Acute Administration Of Verapamil Research Articles

Comparative effects of calcium and potassium channel modulators on ischemia/reperfusion injury in the isolated rat heart.

The aim of this study was to examine and compare the effects of the acute administration of verapamil or amlodipine as representatives of the calcium channel blockers or nicorandil as a representative of the mitochondrial ATP-dependent potassium (KATP) channel opener to cardiac contractility, coronary flow, and oxidative stress markers on ischemia/reperfusion injury in the isolated rat heart. The hearts of adult male Wistar albino rats (n = 60 total, 12 per group) were divided into five groups, two controls (preconditioning with Krebs-Henseleit solution) and three experimental depending on acute administrated pharmacological agents (0,63µmol/L of verapamil, 0,1µmol/L of amlodipine, and 200µmol/L of nicorandil). After stabilization and 5min of preconditioning in experimental groups, hearts from I/R control and all experimental groups underwent global ischemia (20min) and reperfusion (30min). Hearts from sham group were continuously followed for 50min, after stabilization period. Cardiodynamic parameters and coronary flow were recorded at the end of stabilization (S), at the last minute of pharmacological preconditioning (P) and at intervals of 5min after global ischemia, during reperfusion, or in case of sham group during 20-50min after stabilization. At the same intervals, we collected coronary venous effluent from which we spectrophotometrically measured the parameters of oxidative stress: the index of lipid peroxidation, superoxide anion radical, hydrogen peroxide, and nitrite. In summary, our findings clearly indicate that the blocking of the calcium channel or the activation of KATP may mediate the protective effect of myocardial preconditioning. The ex vivo results showed that all examined drugs after ischemia and reperfusion have beneficial cardioprotective properties associated with lower values of major pro-oxidative molecules. Obtained effects seem to be the most convincible in case of nicorandil.

Effects of acute and chronic sunitinib treatment on cardiac function and calcium/calmodulin-dependent protein kinase II.

Calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is an important regulator of cardiac contractile function and dysfunction and may be an unwanted secondary target for anti-cancer drugs such as sunitinib and imatinib that have been reported to alter cardiac performance. This study aimed to determine whether anti-cancer kinase inhibitors may affect CaMKII activity and expression when administered in vivo. Cardiovascular haemodynamics in response to acute and chronic sunitinib treatment, and chronic imatinib treatment, were assessed in guinea pigs and the effects compared with those of the known positive and negative inotropes, isoprenaline and verapamil. Parallel studies from the same animals assessed CaMKIIδ expression and CaMKII activity following drug treatments. Acute administration of sunitinib decreased left ventricular (LV) dP/dtmax. Acute administration of isoprenaline increased LVdP/dtmax dose-dependently, while LVdP/dtmax was decreased by verapamil. CaMKII activity was decreased by acute administration of sunitinib and was increased by acute administration of isoprenaline, and decreased by acute administration of verapamil. CaMKIIδ expression following all acute treatments remained unchanged. Chronic imatinib and sunitinib treatments did not alter fractional shortening; however, both CaMKIIδ expression and CaMKII activity were significantly increased. Chronic administration of isoprenaline and verapamil decreased LV fractional shortening with parallel increases in CaMKIIδ expression and CaMKII activity. Chronic sunitinib and imatinib treatment increased CaMKIIδ expression and CaMKII activity. As these compounds are associated with cardiac dysfunction, increased CaMKII expression could be an early indication of cellular cardiotoxicity marking potential progression of cardiac contractile dysfunction.

ChemInform Abstract: Synthesis and Pharmacological Evaluation of 2,3-Dihydro-3-oxo-4H-thieno[3,4-e][1,2,4]thiadiazine 1,1-Dioxides as Voltage-Dependent Calcium Channel Blockers.

