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PubMed1996

Calcium Channel Blockers and the Gastrointestinal Tract.

Calcium ions play an important role in the normal functioning of the gastrointestinal system. The calcium channel blockers appear to affect all the organs of the gastrointestinal tract and may have therapeutic efficacy on esophageal spasm, irritable bowel syndrome, mesenteric vascular insufficiency, dyskinesis of the Sphincter of Oddi, and insulinoma. Adverse effects are limited predominantly to constipation and some aggravation of ethanol-induced ulcer disease. In addition, the drugs continue to serve as important biologic probes for understanding the normal and abnormal functioning of the gastrointestinal tract.

Journal Article↗

PubMed1994

Effects of calcium channel blockers on rabbit corneal endothelial function.

The effects of calcium channel antagonists and agents that alter intracellular Ca2+ mobilization on corneal endothelial function have been examined. All experiments, except where specifically designated, were performed in the continuous presence of extracellular Ca2+. Verapamil (at 50 microM) increased the swelling rate of corneas bathed in normal Ringer solution whereas nifedipine and diltiazem (both up to 100 microM) were without effect. The nifedipine analog nisoldipine caused corneal swelling at 10 microM and 50 microM but nimodipine was without effect. When briefly exposed to a Ca(2+)-free solution corneal swelling was enhanced after subsequent exposure to 50 microM verapamil in normal Ringer but not after 50 microM diltiazem in normal Ringer, indicating that Ca2+ entry from the bathing solution into the cell was important and was apparently impeded by verapamil. Cadmium (0.6 and 1 mM) but not nickel (up to 250 microM) caused swelling of corneas bathed in normal Ringer. A Ca2+ channel agonist, BAY-K-8644, alone did not influence corneal thickness but when presented to the endothelium with 50 microM verapamil the swelling rate was much reduced compared to verapamil alone. The agonist, therefore, presumably maintained some Ca2+ channels open in face of the Ca2+ channel blocker. An agent that inhibited the release of intracellular Ca2+ stores (TMB-8) caused an initial corneal swelling over the first 1.5 hr of perfusion but thereafter had no effect on corneal thickness. In the presence of continued extracellular Ca2+ one explanation for the results is that modulation of intracellular Ca2+ by agents that alter plasma membrane transfer of Ca2+ influences apical junction permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

The effect of calcium channel blockers on the H(+)-ATPase and bioenergetics of catecholamine storage vesicles.

A number of commonly used calcium channel blockers have been compared with respect to their effects on the bioenergetics of catecholamine storage vesicles. Chromaffin granule ghosts with a well-preserved ability to actively transport and store catecholamines, were used as a model for adrenergic synaptic vesicles due to their functional similarity. Nicardipine, verapamil, terodiline and diltiazem were found to have effects comparable to that of prenylamine (Grønberg, M., O. Terland, E.S. Husebye and T. Flatmark, 1990. Biochem. Pharmacol. 40, 351) by inhibiting the generation of a transmembrane proton electrochemical gradient driven by the vesicular H(+)-ATPase, mainly by loose-coupling/uncoupling of this ATPase. Amlodipine inhibited the internal acidification of the vesicles in a tyramine-like manner and increased the steady-state membrane potential (positive inside) generated by the MgATP-dependent proton translocation. Nifedipine and felodipine also inhibited the efficiency of the proton pump, but their mechanisms of action require further investigation. The concentrations giving 50% inhibition of the H(+)-ATPase-dependent generation of a pH-gradient were found to be: 12 microM felodipine, 16 microM nicardipine, 25 microM terodiline, 50 microM nifedipine, 60 microM verapamil, 65 microM amlodipine and 150 microM diltiazem. The effects of the calcium channel blockers on the bioenergetics of chromaffin granules explain the release of catecholamines from sympathetic nerves and ganglia in vitro by the calcium channel blockers.

Adrenal Medulla↗

PubMed2000

Three-dimensional solution structure of omega-conotoxin TxVII, an L-type calcium channel blocker.

