Effects Of Dihydropyridine Calcium Antagonists Research Articles

Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats

The aim of this study was to compare the roles of dihydropyridine calcium antagonists nifedipine, nitrendipine, amlodipine on doxorubicin (DXR)-induced nephrotoxicity in rats using biochemical, histopathological and immunohistochemical approaches. Male Sprague–Dawley rats were randomly divided into five experimental groups: control; DXR; DXR + nifedipine (15 mg/kg); DXR + nitrendipine (10 mg/kg); DXR + amlodipine (5 mg/kg). Results showed that treatment with DXR alone caused significant changes in the levels of urinary protein, serum creatinine (SCr), and blood urea nitrogen (BUN). Co-administration with amlodipine effectively reversed the effect of DXR on these parameters. In contrast, nifedipine and nitrendipine either had no effect or worsened DXR induced changes in the levels of urinary protein, SCr and BUN. Furthermore, DXR treatment caused significant increases in the levels of malondialdehyde (MDA), nitric oxide (NO), nitric oxide synthase (NOS) and significant decreases in the levels of reduced glutathione (GSH), glutathione- S-transferase (GST), and superoxide dismutase (SOD). These effects were significantly reduced by co-administration with amlodipine but not affected by nifedipine and worsened by nitrendipine. In addition to the biochemical changes, histopathological studies showed that DXR caused significant structural damages in the kidneys. Glomerular cell apoptosis, a decrease in Bcl-2 expression and an increase in Bax expression were observed in all rats treated with DXR. Co-administration with amlodipine effectively reversed the effect of DXR while nifedipine and nitrendipine had no effect. In conclusion, this study clearly indicated that amlodipine protected against DXR-induced nephrotoxicity while nifedipine and nitrendipine had no effect.

What is the optimal strategy to intensify blood pressure control and prevent progression of renal failure?

Recent clinical trials clearly demonstrate that patients with diabetes and hypertension, and patients with renal disease and hypertension, should have their blood pressure lowered intensively. A recent analysis of long-term clinical trials over the past 8 years clearly demonstrates that the lower the blood pressure over a range of values, the greater the preservation of renal function. It is also readily apparent that monotherapy does not suffice in attaining these more intensified goals. A review of five clinical trials in the recent National Kidney Foundation consensus report demonstrates that patients randomized to the lower level of blood pressure required an average of 3.2 different antihypertensive medications taken daily. Consequently, it is evident that the question is no longer what the initial preferred monotherapy should be, but rather what should be the optimal drug to add to an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. In this paper we review data from several recent studies clearly indicating that to achieve goal blood pressure in the clinical setting of metabolic disarray and hyperglycemia, long-acting calcium antagonists constitute an excellent add-on agent for enhancing efficacy. We anticipate that the data that will accrue from the IDNT and RENAAL studies will further delineate the renal effects of dihydropyridine calcium antagonists.

Nifedipine increases endothelial nitric oxide bioavailability by antioxidative mechanisms.

Short-term treatment of the endothelium with dihydropyridine calcium antagonists resulted in an increased release in NO that is not due to a modulation of L-type calcium channels, because macrovascular endothelial cells do not express this channel. We investigated whether long-term (48 hours) treatment of porcine endothelial cell cultures with the dihydropyridine calcium antagonist nifedipine resulted in a similar enhanced NO liberation. Regarding to the underlying mechanism, we examined whether (1) nifedipine changed the mRNA and protein levels of the constitutive endothelial NO synthase (NOS) in endothelial cell cultures or (2) nifedipine exerts an NO protective effect via its antioxidative properties, as revealed in a cell culture model and with native endothelium from porcine coronary arteries. Nifedipine induced a significant time- and concentration-dependent increase (132+/-47%, 1 micromol/L, 40 minutes' incubation) in the basal NO liberation (oxyhemoglobin assay). This increased NO release was not due to elevated NOS (type III) mRNA (Northern blot analysis) and protein (Western blot analysis) levels. However, nifedipine (both short- and long-term treatment) significantly reduced the basal and glucose (20 and 30 mmol/L)-stimulated formation of reactive oxygen species (lucigenin assay) of endothelial cell cultures and native cells. We conclude that the calcium antagonist nifedipine enhances the bioavailability of endothelial NO without significantly altering the NOS (type III) mRNA and protein expression, possibly via an antioxidative protection. This increased NO availability may cause part of the vasodilation and might contribute to the antithrombotic, antiproliferative, and antiatherosclerotic effects of dihydropyridine calcium antagonists.