Abstract The synthesis of a novel series of 2,3-dihydro-3-oxo-4 H -thieno[3,4- e ][1,2,4]thiadiazine 1,1-dioxides and their pharmacological evaluation as drugs with effects on the rat cardiovascular system are described. The compounds under study were synthesized via Curtius rearrangement of appropriate sulfamoylacylazides which, in turn, were prepared from known starting materials. In isolated rat portal vein, these thienothiadiazines, like verapamil and diazoxide, inhibited the spontaneous motility produced by KCl (20 mM). In addition, the new compounds, like verapamil and unlike diazoxide, also exhibited inhibitory effects in the same preparation when the cell membrane was depolarized by an increased extracellular KCl concentration (80 mM) and, consequently, the membrane potential approached a level close to the K + equilibrium potential. Further characterization of this inhibitory activity led to the identification of a selective inhibitory effect of the new compounds on KCl (80 mM)-induced 45 Ca 2+ uptake in the same vascular tissue. When tested in vivo (anaesthetized normotensive rats), acute administration of verapamil, diazoxide and some of the most in vitro potent compounds in 45 Ca 2+ uptake experiments produced a gradual, dose-dependent and sustained decrease in diastolic arterial blood pressure, devoid of cardiac effects. These results suggest that, like verapamil, the cardiovascular effects produced by the new thienothiadiazines seem to be due, at least in part, to a blockade of transmembrane voltage-dependent calcium channels present in vascular smooth muscle cells and not to an activation of ATP-sensitive K + channels. Compounds 5b , 5e and 5i have been selected for further studies as antihypertensive agents.

Adrenalectomy potentiates the antinociceptive effects of calcium channel blockers

Calcium channel blockers can modulate the nociceptive threshold. However, the underlying mechanism(s), especially the role of hypothalamic–pituitary–adrenal (HPA) axis, on this effect has not yet been clarified. In the present study we investigated the analgesic effect of verapamil, diltiazem and nimodipine in intact and adrenalectomized (ADX) male rats and also measured the effect of these drugs on HPA function. The tail-flick and hot-plate tests were used to assess the nociceptive threshold before and 15, 30, 60 and 120 min after drug administration. Corticosterone level was measured by radioimmunoassay as a marker of HPA function. Our results showed that these drugs could elicit antinociceptive effects which were more prominent in the hot-plate than in the tail-flick tests. Following the exclusion of adrenal glands these drugs showed stronger analgesic effects. Acute administration of verapamil, diltiazem and nimodipine produced significant decrease in plasma corticosterone level that was more prominent by nimodipine. In conclusion, the results of our study show that the HPA function has an important role in the antinociceptive effect of calcium channel blockers.

Mechanical dyssynchrony: another mechanism of left ventricular dysfunction in hypertension?

Mechanical dyssynchrony: another mechanism of left ventricular dysfunction in hypertension?

Effect of verapamil on nitric oxide synthase in a portal vein-ligated rat model: Role of prostaglandin

To investigate the effects of verapamil on nitric oxide (NO) synthesis in a portal vein-ligated rat model. Systemic and splanchnic hemodynamics were measured by radiolabeled microspheres in portal hypertensive rats after acute administration of verapamil (2 mg/kg) on chronic treatment with N(w)-nitro-L-arginine (NNA)(80 mg/kg) and/or indomethacin (2 mg/kg). Verapamil (2 mg/kg) caused a marked fall in both arterial pressure and cardiac output accompanied by an insignificant change in the portal pressure and no change in portal venous inflow. This result suggested that verapamil did not cause a reduction in portal vascular resistance of portal hypertensive rats, which was similar between N(w)- nitro-L-arginine-treated and indomethacin-treated groups. In portal hypertensive rats pretreated with NNA and/or indomethacin, acute verapamil administration can not reduce the portal pressure, suggesting that NO and prostaglandin play an important role in the pathogenesis of splanchnic arterial vasodilation in portal hypertension.

Synthesis and pharmacological evaluationof 2,3-dihydro-3-oxo-4 H-thieno[3,4- e][1,2,4]thiadiazine 1,1-dioxidesas voltage-dependent calcium channel blockers

