Chronic Verapamil Administration Research Articles

Increased Ca2+ influx through CaV1.2 drives aortic valve calcification

Calcific aortic valve disease (CAVD) is heritable, as revealed by recent GWAS. While polymorphisms linked to increased expression of CACNA1C — encoding the CaV1.2 L-type voltage-gated Ca2+ channel — and increased Ca2+ signaling are associated with CAVD, whether increased Ca2+ influx through the druggable CaV1.2 causes CAVD is unknown. We confirmed the association between increased CaV1.2 expression and CAVD in surgically removed aortic valves from patients. We extended our studies with a transgenic mouse model that mimics increased CaV1.2 expression within aortic valve interstitial cells (VICs). In young mice maintained on normal chow, we observed dystrophic valve lesions that mimic changes found in presymptomatic CAVD and showed activation of chondrogenic and osteogenic transcriptional regulators within these valve lesions. Chronic administration of verapamil, a CaV1.2 antagonist used clinically, slowed the progression of lesion development in vivo. Exploiting VIC cultures, we demonstrated that increased Ca2+ influx through CaV1.2 drives signaling programs that lead to myofibroblast activation of VICs and upregulation of genes associated with aortic valve calcification. Our data support a causal role for Ca2+ influx through CaV1.2 in CAVD and suggest that early treatment with Ca2+ channel blockers is an effective therapeutic strategy.

Electrophysiological study of the interactive role of the cannabinoid breakdown inhibitors and L-type calcium channels on granular neurons in the hippocampal dentate gyrus in rats

ABSTRACT The interaction between L-type voltage-dependent Ca2+ channels and the endocannabinoid system (eCs) in synaptic plasticity is controversial. In the present research, the impact of acute administration of URB597, as an endocannabinoid breakdown inhibitor, was evaluated after chronic injection of verapamil, as a Ca2+ channels blocker, on inducing long-term potentiation (LTP) in the rat’s hippocampal dentate gyrus (DG). Treatment of male Wistar rats was done using intraperitoneal(i.p) injection of verapamil hydrochloride (n = 8) and saline (n = 10), as the solvent of verapamil once a day within 13 days. Anesthetization was done by i.p injection of urethane and the rats were located in the stereotaxic apparatus for surgery, electrode implantation, and field potential recording. After observing a steady-state baseline response, saline or URB597 were injected (n = 9). Measurement of the population spike (PS) amplitude and slope of field excitatory postsynaptic potentials (fEPSPs) in the DG region was performed as a result of perforant pathway (PP) stimulation. Our treatments could inhibit LTP. Our results indicated that the chronic administration of verapamil produced a significant decrease in the slope of fEPSP and PS amplitude. Also, acute URB597 administration decreased the slope of fEPSP and PS amplitude compared to the saline group. Moreover, URB597 administration in combination with chronic administration of verapamil produced a greater decrease in fEPSP slope and PS amplitude than the saline group. These findings indicated that verapamil and URB597 disrupted LTP induction in the DG. Moreover, an interaction was observed between Ca2+ channels and eCs. Therefore, the eCs possibly play a selective role in synaptic plasticity.

Chronic verapamil administration alters phenytoin pharmacokinetics in the rat

The interaction of verapamil (4 and 8 mg/kg twice daily for 7 days) and i.v. phenytoin (10 mg/kg) in male Wistar rats has been studied. Increases occurred in phenytoin plasma elimination half-life (61%; p < 0.01 and 80%; p < 0.05), the area under the plasma concentration curve (32% n.s. and 48; p < 0.05) and volume of distribution (17%; p < 0.05 and 14% n.s.) after 4 and 8 mg/kg verapamil, respectively. The clearance was reduced to 75% (n.s.) and 67% ( p < 0.05) of the control value; changes were not dose-dependent.