We determined the three-dimensional structure of omega-conotoxin TxVII, a 26-residue peptide that is an L-type calcium channel blocker, by (1)H NMR in aqueous solution. Twenty converged structures of this peptide were obtained on the basis of 411 distance constraints obtained from nuclear Overhauser effect connectivities, 20 torsion angle constraints, and 21 constraints associated with hydrogen bonds and disulfide bonds. The root-mean-square deviations about the averaged coordinates of the backbone atoms (N, C(alpha), C, and O) and all heavy atoms were 0.50 +/- 0.09 A and 0.99 +/- 0.13 A, respectively. The structure of omega-conotoxin TxVII is composed of a triple-stranded antiparallel beta-sheet and four turns. The three disulfide bonds in omega-conotoxin TxVII form the classical cystine knot motif of toxic or inhibitory polypeptides. The overall folding of omega-conotoxin TxVII is similar to those of the N-type calcium channel blockers, omega-conotoxin GVIA and MVIIA, despite the low amino acid sequence homology among them. omega-Conotoxin TxVII exposes many hydrophobic residues to a certain surface area. In contrast, omega-conotoxin GVIA and MVIIA expose basic residues in the same way as omega-conotoxin TxVII. The channel binding site of omega-conotoxin TxVII is different from those of omega-conotoxin GVIA and MVIIA, although the overall folding of these three peptides is similar. The gathered hydrophobic residues of omega-conotoxin TxVII probably interact with the hydrophobic cluster of the alpha(1) subunit of the L-type calcium channel, which consists of 13 residues located in segments 5 and 6 in domain III and in segment 6 in domain IV.

Amino Acid Sequence↗

PubMed1986

Antihypertensive effect of a new calcium channel blocker, FK 235, in essential hypertension.

The antihypertensive effect of a new calcium channel blocker (FK 235) were evaluated in 10 patients with mild-to-moderate essential hypertension. The study consisted of 4 weeks of placebo and 12 weeks of the drug, 2 to 4 mg twice a day. Overall systolic and diastolic blood pressures (mean +/- SE) were reduced from 173 +/- 4 to 158 +/- 2 mm Hg (p less than 0.001) and from 97 +/- 2 to 89 +/- 1 mm Hg (p less than 0.001), respectively, with a dose of 5.6 +/- 0.7 mg/day. No relevant changes in heart rate, body weight, and plasma levels of renin activity and aldosterone concentration were observed. No side effects were encountered during the therapy. Our data indicate that the novel active calcium channel blocker can be used as a safe, effective and well tolerated antihypertensive for the treatment of essential hypertension.

Adult↗

PubMed1987

Calcium channel blockers and atherogenesis.

The events involved in atherogenesis include platelet deposition on damaged endothelial surfaces; migration and proliferation of smooth muscle cells; the formation of elastin, collagen, and glycosaminoglycans, followed by the penetration and complexing of lipoproteins; and, calcification. Since calcium is involved in these and other events, considerable data exist on the effects of altering calcium influx in experimental atherosclerosis. Interventions that increase calcium deposition tend to increase the severity of experimental atherosclerosis, whereas interventions that reduce calcium entry into cells tend to reduce its progression. Using rabbits, researchers have recently focused on the ability of calcium channel blockers, such as nifedipine, verapamil, and diltiazem, to attenuate the development of experimental atherosclerosis. Studies also suggest that although calcium channel blockers may protect against the development of experimental atherosclerosis, they are less effective in inducing its regression. Further, studies with calcium channel blockers in rabbits deficient in low-density lipoprotein receptors did not show protection against the development of atherosclerosis. However, no clinical studies are yet available to judge the potential protective effects of calcium channel blockers in humans. Since many patients are now receiving long-term calcium blocker therapy for hypertension, these findings may be relevant in the selection of antihypertensive therapy, provided that protective effects can be demonstrated.

Animals↗

PubMed1987

The comparative effects of verapamil and a new dihydropyridine calcium channel blocker on digoxin pharmacokinetics.

Conflicting conclusions have been reported about interaction of calcium channel blockers with digoxin. The effects of verapamil (240 mg/day) and a new dihydropyridine calcium channel blocker, isradipine (15 mg/day), on the pharmacokinetics of 1 mg intravenous digoxin were compared. All 24 volunteer subjects were healthy, male, nonobese, and aged 18 to 38 years. Groups of 12 subjects received each oral agent over 15 days, with collections of blood and urine for 72 hours after intravenous digoxin. Significant (P less than 0.05) reduction in nonrenal (7.01 +/- 1.97 to 4.00 +/- 1.86 L/hr) and total clearance (14.1 +/- 2.6 to 11.5 +/- 2.5 L/hr) were induced by verapamil, without change in renal clearance. A near-significant (P less than 0.1) increase in peripheral volume of distribution contributed to prolonged elimination half-life (23.1 +/- 4.4 to 34.3 +/- 9.7 hours). By contrast, isradipine caused only a 9% reduction in volume of distribution. Verapamil causes digoxin accumulation by reducing nonrenal elimination. No evidence of clinically relevant interaction of isradipine with digoxin was seen.