Calcium antagonists ameliorate ischemia-induced endothelial cell permeability by inhibiting protein kinase C.

Dihydropyridines block calcium channels; however, they also influence endothelial cells, which do not express calcium channels. We tested the hypothesis that nifedipine can prevent ischemia-induced endothelial permeability increases by inhibiting protein kinase C (PKC) in cultured porcine endothelial cells. Ischemia was induced by potassium cyanide/deoxyglucose, and permeability was measured by albumin flux. Ion channels were characterized by patch clamp. [Ca2+]i was measured by fura 2. PKC activity was measured by substrate phosphorylation after cell fractionation. PKC isoforms were assessed by Western blot and confocal microscopy. Nifedipine prevented the ischemia-induced increase in permeability in a dose-dependent manner. Ischemia increased [Ca2+]i, which was not affected by nifedipine. Instead, ischemia-induced PKC translocation was prevented by nifedipine. Phorbol ester also increased endothelial cell permeability, which was dose dependently inhibited by nifedipine. The effects of non-calcium-channel-binding dihydropyridine derivatives were similar. Analysis of the PKC isoforms showed that nifedipine prevented ischemia-induced translocation of PKC-alpha and PKC-zeta. Specific inhibition of PKC isoforms with antisense oligodeoxynucleotides demonstrated a major role for PKC-alpha. Nifedipine exerts a direct effect on endothelial cell permeability that is independent of calcium channels. The inhibition of ischemia-induced permeability by nifedipine seems to be mediated primarily by PKC-alpha inhibition. Anti-ischemic effects of dihydropyridine calcium antagonists could be due in part to their effects on endothelial cell permeability.

Amlodipine lowers blood pressure without increasing sympathetic activity or activating the renin-angiotensin system in patients with essential hypertension.

Recent clinical studies suggest that the reflex increase in sympathetic nervous activity accompanying a reduction in blood pressure may contribute to the untoward effects of dihydropyridine calcium antagonists. The aim of this study was to examine whether plasma noradrenaline levels and renin activity are increased with the reduction of blood pressure during the initial phase of administration of the long-acting dihydropyridine calcium antagonist amlodipine. The effects of amlodipine on ambulatory blood pressure and on diurnal variations in plasma noradrenaline and renin activity were examined 1, 4, and 7 days after the start of amlodipine administration in eight inpatients with essential hypertension. The 24-h mean systolic and diastolic blood pressure on day 7 was significantly lower than it was 1 day before the start of treatment. There was no change in the mean heart rate. The mean trough to peak ratios of systolic and diastolic blood pressure of seven patients were 61% and 71%, respectively. Diurnal patterns of plasma noradrenaline levels and renin activity 1, 4, and 7 days after the start of amlodipine administration were unchanged. The antihypertensive effects of amlodipine were of slow onset and long duration and were not accompanied by an increase in sympathetic activity or activation of the renin-angiotensin system.

Effects of dihydropyridine calcium antagonists on rat midbrain dopaminergic neurones.

1. The effects of the dihydropyridine calcium channel antagonists, nifedepine and nimodipine (300 nM-30 microM) were tested in vitro on intracellularly recorded dopaminergic neurones in the rat ventral mesencephalon. 2. Bath applied nifedipine and nimodipine inhibited in a concentration-dependent manner the spontaneous firing discharge of the action potentials, whereas, the dihydropyridine calcium channel agonist, Bay K 8644 increased the firing rate. 3. Pacemaker oscillations and bursts of action potentials were produced by loading the cells with caesium. Nifedipine and nimodipine reduced the rate and the duration of the caesium-induced membrane oscillations and decreased the number of action potentials in a burst. During the blockade of potassium currents the dopaminergic neurones often developed a prolonged (100-800 ms) afterdepolarization that was also inhibited by dihydropyridines. 4. The spontaneous discharge of calcium spikes was also inhibited by both dihydropyridine calcium antagonists. The apparent input resistance and the level of membrane potential were not affected by the dihydropyridine calcium antagonists. 5. If the action potential duration was less than 150 ms the shape of the spike was not clearly influenced by both calcium antagonists. However, when the duration of the action potential was longer than 150-200 ms due to the intracellular injection of caesium ions plus the extracellular application of tetraethylammonium (10-50 mM), both nifedipine and nimodipine reversibly shortened the plateau potential. 6. It is suggested that nifedipine and nimodipine depress the rhythmic and bursting activity of the dopaminergic cells and shorten the calcium action potential by blocking dihydropyridine-sensitive high-threshold calcium currents.