Concurrent treatment with verapamil prevents diazepam withdrawapl-induced anxiety, in the absence of altered calcium flux in cortical synaptosomes

Rats, chronically treated with diazepam (4 mg/kg/day) for 28 days, displayed increased anxiety when tested in the elevated plus-maze, 42 hr after the last dose. This anxiogenic withdrawal response was entirely prevented by the concurrent administration of the calcium channel antagonist, verapamil. No anxiolytic effect of chronic administration of verapamil was observed in vehicle-treated rats. To investigate the possibility that increased calcium function in nerve terminals might underlie diazepam withdrawal-induced anxiety, the uptake by cortical synaptosomes of 45Ca 2 + was studied. Both fast (3-sec) and slow (60-sec) phase uptake were measured. No changes in basal (5 mM), potassium-stimulated (55 mM) or net uptake were observed during either fast or slow phase uptake. It is concluded that increased calcium influx in nerve terminals in the cortex does not underlie the anxiogenic effect of withdrawal of the benzodiazepine but that further studies must be carried out in other regions of the brain.

Effect of acute and chronic administration of verapamil on cardiac structure and function in essential hypertension without left ventricular hypertrophy

Effect of acute and chronic administration of verapamil on cardiac structure and function in essential hypertension without left ventricular hypertrophy

Therapeutic implications of impaired hepatic oxygen diffusion in chronic liver disease

Therapeutic implications of impaired hepatic oxygen diffusion in chronic liver disease

Evolution of the electrocardiographic changes in patients with hypertrophic cardiomyopathy

In 75 patients with hypertrophic cardiomopathy (HCM) followed for a mean period of 5.5 years (range 2-20 years), evolution of the electrocardiographic (EKG) changes was assessed. Progression of EKG abnormalities occurred in 35 patients (47%). It was manifested by an increase in precordial QRS voltage in 33 patients, development of new P-wave mitral in 11 patients, and development or disappearance of pathologic Q waves in 14 patients. With follow-up times greater than 5 years, 5-8 years, and greater than 8 years, EKG progression was present in 27, 41, and 80% of patients, respectively. Age less than 30 years at the beginning of study and left ventricular outflow obstruction predisposed to EKG progression within 5-8 years. Patients with progressive EKG changes were more prone to experience clinical deterioration than those without EKG progression (63 vs. 15%, p less than 0.001). With chronic verapamil administration, progression of EKG abnormalities occurred insignificantly less often than with propranolol treatment (35 vs. 64%, p = 0.20). It is concluded that with long-term follow-up, HCM tends to progress in a significant proportion of adult patients.

Effect of acute and chronic administration of verapamil on cardiac structure and function in essential hypertension without left ventricular hypertrophy

Cuspidi, Cesare; Sampieri, Lorena; Boselli, Lea; Bragato, Renato; Lonati, Laura; Bocciolone, Monica; Leonetti, Gastone; Zanchetti, Alberto Author Information

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.

Regulation of renin release and renal hemodynamics during acute and chronic verapamil administration

The effects of short- and long-term administration of the calcium-entry blocker verapamil on regulation of renal hemodynamics and renin release were analyzed in anesthetized dogs at controlled levels of renal perfusion pressure between 110 and 60 mmHg. The following three groups of dogs were studied: a control group, an acutely treated verapamil group (initial dose of 150 micrograms/kg followed by 4 micrograms.kg-1.min-1), and a chronically treated verapamil group (240 mg per os twice each day). At 110 mmHg the renal blood flow (RBF) in the acutely and chronically treated groups was 53% greater than (P less than 0.03) and 79% greater than (P less than 0.01) that of the control group. Glomerular filtration rate (GFR) in the acutely and chronically treated groups was 64 and 92%, respectively, greater than (P less than 0.01 for both) that of the control group. Autoregulation of RBF and GFR was extremely effective in the control group, whereas it was severely impaired by acute and long-term treatment with verapamil. Renin release at 110 mmHg in the control and the acutely treated groups were similar, 3.36 +/- 0.96 and 4.46 +/- 0.64 U.min-1.g-1, respectively, although in the chronically treated group the rate of release was 8.89 +/- 2.60 U.min-1.g-1 (P less than 0.03). As perfusion pressure was reduced, the rate of release from the acutely treated group rose to higher levels than that of the control group; at 70 mmHg release from the acutely treated group was 88% greater than that of the control group (P less than 0.01). Verapamil profoundly alters regulation of renal hemodynamics and renin release and the effect is prominent during both short- and long-term administration.

