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PubMed1992

Disparate effects of calcium channel blockers on pressure dependence of renin secretion and flow in the isolated perfused rat kidney.

Using the model of isolated perfused rat kidneys this study was performed to investigate whether or not voltage-operated calcium channels are essentially involved in the pressure control of renin secretion from the kidneys. At a perfusion pressure of 100 mm Hg (13.3 kPa) renin secretory rates were 4.2 +/- 0.7 (ng angiotensin I h-1) min-1 g-1. Stepwise reduction of renal perfusion pressure to 80, 60, and 40 mm Hg (10.6, 8.0, 5.3 kPa) resulted in an increase of renin release yielding a 30-fold stimulation at 40 mm Hg vs 100 mm Hg. Increasing the perfusion pressure above 100 mm Hg did not further significantly decrease renin secretion. The perfusate flow rate was also pressure-dependent. Flow rates increased linearly with pressure and reached a plateau at 100 mm Hg, which was maintained up to 160 mm Hg (21.3 kPa). The averaged flow rate at the plateau was 15.5 ml min-1 g-1. In the presence of the three different calcium antagonists nifedipine (5 microM), nitrendipine (3 microM) and verapamil (5 microM), myogenic autoregulation of flow was abolished as indicated by the rise of the pressure/flow curve between 40 and 160 mm Hg. At the same time, however, these calcium channel blockers did not alter the relationship between perfusion pressure and renin secretion. Moreover, the calcium channel agonist Bay K 8644 (5 microM) caused a strong and long-lasting vasoconstriction, without changing renin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1997

Effects of intracavernous calcium channel blockers in dogs.

Intracavernous injection of smooth muscle relaxing agents can induce penile erection. In this experimental study, we compared the effects of intracavernously injected calcium channel blockers (CCBs) and papaverine in dogs, and investigated their clinical applicabilities. We administered 30 mg papaverine, 10 mg nifedipine, 10 mg nitrendipine and 2.5 mg verapamil to 10 adult male dogs intracavernously, each at different times. Intracavernous pressure values, systemic arterial pressure values and heart rate values were recorded for 45 minutes after the intracavernous injections. We used the paired Student t-test for statistical analysis. Papaverine induced full erection in all of the 10 dogs. Nifedipine induced full erection in 4, nitrendipine in 5, and verapamil in 6 of the 10 dogs. Nifedipine and nitrendipine caused significant decreases in blood pressure and increases in heart rate. In conclusion, the effects of intracavernous CCBs are not superior to those of papaverine. We cannot recommend nifedipine and nitrendipine for intracavernous injection, but verapamil may be included in intracavernous pharmacotherapeutic combinations.

Animals↗
PubMed1992

Dihydropyrimidine calcium channel blockers. 4. Basic 3-substituted-4-aryl-1,4-dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents.

We have examined a series of novel dihydropyrimidine calcium channel blockers that contain a basic group attached to either C5 or N3 of the heterocyclic ring. Structure-activity studies show that a 1-(phenylmethyl)-4-piperidinyl carbamate moiety at N3 and sulfur at C2 are optimal for vasorelaxant activity in vitro and impart potent and long-acting antihypertensive activity in vivo. One of these compounds (11) was identified as a lead, and the individual enantiomers 12a (R) and 12b (S) were synthesized. Two key steps of the synthesis were (1) the efficient separation of the diastereomeric ureido derivatives 29a/29b and (2) the high-yield transformation of 2-methoxy intermediates 30a/30b to the (p-methoxybenzyl)thio intermediates 31a/31b. Chirality was demonstrated to be a significant determinant of biological activity, with the dihydropyridine receptor recognizing the enamino ester moiety (12a) but not the carbamate moiety (12b). Dihydropyrimidine 12a is equipotent to nifedipine and amlodipine in vitro. In the spontaneously hypertensive rat, dihydropyrimidine 12a is both more potent and longer acting than nifedipine and compares most favorably with the long-acting dihydropyridine derivative amlodipine. Dihydropyrimidine 12a has the potential advantage of being a single enantiomer.

