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PubMed1995

Calcium channel blockers. Is it time to split the lump?

Antihypertensive drug classes such as thiazide diuretics, angiotensin-converting enzyme inhibitors, beta-adrenergic blocking agents, peripheral alpha 1-antagonists, and central alpha 2-agonists all describe therapeutic agents that are quite similar to each other and strikingly different from members of the other classes. A glaring exception is the rubric "calcium channel blocker," under which strikingly dissimilar drugs have been lumped. Although the phenylalkylamines (verapamil and gallapamil) and benzothiazepines (diltiazem and TA3090) bind at different receptors on the alpha 1 component of the calcium channel, they are reasonably similar in their clinical pharmacology. For example, both types of drugs slow the heart rate and there are intravenous preparations that are used to treat supraventricular tachycardia. The dihydropyridines (nifedipine and many others) bind to another receptor on the alpha 1 component, but have markedly different pharmacologic properties. For example, they tend to increase the heart rate, do not cause constipation, but are more likely to cause peripheral edema. I propose that we refer to this entire class of drugs as "calcium antagonists," that we continue to refer to verapamil, diltiazem, and similar drugs as "calcium channel blockers," but recognize the very different properties of nifedipine and like drugs by referring to them as dihydropyridines or DHPs.

Animals↗
PubMed1993

The effect of nifedipine, a calcium channel blocker, on human spermatozoal functions.

In vitro addition of 0.1-100 microns of a calcium channel blocker, Nifedipine, resulted in a significant non-competitive inhibition in the uptake of Ca++. The activity of Ca(++)-dependent ATPase enzyme was also decreased. Motility of the spermatozoa was significantly arrested following incubation with different doses of the drug at 37 degrees C for different durations. The pattern of motility changed within two hours from rapid and linear progression to slow or sluggish linear or non-linear movement and finally to non-progressive motility or even immotility. Scanning electron microscopic studies revealed disruptive changes in the head as well as tail region and coiling of spermatozoa after Nifedipine treatment. An increase in the formation and release of malonyldialdehyde was observed following Nifedipine addition in a dose-dependent fashion. The membrane cholesterol and phospholipid contents were considerably lowered in the treated samples. The potential of such calcium channel blocking agent in the designing of male contraceptive programme is discussed.

Calcium↗
PubMed2005

Benidipine, a dihydropyridine-calcium channel blocker, inhibits lysophosphatidylcholine-induced endothelial injury via stimulation of nitric oxide release.

Benidipine hydrochloride (benidipine), which is a long-lasting dihydropyridine calcium channel blocker, exerts antihypertensive action via inhibition of Ca(2+) influx through L-type voltage-dependent calcium channels. In addition, benidipine is shown to restore endothelial function. However, the mechanisms whereby benidipine has protective effects on endothelium are poorly defined. Nitric oxide (NO), which is produced by endothelial NO synthase (eNOS), plays important roles in endothelial function. In this study, we examined effects of benidipine on NO production from human umbilical vein endothelial cells. Benidipine (0.3-10 microM) augmented eNOS expression and total eNOS enzymatic activities. Benidipine also promoted the production of NO and the accumulation of cGMP, a second messenger of NO. Lysophosphatidylcholine (lysoPC), a component of oxidized low-density lipoproteins, induced caspase-3 activation followed by apoptosis of endothelial cells. Benidipine (0.3-10 microM) prevented lysoPC-induced caspase-3 activation, which was canceled by Nomega-nitro-L-arginine-methyl ester (L-NAME) (250-2500 microM), an inhibitor of NOS. Moreover, diethylenetetraamine NONOate (30-100 microM), a NO donor, inhibited the caspase-3 activation. These results suggested that the increase in NO production by benidipine might be involved in the inhibition of caspase induction. The direct enhancement of endothelial NO release by benidipine may be in part responsible for amelioration of endothelial dysfunction.

Apoptosis↗
PubMed1992

The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension.