The Effect of Verapamil on Carotid Artery Distensibility and Cross-Sectional Compliance in Hypertensive Patients

The effect of chronic administration of verapamil, following a double-blind, crossover protocol, on the distensibility and cross-sectional compliance of the common carotid artery was investigated in 19 patients with essential hypertension. Distensibility was significantly increased during verapamil treatment as compared to placebo for both left and right common carotid artery (p less than 0.01 and p less than 0.05, respectively). The cross-sectional compliance was significantly increased during verapamil treatment for the right common carotid artery (p less than 0.05). For the left common carotid artery, the difference did not reach the level of significance (p = 0.16). The common carotid artery diameter and the arterial pulse pressure were not significantly different during verapamil treatment as compared with placebo. The results of this study indicate that chronic treatment with verapamil increases distensibility and cross-sectional compliance of the common carotid artery in hypertensive subjects. These improvements have to be considered as changes in arterial wall properties because no significant differences in pulse pressure and diameter could be detected between the verapamil and placebo periods. Improved arterial wall properties could result in a better management of the flow jet from the heart, and might protect the patients from atherosclerotic complications of hypertension.

Effect of chronic administration of verapamil in Duchenne muscular dystrophy

1. 1. In DMD patients the effect of chronic treatment with verapamil was investigated in the p-nitrophenylphosphatase from erythrocytes, the CK and LDH in serum and the functional activity of the muscle. 2. 2. A different behaviour in the p-nitrophenylphosphatase from untreated compared to treated DMD patients and controls is supported by the following findings: (a) values of “n” altered in F - inhibition of the enzyme with Hill coefficients −1.43, −2.18 and −2.19; (b) Arrhenius plots between 16 and 40°C with inflection points for the enzyme from treated DMD patients and controls and not from untreated DMD patients. 3. 3. Although CK and LDH in serum and the muscular evaluation showed no statistical difference between both groups, evidence is presented that in treated DMD patients the interaction membrane-enzyme is different from untreated DMD patients.

Effect of Verapamil on the Development of Chronic Experimental Chagas' Disease

In previous work, we have shown that the chronic administration of verapamil, a calcium channel blocker, ameliorated the mortality, pathology, and biochemical alterations associated with acute murine Chagas' disease. To extend these studies to an established chronic model, C3H/Hej mice were infected with the Sylvio X10/4 clone. This clone does not cause symptomatic acute disease but does induce cardiac pathology incorporating several pathological features of human chagasic cardiomyopathy. Cardiac pathology was assessed at 60, 90, and 180 days postinfection. There was a significant decrease in the degree of inflammation and fibrosis in the group infected and treated with verapamil. Myocardial beta-adrenergic adenylate cyclase (AC) activity was determined 180 days postinfection. In the infected group not treated with verapamil, there was no significant change in the maximum rate of conversion of ATP to cAMP (Vmax) or in the concentration of agonist giving 50% of Vmax (apparent Kact) for isoproterenol (ISPN)-dependent AC activation. The increase in Vmax for ISPN determined in the presence of 5'-guanylylimidodiphosphate (Gpp[NH]p) was consistently lower in infected than in uninfected mice, suggesting that infection altered the potential synergistic activation of AC by the guanine nucleotide. In the infected group treated with verapamil, there was a slight increase in the Vmax for ISPN. However, there was a marked enhancement of the synergistic contribution of Gpp(NH)p. These observations suggest that verapamil had preserved that aspect of the AC complex mediating guanine nucleotide sensitive activation of AC. Collectively, the observations in the acute and chronic models of murine Chagas' disease suggest that verapamil may be a useful adjunct in treatment.

