Effect of the calcium entry blocker verapamil on renal ischemia

The ability of the calcium entry blocker verapamil to ameliorate the effects of renal ischemia was studied in ten sheep. Postanesthesia, bilateral cutaneous ureterostomies were placed in each sheep to facilitate urine collection and analysis. Both kidneys were made ischemic for one hour by occluding each renal artery. However, immediately before occlusion of the right renal artery, 0.05 mg/kg of verapamil was injected into the artery. Comparison of urinary creatinine excretion and urine volume for 72 h after reversal of ischemia demonstrated that those kidneys pretreated with verapamil had greater functional preservation (p less than .05). In this study, verapamil appeared to provide protection against renal damage after an ischemic insult.     

Comparative evaluation of the effects of isradipine and diltiazem on antipyrine and indocyanine green clearances in elderly volunteers

Calcium antagonists have been shown to depress hepatic enzymes and accelerate hepatic blood flow. This study was designed to compare the effects of two calcium antagonists, isradipine and diltiazem, on antipyrine and indocyanine green (ICG) clearances in the elderly. Eighteen elderly subjects (aged 65 to 80 years) received either isradipine (5 mg every 12 hours), diltiazem (90 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the third day after the study treatment, a 0.5 mg/kg dose of ICG was administered. Blood samples were obtained over 20 minutes for HPLC determination of ICG plasma concentrations. Ten minutes later, subjects ingested 1.2 gm antipyrine. Blood samples were obtained over 48 hours for HPLC determination of antipyrine plasma concentrations. Mean +/- SD antipyrine clearance after diltiazem (0.0258 +/- 0.0065 L/hr/kg) was significantly lower than that observed after isradipine (0.0334 +/- 0.0098 L/hr/kg) or placebo (0.0329 +/- 0.0082 L/hr/kg). Antipyrine clearance after isradipine was not significantly different from that after placebo. Mean +/- SD ICG clearances after diltiazem (9.17 +/- 1.35 ml/min/kg) or isradipine (9.57 +/- 1.82 ml/min/kg) were significantly higher than that observed after placebo (8.06 +/- 1.45 ml/min/kg). These findings suggest that diltiazem, but not isradipine, affects hepatic enzyme activity in the elderly. Both agents accelerate ICG clearance, a marker of hepatic blood flow.     

Lack of efficacy of high-dose verapamil in preventing brain damage in baboons and pigs after prolonged partial cerebral ischemia

There has been mounting speculation that calcium antagonists may be useful in reducing or preventing brain damage after cardiopulmonary resuscitation. To test the clinical usefulness of these agents in averting such damage, high-dose verapamil was administered to baboons and pigs after partial cerebral ischemia for varying periods of time. In Group A baboons and pigs, the major aortic branches supplying the carotid and vertebral circulations were clamped for periods ranging from 15 to 150 minutes, and neurological recovery was observed. In Group B, verapamil hydrochloride 0.7 mg/kg was given by intravenous infusion after similar periods of arterial occlusion. The administration of verapamil did not lead to any clinically improved neurological outcome. The use of verapamil after prolonged periods of partial cerebral ischemia did not improve neurological recovery in baboons and pigs.     

Comparison of pyrroloquinoline quinone and/or metoprolol on myocardial infarct size and mitochondrial damage in a rat model of ischemia/reperfusion injury

The cardioprotective effectiveness of low-dose pyrroloquinoline quinone (PQQ, 3 mg/kg) was compared with metoprolol, a beta(1)-selective adrenoceptor antagonist. Rats underwent 30 minutes of left anterior descending coronary artery occlusion and 2 hours of reperfusion. Metoprolol and/or PQQ were given at the onset of reperfusion to mimic clinical treatment. Metoprolol and/or PQQ reduced infarct size and protected against ischemia-induced left ventricular dysfunction after 2 hours of reperfusion. Combined therapy augmented left ventricular developed pressure at the end of reperfusion. Metoprolol or PQQ alone enhanced mitochondrial respiratory ratios in ischemic and nonischemic myocardium. Although the PQQ/metoprolol combination therapy increased respiratory ratio values, the effects were small when compared with PQQ alone. Only PQQ decreased lipid peroxidation. Metoprolol and/or PQQ given at the onset of reperfusion reduce infarct size and improve cardiac function. Combination therapy further reduces infarct size. PQQ is superior to metoprolol in protecting mitochondria from ischemia/reperfusion oxidative damage.     