Amlodipine↗
PubMedDate not supplied

Effect of long-acting somatostatin analogue (octreotide, SMS 201-995) plus calcium channel blocker (verapamil) on gallbladder contraction.

BACKGROUND/AIMS: In this study we investigated the effect of the long-acting somatostatin analog octreotide (SMS 201-995) plus calcium channel blocker (Verapamil) on gallbladder contraction. METHODOLOGY: Fourty healthy volunteers participated in this study. Gallbladder volumes were measured by ultrasonography. After recording the baseline measurement, the volunteers received either saline (n:10), or SMS 201-995 100 B microgram subcutaneously (s.c.) (n:10) or verapamil 80 mg peroral (po) (n:10), or verapamil plus SMS 201-995 (n:10). Two hours later the gallbladder volumes were rescanned in 15 min intervals for 60 min. At the end all volunteers received standard liquid test meal (ensure 250 Cal/250 ml) and scans were again performed for one hour. RESULTS: The mean baseline gallbladder volume was 18.6 +/- 5.2 ml in all groups. The gallbladder volumes in the placebo group were 18.6 +/- 5.2 to 19.0 +/- 10.2 ml. In this group, after administration of test meal decreased the mean gallbladder volume to 14.3 +/- 7.5 to 8.4 +/- 5.8 ml, but these values were not significantly different from the baseline values. In the verapamil group the volumes increased from 18.6 +/- 5.2 to 28.5 +/- 9.7 to 30.8 +/- 11.6 ml. These values were significantly different from the baseline and the control group (p < 0.05). In this group, post-prandial mean volumes decreased to baseline in 30 min, but these values were higher than in the placebo group (p < 0.01). Verapamil-induced fasting the gallbladder relaxation was totally abolished to the placebo value by SMS 201-995. In verapamil plus SMS 201-995 and SMS 201-995 alone groups, the fasting and post-prandial volumes did not change when compared to the baseline value, but post-prandial volumes were higher than the placebo (p < 0.01). CONCLUSION: These results suggest that verapamil-induced gallbladder relaxation was totally abolished by SMS 201-995.

Adult↗
PubMed2000

Effect of a calcium channel blocker and antispasmodic in diarrhoea-predominant irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a colonic function disorder. Both pinaverlum bromide (a selective calcium channel blocker) and mebeverine (an antispasmodic) are reported to be effective in the long-term (12-16 weeks) treatment of IBS patients. Their efficacy in the short-term treatment of IBS patients and colonic transit time is unclear. Furthermore, substance P and neuropeptide Y have either excitatory or inhibitory effects on colonic motility. Whether the efficacy of both drugs is mediated through these neuropeptides remains unknown. METHODS AND RESULTS: A clinical trial was conducted with 91 patients with diarrhoea-predominant IBS. After basal measurement of the total colonic transit time, IBS patients were randomized to receive either pinaverlum bromide (50 mg, t.i.d.) or mebeverine (100 mg, t.i.d.) for 2 weeks. The symptomatic scores regarding defaecation, total colonic transit time and serum levels of substance P and neuropeptide Y were measured before and after treatments. The daily defaecation frequency was markedly decreased after treatment (pinaverlum bromide, 2.9+/-1.2 vs 2.0+/-1.0, P< 0.05; mebeverine, 2.7+/-1.1 vs 2.1+/-1.0, P< 0.05). The stool consistency became well formed after both treatments (P< 0.05). Both drugs similarly improved the global well-being in these IBS patients (pinaverlum bromide vs mebeverine 73.4 vs 71.8%, P> 0.05). The total colonic transit time was significantly prolonged only after pinaverlum bromide treatment (21.4+/-15.5 vs 30.8+/-14.8 h, P< 0.01). Neither substance P nor neuropeptide Y serum level was significantly changed after either treatments. CONCLUSION: Pinaverlum bromide and mebeverine have similar therapeutic efficacies on diarrhoea-predominant IBS patients. Prolonged colonic transit time may be one of the factors responsible for the efficacy of pinaverlum bromide on the IBS patients. Substance P and neuropeptideY appear less important in the pathogenesis of diarrhoea-predominant IBS.

