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PubMed1992

Use of pseudoracemic nitrendipine to elucidate the metabolic steps responsible for stereoselective disposition of nitrendipine enantiomers.

1. The pharmacokinetics, protein binding, bioavailability and metabolism of (+)-R- and (-)-S-nitrendipine were studied in six healthy subjects following random oral administration of 20 mg (+)-R-, 20 mg (-)-S- and 20 mg R,S-nitrendipine (pseudoracemic mixture of 10 mg [13C4)-(+)-R- and 10 mg (-)-S-enantiomer). 2. After administration of the enantiomers pronounced differences in AUC (R: 29.9 +/- 20.1; S: 123.8 +/- 63.7 ng ml-1 h; P less than 0.05), bioavailability (R: 10.7 +/- 7.4%; S: 44.6 +/- 23.1%; P less than 0.05) and Cmax (R: 14.4 +/- 7.7; S: 72.5 +/- 40.5 ng ml-1; P less than 0.05) were observed between R- and S-nitrendipine. When racemic nitrendipine was given bioavailability and dose normalized AUC and Cmax values of the S-enantiomer were not different from the values after S-nitrendipine-administration. In contrast, bioavailability (R: 10.7% R,S: 22.1%) and dose normalized AUC (R: 15.0; R,S: 29.5 ng ml-1 h and Cmax (R: 7.2; R,S: 16.8 ng ml-1) of R-nitrendipine were doubled following R,S- as compared with R-nitrendipine administration. t1/2 (R: 9.8; S: 9.1 h) and tmax were not different between the enantiomers nor were the values different after administration of the enantiomers or racemate. The fraction unbound in serum of R-nitrendipine was 0.0098 +/- 0.0032 (s.d.) and that of S-nitrendipine was 0.0083 +/- 0.0015 (s.d.). 3. The AUC values of the major pyridine metabolite M1 were similar after administration of R- and S-nitrendipine (S: 114.7 +/- 48.5; R: 71.7 +/- 29.9 ng ml-1 h).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1984

Comparison of the acute hemodynamic effects of nifedipine with nitrendipine and a study of the electrophysiological effects of nitrendipine in man.

Calcium antagonists are known to have an inhibitory effect on the contractile status of the smooth muscle of the arterioles, the muscle fibers of the heart, and the cardiac conduction system, especially the atrioventricular node. The vasodilatation that is produced may be observed in the coronary arteries but predominates in the peripheral resistance vessels. Nifedipine and its 1,4-dihydropyridine derivative, nitrendipine, are not only useful in coronary artery disease but also have potential as antihypertensive agents. The acute hemodynamic effects of both nifedipine and nitrendipine, administered in a 1.0 mg intravenous dose, were studied. The compounds were randomly allocated to six patients, where each served as his own control. In addition, the effect of 1 mg of nitrendipine intravenously on the electrophysiological impulse formation and conduction was investigated in a second group of six patients. There were substantial differences in the intensity and duration of the hemodynamic effects of both drugs. The total peripheral resistance (TPR) fell after nifedipine from 1,730 +/- 240 to 1,280 +/- 120 and after nitrendipine from 1,960 +/- 420 to 1,200 +/- 150 dynes-s-cm-5. There was a concurrent significant reduction in the systolic aortic and left ventricular pressure after nifedipine and nitrendipine from 152 +/- 8 to 128 +/- 13 and 161 +/- 19 to 122 +/- 18 mm Hg, respectively. Heart rate increased due to baroreceptor stimulation by 21% with nifedipine and by 32% with nitrendipine. From the results of the electrophysiological study, nitrendipine did not have any significant effect on the sinus or atrioventricular node function. The substance may be safely used in patients with conduction disturbances.

Angina Pectoris↗

PubMed1991

Once- vs. twice-daily nitrendipine in the treatment of mild to moderate hypertension, Canadian Nitrendipine Study Group.