Inhibition of ischemia-induced subcellular redistribution of lysosomal enzymes in the perfused rat heart by the calcium entry blocker, diltiazem

Effect of diltiazem on subcellular distribution of lysosomal enzymes, high-energy phosphate metabolism and mechanical function in the ischemic heart was studied. Ischemia was induced by lowering the afterload pressure of the perfused working rat heart. The activities of cathepsin D, beta,N-acetylglucosaminidase and acid phosphatase were determined in the nonsedimentable and sedimentable fractions after centrifugation of the tissue extract to assess the subcellular distribution of lysosomal enzymes. After ischemia, decreases in the mechanical function and the tissue level of high-energy phosphates were observed. In addition, ischemia caused subcellular redistribution of lysosomal enzymes from the lysosomes to the cytoplasm. Reperfusion of the ischemic heart did not restore the mechanical function and the level of high-energy phosphates completely. Diltiazem (2.21 X 10(-6), 1.11 X 10(-5) and 2.21 X 10(-5) M) was provided for the heart 5 min before the onset of ischemia. Diltiazem preserved high-energy phosphates in the ischemic heart, and inhibited the subcellular redistribution of lysosomal enzymes being caused by ischemia, depending on its concentration. Reperfusion after ischemia with diltiazem recovered the mechanical function that had been decreased by ischemia. These results may indicate that diltiazem can protect the myocardium against ischemic damage.     

Failure of interventions to maintain mitochondrial function in ischemic myocardium

The purpose of this study was to investigate whether pyruvate (2.5 mmol/kg), the combination of glucose (3.9 mmol/kg) and insulin (0.13 unit/kg) with potassium (9.27 meq/kg), or sodium dichloroacetate (120 mg/kg) infused for 15 minutes before and 20 minutes after ligation of the left anterior descending coronary arterv in anesthetized dogs restricted the depression in mitochondrial respiratory function induced by ischemia. Myocardial blood flow after ligation in the three groups was o.2 ml/min per gram or less in ischemic subendocardium and was similar to that in saline-infused controls that had also undergone coronary artery ligation. The depressions induced in mitochondrial respiratory control index and state 3 respiration by ischemia in the subendocardium and subepicardium of the three treatment groups, when compared with corresponding nonischemic tissue, were not significantly improved from the control values. It was concluded that these three interventions fail to preserve mitochondrial respiration in ischemic myocardium.     

大鼠脑缺血再灌注损伤与盐酸法舒地尔的保护作用

背景传统钙离子拮抗剂脑保护作用并不确实,盐酸法舒地尔是一种新型钙离子拮抗剂,具有强大的扩血管作用和保护缺血脑组织的作用.目的研究盐酸法舒地尔作为细胞内钙离子拮抗剂对大鼠缺血再灌注损伤的保护作用.设计随机对照的实验研究.地点和对象全部实验于解放军总医院实验动物中心完成.选择体质量250～300 g健康SD大鼠30只(解放军总医院实验动物中心提供),以Haruo Nagasawa法建立脑缺血模型,分为盐酸法舒地尔组15只和生理盐水组15只.另选体质量250～300 g健康SD大鼠50只(解放军总医院实验动物中心提供),以Carys M Bannister转流法制作局灶缺血模型.转流法模型50只大鼠5只一组分为10组,各用于测定盐酸法舒地尔和生理盐水治疗动物缺血前,缺血60min,再灌注20,60,120min缺血区脑组织乳酸含量.干预用线栓法和转流法制作大鼠大脑中动脉区缺血再灌注模型,于缺血前30 min分别给予盐酸法舒地尔和生理盐水.主要观察指标缺血后5,60 min和再灌注30 min的局部脑血流量(rCBF);术后3,24,48 h神经功能;缺血60 min,再灌注20,60,120 min缺血脑组织乳酸含量.结果法舒地尔组缺血5,60 min,再灌注30 min局部脑血流(rCBF)为[(3.11±0.02),(3.60±0.02),(8.04±0.10)mL/(100 g·min)]明显高于对照组[(2.63±0.04),(3.17±1.29),(6.74±0.03)mL/(100 g·min)];法舒地尔组神经功能好于对照组;再灌注60,120min乳酸含量法舒地尔组[(7.2±0.3),(7.4±0.2)mmol/kg]少于对照组[(10.2±0.3),(10.0±0.3)mmol/kg].结论盐酸法舒地尔能改善动物模型缺血脑组织局部血流量,加速再灌注过程乳酸清除,具有脑保护作用.     