Effect of Chronic Verapamil Therapy on Cardiac Norepinephrine and β-Adrenoceptor Density

Experiments were undertaken to establish whether the chronic administration of verapamil, to provide a therapeutically relevant plasma level, results in a loss of cardiac norepinephrine (NE) and, if so, whether this is accompanied by a change in cardiac beta 1-adrenoceptor density, affinity, or selectivity. Adult male Sprague-Dawley rats were used. Verapamil was mixed with the food to provide a daily verapamil intake of 50 mg/kg body weight. This yielded a plasma level of 80-110 ng/ml and caused a significant but reversible decrease in left ventricular NE (77%, p less than 0.001), dopamine (43%, p less than 0.02), and 3,4-dihydroxyphenylethyleneglycol (30%, p less than 0.02). Cardiac membranes prepared from rats maintained on standard (control) diet contained a single population of high affinity beta 1-adrenoceptor binding sites, with an affinity (Kd) of 0.24 +/- 0.02 nM and a density (Bmax) of 35.5 +/- 19.5 fmol/mg protein. Including verapamil (dissolved in either ethanol or water) in the diet for less than or equal to 6 weeks had no effect on the Kd, Bmax, or selectivity of these sites. However, the ethanol containing, but not the ethanol-free, placebo diet caused a small (p less than 0.05) reduction in Bmax after 6 but not after 2 weeks treatment. These results show that the chronic oral administration of verapamil to provide a clinically relevant plasma level depletes the cardiac stores of NE by 77% without causing an increase in beta 1-adrenoceptor density during 6 weeks therapy.

Glomerular hemodynamic adaptations in remnant nephrons: effects of verapamil.

Chronic verapamil administration has been shown to reduce the renal dysfunction, glomerular sclerosis, and mortality in partially nephrectomized rats; the mechanism is unknown. Therefore, the present micropuncture study examines the effect of verapamil on glomerular hemodynamics of Munich-Wistar rats 4 wk after five-sixths nephrectomy. Whole-kidney function was similar in nephrectomized rats treated with verapamil (Nx-VER) and saline (Nx-SAL), and glomerular filtration rate (GFR) was one-third of control. Both Nx-VER and Nx-SAL rats exhibited a similar degree of glomerular hyperperfusion and hyperfiltration. However, mean glomerular capillary hydrostatic pressure difference (delta P) was lower in Nx-VER than Nx-SAL rats (42.4 +/- 1.2 vs. 47.2 +/- 1.0 mmHg, P less than 0.005) because of an increase in Bowman's space hydrostatic pressure (PBS) in Nx-VER rats (15.5 +/- 0.8 vs. Nx-SAL 11.9 +/- 0.7 mmHg, P less than 0.005). Glomerular ultrafiltration coefficient (LpA) was significantly lower in Nx-SAL (P less than 0.005) than in Nx-VER or control rats. Urinary protein excretion and the magnitude of glomerular sclerosis in Nx-SAL and Nx-VER rats were not different. In conclusion, chronic VER administration normalizes LpA and reduces delta P, by increasing PBS, in Nx rats, alterations that neutralize each other, leading to the constancy of single-nephron GFR.

Verapamil protects against progression of experimental chronic renal failure

Chronic administration of verapamil (Ver) decreases nephrocalcinosis and tubular ultrastructural abnormalities in the remnant model of chronic renal disease. In the present study, the effect of chronic Ver administration on renal function, renal histology and mortality after subtotal nephrectomy was examined. Fourteen days after staged subtotal nephrectomy rats were paired according to renal functional impairment, mean arterial pressure (MAP), and body weight. Rats were pair fed and received either Ver (0.1 micrograms/g sc bid, N = 10) or saline (0.1 ml sc bid, N = 10) for up to 23 weeks. Both members of each pair were sacrificed shortly before the uremic death of controls. At sacrifice, rats treated with Ver had a lower serum creatinine (2.29 vs. 2.99 mg/dl, P less than 0.05) and a higher creatinine clearance (318 vs. 164 microliters/min, P less than 0.05) than controls. In a second experiment, survival was superior in rats treated with Ver than in controls from week seven (P less than 0.0025 by week 14). Serum creatinine was higher at week 10 in control rats (1.68 vs. 1.10 mg/dl, P less than 0.05). MAP was no different between the two groups, irrespective of the time between Ver administration and the measurement of MAP. Histological damage and nephrocalcinosis were worse, and renal and myocardial calcium content was higher in controls. In conclusion, independent of any effect on systematic MAP, chronic administration of Ver protects against renal dysfunction, histological damage, nephrocalcinosis and myocardial calcification, and improves survival in the remnant model of chronic renal disease.

