Calcium Channel-blocking Agents Research Articles

Noninvasive Quantitative Evaluation of Early Atherosclerosis and the Effect of Monatepil, a New Antihypertensive Agent An Interim Report

In two studies on the same group of patients we evaluated noninvasive methods of assessing atherosclerosis and determined the effect of the new calcium channel-blocking agent monatepil on the progression of early atherosclerosis in humans. Computed tomography (CT) of the lower abdominal aorta and ultrasonography of the carotid arteries were used as noninvasive methods to determine the extent of atherosclerosis. To evaluate the CT images, we developed a new medical image analysis program. This enabled aortic calcification volume (ACV) to be quantified using plain CT images, and aortic wall volume (AWV) and aortic wall and calcification volume (AWCV) to be quantified from contrast CT images. Interobserver coefficients of variation of ACV, AWV, and AWCV (n = 8) were 4.7, 2.4, and 5.0%, respectively. In the monatepil study, the effect of the drug on serum lipid profiles was evaluated. Preliminary results show that shortly after monatepil administration, total serum cholesterol levels decreased significantly from 253.8 +/- 35.6 to 244.8 +/- 38.6 mg/dL (P < .009) and triglyceride levels tended to decrease. A positive correlation between the change in total cholesterol and changes in mean platelet volume was found (P = .028). Fasting immunoreactive insulin levels decreased in the four patients in which they were determined. Although this is a preliminary study, results indicate that CT of the lower abdominal aorta in combination with our new analysis program may be a precise, reproducible means of assessing early atherosclerosis. We have also shown that monatepil significantly decreases total cholesterol levels. However, the long-term effects of monatepil on the progression of atherosclerosis remain to be determined.

Investigation of therapeutic mechanisms of atenolol and diltiazem in patients with variable-threshold angina

The effects of β-adrenoreceptor and calcium channel-blocking agents on the balance of myocardial oxygen supply and demand were studied in 15 patients (2 women and 13 men), aged 46 to 69 (mean 62) years, with variable-threshold angina. An exercise test was performed before therapy was begun, and 24-hour ambulatory ECG monitoring was performed after 1 week of long-acting nitrate therapy, in the third week after random assignment to either atenolol or diltiazem, and in the third week after crossover. All exercise tests were positive except in one patient taking diltiazem. The exercise time to 0.1 mV ST change was 4.2 ± 1.7 minutes with no therapy, 5.1 ± 1.6 minutes with nitrates, 6.6 ± 0.8 minutes with diltiazem, and 6.5 ± 2.1 minutes with atenolol. The rate-pressure product at 0.2 mV ST change was 20.9 ± 4.6 with no therapy and 21.2 ± 5.7 and 22 ± 4.6 with nitrates and diltiazem, respectively, but fell to 15 ± 3.9 beats · min.−1 mm Hg 10−3 after atenolol (p < 0.01). There was no significant difference in the number of anginal attacks or in nitroglycerin consumption per week. The heart rate at the onset of ST-segment change during the exercise test and during ambulatory ECG monitoring was significantly lower during atenolol than during diltiazem treatment. Both atenolol and diltiazem were of similar efficacy in increasing nonischemic exercise duration in patients with variable-threshold angina and acted primarily by slowing the resting heart rate. Atenolol had a more pronounced effect on heart rate, but its effect on angina appeared to be limited by a β2-receptor blockade-induced increase in coronary vascular tone.

Hypertension and the kidney: Determinants of the response to antihypertensive therapy and their implications

Medicine has long recognized an association between hypertension and the kidney. The kidney may be a culprit or a victim in the process. As a culprit, the kidney may be responsible for the pathogenesis of hypertension in many patients, and in virtually all patients the renal response to antihypertensive therapy is a major determinant of its success or failure. In some patients, hypertension can lead to renal injury and even end-stage renal disease. Indeed, 25% of patients entering dialysis or transplant programs in the United States today have hypertension as the primary or sole mechanism, and another 25% have the complex combination of diabetes and hypertension as the cause. Antihypertensive therapy appears to be successful in preventing or arresting the renal response in accelerated hypertension, regardless of the treatment used to reduce blood pressure. However, treatment appears to be less successful in preventing the progression of moderate hypertension to end-stage renal disease. Substantial evidence suggests that angiotensin-converting enzyme inhibition and calcium channel blockade may prevent this progression when other antihypertensive therapy does not. The renal response to an angiotensin-converting enzyme inhibitor or a calcium channel-blocking agent appears to be determined by the pathogenetic features of the hypertension, and this may be an important determinant of the efficacy of the agents selected. Although still indistinct, the guidelines favoring selection of a specific antihypertensive agent are gradually emerging.