Improved measurement of the plasma concentration of nitrendipine demonstrated a plasma half-life of 17-21 h, allowing once-daily (o.d.) instead of currently twice-daily (b.i.d.) dosing. To determine the effectiveness of nitrendipine given o.d. vs. b.i.d., 78 hypertensive patients, [supine diastolic blood pressure (DBP) of 95-114 mm Hg] were randomized in a double-blind fashion to 12 weeks of treatment with either nitrendipine 10 mg b.i.d. (n = 39) or nitrendipine 20 mg o.d. (n = 39) after a 2-week placebo baseline period. Blood pressures (BPs) were measured in the morning at the end of the dosing interval. Mean +/- SD reduction in supine systolic BP (SBP) and DBP in patients evaluable for efficacy (greater than or equal to 14 days treatment) were 7.2 +/- 16.5 and 7.7 +/- 10.3 mm Hg, respectively, after nitrendipine b.i.d. (n = 38) and 9.4 +/- 15.1 and 9.5 +/- 7.0 mm Hg, respectively, after nitrendipine o.d. (n = 36). Similar falls in BP were found for both regimens in patients completing the full 12 weeks of treatment period (n: o.d. = 28, b.i.d. = 32). Discontinuation due to adverse experiences (AEs) occurred in three patients on b.i.d. and eight patients on o.d., the latter mostly in the first 2 weeks of therapy. Overall, AEs were higher in the o.d. group (% AEs at least possibly related to study medication: o.d. = 44%, b.i.d. = 33%). Most frequent AEs were headache and flushing.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗

PubMed1991

Effectiveness and tolerability of once versus twice daily nitrendipine in the treatment of mild to moderate hypertension. The Canadian Nitrendipine Study Group.

Improved measurement of plasma concentrations of nitrendipine demonstrates a plasma half-life of 17 to 21 h allowing once daily dosing for antihypertensive treatment. To determine the effectiveness and tolerability of nitrendipine given once versus twice daily, 78 patients with mild to moderate essential hypertension were randomized in a double-blind fashion to 12 weeks of treatment with either nitrendipine 20 mg once daily (n = 39) or nitrendipine 10 mg bid (n = 39). Blood pressures measured at the end of the dosing interval were similar on 20 mg once daily and 10 mg bid. Adverse events considered to be drug related (flushing and headaches) occurred mostly at the beginning of active treatment and more frequently on the once daily dosing, resulting in a greater number of patients being withdrawn from the once daily treatment group. Thus, nitrendipine 20 mg once daily lowered blood pressure as effectively as 10 mg bid but was associated with a higher incidence of adverse events. These could be minimized by starting at nitrendipine 10 mg once daily and increasing to 20 mg once daily after two to four weeks.

Blood Pressure↗

PubMed1992

[The efficacy of nitrendipine in patients with stable arterial hypertension. The data from a cooperative study in the USSR. The Working Group for the Cooperative Study of Nitrendipine].

Nitrendipine (bypress) manufactured by Bayer Company in the form of 10 and 20 mg tablets and administered in a dose of 20-40 mg/day turned out an effective antihypertensive remedy in 65% of patients with arterial hypertension largely running a mild course. The effect of nitrendipine administered in a single daily dose of 20 mg did not differ from that attained with the same dose given in two intakes. The raising of the daily dose of nitrendipine from 20 to 40 mg was associated with augmentation of the hypotensive effect in 43.8% of the patients in whom the treatment in a dose of 20 mg a day had turned out ineffective. Under the conditions of the cross-over method with the use of the reference drugs belonging to three groups of the basic antihypertensive agents (nifedipine, propranolol, hydrochlorothiazide), the hypotensive effect of nitrendipine did not differ from that produced by the drugs under comparison (according to the mean group indicators and individual assessment of the efficacy). The tolerance of nitrendipine administered in a dose of 10 mg twice a day or in a dose of 20 mg once or twice a day was satisfactory.

Adult↗

PubMed1986

Effects of bepridil and diltiazem on [3H]nitrendipine binding to canine cardiac sarcolemma. Potentiation of pharmacological effects of nitrendipine by bepridil.