Comparative hemodynamic dose-response effects of five slow calcium channel-blocking agents in coronary artery disease

A prospective, randomized study compared the hemodynamic effects of equivalent doses of five slow calcium channel blockers (verapamil, diltiazem, nicardipine, nisoldipine, and amlodipine) in 50 patients with ischemia. After a stable control period, dose-response curves were constructed for each drug with hemodynamics measured 10 minutes after intravenous boluses. Each drug reduced mean systemic arterial pressure (P less than 0.01) and systemic vascular resistance index (P less than 0.01). The heart rate increased after nicardipine, nisoldipine, and amlodipine (P less than 0.01) but was unchanged after verapamil and reduced after diltiazem (P less than 0.01). The left ventricular filling pressure increased after amlodipine (P less than 0.05) and verapamil (P less than 0.01) but was unchanged with the other compounds. Cardiac index increased substantially after the dihydropyridines (P less than 0.01), with little change after verapamil or diltiazem. Cardiac double product fell only after verapamil and diltiazem. These studies provide quantitation of the comparative actions of acute intravenous calcium channel blockade in coronary disease.     

Calcium ions, drug action and the heart--with special reference to calcium antagonist drugs

Calcium antagonists, of which the best known are verapamil, nifedipine and diltiazem, are a powerful group of cardioactive agents with a clinical spectrum of indications rather similar to those of beta-adrenoceptor blockade, including angina of effort, angina at rest, hypertension and supraventricular tachycardias (nifedipine is ineffective for the latter). In angina caused by coronary spasm, calcium antagonists are preferred to beta-blockade. Calcium antagonists have a basically different mode of action from beta-adrenoceptor blockade, although both ultimately act on the free cytoplasmic calcium ion concentration. Critical differences between the calcium antagonists are dependent on the individual properties of the calcium antagonists concerned. Different binding sites on the sarcolemma have been identified for nifedipine-like agents and verapamil, but with a different interaction with the nifedipine site. None of these sites might be relevant to the binding of calcium antagonists to the tissue of their therapeutic site of action (arterial smooth muscle for all; atrioventricular node for verapamil and diltiazem). As a group, calcium antagonists cause vascular dilation and do not cause bronchial constriction, in contrast to the beta-adrenoceptor blocking agents. In many patients, these diverse properties allow safe combination of calcium antagonists and beta-adrenoceptor blockers if due care is observed, especially in the case of nifedipine. The clinical differences between the effects of various calcium antagonists reflect: (i) the greater vasodilator capacity of nifedipine, so that at a given concentration the afterload effect dominates over possible effects on the nodal or myocardial tissue; (ii) the greater inhibition of vagal tone by nifedipine than by verapamil or diltiazem; and (iii) the greater inhibition of the atrioventricular node by verapamil and diltiazem. In angina of effort, calcium antagonists are now becoming the agents of first choice in some centers. Experimental use of calcium antagonists include the possible prevention of ventricular fibrillation, the inhibition of ischemic injury, the prevention of catecholamine mediated injury to the myocardium and decreased arterial calcinosis.     