BACKGROUND: Primary pulmonary hypertension is a progressive, fatal disease of unknown cause. Vasodilator drugs have been used as a treatment, but their efficacy is uncertain. METHODS: We treated 64 patients with primary pulmonary hypertension with high doses of calcium-channel blockers. Patients who responded to treatment (defined as those whose pulmonary-artery pressure and pulmonary vascular resistance immediately fell by more than 20 percent after challenge) were treated for up to five years. Their survival was compared with that of the patients who did not respond and with patients enrolled in the National Institutes of Health (NIH) Registry on Primary Pulmonary Hypertension. Warfarin was given to 55 percent of the patients as concurrent therapy, on the basis of a lung scan showing nonuniformity of pulmonary blood flow (47 percent of patients who responded and 57 percent of those who did not respond). RESULTS: Seventeen patients (26 percent) responded to treatment, as indicated by a 39 percent fall in pulmonary-artery pressure and a 53 percent fall in the pulmonary-vascular-resistance index (P less than 0.001). Nifedipine (mean [+/- SD] daily dose, 172 +/- 41 mg) was given to 13 patients, and diltiazem (mean daily dose, 720 +/- 208 mg) was given to 4 patients. After five years, 94 percent of the patients who responded (16 of 17) were alive, as compared with 55 percent of the patients who did not respond (26 of 47, P = 0.003). The survival of the patients who responded was also significantly better than that of the NIH registry cohort (P = 0.002) and patients from the NIH registry who were treated at the University of Illinois (P = 0.001). The use of warfarin was associated with improved survival (P = 0.025), particularly in the patients who did not respond. CONCLUSIONS: This study suggests that high doses of calcium-channel blockers in patients with primary pulmonary hypertension who respond with reductions in pulmonary-artery pressure and pulmonary vascular resistance may improve survival over a five-year period.

Adult↗
PubMedDate not supplied

Cardiovascular profile of oxodipine, a novel dihydropyridine calcium channel blocker, in anesthetized open-chest dogs: a comparison with nitrendipine.

The cardiovascular effects of oxodipine, a new dihydropyridine calcium channel blocker, were studied after i.v. administration to chloralose-anesthetized dogs, and compared with those of nitrendipine. Nitrendipine produced more marked decreases than oxodipine in both systolic and diastolic blood pressure and in total peripheral resistance. No significant modification of heart rate was observed. Oxodipine decreased cardiac contractility, whereas nitrendipine increased it. This difference originated in reflex modifications, since both drugs, administered at doses of 30 and 60 micrograms/kg, decreased cardiac contractility during studies performed after cardiac autonomic blockade. Under these conditions, nitrendipine decreased heart rate, whereas oxodipine had no effect. The two drugs showed comparable effects on coronary and femoral vascular resistance. However, oxodipine caused a very marked persistent decrease of vertebral vascular resistance. On this local circulation, nitrendipine had a weak effect. The results from the present study indicate that oxodipine predominantly increases vertebral blood flow with a concomitant hypertension which is more moderate than after nitrendipine.

Analysis of Variance↗
PubMed1992

[Cerebral blood flow in elderly hypertensives after enalapril of calcium channel blockers].

25 elderly hypertensive patients (mean age 66.5 +/- 5.0 years) were given enalapril (E) 20-40 mg daily, or calcium channel blockers (CCB): either slow-release nifedipine (40 mg) or long-acting verapamil (120-360 mg) daily, 6 weeks each, in a single-blind crossover study. At the end of each treatment period cerebral blood flow (CBF) was assessed by single proton emission, computed tomography, using 99m-Tc-exametazime. In the 20 patients who completed the study, supine BP was lowered from 194/106 to 167/90 mmHg (p less than 0.001/0.001) by E and from 185/104 to 172/91 (p less than 0.01/0.001) by CCB. Standing BP was lowered from 184/106 to 160/93 (p less than 0.001/0.001) by E and from 175/102 to 162/93 (p less than 0.01/0.01) by CCB. Although there were great interpatient differences in CBF, the individual pattern remained unaltered by either E or CCB and mean quantitative changes were not significant. We conclude that in elderly hypertensives both E and CCB effectively lower BP, while cerebral perfusion is not adversely affected by either.

Aged↗
PubMedDate not supplied

Antihypertensive activity of a new calcium channel blocker LF 2.0254, in spontaneously hypertensive rats: a comparison with nifedipine and nicardipine.