Calcium Channel Blockers↗
PubMed1998

Effects of dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibition, and blood pressure control on chronic, nondiabetic nephropathies. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN).

Dihydropyridine-type calcium channel blockers (dihydropyridine CCB) adversely affect renal function in diabetes. The effects of dihydropyridine CCB on 24-h urinary protein excretion rate and GFR decline (deltaGFR) were prospectively evaluated in 117 nondiabetic patients with chronic, proteinuric nephropathies enrolled in the Ramipril Efficacy in Nephropathy study and randomized to angiotensin-converting enzyme inhibition (ACEI) or placebo plus conventional antihypertensive therapy. Sixty-three percent of patients were treated with dihydropyridine CCB. During follow-up, CCB-treated compared with no CCB patients had higher proteinuria (mean+/-SEM: 4.8+/-0.2 g/24 h versus 4.2+/-0.2 g/24 h, respectively, P = 0.015) and mean arterial BP (MAP). The difference in proteinuria was significant in the placebo group (5.1+/-0.2 g/24 h versus 4.3+/-0.3 g/24 h, P = 0.02), but not in the ACEI group (4.4+/-0.2 g/24 h versus 4.1+/-0.2 g/24 h). Of note, CCB-treated patients had significantly less proteinuria (P = 0.028) in the ACEI group compared with placebo. CCB-treated versus no CCB patients had a faster deltaGFR in the overall study population and in the placebo group, but not in the Ramipril group. Proteinuria was comparable in CCBtreated and no CCB patients for MAP < or = 100 mmHg, but was higher in CCB-treated patients for MAP >100 mmHg. Similarly, proteinuria was comparable in the placebo and in the ACEI group for MAP < or = 100 mmHg, but was higher in the placebo group for MAP >100 mmHg. In CCB- and placebo-treated patients, a linear correlation (P = 0.006 for both groups) was found between proteinuria and MAP values. MAP, proteinuria, and deltaGFR in patients given nifedipine versus those given other dihydropyridine CCB were comparable. Thus, in nondiabetic proteinuric nephropathies, dihydropyridine CCB may have an adverse effect on renal protein handling that depends on the severity of hypertension and is minimized by ACEI therapy or tight BP control. ACE inhibitors may electively limit proteinuria in patients on dihydropyridine CCB treatment and/or with uncontrolled hypertension.

Adolescent↗
PubMed1990

Modification of phenyl saligenin phosphate-induced delayed effects by calcium channel blockers: in vivo and in vitro electrophysiological assessment.

Effects of organophosphorus esters (OPs) inducing delayed neuropathy in the adult hen have traditionally been evaluated by assessment of morphology and function of nerve and muscle in the rear limbs of animals exposed. In this study, organophosphorus-induced delayed neuropathy (OPIDN), including neuromuscular function and histology, were studied in vivo using sciatic nerve, tibial nerve and gastrocnemius muscle in anesthetized hens that had been administered phenyl saligenin phosphate (PSP), 2.5 mg/kg by intramuscular injection. In addition, OPIDN was examined in vitro using the biventer cervicis nerve and muscle of the same adult hens. Both nerve-muscle preparations were used for construction of strength duration curves (SDC) on days 4-5, 7-8, and 15-16 after PSP; the biventer cervicis preparation was also used 21-22, 37 and 64 days after PSP administration. Histological examination was done at these same time periods. SDC revealed significant increases in excitability thresholds for preparations from hens receiving PSP only compared to preparations from control hens, or compared to preparations from hens treated with PSP and either nifedipine (1 mg/kg intramuscularly for 5 days), or verapamil (7 mg/kg intramuscularly for 4 days), with treatment beginning 24 hours before administration of PSP. Ataxia, which appeared 7-10 days after hens were given PSP, was less pronounced in hens given PSP plus either calcium channel blocker than in hens given PSP alone. Whether treatment was initiated before or after PSP, verapamil, a phenylalkylamine, reduced sensitivity of the biventer cervicis muscle to acetylcholine-induced stimulation. The dihydropyridine, nifedipine, was less effective at reducing muscle sensitivity to acetylcholine post-exposure than when used as a pretreatment. Lesions were extensive in the biventer cervicis nerve after PSP administration and modification by treatment with calcium channel blockers was evident.