Effects of a Static Magnetic Field on Hemodynamics During Administration of a Cell Membrane Calcium Channel Blocking Agent

We investigated the influence of a 0.2 T static magnetic field (SMF) on the carotid sinus region in rabbits during infusion of a cell membrane calcium channel blocking agent (verapamil). The experiments were carried out under pentobarbital anesthesia. Blood pressure, heart rate, and respiration were also monitored. Contrary to our earlier studies without verapamil (1–4), the SMF had no significant effect on blood pressure and heart rate during verapamil infusion. Changes in calcium membrane channel transport might be participants in SMF effects on sinocarotid baro-receptors.

Effect of Calcium Channel Blocking Agents on Infarct Size After Ischaemia-Reperfusion in Anaesthetised Pigs

We compared the abilities of verapamil and nicardipine to protect the porcine myocardium from the consequences of ischaemia-reperfusion in vivo. Infusion of verapamil (50 micrograms/kg) into the left anterior descending coronary artery LAD (i.c.a.), in 15 min immediately before ligation depressed regional contractile function, reduced infarct size by 80%, and enabled contractile function to recover partially during reperfusion. Verapamil (10 micrograms/kg i.c.a.) did not depress contractile function before ligation or permit its recovery during reperfusion, despite reducing infarct size by 80%. Lower doses of verapamil were not cardioprotective. Nicardipine (10 and 30 micrograms/kg i.c.a.) depressed contractile function before ligation but did not permit its recovery during reperfusion. Nicardipine did not reduce infarct size development. Thus, drug-induced negative inotropic activity (which presumably reflects myocardial calcium channel blockade) and cardioprotection are not linked. Verapamil can markedly reduce infarct size development at a dose that exerts no detectable negative inotropic activity. This cardioprotective effect of verapamil was greatly reduced by intravenous (i.v) pretreatment with aspirin (30 mg/kg), which alone did not alter infarct size development. Thus, the cardioprotective effect of verapamil (10 micrograms/kg i.c.a.) appears to be mediated by a cyclooxygenase product, possibly prostacyclin.

The Management of Primary Pulmonary Hypertension

Primary pulmonary hypertension is a clinical syndrome characterized by pulmonary hypertension in the absence of sufficient underlying cardiac, parenchymal pulmonary, or systemic disease to account for it. The population of patients with primary pulmonary hypertension is a heterogeneous one, both clinically and histologically. As the etiologic mechanisms are unknown, therapy is directed toward the consequences of the pulmonary vascular process. Oxygen supplementation, the use of digoxin and diuretics for symptomatic heart failure, and anticoagulation all may have a role in treating primary pulmonary hypertension, although vasodilator therapy has been the main area of investigation. Screening for vasodilator responsiveness, defining a favorable vasodilator effect, predicting long-term effectiveness, and deciding who to treat have all been controversial. New approaches, such as use of high-dose calcium channel-blocking agents and continuous intravenous infusion of prostacyclin (an investigational agent), have recently been proposed. When medical therapies are exhausted, heart-lung or lung transplantation has increasingly become an option for selected patients.

NIFEDIPINE MAY WORSEN HEART FAILURE.

Calcium channel-blocking agents such as nifedipine are sometimes prescribed for patients with congestive heart failure in an attempt to improve cardiac

Assessment of Left Ventricular Diastolic Function and Effect of Calcium Channel-Blocking Agent on Diastolic Function by Pulsed Doppler Echocardiography in Patients with Hypertrophic Cardiomyopathy

Assessment of Left Ventricular Diastolic Function and Effect of Calcium Channel-Blocking Agent on Diastolic Function by Pulsed Doppler Echocardiography in Patients with Hypertrophic Cardiomyopathy

Effects of calcium channel‐blocking agents on platelet–osteogenic sarcoma interaction: Platelet aggregation and electron microscopic findings

A variety of tumors stimulate platelet activation. Because platelet activation may, in part, require calcium channel mobilization, we evaluated whether calcium channel blocking agents inhibit osteogenic sarcoma induced platelet aggregation. Platelet rich plasma (PRP) from normal subjects was incubated with one of four calcium channel-blocking agents: nifedipine, diltiazem, verapamil, or amlodopine, all 0-25 micrograms/ml, or diluent. Osteogenic sarcoma cells (2 or 4 x 10(6)/ml) were then added. Platelet aggregation was monitored by light transmission through PRP, and residual PRP was processed for electron microscopy. MG63 cells caused aggregation of PRP in most subjects (mean, 36 +/- 3%). Calcium channel-blocking agents (nifedipine greater than diltiazem greater than amlodopine greater than verapamil) caused partial inhibition of osteogenic sarcoma-induced platelet aggregation, at high concentrations only. Electron microscopy showed platelets aggregating to each other and to tumor cell membranes within 1-5 minutes. Changes in pattern of platelet clumping around tumor cells occurred when PRP was incubated with high concentration of diltiazem (50 micrograms). This study shows that calcium channel-blocking agents inhibit osteogenic sarcoma-induced platelet aggregation when used in high doses.