LF 2.0254 is a new dihydropyridine calcium channel blocker with a long-lasting antihypertensive action in spontaneously hypertensive rats. In acute experiments, LF 2.0254 was shown to be more potent than nifedipine and nicardipine in reducing blood pressure after i.v. and oral administration with less tachycardia. The hypotensive effects of LF 2.0254 (10 mg/kg) lasted for greater than 24 hr, whereas the blood pressure-lowering effects of nifedipine and nicardipine (10 mg/kg) had disappeared after 6 hr. LF 2.0254 given orally once a day at 10 mg/kg for 14 days to spontaneously hypertensive rats, led to a marked and persistent decrease in blood pressure, with no significant changes in heart rate. In an attempt to prevent the development of hypertension, LF 2.0254 (3 and 10 mg/kg) was given once a day for 8 weeks to 5 week-old SHR. On the last day of treatment, LF 2.0254 had markedly reduced blood pressure over a 24 hr period, however, there was no reduction of left ventricular hypertrophy, since body weight and left ventricular weight were not significantly different between control and treated groups.

Animals↗
PubMed1990

Protective effects of calcium channel blockers on hydrogen peroxide induced increases in endothelial permeability.

STUDY OBJECTIVE: The aim was to examine the effects of calcium channel blockers on the permeability of endothelial cells and to determine whether these agents could protect against increases in endothelial permeability induced by hydrogen peroxide (H2O2). DESIGN: Endothelial cells were cultured on collagen coated micropore filters. When they were confluent on the filter, albumin transfer and electrical resistance across the endothelial monolayers were measured. EXPERIMENTAL MATERIAL: Endothelial cells were obtained from human umbilical veins. The cells at the 2nd to 4th passage were used for the experiments. MEASUREMENTS AND MAIN RESULTS: Nilvadipine (10(-8) M) suppressed endothelial albumin transfer by 37.2% (p less than 0.01) and enhanced electrical resistance by 25.8% (p less than 0.01), whereas nicardipine (10(-7) M), diltiazem (10(-7) M), and verapamil (10(-7) M) had no significant effect on either variable without the addition of H2O2. H2O2(0.2 mM) increased albumin transfer by 164% (p less than 0.01) and reduced electrical resistance by 67% (p less than 0.01) across endothelial monolayers without endothelial cell lysis. Nilvadipine (10(-8) M) and nicardipine (10(-7) M) inhibited the (0.2 mM) H2O2 induced increases in endothelial albumin transfer and decreases in electrical resistance more strongly than diltiazem and verapamil, although all of these agents significantly reduced such injury. CONCLUSIONS: Nilvadipine is a potent inhibitor of endothelial permeability and of hydrogen peroxide induced increases in permeability.

Albumins↗
PubMed2000

Natriuretic effect of barnidipine, a long-acting dihydropyridine calcium channel blocker, in patients with essential hypertension.

OBJECTIVE: To evaluate the effect of barnidipine hydrochloride, a long-acting dihydropyridine calcium channel blocker on urinary sodium excretion in patients with essential hypertension. PATIENTS: Twelve patients (2 males, 10 females) with mild to moderate essential hypertension. METHODS: A single-blinded study. After the control (placebo) period, 10 to 15 mg barnidipine hydrochloride was administered for 7 days, followed by a post-treatment (placebo) period. Daily changes in blood pressure, urinary volume, and urinary electrolyte excretions were evaluated. Plasma levels of atrial natriuretic peptide (ANP) and aldosterone were also determined in each period. Daily sodium intake was kept at 120 mEq. RESULTS: Blood pressure decreased from 161 +/- 4/92 +/- 2 mmHg to 146 +/- 4/85 +/- 2 mmHg (p<0.05) after 7-day-treatment with barnidipine. Barnidipine significantly increased urinary sodium excretion; the change was evident on the first day of administration (control period 41 +/- 3 mEq/day, and first day 59 +/- 3 mEq/day, p < 0.05). Drug discontinuation transiently decreased sodium excretion to 35 +/- 3 mEq/day. Cumulative sodium balance after 7-day-treatment reached 47 +/- 19 mEq. Urine volume, potassium excretion, and creatinine excretion did not change during the treatment period. The plasma levels of ANP tended to increase, but those of aldosterone did not change with barnidipine. CONCLUSION: Barnidipine administration for a week decreased the blood pressure and made the sodium balance negative by increasing the urinary sodium excretion in patients with essential hypertension. The natriuretic effect of this drug could contribute at least in part to its antihypertensive effect.

Adult↗
PubMedDate not supplied

Extent of use of immediate-release formulations of calcium channel blockers as antihypertensive monotherapy by primary care physicians: multicentric study from Bahrain.