Acetylcholine↗
PubMed1997

Myocardial infarction in newly diagnosed hypertensive Medicaid patients free of coronary heart disease and treated with calcium channel blockers.

PURPOSE: A retrospective cohort analysis of 1,406 newly diagnosed hypertensive patients, aged 18 to 59, without prior coronary heart disease and initially treated with calcium channel blockers (CCBs) or eight other drug regimens was conducted to evaluate the relative risk of acute myocardial infarction (AMI) among patients on CCBs alone or with a diuretic. MATERIALS AND METHODS: Administrative claims data from Pennsylvania's Medicaid program were the data source. Patients were followed up from 1987 to 1994. RESULTS: There was a highly significant trend towards prescribing CCBs between 1988 and 1991 (P = 0.0001). A total of 67 AMIs occurred, 33 of which were during original drug therapy. Compared with those treated with beta blockers, the relative risk of AMI among patients treated only with CCBs was 0.49 (95%) confidence interval [CI] 0.11 to 2.20). Compared with diuretic therapy, the AMI relative risk associated with CCB therapy was 0.60 (95% CI 0.16 to 2.32) when patient drug regimen was classified based on the first six prescriptions. Several alternative drug regimen classification schemes were tested to evaluate the sensitivity of relative risk of AMI to classification of drug therapy. CONCLUSIONS: The measurement of relative risk of AMI was highly dependent on the study design, including patient selection criteria and classification of patient drug therapy. Previous findings of elevated risk of AMI from CCB antihypertensive therapy could not be confirmed.

Adolescent↗
PubMed1990

Hemodynamic mechanisms of antianginal action of calcium channel blocker nisoldipine in dynamic exercise-induced angina.

To investigate the mechanism of antianginal action of the calcium channel blocker nisoldipine and to determine the reproducibility of the clinical and hemodynamic events induced by supine leg exercise, 30 patients with stable effort angina pectoris were studied. They were divided into two groups; one group of 19 patients received a single 10-mg dose of nisoldipine orally, and the other group of 11 patients received a single dose of placebo orally. Chest pain was induced in all of 30 patients during the control exercise test. After nisoldipine administration, chest pain was not induced in 13 of 19 patients and was of lessened severity in five patients with the same work load as those performing control exercise. ST segment at peak exercise showed less severe depression after nisoldipine. Systemic vascular resistance was reduced by 38% (p less than 0.001) at rest and 22% (p less than 0.001) at peak exercise, and coronary vascular resistance was reduced by 31% (p less than 0.01) at rest and 18% (p less than 0.01) at peak exercise. Pulmonary artery wedge pressure fell from 6 +/- 1 to 3 +/- 1 mm Hg (p less than 0.001) at rest and from 28 +/- 3 to 11 +/- 2 mm Hg (p less than 0.001) at peak exercise. Coronary sinus flow at rest and myocardial oxygen uptake both at rest and during exercise was not modified by nisoldipine. However, coronary sinus flow at peak exercise increased significantly from 219 +/- 24 to 249 +/- 31 ml/min (p less than 0.01) after nisoldipine, and myocardial oxygen uptake was not significantly changed despite decreased coronary vascular resistance. The clinical and hemodynamic events induced by the exercise during invasive studies (except pulmonary artery wedge pressure at rest) were reproducible after placebo administration. Our data demonstrate that increased coronary blood flow could be the major mechanism of the antianginal action of nisoldipine in supine leg exercise-induced angina.