Ventricular Tachyarrhythmias Related to Early Afterdepolarizations and Triggered Firing: Relationship to QT Interval Prolongation and Potential Therapeutic Role for Calcium Channel Blocking Agents

Ventricular Tachyarrhythmias Related to Early Afterdepolarizations and Triggered Firing: Relationship to QT Interval Prolongation and Potential Therapeutic Role for Calcium Channel Blocking Agents

Relationship between antecedent angina pectoris and short-term prognosis after thrombolytic therapy for acute myocardial infarction

The relationship between preinfarction clinical status and short-term outcome was prospectively evaluated in 775 patients hospitalized with acute myocardial infarction after reperfusion therapy. It was anticipated that a history of angina preceding myocardial infarction by more than 7 days would be associated with more extensive underlying coronary artery disease and a more complicated in-hospital course. However, although this group did have a higher risk profile for coronary artery disease (hypertension 53.6% vs 37.2%; diabetes 22.5% vs 12.1%; hyperlipidemia 19.4% vs 9.8%; mean number of risk factors 2.2 vs 1.7, p = 0.0001), a higher incidence of multivessel disease (57.7% vs 39.6%, p less than 0.0001), worse baseline global left ventricular function (left ventricular ejection fraction 48.8% vs 51.3%, p = 0.03), and impaired function of the noninfarct zone (-0.05 vs +0.46 SD/chord, p = 0.002), the in-hospital course was less complicated than in the group without prior angina. Patients without antecedent angina had a higher rate of reocclusion of the infarct-related artery (13.6% vs 8.2%; p = 0.048). Although the difference did not reach statistical significance (7.2% vs 4.6%; p = 0.21), the in-hospital mortality rate was also higher in this group. These findings suggest that a history of prior angina is not necessarily associated with an unfavorable short-term prognosis after reperfusion therapy. This may be related to the greater prior use by this group of beta-adrenergic- and calcium channel-blocking agents (23.1% vs 8.5% and 20.7% vs 3.8%, respectively). It may also be related to the beneficial effects of collateral vessels, myocardial preconditioning, or differences in the native fibrinolytic system.

Metabolic protection by verapamil during graded coronary flow reduction independent of effect on baseline systolic function. Separation of mechanical and ionic markers of ischemia.

Pretreatment with the calcium channel-blocking agent verapamil lowers the coronary flow associated with the first rise in myocardial extracellular potassium [( K+]e). The mechanisms underlying this effect are unclear. It is not known whether this effect is a manifestation of verapamil-induced reduction in baseline cardiac work before the reduction in coronary flow, is dependent on a selective depression of contractility within the low-flow region, or is independent of an effect on myocardial work. This study was performed to determine the relations between changes in regional contractility and [K+]e before and after verapamil (0.2 mg/kg followed by 6.5 micrograms/kg/min) when left anterior descending (LAD) coronary flow is progressively reduced and when verapamil-induced alterations in baseline myocardial work are prevented by atrial pacing and by dobutamine (4.3 +/- 2.2 micrograms/kg/min) to maintain systemic arterial blood pressure and contractility. Before verapamil-dobutamine, myocardial [K+]e rose and regional contractility fell when LAD coronary flow was reduced to 87.7 +/- 9.6% and 83.4 +/- 7.4%, respectively, of the unrestricted control value (p = NS). After verapamil-dobutamine, the threshold flow for rise in [K+]e decreased to 56.4 +/- 13.5% of the unrestricted control flow (p = 0.003), but the threshold flow for regional contractility fall was unchanged (84.8 +/- 11.3%). Our results indicate that the protective effect of verapamil on preventing ischemia-induced [K+]e release is not dependent on a reduction in baseline myocardial work. In this setting, calcium channel blockade by verapamil results in a dissociation between the ionic and mechanical events that occur when coronary flow is reduced.