The synthesis of a novel series of 2,3-dihydro-3-oxo-4 H-thieno[3,4- e][1,2,4]thiadiazine 1,1-dioxides and their pharmacological evaluation as drugs with effects on the rat cardiovascular system are described. The compounds under study were synthesized via Curtius rearrangement of appropriate sulfamoylacylazides which, in turn, were prepared from known starting materials. In isolated rat portal vein, these thienothiadiazines, like verapamil and diazoxide, inhibited the spontaneous motility produced by KCl (20 mM). In addition, the new compounds, like verapamil and unlike diazoxide, also exhibited inhibitory effects in the same preparation when the cell membrane was depolarized by an increased extracellular KCl concentration (80 mM) and, consequently, the membrane potential approached a level close to the K + equilibrium potential. Further characterization of this inhibitory activity led to the identification of a selective inhibitory effect of the new compounds on KCl (80 mM)-induced 45Ca 2+ uptake in the same vascular tissue. When tested in vivo (anaesthetized normotensive rats), acute administration of verapamil, diazoxide and some of the most in vitro potent compounds in 45Ca 2+ uptake experiments produced a gradual, dose-dependent and sustained decrease in diastolic arterial blood pressure, devoid of cardiac effects. These results suggest that, like verapamil, the cardiovascular effects produced by the new thienothiadiazines seem to be due, at least in part, to a blockade of transmembrane voltage-dependent calcium channels present in vascular smooth muscle cells and not to an activation of ATP-sensitive K + channels. Compounds 5b, 5e and 5i have been selected for further studies as antihypertensive agents.

Effect of verapamil on renal haemodynamics in a portal hypertensive rat model

In order to investigate the effects of verapamil on renal haemodynamics in rats with portal hypertension, verapamil was given at either a low (0.2 mg/kg) or high (2 mg/kg) dose to rats after portal vein ligation. An approximate 12% decrease in mean arterial pressure followed administration of low dose verapamil, with a significant decrease in cardiac output and renal blood flow, as well as reduced portal pressure, observed; these signs were all indicative of a rise in renal vascular resistance. In contrast, the marked fall in both mean arterial pressure and cardiac output with high dose verapamil, accompanied by a significant decrease in portal pressure and no change in renal blood flow, suggests a reduction in renal vascular resistance. This study shows that the acute effects of verapamil on renal haemodynamics may vary with the dose used. Also, acute verapamil administration tends to decrease renal blood flow to alter the autoregulation of the kidney; thus, caution should be taken in the clinical use of verapamil in the treatment of cirrhosis with portal hypertension.

Effect of verapamil on portal blood flow in patients with liver cirrhosis.

The effect of acute (80 mg orally) and prolonged (240 mg orally daily for 2 weeks) verapamil administration on portal blood flow was studied in 12 patients with histologically proved alcoholic liver cirrhosis. Portal hemodynamics were examined by the ultrasonic duplex Doppler system. Thirty minutes after acute verapamil administration, the following parameters remained unchanged: (1) cross-sectional area of the portal vein, from 1.52 +/- 0.41 to 1.51 +/- 0.43 cm2; (2) portal blood velocity, from 13.2 +/- 1.6 to 13.4 +/- 1.6 cm/s; (3) estimated volume of portal blood flow, from 931 +/- 96 to 954 +/- 103 mL/min; and (4) congestion index of the portal vein, from 15.1 +/- 8.3 to 15.6 +/- 8.8 cm, respectively (P = > 0.05). In addition, no significant changes in portal blood hemodynamics were noted after prolonged verapamil administration (P > 0.05). These results demonstrated that verapamil did not alter portal blood flow in patients with alcoholic liver cirrhosis.

Cardiac function and metabolism after chronic alcohol consumption: Adaptation, reversibility, and effects of verapamil

Hamsters were fed 50% alcohol instead of drinking water for up to 42 weeks (average serum alcohol levels were 0.12 ± 0.06 gm/dl during the 42 weeks). One group of hamsters (28 weeks) was given verapamil 3 days before they were killed. Two groups were withdrawn from alcohol acutely (3 days before they were killed) at 14 and 28 weeks. High-energy phosphate compounds were studied in isolated hearts with 31P-MRS standardized by freeze clamping the tissue. Hemodynamics of the heart were monitored throughout the study. After 7 and 14 weeks of alcohol ingestion, developed pressure and the phosphorylation potential were depressed in the hearts of chronically treated hamsters. At 28 and 42 weeks developed pressure increased but was significantly below baseline values; however, the phosphorylation potential and [pH] i returned to baseline values at 28 and 42 weeks. Throughout the 7 to 42 weeks of alcohol ingestion the alcohol-treated hamsters had a significantly higher end-diastolic pressure as compared with control animals. Withdrawal of alcohol (3 days before the hamsters were killed) reversed the depression of developed pressure and the phosphorylation potential. Acute administration of verapamil (therapeutic dose 3 days before they were killed) to hamsters given alcohol for 28 weeks reversed the depressed hemodynamic values. Overall the data suggest an adaptation of the heart to continuing alcohol consumption, which was related to normalization of the phosphorylation potential and [pH] i and partial alleviation of functional depression.