BACKGROUND: The issue of cardiovascular safety of calcium channel blockers (CCBs) has been widely debated in view of reflex increase in sympathetic activity induced by immediate release (IR) / short acting formulations. It is generally agreed that such CCBs should not be used alone in the management of hypertension. AIMS: We have determined the extent to which primary care physicians prescribe CCBs as monotherapy, especially the immediate release formulations, in the management of uncomplicated hypertension and diabetic hypertension - with an emphasis upon the age of the patients. SETTING, DESIGN AND METHODS: A retrospective prescription-based study was carried out in seven out of 18 Health Centres in Bahrain. The study involved a registered population of 229,300 representing 46% of registered individuals, and 35 physicians representing 43% of all primary care physicians. The data was collected between November 1998 and January 1999 using chronic dispensing cards. RESULTS: In all categories CCBs were the third commonly prescribed antihypertensive as monotherapy, with a prescription rate of 11.1% in uncomplicated hypertension, 18% in diabetic hypertension and 20.1% in elderly patients above 65 years of age. Nifedipine formulations were the most extensively prescribed CCBs. Almost half of the CCB-treated patients were on IR-nifedipine, whereas IR-diltiazem and IR-verapamil, and amlodipine were infrequently prescribed. CONCLUSION: Prescription of IR-formulations of CCBs as monotherapy by primary care physicians does not conform with recommended guidelines. In view of concerns about the safety of such practice, measures to change the prescribing pattern are required.

Adult↗
PubMed1999

Recalcitrant oral ulcers caused by calcium channel blockers: diagnosis and treatment considerations.

BACKGROUND: Oral ulcers often pose a dilemma in diagnosis and treatment. Patients seen routinely in dental practices are frequently receiving multiple medications. The authors discuss the pathogenesis, clinical appearance and treatment of drug-induced oral ulcers. CASE DESCRIPTIONS: Two patients with recalcitrant painful oral ulcers caused by calcium channel blockers are described. These ulcers failed to heal despite repeated interventions, including surgery, laser ablation, and topical and systemic steroid therapy. Results of the histopathologic examinations were nonspecific. The patients were in a great deal of pain because of the initial failure to recognize the cause of these ulcers. CLINICAL IMPLICATIONS: A careful medical history, including a detailed list of medications received, is critical in identifying drug-induced oral ulcerations, especially when the ulcer is resistant to treatment and of indeterminate cause. To date, calcium channel blockers have not been reported to cause oral ulcerations.

Aged↗
PubMed1996

Influence of calcium channel blocker treatment on the mechanical properties of diabetic rat myocardium.

The objective of this investigation was to determine whether calcium channel blocker (CCB) treatment effectively restores normal baseline mechanical function in diabetic myocardium and to evaluate its effect on the interval-strength relationship. Wistar rats were made diabetic with streptozotocin (55 mg/kg, IV). Left-ventricular papillary muscles from normal and diabetic (10 weeks) rats were superfused with Tyrode's solution at 30 degrees C. A subgroup of diabetic and normal animals received daily injections of verapamil or nifedipine (10 mg/kg, IP; 8 weeks) to compare the effectiveness of a phenylalkylamine to a dihydropyridine in reversing diabetes-induced contractile dysfunction in vitro. Muscles were electrically stimulated at 0.5 Hz with suprathreshold stimuli, and the following parameters were measured: peak tension developed, time to-peak tension, time-to-90% relaxation, and the maximum velocities of tension development and decay. Experimental diabetes was characterized by: severe hyperglycemia, hepatomegaly, reduced body weight gain, cardiomegaly, and increased plasma phospholipid levels. In addition, baseline values of peak tension developed, time to-peak tension, and time-to-90% relaxation were significantly greater in muscles from diabetic animals. Chronic nifedipine treatment reduced hyperglycemia and plasma phospholipid levels, normalized body weight gain, and reduced both heart and liver sizes in diabetic animals. Nifedipine treatment completely reversed diabetes-induced prolongation in both time-to-peak tension and time-to-90% relaxation. In diabetic myocardium, a slightly positive component was present in the interval-strength relationship between 0.01 and 1 Hz, resulting in a rightward shift in the entire curve across a wide range of stimulation frequencies (0.01-5 Hz). This positive component was absent in muscles from diabetic animals treated with both CCBs, and verapamil produced a leftward shift in the frequency response curve. The results of this study suggest that chronic nifedipine treatment may be more effective than verapamil in restoring normal baseline myocardial mechanical function, reducing hyperglycemia and hyperlipidemia, as well as attenuating both cardiac and liver enlargement in experimental diabetes. In contrast, verapamil treatment tended to normalize more effectively the inotropic response to changes in stimulation frequency in diabetic myocardium.