Adolescent↗

PubMed1997

A high cholesterol diet blocks the effect of calcium channel blockers on the uptake of sugars in rabbit intestine.

Two classes of calcium channel blockers, nisoldipine (NIS) and verapamil (VER), alter the intestinal uptake of sugars, and varying the lipid composition of the diet also modifies intestinal transport function. This study was undertaken in adult male New Zealand rabbits to assess the effect of 3 weeks of dosing with NIS (1 mg.kg-1.day-1) or VER (4 mg.kg-1.day-1) on the in vitro jejunal uptake of D-galactose and L- or D-glucose. The value of the maximal transport rate of D-galactose (Vmax) increased with NIS and VER, compared with control vehicle. The value of the apparent Michaelis constant (K(m)) rose with NIS and fell with VER, and the value of the passive permeability coefficient (Pd) estimated from the uptake of L-glucose fell with NIS and rose with VER. These effects of NIS and VER on Vmax, K(m), and Pd were prevented by feeding a high cholesterol (2.8%) supplemented chow diet (HCD), as compared with chow alone. These effects were not due to any change in the animal's weight gain or intestinal mucosal surface area. The acute exposure of the jejunal tissue in vitro to varying concentrations of NIS but not VER reduced the uptake of D-glucose but had no effect on basal short circuit current (Isc) in either chow or HCD. Isc stimulated with glucose or theophylline was less in chow-fed rabbits compared with HCD-fed rabbits given NIS or VER. Thus, the active transport of sugars by the sodium-dependent transporter in the brush-border membrane, SGLT1, and the passive uptake by the paracellular route are variably influenced by these two classes of calcium channel blockers, and this effect is modified by the cholesterol content of the diet.

Animals↗

PubMed2003

Calcium channel blockers as the treatment of choice for hypertension in renal transplant recipients: fact or fiction.

Posttransplantation hypertension has been identified as an independent risk factor for chronic allograft dysfunction and loss. Based on available morbidity and mortality data, posttransplantation hypertension must be identified and managed appropriately. During the past decade, calcium channel blockers have been recommended by some as the antihypertensive agents of choice in this population, because it was theorized that their vasodilatory effects would counteract the vasoconstrictive effects of the calcineurin inhibitors. With increasing data becoming available, reexamining the use of traditional antihypertensive agents, including diuretics and beta-blockers, or the newer agents, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, may be beneficial. Transplant clinicians must choose antihypertensive agents that will provide their patients with maximum benefit, from both a renal and a cardiovascular perspective. Beta-blockers, diuretics, and ACE inhibitors have all demonstrated significant benefit on morbidity and mortality in patients with cardiovascular disease. Calcium channel blockers have been shown to possess the ability to counteract cyclosporine-induced nephrotoxicity. When compared with beta-blockers, diuretics, and ACE inhibitors, however, the relative risk of cardiovascular events is increased with calcium channel blockers. With the long-term benefits of calcium channel blockers on the kidney unknown and a negative cardiovascular profile, these agents are best reserved as adjunctive therapy to beta-blockers, diuretics, and ACE inhibitors.

Adrenergic beta-Antagonists↗

PubMed1994

Clinical pharmacology of converting enzyme inhibitors, calcium channel blockers and diuretics.

The predominant trend in pediatric antihypertensive management is towards increasing reliance on angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers because of their general effectiveness, low incidence of adverse reactions and potential specific benefit in patients with renal disease. The common aetiological relationship between renal disease and elevated BP also is the reason that diuretic therapy continues to be included in many treatment regimens. A number of ACE inhibitors are available for clinical use, although only captopril has been subjected to any meaningful degree of investigation in children. Initial doses of captopril are 0.5 mg/kg in children > 6 months of age and 0.01-0.1 mg/kg in neonates, because of an apparent increased antihypertensive effect and duration of action in this age group. Side-effects are few and the major adverse effect is a reduction in glomerular filtration in patients with bilateral renal artery stenosis. The calcium channel blockers reduce cytosolic calcium concentration and are particularly effective in patients with volume dependent forms of hypertension. The pharmacokinetic properties of these drugs are similar with drug clearance by hepatic metabolism. In particular, nifedipine has a rapid onset of action and is widely used to treat hypertensive emergencies. Although it has been used sublingually, the effectiveness of the drug is due to absorption from the gastrointestinal tract. Few side-effects from these drugs have been reported in children. Heart rate and cardiac output increase but return to pretreatment levels within a few weeks. As is the case with the ACE inhibitors, calcium channel blockers appear to have a positive effect on renal function.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Calcium channel blockers blunt postural cutaneous vasoconstriction in hypertensive patients.

