spike activity and motility index during phases II and III without disrupting migrating motor complex cycling. The higher dose suppressed migrating motor complex cycling and almost completely abolished both spike and mechanical activities. The two doses of verapamil had effects similar to those of the two doses of nifedipine. Both doses of diltiazem significantly reduced (P less than 0.05) spike activity and motility index during phases II and III without disrupting migrating motor complex cycling. We conclude that all the agents tested, apart from their well known cardiovascular effects, also have a profound inhibitory effect on intestinal motility in vivo, the order of potency being nifedipine greater than verapamil greater than diltiazem. The search for more selective calcium channel blockers for the treatment of intestinal motor disorders with minimal cardiovascular effects is warranted.

Animals↗