[3H]Nitrendipine binds to canine cardiac sarcolemma in a specific, saturable and rapid manner. Bepridil, a Ca++ channel inhibitor, stimulates this binding at submicromolar concentrations, but inhibits it noncompetitively at higher concentrations (IC50 = 15.8 microM). The increase in binding was due primarily to a 30% increase in the association rate constant (k+1) of [3H]nitrendipine, causing a decrease in the KD from a control value of 0.40 to 0.28 nM. In contrast to bepridil, diltiazem causes only an increase in [3H] nitrendipine binding without any inhibition. The increase was due primarily to an increase in receptor site density (maximum binding). These results show that the regulatory effects of bepridil and diltiazem on [3H]nitrendipine binding to cardiac tissue are different. The stimulatory effects of bepridil appeared to be pharmacologically relevant as low concentrations of bepridil potentiated the negative inotropic effect of nitrendipine in isolated perfused rat hearts.

Animals↗

PubMed1988

The pharmacokinetics of nitrendipine. I. Absorption, plasma concentrations, and excretion after single administration of [14C]nitrendipine to rats and dogs.

[14C]nitrendipine (3-ethyl 5-methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate, Bay e 5009, Baypress, Bayotensin) was administered to rats and dogs (intravenously, orally, intraduodenally, 0.5-50 mg/kg) in order to investigate absorption, disposition, and excretion of parent compound and metabolites. The absorption of radioactivity following oral administration of [14C]nitrendipine was rapid and almost complete in both species. Maximum concentrations of total radioactivity in plasma were reached after 1.2 (rat) or 0.7 h (dog). The radioactivity was eliminated from plasma with terminal half-lives of 57 (rat) and 188 h (dog) during an observation period up to 10 and 9 days, respectively. Unchanged nitrendipine contributed to the AUC of total radioactivity only 8-9% after intravenous and 1-2% after oral administration. The bioavailability of nitrendipine after oral administration amounted to 12% in rats and 29% in dogs due to a strong first pass elimination process. About two thirds of the radioactivity administered were excreted via faeces, one third via urine. Distinct sex-differences in the excretion pattern could be found in rats but not in mice. They were attributed to well-known sex differences of the metabolic capacities in rat liver. In rats the radioactivity excreted via bile (about 75% of the dose) was subject to a marked entero-hepatic circulation, about 50% of the amount excreted being reabsorbed. The radioactive residues in the body were low (0.5% of the dose after 2 days in rats; less than or equal to 0.6% after 9 days in dogs).

Absorption↗

PubMed1988

The pharmacokinetics of nitrendipine. II. Distribution to and elimination from organs and tissues of rats and dogs after single or repeated administration of [14C]nitrendipine.

[14C]nitrendipine (3-ethyl 5-methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate, Bay e 5009, Baypress, Bayotensin) was administered to male rats, pregnant and lactating female rats, and female dogs intravenously or orally once as well as to male rats repeatedly over a period of 4 weeks (rat 5 (and 10) mg/kg, dog approximately 3 mg/kg). The distribution of radioactivity (unchanged compound and metabolites) was investigated using whole-body autoradiography as well as quantitative measurements of the organ and tissue concentrations of radioactivity after necropsy. [14C]nitrendipine was distributed rapidly and heterogeneously into the organs and tissues of rats. Already 24 h after administration most of the radioactivity had reached the gastro-intestinal (GI) tract via biliary secretion. High concentrations were also detectable in liver and kidneys. The radioactivity was eliminated from the tissues with terminal half-lives lying between 52 (plasma) and 360 h (muscle). Only 0.13% of the administered radioactivity was detectable in the body (excl. GI-tract) after 10 days. In dogs, the distribution pattern was similar to that observed in rats. After 28 daily administrations of [14C]nitrendipine to male rats the plasma and tissue equivalent concentrations were 3 (plasma) to 12 times (adipose tissue) higher than after single administration. The half-lives were increased by 20 to 70%, lying between 2 and 15 days. There were no indications for any specific retention of the radioactivity. The radioactivity from [14C]nitrendipine was secreted into the milk of lactating rats and crossed the placental barrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗

PubMed2005

Preparation and evaluation of solid dispersion for nitrendipine-carbopol and nitrendipine-HPMCP systems using a twin screw extruder.