Analysis of Variance↗
PubMed1995

Use of calcium channel blockers in acute ischemic cerebrovascular disease.

Many studies have shown that increased intracellular concentration of calcium ions is an important factor influencing neuronal damage in acute ischemic cerebrovascular disease (ICVD) and administration of calcium-channel blockers during the "open therapeutic window" have beneficial cytoprotective effects. In a prospective ICVD study we administered dihydropyridine compound "nimodipine" (1.5 to 2.0 mg/kg/day) either orally or as continuous intravenous drip round the clock for the first three days followed by oral therapy along with standard treatment after the diagnosis of a stroke was confirmed by CT Scan. The "ICVD" control cases received best medical care (BMC). The degree of functional neuronal recovery (using modified Mathew's scale) was assessed after three weeks of therapy. Our study shows significant improvement in the quality of neurologic recovery though there was no change in mortality rate in both the groups.

Acute Disease↗
PubMed1998

ω-Phonetoxin-IIA: a calcium channel blocker from the spider Phoneutria nigriventer.

A peptide with neurotoxic effect on mammals, purified from the venom of the spider Phoneutria nigriventer, was studied regarding its primary structure and its effects on voltage-gated calcium channels. The peptide, named ω-phonetoxin-IIA, has 76 amino acids residues, with 14 Cys forming 7 disulphide bonds, and a molecular weight of 8362.7 Da. The neurotoxicity is a consequence of the peptide’s blocking effects on high-voltage-activated (HVA) calcium channels. N-type HVA calcium channels of rat dorsal root ganglion neurons are blocked with affinity in the sub-nanomolar concentration range. The toxin also blocks L-type channels of rat β pancreatic cells, with an affinity 40 times lower. Although not studied in detail, evidence indicates that the toxin also blocks other types of HVA calcium channels, such as P and Q. No effect was observed on low-voltage-activated, T-type calcium channels. The significant homologies between ω-phonetoxin-IIA and the peptides of the ω-agatoxin-III family, and the overlapping inhibitory effects on calcium channels are discussed in terms of the structure-activity relationship.

Amino Acid Sequence↗
PubMed1986

Nifedipine: more than a calcium channel blocker.

Nifedipine exhibits a greater incidence of side effects than the other currently marketed calcium channel antagonists. In addition to those effects attributable to calcium channel blockade, nifedipine produces side effects similar to the effects of adenosine. It is probable that nifedipine exerts part of its physiological actions through potentiation of adenosine. Adenosine, an endogenous calcium channel blocker, modifies synaptic events throughout the nervous system and causes sedation, smooth and skeletal muscle relaxation, anticonvulsion, hypotension and hypothermia, all reversible by caffeine or theophylline administration. Nifedipine inhibits adenosine uptake from, and release into, the extracellular space and binds at an adenosine receptor. Both nifedipine and adenosine interact with benzodiazepine binding sites. Interaction between nifedipine and adenosine should be kept in mind when treating patients with nifedipine.

Adenosine↗
PubMed1996

Pharmacokinetics and Pharmacodynamics of a New Calcium Channel Blocker MPC-1304 in Hypertensive Subjects.

The pharmacokinetic and pharmacodynamic properties of a new calcium channel blocker MPC-1304 (MPC) were examined following a single 10 mg oral dose of MPC in six hypertensive subjects. Blood samples for measurement of MPC and its active metabolite (MPC-Keto-H(2)) were obtained, and blood pressure was measured just before and at 1, 2, 4, 6, 8, 12 and 24 h after administration. Plasma concentrations of MPC-Keto-H(2) were significantly higher than those of MPC at every observation point. The value of maximum plasma concentration of MPC-Keto-H(2) was 10 times greater than that of MPC. The antihypertensive effect of MPC was observed at 4 h after administration and persisted up to 8 h. A plot of plasma concentrations of MPC versus reductions in blood pressure showed an anticlockwise hysteresis loop. These results suggest that the active metabolite MPC-Keto-H(2) contributes in part to the antihypertensive action of MPC, the delayed distribution of MPC into the effector site, or both.

Journal Article↗