The effect of dihydropyridine calcium antagonists on heart rate: Studies of felodipine

Blood pressure reduction with dihydropyridine calcium antagonists results in an initial activation of the baroreceptor reflex, which causes a transient increase in heart rate. The present double-blind, cross-over, single-dose study investigated the effect of felodipine extended-release (ER) tablets (5 mg), conventional nitrendipine immediate-release tablets (10 mg), and placebo on heart rate in 12 patients with hypertension. Furthermore, an analysis of pooled heart rate data from four double-blind, monotherapy studies of felodipine ER in hypertension was performed. The effect of felodipine ER 5 to 10 mg once daily (n = 213) compared with placebo (n = 196), on heart rate was measured 24 hours postdose after 4 weeks of treatment. In the single-dose study, the blood pressure reduction with both felodipine and nitrendipine was associated with a modest reflexogenic increase in heart rate. This tended to occur faster with nitrendipine, and the increase in heart rate at 1 hour after administration was significant with nitrendipine, but not with felodipine. However, the effect on heart rate was modest for both drugs. By comparison, the effect of a standardized lunch meal on heart rate (+7 beats/min) was at least as great as that of felodipine (+2 to 6 beats/min). The analysis of pooled heart rate data showed that continued treatment with felodipine did not significantly affect heart rate compared with placebo; the mean difference in change was 1.1 beats/min ( P > 0.20). In conclusion, the recommended starting dose of felodipine ER for the treatment of hypertension (5 mg once daily) causes an initial, clinically insignificant increase in heart rate. During long-term treatment, however, heart rate is completely normalized and no different from heart rate in patients in the placebo group.

Effects of dihydropyridines on cerebral blood vessels

To evaluate the effects of dihydropyridine calcium antagonists on the cerebral circulation in stroke patients. DESIGN OF STUDIES: Mean cerebral circulation parameters were studied in chronic stroke patients with hypertension and treated acutely or chronically (2 weeks) with nicardipine or nifedipine retard. The effects of nicardipine on local cerebral blood flow were also studied in patients with a subacute brain infarction. Mean cerebral blood flow was significantly increased after a single oral administration of nicardipine but not after nifedipine retard. Both calcium antagonists reduced mean arterial pressure. Nifedipine retard acted mainly by reducing blood pressure and nicardipine mainly by reducing cerebrovascular resistance. Dihydropyridines have a beneficial effect in the control of hypertension in stroke patients.

Pharmacokinetics of Nilvadipine

Nilvadipine is absorbed rapidly and completely and its absolute bioavailability is about 14-19% because of its high first-pass metabolism. Maximum plasma levels and the extent of bioavailability increase proportionally with the dose. Nilvadipine is mainly excreted via the kidney as inactive metabolites. Slow tissue redistribution is probably the reason for the terminal elimination half-life of 15-20 h. There was a good correlation between the estimated tissue concentration and the reduction in blood pressure in patients. The use of the sustained-release pellet formulation can prevent plasma level peaks and thereby lessen the typical side effects of dihydropyridine calcium antagonists. The pharmacokinetics of nilvadipine were not affected by impaired renal function, and although the bioavailability was increased in liver cirrhosis, there was no accumulation after repeated doses. There was no effect on plasma digoxin levels. The plasma concentration of nilvadipine can be affected by either activation or inhibition of the cytochrome P450 system. The use of a sustained-release once-a-day formulation to lower the peaks in plasma levels along with nilvadipine's long terminal half-life means that this well-tolerated pharmaceutical formulation can be employed in clinical trials for the treatment of hypertension and expected to work over 24 h.