Chronic verapamil administration lowers portal pressure and improves hepatic function in rats with liver cirrhosis

The effects of verapamil on portal pressure, microsomal liver function and extravascular albumin space were investigated in rats rendered cirrhotic by chronic exposure to phenobarbital and carbon tetrachloride. Verapamil significantly decreased splenic pulp pressure by 28% (P less than 0.05). In cirrhotic animals it improved liver function, measured by the aminopyrine and caffeine breath tests, by 36% (P less than 0.025) and 53% (P less than 0.05), respectively. The extravascular albumin space, an important determinant of drug clearance, was measured by a multiple indicator dilution technique. It was significantly larger in verapamil treated than in untreated cirrhotics (4.41 +/- 1.06 vs 2.73 +/- 0.79 ml/g; P less than 0.01). We conclude that verapamil has significant potential as a portal antihypertensive agent and its value in treating cirrhosis in man should be explored by controlled studies.

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 metabolism in uremic nephrocalcinosis: Preventive effect of verapamil

AbstractCalcium metabolism in uremic nephrocalcinosis: Preventive effect of verapamil. The aim of the present study was to examine calcium metabolism of the renal cortex in experimental chronic renal failure, together with morphologic criteria of nephrocalcinosis and to determine the effect of chronic verapamil administration on these parameters. In subtotally nephrectomized (SNX) rats 3 weeks after surgery, renal cortical calcium content increased more than two-fold,45Ca incorporation into renal cortical slices in SNX revealed a 35% increase, associated with a 50% increase in a lanthanum-resistant fraction of45Ca uptake. Radiocalcium wash-out curves in this group demonstrated abnormal retention of the isotope for up to 30min of incubation, In contrast, radiocalcium incorporation and wash-out in SNX rats chronically treated with verapamil were similar to that obtained in the sham group. Verapamil administration significantly reduced, but did not normalize, renal cortical calcium content. Von Kossa staining demonstrated the deposition of calcium in the renal parenchyma of SNX rats. Ultrastructurally, it was accompanied by mitochondrial disorganization and calcification, as well as by the tubular basement membrane destruction and mineralization. These morphologic patterns of nephrocalcinosis were significantly ameliorated in SNX rats treated with verapamil. We conclude that chronic verapamil administration results in amelioration of uremic nephrocalcinosis.Métabolisme du calcium au cours de la néphro-calcinose urémique: effet préventif du vérapamil. Le but de cette étude a été d'examiner le métabolisme calcique du cortex rénal au cours d'une insuffisance rénale chronique expérimentale en même temps que les critères morphologiques de néphrocalcinose, et de déterminer l'effet de l'administration chronique de vérapamil sur ces paramètres. Chez des rats néphrectomisés partiellement (SNX), 3 semaines après la chirurgie le contenu en calcium de la corticale rénale augmentait plus de deux fois. L'incorporation de45Ca aux coupes de corticale rénale chez les SNX révélait une augmentation de 35%, associée à une élévation de 50% de la fraction lanthanum-résistante de la captation de45Ca. Les courbes de disparition du radiocalcium dans ce groupe démontraient une rétention anormale de l'isotope jusqu'à 30min d'incubation. A l'opposé, l'incorporation et la disparition du radiocalcium chez les rats SNX traités chroniquement au vérapamil étaient identiques à celles obtenues dans le groupe simulacre. L'administration de vérapamil a réduit significativement, mais n'a pas normalisé le contenu cortical rénal en calcium. Une coloration de Von Kossa a démontré des dépôts de calcium dans le parenchyme rénal des rats SNX. Ultrastructurallement, cela a été accompagné d'une désorganisation et de calcifications mitochondriales, et par une destruction et une minéralisation de la membrane basale tubulaire. Ces aspects morphologiques de néphrocalcinose étaient significativement améliorés chez les rats SNX traités au vérapamil. Nous concluons que l'administration chronique de vérapamil améliore la néphrolcalcinose urémique.

Chronic verapamil administration improves liver function and diffusional exchange in a rat model of liver cirrhosis

Chronic verapamil administration improves liver function and diffusional exchange in a rat model of liver cirrhosis