In the present study, we prepared solid dispersions of the poorly water-soluble drug nitrendipine (NIT) using the twin screw extruder method with high-molecular-weight substances, hydroxypropylmethylcellulosephthalate (HPMCP) and Carbopol (CAR), as carriers. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) evaluation showed that solid dispersions can be formed when NIT-HPMCP and NIT-CAR mixtures are treated with the twin screw extruder method. Fourier Transformation IR Spectroscopy (FT-IR) obtained with NIT-HPMCP and NIT-CAR solid dispersions indicated the presence of hydrogen bonding between the drug and the carriers. NIT-CAR solid dispersions were found to give somewhat higher dissolution than crystalline NIT and physical mixtures, while the dissolution of NIT-HPMCP solid dispersions was markedly decreased compared with the crystalline NIT and physical mixtures. These findings indicated that CAR has a greater ability to improve the dissolution of NIT than HPMCP when a twin screw extruder was employed to prepare the solid dispersions. The twin screw extruder method can be used as a simple and effective method for the preparation of solid dispersions to improve the dissolution properties of poorly water-soluble drugs when choosing proper polymers as carriers.

Acrylic Resins↗

PubMed1986

Characteristics of a Ca2+/calmodulin-dependent binding of the Ca2+ channel antagonist, nitrendipine, to a postsynaptic density fraction isolated from canine cerebral cortex.

Synaptic membrane (SM) and postsynaptic density (PSD) fractions isolated from the cerebral cortex (CTX) and cerebellum (CL) of the canine brain were found to contain one class of specific nitrendipine binding sites. The specific binding constants were: CTX-SM, Kd = 110 pM (Bmax = 126 fmol/mg protein); CTX-PSD, Kd = 207 pM (Bmax = 196 fmol/mg); CL-SM, Kd = 100 pM (Bmax = 65 fmol/mg); CL-PSD, Kd = 189 pM (Bmax = 80 fmol/mg). Treatment of the CTX-SM and CTX-PSD fractions with 0.5% deoxycholate and 1.0% N-lauroyl sarcosinate removed 88-91% and 42-51% of the nitrendipine binding, respectively, indicating that the major nitrendipine binding present in the SM fractions are of non-synaptic origin. Moreover, the percentages of total protein and specific nitrendipine binding removed from PSDs by these detergents were similar, indicating no preferential dissociation of the latter, and suggesting that the receptor protein is firmly bound and is probably an intrinsic component of the PSD fraction. Both Ca2+ and calmodulin were found to be important for the binding of nitrendipine to the CTX-SM and CTX-PSD fractions since: R24571, a calmodulin antagonist, was found to inhibit nitrendipine binding to the CTX-SM and CTX-PSD fractions with IC50 values of 1.1 microM and 0.9 microM, respectively; removal of Ca2+ from the CTX-SM and CTX-PSD fractions with 0.2 mM EGTA resulted in losses of specific nitrendipine binding of 80 and 90%, respectively; Ca2+ alone restored nitrendipine binding to EGTA-pretreated CTX-SM fractions and not to CTX-PSD fractions, with the latter needing both Ca2+ and calmodulin to restore nitrendipine binding; EGTA treatment removed 14-16% and 89-91% of nitrendipine bound to the CTX-SM and CTX-PSD fractions, respectively, suggesting that calmodulin (but not Ca2+) is needed to maintain the nitrendipine-nitrendipine receptor-calmodulin complex; Ca2+-reconstituted EGTA-pretreated CTX-SM fractions and the Ca2+ plus calmodulin-reconstituted EGTA-pretreated CTX-SM and CTX-PSD fractions were found to have similar binding constants to those for the corresponding native, untreated fractions; and the Ca2+/calmodulin dependency on nitrendipine binding was similar to the well-known Ca2+/calmodulin dependency on phosphorylation in EGTA-pretreated PSD fractions. It needed much less Ca2+ to saturate Ca2+/calmodulin-dependent phosphorylation of the pretreated CTX-PSD fractions than the nitrendipine binding. Yet, less calmodulin was needed to saturate nitrendipine binding than the phosphorylation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1984

Differentiation of receptor sites for [3H]nitrendipine in chick hearts and physiological relation to the slow Ca2+ channel and to excitation-contraction coupling.