The aim of this work was to test whether calcium channel blockers interfere with skin vasoconstrictor reflexes that minimize postural increases in capillary pressure and avoid fluid extravasation and eventually subcutaneous edema. Studies were conducted in 23 untreated mild to moderate essential hypertensives; drugs, either calcium channel blockers or not, were given for 2 weeks according to a crossover, sequence-randomized design. Skin blood flow was measured by laser Doppler flowmetry in two skin areas: (1) the dorsum of the foot, where arteriovenous anastomoses are poorly represented, and (2) the plantar surface of the great toe, where those anastomoses are predominant. Determinations were obtained both with the foot at heart level and with it placed passively 50 cm below the heart level; percent flow changes from the horizontal to the dependent position were the measure of postural vasoconstriction. Two dihydropyridine derivatives, amlodipine (10 mg UID) and nifedipine (60 mg UID), and verapamil (240 mg BID), a chemically unrelated compound, diminished to similar extents the postural fall in skin blood flow at the dorsum of the foot. Blockade of alpha1-adrenergic and AT-1 subtype angiotensin II receptors by doxazosin (4 mg UID) and losartan (50 mg UID), respectively, exerted no effect. Postural skin blood flow responses at the plantar surface of the great toe were unmodified during the pharmacological trials. Thus, calcium channel blockers of different chemical origins antagonized postural skin vasoconstriction at the dorsum of the foot. The data indicate altered postural capillary blood flow regulation, since arteriovenous anastomoses are anatomically absent at this site; the effect was independent of either alpha1-adrenoceptor or angiotensin II receptor antagonism. Interference with skin postural vasoconstrictor mechanisms may result in net filtration of fluid to the extravascular compartment. This mechanism might explain the as yet unknown pathogenesis of ankle edema during treatment with calcium antagonists.

Adult↗

PubMed1997

Angiotensin converting enzyme inhibitors, calcium channel blockers, and their combination in the treatment of glomerular disease.

BACKGROUND: Glomerular diseases may progress to end-stage renal failure via the development of glomerulosclerosis. Systemic hypertension and intraglomerular hypertension are important, although not the only, determinants of this process. Proteinuria (albuminuria) is a surrogate marker for glomerular damage and renal prognosis. EFFICACY OF ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS: In animal experiments and in controlled clinical studies, ACE inhibitors have proved to be effective in reducing proteinuria and in preventing glomerulosclerosis or progression to end-stage renal failure, possibly more than can be explained by their effects on blood pressure. EFFICACY OF CALCIUM CHANNEL BLOCKERS: In contrast to the uniform efficacy of ACE inhibitors, the effect of calcium channel blockers is less uniform. It depends on the model of renal damage used, the extent of the fall in systemic blood pressure and the type of calcium channel blocker used. Nevertheless, clinical studies have shown a reduction in proteinuria and at least an attenuation of progression with the use of long-acting calcium channel blockers. RATIONALE FOR THE COMBINATION OF ACE INHIBITORS AND CALCIUM CHANNEL BLOCKERS: If angiotensin II influences the progression of renal failure, as is universally accepted, then the combination of an ACE inhibitor (reducing the generation of angiotensin II) and a calcium channel blocker (reducing target-organ responsiveness to angiotensin II) appears a promising one. EVIDENCE FOR THE EFFECTIVENESS OF THIS COMBINATION: In animal experiments, co-administration of an ACE inhibitor and a calcium channel blocker caused a more marked reduction in glomerulosclerosis, and this was seen in the stroke-prone spontaneously hypertensive rat model even at non-antihypertensive doses. In human diabetic nephropathy at least, proteinuria (measured as a surrogate marker of the illness) was lowered more effectively by the combination of an ACE inhibitor and a calcium channel blocker than either drug used as monotherapy despite a similar fall in blood pressure.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Comparative study on the effect of calcium channel blockers on basal and parathyroid hormone-induced bone resorption in vitro.

A number of clinical and experimental studies suggest that the effects of calcium channel blockers are not limited to the cardiovascular system but might also involve skeletal calcium metabolism due to the presence of L-type calcium channels in osteoblastic cells. We therefore investigated the influence of calcium channel blockers of the dihydropyridine type (nifedipine, amlodipine) as well as of the phenylalkylamine type (verapamil, gallopamil) on basal and parathyroid hormone-induced bone resorption utilizing organ-cultured neonatal mouse calvaria. Only at 10(-4) M, amlodipine, verapamil and gallopamil reduced basal and parathyroid hormone-induced resorption In contrast, nifedipine, between 10(-5)-10(-4) M, exhibited a dose-dependent inhibitory effect on parathyroid hormone-related bone resorption by up to 50%. When calvariae were cultured for 48 hr in the presence of inhibitory concentrations of the calcium channel blockers and then stimulated with parathyroid hormone, only parietal bones pretreated with nifedipine remained completely responsive to the bone resorbing action of the hormone.