Cardiac Structure and Function before and after Acute and Chronic Verapamil Administration in Hypertensive Patients

The aim of this study has been to analyze the acute and chronic effects of oral verapamil on diastolic function indices, derived from Doppler echocardiography, and left-ventricular (LV) dimensions and mass, assessed by M-mode echocardiography, in hypertensive patients without LV hypertrophy. 12 patients with essential hypertension were studied in basal conditions and (1) after a single oral administration of verapamil 160 mg and placebo in a double-blind protocol and (2) over chronic treatment (12 months) with verapamil 240 mg/day. At baseline, the ratio between early and atrial-induced transmitral velocities (E/A ratio) was lower in patients than in 12 age-matched normal subjects (1.08 +/- 0.2 vs. 1.51 +/- 0.3, p less than 0.01). Acute verapamil administration significantly decreased arterial blood pressure (162 +/- 26/101 +/- 8 to 142 +/- 12/88 +/- 7 mm Hg, p less than 0.01 after 2 h) and increased the E/A ratio to 1.26 +/- 0.3 (p less than 0.05) after 3 h. No change in ventricular dimensions and heart rate was observed. After chronic therapy, we found a further increase in the E/A ratio in 10 responder patients (1.49 +/- 0.3, p less than 0.01). The LV mass index, that was higher than in normal subjects before the treatment (118 +/- 16 vs. 91 +/- 11 g/m2, p less than 0.01), was significantly reduced (100 +/- 17 g/m2, p less than 0.05 vs. basal, nonsignificant vs. normal subjects). Our results demonstrate that acute administration of verapamil only partially improves the abnormal indices of diastolic function in hypertensive patients, whereas chronic treatment, by reducing LV mass indices and blood pressure to normal values, can completely normalize the indices of LV diastolic filling.

Potentiation of Neuromuscular Blocking Agents by Calcium Channel Blockers in Rats

The effect of calcium channel blockers (Ca-antagonists) on the potency and reversibility of muscle relaxants (MR) was investigated in the in vitro phrenic nerve-hemidiaphragm and in vivo sciatic nerve-tibialis anterior preparation of rats. To increase the relevance of the experimental findings to the clinical situation, the [Ca++] and [Mg++] in vitro were the same as in the plasma of rats and humans and the stimulation parameters used in vitro and in vivo were similar to those that elicit voluntary movements of the muscles used. Both verapamil and nifedipine significantly decreased the I50 and I90 of d-tubocurarine (d-Tc), pancuronium, vecuronium, and atracurium in vitro and those of the first three MR in vivo (P less than 0.001). In vitro, the depression of the force of contraction of the diaphragm (P) caused by all the Ca-antagonist-MR combinations could be reversed only partially by washout, neostigmine, or 4-aminopyridine. In vivo, because of limitations imposed by their cardiovascular depressant effect, the muscles were exposed to lower concentrations of Ca-antagonists for shorter periods. Under these circumstances the decrease of P caused by all Ca-antagonist-MR combinations recovered spontaneously close to control levels. This study indicates that acute administration of verapamil during anesthesia may increase MR potency, but it is unlikely that spontaneous recovery or reversibility of the residual neuromuscular (NM) block at the end of anesthesia will be significantly affected. However, long-term administration of Ca-antagonists may make difficult the reversal of the residual NM block.

Interaction of calcium antagonists with beta-adrenoceptor blocking agents.