Effects of calcium entry blockers on coronary constriction and myocardial ischemia due to leukotriene D4

Recent studies show that leukotrienes (LTs) produce profound coronary artery constriction. Although calcium entry blockers are commonly used to remedy coronary vasospasm, their capacity to interfere with LT-mediated coronary constriction is unknown. Therefore, we compared effects of intracoronary LTD4 before and during treatment with calcium entry blockers in the in situ, blood-perfused hearts of domestic pigs. Intravenous administration of verapamil (0.1-1.6 mg/kg), nifedipine (10 or 100 micrograms/kg) or diltiazem (0.6-2.0 mg/kg) sufficient to increase base-line coronary blood flow (CBF) and decrease mean arterial pressure did not change decrement in CBF after LTD4. Infusion of verapamil (0.01-0.04 mg/min) into the left anterior descending coronary artery raised pre-LTD4 CBF almost 2-fold without alteration in mean arterial pressure, heart rate or left ventricular end-diastolic pressure. Intracoronary boluses of LTD4 (0.3, 1.0 and 3.0 micrograms) during verapamil infusion into the same vessel caused dose-dependent decreases in CBF identical to those observed when LTD4 was injected during control infusion. ECGs showed myocardial ischemia during severe flow reduction after high dose intracoronary LTD4 (3.0 or 10.0 micrograms). When the same LTD4 doses were injected during intracoronary verapamil, electrocardiographic changes did not occur despite similar decreases in CBF. The capacity of verapamil to prevent LTD4-induced ischemia may be caused by higher residual CBF after LTD4 even though the magnitude of LTD4-induced CBF decrement was unaltered. LTD4-induced coronary constriction seems to be mediated by a mechanism unrelated to calcium entry channels blocked by verapamil, nifedipine or diltiazem.     

The effect of intracoronary diltiazem on regional myocardial function and development of infarcts in porcine hearts

The effect of intracoronary (i.c.) pretreatment with diltiazem on regional myocardial function and the development of infarcts was investigated in regionally ischemic, reperfused porcine hearts. The left anterior descending coronary artery (LAD) was distally ligated in 16 pigs for 20-90 min followed by 24 h of reperfusion. Eight pigs were treated with increasing doses of i.c. diltiazem (0.375 mg/min, 0.75 mg/min, 1 mg/min) prior to ischemia. Eight pigs served as controls. Regional myocardial function was assessed by implanted ultrasonic crystals. Infarct size was determined as ratio of infarcted (tetrazolium stain) to ischemic myocardium (dye technique). I.c. diltiazem mainly depressed early systolic shortening (isovolumetric contraction) and lengthening during the first half of diastole. Pretreatment with this calcium antagonist significantly delayed the development of infarcts. In control experiments, a mean infarct size of 74% was found after 45-min ischemia. At that time no infarction was observed in the treated group, where infarcts started to evolve after 60-min ischemia. It is concluded that the favorable action of i.c. diltiazem can mainly be ascribed to a reduced myocardial oxygen consumption at the onset of ischemia.     

Comparison of Verapamil and Diltiazem in the Suppression of Idiopathic Ventricular Tachycardia

This study examines the efficacy of verapamil and diltiazem in the suppression of idio-pathic ventricular tachycardia (VT). Eight patients (mean age 29.8 ± 12.3 years, two males and six females) with VT, without any underlying cardiac abnormality on clinical examination and noninvasive investigation, were studied. The inducibility of the clinical VT was examined by treadmill exercise testing and programmed ventricular stimulation (PVS). In six patients, VT was inducible by exercise testing and in the remaining two by PVS. Following baseline testing, verapamil (120-mg thrice daily) and diltiazem (60-mg thrice daily) were administered in random order, allowing 5 half-lives for the drug to load before evaluation. Two patients had complete suppression of the VT and the remaining six patients demonstrated a partial response to both calcium antagonists. In the patients with a partial response, the duration of the longest run of VT was reduced (baseline 96.0, 34.2 SEM); verapamil 19.2 (7.5); diltiazem 45.3 (21.4 beats), whereas, there was no change in the rate of VT (baseline 199.7 (8.0); verapamil 184.5 (11.4); diltiazem 201.0 (9.5 beats/min). No proarrhythmic effect was observed with either of the drugs in these patients. We conclude that idiopathic VT can be suppressed in some patients by calcium antagonists. In patients with a partial response, the length of run of the VT can be reduced, but the rate is unaffected. Verapamil and diltiazem do not differ in their ability to suppress VT in individual patients.     