Follicle-Stimulating Hormone Receptor-Mediated Uptake of45Ca2+by Proteoliposomes and Cultured Rat Sertoli Cells: Evidence for Involvement of Voltage- Activated and Voltage-Independent Calcium Channels*

We have previously reported incorporation into liposomes of Triton X-100-solubilized FSH receptor-G-protein complexes derived from purified bovine calf testis membranes. In the present study we have used this model system to show that FSH induces flux of 45Ca2+ into such proteoliposomes in a hormone-specific concentration-dependent manner. FSH, inactivated by boiling, had no stimulatory effect on 45Ca2+ flux, nor did isolated alpha- or beta-subunits of FSH. Addition of GTP (or its analogs 5'-guanylylimidodiphosphate and guanosine-5'-O-[3-thiotriphosphate]) or sodium fluoride (in the presence or absence of GTP or its analogs) failed to induce 45Ca2+ flux into proteoliposomes, suggesting that the uptake of 45Ca2+ was receptor, and not G-protein, related. Voltage-independent (ruthenium red and gadolinium chloride) and voltage-activated (methyoxyverapamil and nifedipine) calcium channel-blocking agents reduced FSH-stimulated 45Ca2+ flux into proteoliposomes to control levels. FSH also induced uptake of 45Ca2+ by cultured rat Sertoli cells. Ruthenium red and gadolinium chloride had no effect on basal levels of 45Ca2+ uptake or estradiol secretion by cultured rat Sertoli cells, nor did methoxyverapamil or nifedipine. All four calcium channel blockers, however, were able to reduce FSH-induced 45Ca2+ uptake to basal levels and FSH-stimulated conversion of androstenedione to estradiol by up to 50%, indicating an involvement of Ca2+ in FSH-stimulated steroidogenesis. Our results suggest that the well documented changes in intracellular calcium levels consequent to FSH binding may be due, at least in part, to an influx of calcium through FSH receptor-regulated calcium channels.

Growth Hormone-Releasing Factor Production by Fetal Rat Cerebrocortical and Hypothalamic Cells in Primary Culture*

Recent data from our laboratory and others have shown radioimmunoassayable GRF (IR-GRF) in the rat brain cortex. In the present study the ontogenesis of immunoreactive rat(r) GRF (IR-GRF) in long term dissociated fetal rat cerebrocortical and hypothalamic cell cultures and the regulation of its secretion by potassium depolarization and calcium channel-blocking agents were investigated. The chromatographic profiles of IR-rGRF from cell extracts were determined and compared with those from in vivo cerebrocortical and hypothalamic tissues. Mechanically dispersed cultured telencephalic and diencephalic cells from 17- to 21-day-old fetal rats showed a progressive increase in IR-rGRF, reaching maximum values (media plus cells) between 775-1020 (pg/mg protein) in hypothalamic cells on days 10-20 and between 450 and 950 pg/mg protein in cortical cells on days 25-30. IR-rGRF from acidic extracts of cells and adult cortical and hypothalamic tissues adsorbed onto octadecylsilyl-silica columns corresponds primarily to rGRF-(1-43)OH on HPLC. In gel filtration chromatography, almost all IR-rGRF from cultured cerebrocortical cells and fetal and adult cortical tissues coeluted with rGRF-(1-43)OH. IR-rGRF from cultured hypothalamic cells showed an additional component with a higher mol wt eluting in the void volume. To determine the influence of membrane depolarization of rGRF release, potassium (K+) concentrations in the medium were increased to 30 and 56 mM, inducing a marked increase in medium rGRF concentrations. Verapamil, a Ca2+ channel blocker (20 microns) reverses the effect of 56 mM potassium depolarization, suggesting that it is at least partially dependent upon Ca2+ transport. These data indicate that fetal rat cerebrocortical and hypothalamic cells in culture produce and release rGRF in response to depolarizing agents. The presence of rGRF in cortical tissue suggests that there are other physiological roles besides those implicated in the stimulation of GH secretion.

The effects of calcium-blocking agents on sympathetic responses to acute haemorrhagic shock in dogs

The effects of three calcium channel-blocking agents, verapamil, nifedipine and diltiazem, given intravenously, have been studied on the cardiovascular and sympathetic responses to acute haemorrhagic shock in anaesthetized dogs. Following acute haemorrhage, cardiac output, mean pulmonary artery pressure, mean right atrial pressure, and pulmonary capillary wedge pressure all fell, and adrenaline, noradrenaline and plasma renin activity rose. In the presence of each calcium antagonist the fall in cardiac output, mean pulmonary artery pressure, central venous pressure and pulmonary capillary wedge pressure was similar, and the rise in catecholamine levels unaffected. The rise in plasma renin activity following diltiazem 0.02 mg kg-1 or 0.1 mg kg-1 or nifedipine 0.01 mg kg-1 was similar to values in a control group, whereas in those receiving verapamil 0.15 mg kg-1 or 0.6 mg kg-1, or nifedipine 0.05 mg kg-1, the rise was greater.