The properties of interaction of the Ca2+ channel antagonist [3H]nitrendipine have been investigated in chick hearts at various stages of in ovo and post-natal development and in cultured cells. The dissociation constant of the [3H]nitrendipine-receptor complex is between 0.4 nM and 0.5 nM for intact ventricle and cultured cells. [3H]Nitrendipine binding is antagonized by nitrendipine analogs. The order of efficacy of the different dihydropyridine molecules is nitrendipine greater than nimodipine greater than nifedipine greater than nisoldipine with Kd values ranging from 0.5 to 4 nM. Inhibition of [3H]nitrendipine binding by other antiarrhythmic molecules like amiodarone, F13004 and bepridil was observed. Half-maximum inhibitions (K0.5) were found for verapamil and D600 at concentrations between 0.23 and 0.26 microM. The potency of organic Ca2+ blockers to depress by 50% the maximum amplitude of spontaneous beating of heart cells is closely related to K0.5 values obtained from [3H]nitrendipine binding experiments. Electrophysiological results indicate that the slow channel is insensitive to nitrendipine at the younger stage of development (3-day-old) whereas, in adult like cells, nitrendipine (50 nM) abolished both slow action potential due to the slow Ca2+ channel and contraction. The maximum binding capacity for [3H]nitrendipine is found to increase during development of the embryonic heart from 40 fmol/mg protein at day 3 to 100 fmol/mg protein at day 14, to stay relatively stable until day 18. Then the number of sites increases rapidly to reach a second plateau at 210 fmol/mg protein on day 4 after hatching. Treatment with 6-hydroxydopamine results in 35% increase in [3H]nitrendipine binding, whereas reserpine treatment is without effect. Developmental properties of nitrendipine-sensitive Ca2+ channels have been compared with those of tetrodotoxin-sensitive Na+ channels and muscarinic receptors. These results indicate that nitrendipine receptors exist at the early stage of development (3-day-old-hearts) but that they do not correspond to functional slow Ca2+ channels, that in ovo development corresponds both to an increase of the number of [3H]nitrendipine receptors and to the transformation of silent Ca2+ channels into functional Ca2+ channels, and that there is a regulation of the level nitrendipine-sensitive Ca2+ channels by innervation.

Animals↗

PubMed1994

The differential effects of felodipine and nitrendipine on cerebral dihydropyridine binding ex vivo and the ethanol withdrawal syndrome in mice.

1. The ability of two dihydropyridine calcium channel antagonists, felodipine and nitrendipine both to displace [3H]-isradipine binding in CNS tissue measured ex vivo and to protect against the ethanol withdrawal syndrome has been investigated. 2. Mice were injected with various doses of felodipine or nitrendipine and [3H]-isradipine binding measured in brain homogenates prepared 0.5, 3 or 5 h later. Inhibition versus dose curves were sigmoid and the dose required to produce 50% inhibition increased linearly with time after administration. Felodipine was approximately 10 times more potent than nitrendipine. 3. Nitrendipine (50 mg kg-1, i.p.) and felodipine (10 mg kg-1, i.p.) produced around a 75% inhibition of [3H]-isradipine binding 3 h later. Binding of [3H]-nitrendipine to cerebral tissues measured after in vivo injection of the ligand was decreased by nitrendipine (50 mg kg-1) and felodipine (10 mg kg-1) to a similar extent. 4. Nitrendipine (50 mg kg-1) prevented the behavioural signs of ethanol withdrawal as measured by handling induced convulsions, but felodipine (10 mg kg-1 or 2 mg kg-1) did not provide any protection against this effect of ethanol withdrawal. Felodipine (10 mg kg-1, twice daily) during the course of ethanol treatment also failed to attenuate the withdrawal syndrome. 5. The convulsive response to a mild audiogenic stimulus during ethanol withdrawal was increased following one dose of felodipine (5 mg kg-1, i.p.) but unaffected by nitrendipine. 6. Injection of Bay K 8644 (60 microgram, i.c.v.) produced a significant increase in handling-induced convulsive behaviour. Felodipine (10 mg kg-1, i.p.) reduced this behaviour both 60 and 120 min later, while nitrendipine (50 mg kg-1) showed a modest reduction only at 120 min.7. In contrast, nitrendipine (50mg kg-1) and felodipine (10 mg kg-1) produced similar effects on the hyperexcitability produced by handling following administration of bicuculline. Hexamethonium(8 mg kg-1) had no effect on this response.8. No change was found in [3H]-isradipine or [125I]-w-conotoxin binding to cerebral tissue prepared from ethanol-dependent mice.9. These results demonstrate that while felodipine and nitrendipine have similar actions on some CNS-mediated effects (raising seizure thresholds to several convulsant drugs), felodipine, in contrast to nitrendipine, has no effect on the ethanol withdrawal syndrome. Suggested explanations for the results include the possibility that nitrendipine may protect against the ethanol withdrawal syndrome via sites other than dihydropyridine receptors: that felodipine has partial agonist actions at dihydropyridine receptors in the CNS or that felodipine has actions which mask its protective effect in ethanol withdrawal.