Comparative Anti-Ischemic Effects of Dihydropyridine Calcium Antagonists in Isolated Perfused Rat Hearts: Relationship of Cardiodepression and Cardioprotection

A comparison was made of the anti-ischemic effects of dihydropyridine calcium antagonists in isolated globally ischemic rat hearts. Pretreatment with amlodipine, nifedipine, nitredipine, or nisoldipine reduced reperfusion enzyme (lactate dehydrogenase) release and contracture after 25 min of global ischemia and 30 min of reperfusion. Increasing concentrations of all compounds resulted in proportionally smaller reductions in the severity of ischemia, with larger decreases in nonischemic tissue contractility occurring. Reperfusion function was significantly improved at 30 min with nifedipine only; however, at 60 min reperfusion function was significantly improved for all except nisoldipine. Washout data from nonischemic hearts (rate of disappearance of cardiodepressant effects) showed that the dihydropyridines washed out in the following order (fastest to slowest): nifedipine greater than nitrendipine greater than nisoldipine greater than amlodipine. Thus, these dihydropyridines are anti-ischemic, though at higher concentrations cardiodepressant effects increase disproportionately. Differences in washout also effect the ability of these compounds to improve reperfusion function.

Antiperoxidant effects of dihydropyridine calcium antagonists

Etude du potentiel antiperoxydant de 5 antagonistes du Ca 2+ dans des liposomes prepares a partir de phospholipides issus de myocarde de rat: Niludipine, Ninodipine, Nisoldipine, Nicardipine et Telodipine. On montre que ces antagonistes du Ca 2+ ont une large capacite antioxydante et peuvent proteger les phospholipides de la membrane du myocarde contre des agents peroxydants

The Effect of Dihydropyridine Calcium Antagonists in Hypertensive Patients with Impaired Renal Function

Dihydropyridine calcium antagonists play an important role in the treatment of arterial hypertension. In many centers, they are used as first-line treatment. Since impaired renal function can be a complication of long-standing blood pressure elevation, the usefulness of dihydropyridine calcium antagonists in hypertensive patients with reduced glomerular filtration rate is an important clinical issue. Several studies of the pharmacokinetics of calcium antagonists, such as nifedipine and related compounds, clearly show that the important pharmacokinetic variables are not affected by impaired renal function. Moreover, the antihypertensive efficacy is not reduced in patients with reduced glomerular filtration rate. A matter of potentially great clinical importance is the fact that several studies have shown that treatment with dihydropyridine calcium antagonists in patients with impaired renal function has reduced the rate of deterioration in filtration rate, leading to a preservation of renal function. It can therefore be concluded that dihydropyridine calcium antagonists are useful in the treatment of hypertensive patients with impaired renal function, that the major pharmacokinetic and pharmacodynamic variables are not negatively affected, in particular that the antihypertensive effect is maintained in such patients, and that there is no retention of metabolites. Finally, the observation that the decline in renal function can be slowed down suggests that dihydropyridine calcium antagonists may be the preferential treatment in hypertensive patients with reduced renal function.

The Effect of Dihydropyridine Calcium Antagonists in Hypertensive Patients with Impaired Renal Function

Journal of Cardiovascular Pharmacology™ is a peer reviewed, multidisciplinary journal that publishes original articles and pertinent review articles on basic and clinical aspects of cardiovascular pharmacology. Appropriate subjects include new drug development and evaluation, physiological and pharmacological bases of drug action, metabolism, drug interactions and side effects, clinical results with new and established agents and novel methods. The focus is on pharmacology in its broadest applications, incorporating not only traditional approaches, but new approaches to the development of pharmacological agents and the prevention and treatment of cardiovascular diseases.

Effects of dihydropyridine calcium antagonists on rabbit renal Na,K-ATPase activity in vitro

Dihydropyridines are reported to have a stimulatory effect on vascular smooth muscle Na, K-ATPase activity in vitro. We studied the effects of the dihydropyridine calcium antagonists nimodipine, nitrendipine, nitoldipine, niludipine, nifedipine and felodipine (10 −5 M) on purified Na,K-ATPase isolated from rabbit kidney outer medulla. We were unable to detect an effect of the drugs on the enzyme activity, either under optimal or suboptimal substrate conditions. Likewise, NaK-ATPase activity, partly inhibited by the addition of ouabain (10 −6 M), Ca 2+ (10 −3 M) or arachidonic acid (4×10 −5 M), was not influenced by the dihydropyridines. The absence of a stimulatory effect of dihydropyridines on renal Na,K-ATPase is in agreement with the known diuretic and natriuretic effects of the drugs in normotensive and hypertensive men.