Adult↗
PubMed1986

In vivo actions of a calcium channel blocker (nimodipine) on the cerebrovascular response to infused 5-hydroxytryptamine.

Previous in vitro studies show that the calcium channel blocker, nimodipine, inhibits the cerebrovascular contraction elicited by 5-hydroxytryptamine (5-HT). The present study determined if this effect was present in vivo in the baboon cerebral circulation rendered sensitive to infused 5-HT by prior intracisternal injection of autologous blood. Five to seven days after injection of this blood the five baboon displayed a vasoconstrictor response to intracarotid 5-HT at 10 micrograms/kg/min (cerebrovascular resistance increased from 2.19 +/- 0.16 to 2.75 +/- 0.30 mm Hg/ml X min-1). Subsequent i.v. infusion of nimodipine produced cerebral vasodilation with an efficacy similar to that in normal baboons. Reinfusion of 5-HT during nimodipine infusion caused a cerebrovascular resistance increase of similar magnitude to that in the prenimodipine test. These results suggest that nimodipine produces cerebral vasodilation after a mild cerebrovascular insult but did not significantly reduce the vasoconstrictor response to 5-HT.

Animals↗
PubMed1993

Suppression of the purgative action of rhein anthrone, the active metabolite of sennosides A and B, by calcium channel blockers, calmodulin antagonists and indomethacin.

The involvement of Ca2+ in the mechanism of the purgative action of rhein anthrone was studied. Among individual or combination pretreatments with calcium channel blockers, calmodulin antagonists and prostaglandin biosynthesis inhibitors, the combination of indomethacin and nifedipine completely blocked the diarrhoea induced by rhein anthrone and also inhibited its effects on colonic fluid and electrolyte transport, and large intestinal motility. Calmodulin antagonists were less active regarding suppression of the effects of rhein anthrone. We concluded that, in addition to prostaglandins, diarrhoea induced by rhein anthrone must also involve the calcium channel which can be blocked by nifedipine, but not verapamil.

Animals↗
PubMedDate not supplied

Catabolism of high energy phosphates during long-term cold storage of donor hearts: effects of extra- and intracellular fluid-type cardioplegic solutions and calcium channel blockers.

Dog hearts were harvested and stored cold (0.5 degree C) for 24-hours. Cardiac arrest was induced by means of low-sodium and calcium-free cardioplegic (n = 6) or hyperkalemic cardioplegic (n = 6) solution. Nifedipine (2 micrograms/gm estimated heart weight) was added to each cardioplegic solution in two additional groups (n = 6 each). High energy phosphates (creatine phosphate and adenosine triphosphate) and catabolites (adenosine diphosphate and monophosphate, adenosine, inosine, hypoxanthine, xanthine) were determined in the myocardium before and during 24 hours of cold storage. With use of the standard hyperkalemic cardioplegic solution, breakdown of high energy phosphates was less pronounced than after the use of a low sodium, calcium-free solution: after 24 hours of cold storage myocardial ATP content was 57% of control versus 32% (p less than 0.05). The addition of nifedipine to the hyperkalemic cardioplegic solution delayed ATP breakdown during the first hours of cold storage: at 5 hours of preservation the myocardial ATP level was significantly higher (p less than 0.05) than in hearts preserved without nifedipine. Addition of nifedipine to the low-sodium, calcium-free solution did not influence catabolism of high energy phosphates significantly. It is concluded that preservation of high energy phosphates during long-term cold storage of donor hearts can be best achieved by simultaneous myocardial metabolic blockade at two specific sites: at the "fast" sodium-potassium channels by hyperkalemic depolarization and at the "slow" channels by means of calcium channel blockers.