Effect of calcium channel antagonists on susceptibility to sudden cardiac death: protection from ventricular fibrillation

The effects of calcium channel antagonists and an agonist on susceptibility to ventricular fibrillation were investigated using chronically instrumented dogs with a healed anterior wall myocardial infarction. Three to 4 weeks after the infarction, a 2-min coronary occlusion was initiated during the last minute of exercise and continued for 1 min after cessation of exercise. Twenty-two dogs developed ventricular fibrillation (susceptible) whereas the remaining 14 animals did not (resistant) during this exercise plus ischemia test. The exercise plus ischemia test was repeated in the susceptible dogs after the following treatments: verapamil (n = 17, 250 micrograms/kg), nifedipine (n = 9, 10 and 100 micrograms/kg) and magnesium sulfate (n = 9, 100 mg/kg). Verapamil prevented ventricular fibrillation in all dogs whereas the high dose of nifedipine protected eight of nine animals; the low dose of nifedipine protected one of nine animals and magnesium sulfate protected seven of nine dogs. Finally, the calcium channel agonist Bay K8644 (n = 9, 30 micrograms/kg) was given to resistant animals. All resistant dogs developed ventricular fibrillation when the exercise plus ischemia test was repeated after Bay K8644. These data suggest that calcium entry may play a critical role in the development of arrhythmias during ischemia, with increased calcium entry provoking arrhythmias and calcium entry blockade preventing the lethal events.     

Calcitonin gene-related peptide receptor antagonism does not affect the severity of myocardial ischemia during atrial pacing in dogs with coronary artery stenosis

Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide that also has potent vasodilator activity. There are conflicting preclinical reports regarding the effect of CGRP receptor antagonism in the setting of myocardial ischemia. The present study was conducted in a canine model in which regional myocardial ischemia was reproducibly evoked by serial periods of atrial pacing (80 beats per min above baseline rate) in the presence of a 40% stenosis of the left anterior descending (LAD) coronary artery. Ischemia severity was quantitated by changes in unipolar epicardial electrograms (EG) recorded in the area of ischemia. In validation studies, the calcium entry blocker diltiazem reduced ischemia severity (before versus after treatment: DeltaEG, 1.92 +/- 0.23 versus 0.54 +/- 0.24 mV; p < 0.05) and tended to increase LAD flow (7.7 +/- 0.7 versus 9.4 +/- 1.4 ml/min; p = 0.10), whereas the coronary constrictor serotonin increased ischemia severity (before versus after treatment: DeltaEG, 2.11 +/- 0.44 versus 4.90 +/- 1.46 mV; p < 0.05) concomitant with a reduction in LAD flow (9.1 +/- 1.1 versus 5.4 +/- 1.5 ml/min; p < 0.05). A 30 microg/kg/min i.v. infusion test dose of the CGRP receptor antagonist CGRP((8-37)) was validated by demonstrating complete block of the depressor effects of exogenous i.v. 0.03 to 0.3 microg/kg CGRP. This dose of CGRP((8-37)), administered either intravenously or intra-atrially, had no effect on ischemia severity or paced LAD flow, indicating no intrinsic effect of CGRP receptor antagonism on the severity of acute myocardial ischemia. Likewise, the administration of a hemodynamically active dosing regimen of CGRP (0.03 microg/kg/min i.v.) had no effect on paced coronary flow or ischemia severity, suggesting no major role of CGRP in regulating ischemic blood flow.     

Acute regional myocardial ischemia identified by 2-dimensional multiregion tissue Doppler imaging technique.