Responsiveness to verapamil, the best studied calcium antagonist, was examined in cardiac preparations of rabbits pretreated with beta-adrenoceptor blockers (propranolol 2 mg/kg or oxprenolol 4 mg/kg s.c.) twice daily for either one or six weeks. Using this dose-regimen, the degree of cardiac beta-adrenoceptor blockade in conscious rabbits was substantial and similar for propranolol and oxprenolol. When administered for one week, neither propranolol nor oxprenolol affected to any marked extent the electrical and mechanical response to verapamil, diltiazem or fendiline in tissues isolated from various parts of the heart. In contrast, pretreatment with propranolol for six weeks resulted in a significant aggravation of the negative inotropic effect of verapamil in both atrial and ventricular muscle, and the verapamil-induced delay in atrio-ventricular and intra-ventricular conduction also became more pronounced. The same long-term administration of oxprenolol, one of the beta-blockers with "intrinsic" sympathomimetic activity, did not alter the atrial or ventricular contractile response to verapamil and did not significantly increase the lengthening of atrio-ventricular conduction time occurring in the presence of verapamil. It is concluded that from the point of view of adverse direct cardiac interactions with verapamil prolonged administration of oxprenolol appears to be less dangerous than chronic treatment with propranolol. It is also assumed that in those cases in which acute administration of verapamil may be necessary, concomitant chronic blockade of cardiac beta-adrenoceptors is less dangerous if drugs known to possess not only beta-adrenoceptor blocking properties, but also some "intrinsic" sympathomimetic activity are applied.

Verapamil pharmacokinetics and apparent hepatic and renal blood flow.

The effect of acute and continued administration of verapamil on pharmacokinetics and regional blood flow has been studied in eight normotensive subjects. Continued administration resulted in a significant decrease in verapamil clearance, compared to that following acute dosing, as assessed by increases in both terminal elimination half-life (from a mean +/- s.d. of 5.2 +/- 2.3 h to 6.7 +/- 2.0 h) and AUC (from a mean +/- s.d. of 800 +/- 353 ng ml-1 h to 1455 +/- 244 ng ml-1 h). The relative clearance of norverapamil was not changed. Acute administration of verapamil resulted in a significant increase (P less than 0.005) in apparent liver blood flow which with continued administration fell significantly (P less than 0.01) towards placebo values. Effective renal plasma flow similarly increased with acute verapamil administration (P less than 0.05) and with chronic administration reduced again to be not significantly different from placebo. Acute and chronic verapamil administration did not significantly alter glomerular filtration rates. These results suggest that there may be a relationship between the acute increase in liver blood flow and the relatively increased clearance of verapamil following acute dosing.

Calcium influx blockers in the treatment of essential hypertension.

Elevated vascular resistance is the key factor in most cases of essential hypertension. Vascular resistance is determined by the sarcoplasmatic concentration of free Ca2+. Experimental studies have shown an increased dependence for the noradrenaline-induced contraction on extracellular Ca2+ from the aorta to the small resistance vessels. This is in accordance with the potent vasodilating effect found with Ca2+-influx inhibitors in man. Furthermore, a selective enhancement of the vasodilating response to verapamil has been found in patients with essential hypertension as compared to normotensive subjects. The verapamil-induced vasodilation in the hypertensive patients was positively correlated to plasma adrenaline concentration. These findings suggest accentuated Ca2+-influx dependent vasoconstriction in essential hypertension, which is related to the activity of the sympathetic nervous system. Acute administration of verapamil and nifedipine results in a distinct fall in blood pressure in patients with essential hypertension but not in normotensive subjects. Generally, the percentage fall in blood pressure with Ca2+-channel blockers has been closely positively correlated to the initial blood pressure level and in an open study with 43 patients with essential hypertension the decrease in blood pressure to verapamil was also positively correlated to the age of patients. These data may provide the basis for a new treatment concept for essential hypertension proposing a Ca2+-channel blocker as the first choice for the older patients and a beta-adrenoceptor blocking agent as the first line drug for the younger patients. Combined treatment with a beta-adrenoceptor blocking agent and a Ca2+-channel blocker seems most efficient in normalizing blood pressure in many therapy-resistant hypertensive patients.

Acute and chronic pharmacodynamic interaction of verapamil and digoxin in atrial fibrillation.