Adenosine Triphosphate↗
PubMed1996

Clinical outcome of a mandatory formulary switch for dihydropyridine calcium channel blocker therapy at a Veteran's Administration Medical Center.

Recently, changes in antihypertensive therapies with similar properties have been made based primarily on cost savings for hospital formularies. To assess blood pressure (BP) control and adverse side effects associated with a switch of patients on nifedipine GITS to felodipine at our Veteran's Administration Medical Center (VAMC), we prospectively studied physician records and patient-reported side effects (both from the medical record and patient questionnaires) in 127 hypertensive patients (70 +/- 10 years, 95% men, 88% nonblack, 44% with coronary disease) who underwent the forced switch in therapy. During the period of patient visits/chart review, physicians were unaware that the study was being conducted. A minimum of 2 months and two visits on each therapy was required for patient inclusion. The mean doses of nifedipine GITS and felodipine used were 55 +/- 24 mg/day and 8 +/- 2.6 mg/day, respectively. The use of supplemental antihypertensive agents was similar in both calcium channel blocker groups. Systolic BPs and heart rates were similar in patients taking the two drugs, and the diastolic BP was modestly lower in patients taking felodipine (78 +/- 10 mm Hg for felodipine and 80 +/- 10 mm Hg for nifedipine, P < .05). There were no differences in the incidence of side effects (both patient-reported and provider-reported) for the two antihypertensive therapies. These data demonstrate that in an hypertensive population followed in a VAMC, mandatory switching of stable dihydropyridine calcium channel blocker therapy did not result in any significant changes in short-term (2 to 3 months) BP control nor were adverse side effects different based on both physician- and patient- reported sources of information.

Aged↗
PubMed1987

Antihypertensive and hormonal effects of PN 200-110, a new calcium-channel blocker, in essential hypertension.

Twenty-four patients (aged 34-68), with mild to moderate essential hypertension, received 10 weeks of treatment with the new calcium-channel blocker PN 200-110. Eighty-six percent of the patients achieved goal blood pressure (i.e., sitting diastolic pressure less than or equal to 90 mmHg). The average reduction in sitting and standing systolic and diastolic blood pressure (-14 +/- 2/-15 +/- 1 mmHg, -14 +/- 3/-13 +/- 2 mmHg, respectively) was highly significant (p less than 0.001). No reflex tachycardia (sitting pulse 1 +/- 2 bpm; standing pulse 3 +/- 2 bpm) or weight change (-0.3 +/- 0.9 pounds) accompanied the hypotensive response. Although the fall in blood pressure was accompanied by a small but significant increment in plasma renin activity (0.5 +/- 0.2 ng/ml/hr [p less than 0.05]), no significant changes in plasma angiotensin II, aldosterone, or prostaglandin E2-metabolite occurred. There was no significant correlation between the fall in blood pressure and baseline (pretreatment) or stimulated (posttreatment) levels of plasma renin activity, angiotensin II, aldosterone, or prostaglandin E2-metabolite.

Adult↗
PubMed2003

Calcium channel blockers for reducing cardiac morbidity after noncardiac surgery: a meta-analysis.