BACKGROUND AND OBJECTIVE: Tissue Doppler echocardiography (TDE) is a promising method for the assessment of regional myocardial function, but pulsed TDE does not provide quantitative data from multiple regions simultaneously. This feature is important for the objective assessment of regional differences in myocardial function. In the present study, we investigated a new off-line TDE method that provides quantitative pulsed velocity data from an unlimited number of regions selected within a 2-dimensional (2D) image. The goal of the study was to determine the ability of this new approach to quantify regional myocardial function during acute myocardial ischemia induced by balloon angioplasty. METHODS: Twenty-two patients undergoing angioplasty of the left anterior descending coronary artery (LAD) were studied. Left ventricular longitudinal wall motion was assessed by 2D TDE from the apical 4-chamber view before, during, and after angioplasty. Images were sampled at a rate of 69 +/- 15 frames/s, and the off-line analysis allowed simultaneous measurement of velocities in multiple myocardial segments. RESULTS: There were 3 major alterations in the systolic velocity pattern during LAD occlusion. Peak early systolic velocities along the apical septum were significantly reduced during LAD occlusion (2.8 +/- 1.2 cm/s to 0.6 +/- 1.7 cm/s, P <.001). Myocardial velocities in mid systole suggested paradoxical wall motion (1.0 +/- 1.2 cm/s to -0.8 +/- 0.9 cm/s, P <.001). When comparing the ischemic regions of the left ventricle with the nonischemic regions, each patient demonstrated lower myocardial systolic velocities in the ischemic region. Furthermore, during early diastole, the wall motion of the ischemic segments showed a postsystolic contraction pattern with velocities changing from -0.9 +/- 1.0 cm/s to 1.9 +/- 1.3 cm/s (P <.001). CONCLUSION: This new 2D TDE approach is able to quantify detailed myocardial velocity profiles from multiple regions simultaneously. Single-beat comparisons of ischemic and nonischemic regions might enhance the sensitivity for diagnosing ischemic heart disease. Reversed systolic wall motion during midsystole and marked positive velocity during early diastole might be new and important markers of myocardial wall ischemia.     

Role of sympathetic nervous system in ischemia-induced reduction of digoxin tolerance in anesthetized cats

Acute myocardial ischemia reduces tolerance of the heart to arrhythmogenic actions of digitalis glycosides. Because both ischemia and the glycoside produce profound changes in activity of the autonomic nervous system and because sympathetic discharge or catecholamines enhance toxic actions of the cardiac glycosides, the possibility that alterations in digitalis sensitivity of ischemic heart involve changes in sympathetic nerve activity was examined using alpha-chloralose-anesthetized cats. Left anterior descending coronary artery (LAD) was completely occluded by ligation and, 40 min later, a slow i.v. infusion of digoxin was started at a rate of 1 microgram/kg/min. LAD ligation alone did not produce arrhythmias in that condition, but shortened the time to onset of digoxin-induced arrhythmias and thereby reduced the amount of digoxin required to produce the toxic manifestation. Concomitantly, digoxin concentration in plasma and nonischemic areas of the heart were lower in LAD-ligated cats at the onset of arrhythmias than those in sham-operated cats. Myocardial digoxin content in the ischemic area of the LAD-occluded heart was lower than that in nonischemic areas of the same heart. At the onset of digoxin-induced arrhythmias, Na,K-adenosine triphosphatase activity of ischemic myocardium was significantly higher than that in the nonischemic area, reflecting a lower digoxin occupancy of the glycoside binding sites on the sodium pump. Spinal cord (C1) transection or propranolol treatment prolonged the time to arrhythmias in both control and LAD-ligated cats, but failed to abolish the effect of LAD ligation to augment digoxin toxicity. Bilateral vagotomy also did not alter the enhancement of digoxin toxicity caused by ligation of LAD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of calcium channel blockers on theophylline disposition