SUMMARY The safety, efficacy, and pharmacologic effect of combined verapamil and digoxin were studied in 10 patients with chronic atrial fibrillation. Heart rate recordings, treadmill exercise tests, physical examinations and serum digoxin concentrations during chronic digoxin therapy were compared with those after the acute administration of verapamil and 1, 2, 4, 6 and 10 weeks after the addition of oral verapamil to digoxin therapy. After both i.v. and chronic oral verapamil administration, resting and exercise heart rates were significantly lower. Increasing serum concentrations of verapamil correlated with increasing suppression of heart rate at rest and during exercise. The mean resting heart rate by 24-hour ambulatory ECG decreased from 87 ± 9 beats/min to 72 6 beats/min. The mean treadmill exercise heart rate decreased more markedly, from a mean of 151 26 beats/min to 106 ± 22 beats/min (both p < 0.001). During chronic therapy, heart rate reductions were seen 1 week after the addition of verapamil and were maintained without change for the duration of the trial. Blood pressures at rest and during exercise were unchanged. Cardiomegaly was present on the entry chest x-ray in six patients; after verapamil, heart size decreased in three and was unchanged in one; two patients had transient congestive heart failure that responded to diuretics. Serum digoxin levels increased from a mean of 1.6 ± 0.4 ng/ml to 2.7 + 0.9 ng/ml (p < 0.001) during verapamil. The increase was observed in hine of 10 patients but was not related to clinical signs of digitalis excess and no episodes of asystole were seen on the serial 24-hour ECGs. Chronic oral administration of verapamil, 320 mg/ day, resulted ih mean verapamil concentrations of 130–280 ng/ml (mean interdose concentration 140 ± 41 ng/ml) with great intersubject and intrasubject variability. We conclude that verapamil is effective in further suppressing the ventricular response rate in atrial fibrillation when given in combination with digitalis and can serve as an adjunct to digitalis therapy in the chronic management of patients with atrial fibrillation.

Electrophysiological effects of verapamil.

Previous studies have demonstrated that verapamil possess potent anti-arrhythmic effects. The present study has been designed to define the cardiovascular effects of this drug. Isolated tissue studies performed in rabbit right atrium demonstrated that prompt and prominent slowing of the sinus rate even at a dose of 1 X 10(-7) mol . litre-1. This dose produced significant decrease in action potential amplitude and phase 4 slope, shifted the 'threshold potential' to a less negative value, prolonged action potential duration but did not change maximum diastolic potential. At this dose of verapamil, sinoatrial conduction time prolonged significantly (control: 40.0 +/- 4.8 ms; 1 X 10(-7) mol . litre-1 verapamil: 50.0 +/- 6.4 ms). Purkinje fibre studies demonstrated decreases in dV/dt, resting potential, total amplitude, action potential duration at 75, 95% of recovery and effective refractory period only after exposure to greater than or equal to 1 X 10(-5) mol . litre-1 verapamil. Electrophysiological studies in conscious dogs demonstrated, after bolus administration of verapamil, progressive increases in the A-H interval and heart rate, but no changes in H-V and QRS intervals. Anaesthetised dog studies showed the lack of significant effect on A-H and H-V intervals or QRS duration regardless of the bolus dose of verapamil. However, verapamil produced statistically significant increases in heart rate after 0.025 mg . kg-1. Verapamil administration did not produce a statistically significant change in escape pacemaker rate in vagal stimulation experiments or with spontaneously beating isolated Purkinje fibres. Finally, the effect of increasing intravenous bolus does of verapamil on ischaemic arrhythmias was studied in five conscious dogs 24 h following LAD ligation. Only one dog with ventricular tachycardia and another dog with junctional escape rhythm were converted to sinus rhythm after the 0.05 mg . kg-1 and 0.2 mg . kg-1 doses, respectively. In conclusion, these studies demonstrated that administration of verapamil specifically depresses tissue with electrophysiological dependence on slow channel current. Therefore, sinus and A-V nodal events would be suppressed and slow-channel mediated events in ischaemic ventricle also would be inhibited. Clinically, acute administration of verapamil would lead to depression of sinus and A-V nodal function as well as potentially eliminate slow current mechanisms in ischaemic arrhythmias.