Cardiac complications are the leading cause of death after noncardiac surgery. Despite theoretical benefits, calcium channel blockers (CCB) are not widely used in the perioperative setting. This systematic review assessed the efficacy of CCBs during noncardiac surgery. MEDLINE, EMBASE, Science Citation Index, PubMed, and reference lists were searched without language restriction for randomized controlled trials (RCT) evaluating CCBs during noncardiac surgery. Two reviewers independently abstracted data on death, myocardial infarction (MI), ischemia, supraventricular tachyarrhythmia (SVT), and congestive heart failure (CHF). Treatment effects were calculated as relative risks (RR) with 95% confidence intervals (CI). Eleven studies (1007 patients) were included. CCBs significantly reduced ischemia (RR, 0.49; 95% CI, 0.30-0.80; P = 0.004) and SVT (RR, 0.52; 95% CI, 0.37-0.72; P < 0.0001). CCBs were associated with trends towards reduced death and MI. In post hoc analyses, CCBs significantly reduced death/MI (RR, 0.35; 95% CI, 0.15-0.86; P = 0.02) and major morbid events (MME), defined as death, MI, or CHF (RR, 0.39; 95% CI, 0.17-0.89; P = 0.02). In subgroup analyses, diltiazem significantly reduced ischemia, SVT, death/MI, and MMEs. This meta-analysis shows CCBs significantly reduced ischemia, SVT, and combined end-points in the setting of noncardiac surgery. The majority of these benefits are attributable to diltiazem, suggesting the need for further evaluation of this drug in a large RCT.

Calcium Channel Blockers↗
PubMed1998

The effect of calcium channels blockers in the K+-evoked release of [3H]adenine nucleotides from rat brain cortical synaptosomes.

The role of L-,N-, P- and Q-type voltage-dependent calcium channels in K+-induced release of [3H]adenine nucleotides from rat brain cortical synaptosomes was investigated. Cd2+, a non-specific blocker of calcium channels, inhibited by 69% the release of the nucleotides induced by 33 mM K+. Nifedipine, omega-Conotoxin GVIA and omega-Agatoxin IVA had no effect whereas omega-Conotoxin MVIIC inhibited by 62% the K+ induced release of adenine nucleotides in rat brain cortical synaptosomes. It is concluded that Q-type calcium channels are directly involved in the release of adenine nucleotides in rat brain cortical synaptosomes.

Adenine Nucleotides↗
PubMed2004

The calcium channel blocker amlodipine exerts its anti-proliferative action via p21(Waf1/Cip1) gene activation.

Proliferation of vascular smooth muscle cells (VSMC) contributes to the progression of atherosclerotic plaques. Calcium channel blockers have been shown to reduce VSMC proliferation, but the underlying molecular mechanism remains unclear. p21(Waf1/Cip1) is a potent inhibitor of cell cycle progression. Here, we demonstrate that amlodipine (10(-6) to 10(-8) M) activates de novo synthesis of p21(Waf1/Cip1) in vitro. We show that amlodipine-dependent activation of p21(Waf1/Cip1) involves the action of the glucocorticoid receptor (GR) and C/EBP-alpha. The underlying pathway apparently involves the action of mitogen-activated protein kinase or protein kinase C, but not of extracellular signal-related kinase or changes of intracellular calcium. Amlodipine-induced p21(Waf1/Cip1) promoter activity and expression were abrogated by C/EBP-alpha antisense oligonucleotide or by the GR antagonist RU486. Amlodipine-dependent inhibition of cell proliferation was partially reversed by RU486 at 10(-8) M (58%+/-29%), antisense oligonucleotides targeting C/EBP-alpha (91%+/-26%), or antisense mRNAs targeting p21(Waf1/Cip1) (96%+/-32%, n=6); scrambled antisense oligonucleotides or those directed against C/EBP-beta were ineffective. The data suggest that the anti-proliferative action of amlodipine is achieved by induction of the p21 (Waf1/Cip1) gene, which may explain beneficial covert effects of this widely used cardiovascular therapeutic drug beyond a more limited role as a vascular relaxant.

Amlodipine↗
PubMed1987

Comparison of nifedipine with a new calcium channel blocker, flordipine, in exercise-induced asthma.

Four patients with documented exercise-induced asthma (EIA) were pretreated orally in random, double-blind fashion with the calcium channel blockers nifedipine 20 mg and flordipine 25 and 50 mg and placebo, then subjected to exercise challenge on a cycloergometer. Each patient served as his own control, undergoing exercise challenge with the different pretreatments on 4 separate days. No statistically significant protection from EIA was found with either nifedipine or flordipine.

Adult↗