Twelve healthy subjects received a single oral dose of theophylline, 5 mg/kg alone, and after 7 days of oral verapamil, 120 mg every 8 hours, diltiazem, 90 mg every 8 hours, and nifedipine, 20 mg every 8 hours, in randomized crossover fashion. Mean theophylline oral clearance decreased 18% and 12% after verapamil and diltiazem, respectively (p less than 0.05). No significant change in theophylline oral clearance was observed after nifedipine. Increases in mean theophylline half-life were observed after verapamil (10.8 +/- 3.2 hours) and diltiazem (9.9 +/- 2.4 hours) (p less than 0.05) but not after nifedipine (8.6 +/- 2.4 hours) when compared with control (8.6 +/- 1.9 hours). Apparent volume of distribution was unchanged. Urinary excretion data showed that the relative formation rate constants of 3-methylxanthine and 1,3-dimethyluric acid were decreased during verapamil and diltiazem (p less than 0.05) but not during nifedipine. No change in 1-methyluric acid excretion was observed. Increases in urinary elimination of unchanged theophylline were observed after verapamil, diltiazem, and nifedipine. The modest reduction in theophylline clearance observed after verapamil and diltiazem is not likely to produce clinically significant increases in theophylline concentrations in most patients.     

Antagonistic effects of epinephrine, glucagon and methylatropine but not calcium chloride against atrio-ventricular conduction disturbances produced by high doses of diltiazem, in conscious dogs

Conscious dogs (n = 6) with chronically implanted electrocardiogram electrodes and arterial and venous catheters were infused with a large dose of diltiazem (1 mg/dog per min i.v. over 60 min) to evoke hypotension and atrioventricular disturbances (AVII and AVIII blocks) which lasted for several hours. These effects are also observed in humans after accidentally or intentionally taking overdoses of diltiazem and particularly verapamil. In the intoxicated dog, administration of methylatropine (50 micrograms/kg per min i.v. over 10 min), epinephrine (0.2 and 0.4 microgram/kg per min i.v. over 60 min) and glucagon (2 micrograms/kg/min i.v. over 15 min) but not CaCl2 (3 mg/kg/min i.v. over 15 min) abolished almost entirely the AVII and AVIII blocks produced by diltiazem and re-established a normal sinus rhythm. However, these treatments failed to normalize AV conduction, and did not modify the moderate hypotensive effects of diltiazem. These findings support available clinical observations that beta-adrenoceptors agonists, glucagon and atropine rather than calcium salts are beneficial for the successful treatment of cardiovascular toxicity associated with the intake of supratherapeutic doses of diltiazem or verapamil.     

Changes in antipyrine and indocyanine green kinetics during nifedipine, verapamil, and diltiazem therapy

Ten healthy subjects received oral antipyrine and intravenous indocyanine green (ICG) alone and after 5 days of oral nifedipine, diltiazem, and verapamil. Antipyrine clearance decreased during verapamil (range 4% to 26%) and diltiazem (6% to 24%) therapy (P less than 0.001) but did not change during nifedipine treatment. Antipyrine t1/2 also increased during verapamil and diltiazem treatment (P less than 0.001). ICG clearance did not change during diltiazem therapy but increased during dosing with nifedipine and verapamil (P less than 0.05). Estimated liver blood flow (derived from ICG clearance and hematocrit) also increased during verapamil (mean 33%) and nifedipine (mean 27%) treatment (P less than 0.05). Drug interactions with other liver-metabolized drugs may occur during therapy with these calcium antagonists. Nifedipine appears to increase liver blood flow whereas diltiazem inhibits oxidative drug metabolism. Drug interactions with verapamil could involve both mechanisms.     

Potentiation of cocaine toxicity with calcium channel blockers

Three calcium channel blockers were studied for efficacy in preventing seizures and death from cocaine intoxication. Rats were first pretreated with a test drug then subjected to high dose intraperitoneal cocaine. In this model, control animals developed seizures within six minutes, followed by death within ten minutes. Animals that were pretreated with diltiazem, nifedipine, or verapamil developed seizures significantly faster than controls, and at specific doses the death rate was higher than in controls for all three drugs. The potentiation of seizures and death by 2 mg/kg nifedipine pretreatment was further shown by challenge with three different doses of cocaine. This study fails to demonstrate a protective effect and suggests augmentation of cocaine toxicity by pretreatment with the three currently available calcium channel blockers. Several mechanisms by which calcium channel blockers may augment cocaine-induced toxicity are discussed.