High-dose monotherapy and combination therapy with calcium channel blockers for angina: A comprehensive review of the literature

Clinical experience with the calcium channel-blocking agents has established their efficacy in the therapy of painful and silent myocardial ischemia. Questions have arisen, however, about side-effect characteristics of these medications as clinical practice has led to utilization of higher doses of individual drugs than employed in large numbers of patients in early clinical trials as well as combinations with other antianginal agents including beta-blockers. A study was undertaken to examine the published literature regarding side effects associated with high-dose versus low-dose therapy with nifedipine and diltiazem and the use of these agents in combination with beta-blockers. This investigation demonstrated that utilization of high-dose diltiazem (more than 240 mg per day) as opposed to low-dose diltiazem (no more than 240 mg per day) was associated with an increased incidence of atrioventricular block, and increased peripheral vasodilatory effects. In contrast, the use of high-dose nifedipine (more than 60 mg per day) was not associated with atrioventricular block. At clinically high dosage levels, the incidence of peripheral edema was comparable for both nifedipine and diltiazem, although low-dose nifedipine resulted in a significantly greater incidence of edema compared with low-dose diltiazem. This analysis also demonstrated that bradyarrhythmia is associated with the combination of a beta-blocking agent and either low- or high-dose diltiazem, but not with nifedipine-beta-blocker combinations. Clinical experience suggests caution in the combined use of diltiazem and a beta-blocking agent because of the demonstrated additional adverse negative chronotropic and dromotropic effects. No additional adverse electrophysiologic effects have been noted for nifedipine-beta-blocker combinations. The literature analysis supports and mirrors widespread clinical experience obtained since nifedipine and diltiazem were introduced. It should be noted, though, that combination therapy with calcium channel blockers and beta-blockers should be done with caution, since there have been occasional reports of congestive heart failure or exacerbation of angina with this combination.

Effects of calcium availability on the release of ovine choriomammotropin from cotyledonary cells incubated in vitro

1. 1. In this study, we examined the basal release of choriomammotropin (oCM) from monolayer cultures of cotyledonary cells obtained from ewes at different gestational ages. 2. 2. oCM release increased with gestational age and displayed a similar profile to the concentration of oCM observed in maternal plasma. 3. 3. Release of oCM was significantly ( P < 0.05; n = 9) increased in calcium-depleted medium, and by treatment with either phospholipase C (0.125 units/ml) or KCl (50 mM). 4. 4. The calcium antagonist MgCl (12mM) and the calcium channel-blocking agents verapamil (50 μM) and nefidipine (10 μM) all significantly stimulated oCM release. 5. 5. These data are consistent with the suggestion that oCM release is inversely related to extracellular calcium concentration.

Modulation of mitoxantrone cytotoxicity by verapamil in human chronic myeloid leukemia cells.

Calcium channel-blocking agent verapamil has been established to be an effective drug to modulate the action of many anticancer drugs. In this study, we examined the effect of verapamil on the cytotoxicity of mitoxantrone in human chronic myeloid leukemia (CML) cells. Mitoxantrone alone exhibited dose-dependent inhibition of DNA biosynthesis in CML cells. The addition of verapamil (3.3 microM) enhanced the responsiveness of CML cells to mitoxantrone (1 microgram/ml) cytotoxicity indicated by significant increased inhibition of thymidine incorporation (p less than 0.001). The present study demonstrates the possible efficacy of verapamil in the chemotherapy of CML with mitoxantrone.

The role of calcium channel blocking agents in the prevention of migraine.

Vascular headache pathophysiology and manifestations are reviewed along with the role that calcium channel blocking agents play in prevention of these vascular headaches. Of the calcium channel blockers presently marketed in the U.S., verapamil has been the most widely studied. Verapamil has been shown to produce a significant improvement in frequency and duration of migraine as compared with placebo. Calcium channel blocking agents that have been studied and used outside of the U.S. are flunarizine and nimodipine, both of which provide significant improvement in measures of migraine severity, duration, frequency, and other pain and severity indices. There have been no controlled trials comparing these agents with each other as with beta-blocking agents and other prophylactic agents presently marketed in the U.S. Calcium channel blocking agents may become the drugs of first choice in migraine prophylaxis due to their effectiveness and mild side effect profile.

Dihydropy ridine Calcium Channel Blocking Agents in Hepatotoxic and Ethanol‐Induced Liver Cell Injury

Dihydropy ridine Calcium Channel Blocking Agents in Hepatotoxic and Ethanol‐Induced Liver Cell Injury