Blockade of Ca2+ and K+ currents in bag cell neurons of Aplysia californica by dihydropyridine Ca2+ antagonists

The effects of dihydropyridine calcium antagonists on whole-cell Ca2+ and K+ currents in the neurosecretory bag cells of the marine mollusc Aplysia californica have been investigated. Nifedipine and nisoldipine blocked bag cell Ca2+ currents with effects similar to those seen previously on Ca2+ currents in cardiac muscle: both compounds appeared to interact with Ca2+ channels when they were closed, open, and inactivated. Also, as seen in cardiac cells, nifedipine apparently binds with higher affinity to Ca2+ channels when they are inactivated than when they are either closed or open. Nifedipine and nisoldipine also inhibited 2 outward K+ currents in bag cells: the "delayed rectifier" (IK) and the "A" (IA) currents. Half-maximal blockade of Ca2+ currents occurred at approximately 1.4 microM nifedipine, compared to approximately 3-5 microM for half-maximal blockade of IK and IA. The effects of these compounds on bag cell Ca2+ and K+ currents are interpreted and discussed here in terms of the "modulated receptor" model of drug action. In contrast, however, no measurable effects of nifedipine or nisoldipine were seen on Ca2+ (and/or K+) currents in several vertebrate neuronal cell types. Our results suggest that there are likely to be structural and/or conformational variations in Ca2+ channels in different cells, tissues, and/or species and also that, in some cells, Ca2+ and K+ channels might be structurally similar. These findings also suggest, therefore, that if dihydropyridine binding is used to identify Ca2+ channels, care should be taken to ensure that binding correlates closely with the Ca2+ channels of interest.

The Natriuretic Effect of the Dihydropyridine Calcium Antagonist Felodipine

Changes in systemic and renal hemodynamics and in the renin-angiotensin system caused by infusion of the calcium antagonist felodipine were investigated in a placebo-controlled study with 12 normotensive volunteers before and during a graded infusion of angiotensin II (AII). In spite of a fall in blood pressure through vasodilatation, felodipine had a natriuretic effect. There was only a transient rise in effective renal plasma flow (ERPF), whereas glomerular filtration rate (GFR) did not change. Urinary sodium excretion remained elevated when ERPF had normalized. Urinary potassium excretion did not change. AII-induced reductions in ERPF, GFR, and sodium excretion were abolished by felodipine. Felodipine also partly antagonized the rise in plasma aldosterone levels caused by AII. We conclude that the natriuretic effect of dihydropyridine calcium antagonists is probably not caused by a single mechanism, but may be dependent on changes in renal hemodynamics together with a diminished sodium reabsorption at multiple tubular sites. Interference with AII-mediated renal mechanisms and an impairment of the action of aldosterone may contribute to this natriuretic effect as well.

The effects of dihydropyridine calcium antagonists on heme biosynthesis in chick embryo liver cell culture.

A variety of 1,4-dihydropyridine calcium antagonists were tested for porphyrinogenic activity in chick embryo liver cell culture. 3,5-Dimethoxycarbonyl-1,4-dihydro-2, 6-dimethyl-4-(ortho-nitrophenyl)pyridine (nifedipine) was shown to be a potent porphyrinogenic agent. This activity was shared by a number of related analogues, viz., the 4-phenyl, 4-(meta-nitrophenyl), 4-(para-nitrophenyl), 4-(ortho-methoxyphenyl), 4-(meta-trifluoromethylphenyl), and 4-(para-trifluoromethylphenyl) analogues and nitrendipine; nicardipine exhibited very weak activity. The porphyrinogenic potency of the 1,4-dihydropyridines did not parallel their calcium antagonist activity. Nifedipine did not exhibit ferrochelatase-lowering activity in chick embryo liver cell culture and uroporphyrin and heptacarboxylic acid porphyrin were the major porphyrins to accumulate. Nifedipine did not cause suicidal destruction of cytochrome P-450 in chick embryo hepatic microsomes. Because nifedipine possesses comparable porphyrinogenic activity to sodium secobarbital in chick embryo liver cell culture, caution is required if nifedipine or related drugs are administered to patients with hereditary hepatic porphyria.