Amlodipine↗

PubMed1989

Calcium-channel blockers in the management of essential hypertension.

The calcium-channel blockers have expanded the therapeutic choices of the practicing physician. The recent changes in the recommendations regarding first-line therapy in the treatment of essential hypertension have allowed the use of a variety of different antihypertensive agents to provide safe and effective therapy.

Calcium Channel Blockers↗

PubMed1985

Calcium channel blockers in primary pulmonary hypertension.

The demonstration that the calcium channel blockers reduce pulmonary vasomotor tone in experimental models of pulmonary hypertension has served as the rationale for their use in the management of primary pulmonary hypertension. The three currently available agents, verapamil, nifedipine, and diltiazem, have varying degrees of pulmonary vasoactivity. Experience with their use is reviewed.

Calcium Channel Blockers↗

PubMed1992

[Effect of nilvadipine on diurnal blood pressure profile. Use of a new calcium channel blocker in mild to intermediate hypertension].

UNLABELLED: QUERY: Influence of Nilvadipine, a new calcium channel blocker on the daytime blood pressure profile and 24-hour blood pressure values in patients with mild-to-moderate hypertension. METHOD: Single-blind study in 20 hospitalized hypertensives over a period of 23 days (10 days placebo, 8 days 1 x 8 mg Nilvadipine, 5 days placebo). Blood pressure was measured at 7.00 a.m. prior to drug ingestion and daytime blood pressure profiles obtained on days 10, 11, 18, 19 and 23. The objectives were to lower the median diastolic blood pressure or daytime blood pressure profiles on the last day vis-a-vis the baseline values, and to establish the response rate (blood pressure diastolic less than 90 mmHg) 24 hours after the last dose of Nilvadipine. RESULTS: After 8 days on Nilvadipine, the median diastolic daytime blood pressure profile had decreased by almost 10 mmHg. The response rate was 42%. In the same period, the systolic blood pressure decreased by 30 mmHg. Six out of 20 patients manifested transient side effects typical of calcium channel blockers.

Adult↗

PubMed1995

Calcium channel blockers antagonize some of cocaine's cardiovascular effects, but fail to alter cocaine's behavioral effects.

The effects of cocaine alone and in combination with the calcium channel blockers nimodipine, verapamil and diltiazem were determined for different groups of squirrel monkeys on cardiovascular function, schedule-controlled behavior and drug self-administration. Cocaine alone (0.3 mg/kg) produced increases in both blood pressure and heart rate. All three calcium channel blockers antagonized the pressor effect, but were ineffective against the tachycardiac effect of cocaine. Nimodipine was the most potent agent in antagonizing the pressor effect of cocaine. Response rates for monkeys responding on a second-order schedule of food presentation were increased by intermediate doses of cocaine (0.1-1.0 mg/kg) and were primarily decreased at a higher dose (3.0 mg/kg). Quarter-life values, an index of response patterning, were only decreased by cocaine. None of the calcium channel blockers altered cocaine's effects on either response rate or response patterning. In the self-administration experiments, the training dose of 56 micrograms/kg cocaine maintained high rates of responding on a simple fixed-ratio schedule. As with schedule-controlled behavior, none of the calcium channel blockers altered cocaine self-administration even when administered before self-administration sessions during 5 consecutive days. These results suggest that the calcium channel blockers may be useful in treating cardiovascular-related complications after cocaine use, but they would not be effective as long-term treatment agents for cocaine abuse.

Animals↗

PubMed1997

[Calcium channel blockers in heart failure].

Patients with heart failure are particularly susceptible to the negative effects of calcium channel blockers because the failing heart demonstrates a defect in the delivery of calcium to the contractile proteins, and an attenuation of the normal sympathetic reflexes. Currently these drugs have no place in the treatment of heart failure caused by systolic dysfunction of the left ventricle. Calcium channel blockers should probably not be described for patients with coronary artery disease and left ventricular dysfunction. When the patient needs additional treatment for angina and beta-blockers or nitrates have not given satisfactory results, it may be appropriate to prescribe amlodipine or felodipine.

Calcium Channel Blockers↗