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

PubMed1999

Effect of nitrendipine on renal function in renal-transplant patients treated with cyclosporin: a randomised trial.

BACKGROUND: Calcium antagonists such as nitrendipine reduce the effects of cyclosporin on renal haemodynamics, however, their long-term efficacy has not been established. We did a randomised trial to investigate the effects of nitrendipine on renal function in renal-transplant patients treated with cyclosporin. METHODS: 253 renal-transplant patients were recruited: 52 normotensive patients (diastolic blood pressure <90 mm Hg) were assigned placebo and 57 nitrendipine 5 mg twice daily; 71 hypertensive patients (diastolic blood pressure >90 to <115 mm Hg) were assigned placebo and 73 nitrendipine 10 mg twice daily. Nitrendipine was increased to 20 mg twice daily if the target diastolic blood pressure (<90 mm Hg) was not achieved. The patients were seen once a month for 24 months; blood pressure and serum creatinine concentration were recorded at each visit. Analysis was by intention to treat. FINDINGS: 63 patients were withdrawn (35 nitrendipine, 28 placebo). The mean serum creatinine concentration at baseline was slightly higher in the nitrendipine group (146.7 micromol/L [SE 4.42]) than in the placebo group (137.0 micromol/L [3.54]. At the 24-month endpoint or at dropout, serum creatinine concentration was significantly higher in the 123 patients in the placebo group than the 130 patients in the nitrendipine group (160.8 [7.1] vs 148.5 [5.3], p for effect of treatment=0.025, analysis of covariance in a two-way classification; 95% CI for difference -1.77 to -22.98). At study entry, the blood pressures of the placebo and the nitrendipine groups were almost identical. At 24 months, blood pressure was higher in the normotensive patients given a placebo than in those patients given nitrendipine. By contrast, blood-pressure values were similar in those hypertensive patients given a placebo and those given nitrendipine at the end of treatment. INTERPRETATION: The calcium antagonist nitrendipine has no adverse effects on kidney function in renal-transplant patients with cyclosporin. The drug has a small but significant nephroprotective effect, that is independent of the drug's antihypertensive action.

Adult↗

PubMed1986

Hemodynamic and metabolic effects of the calcium channel blocking agent nitrendipine.

In an open crossover comparison of propranolol and nitrendipine, 19 patients with hypertension received 40 to 160 mg propranolol and 5 to 20 mg nitrendipine twice a day. Mean (+/- SD) predose supine blood pressure fell from 145/98 +/- 11/7 to 132/88 +/- 12/8 mm Hg with propranolol and to 135/92 +/- 11/9 mm Hg with nitrendipine. Resting heart rate was reduced by propranolol but was unchanged 12 hours after nitrendipine dosing. Neither propranolol nor nitrendipine altered plasma glucose or insulin after oral glucose. Propranolol significantly increased fasting triglyceride levels and reduced high-density lipoprotein cholesterol levels, but nitrendipine induced no change. Propranolol reduced and nitrendipine increased plasma renin activity after exercise. Peak plasma nitrendipine levels were dose proportional and occurred at 1 to 2 hours after dosing, whereas peak blood pressure reductions occurred 4 hours after the last dose of nitrendipine and were associated with mean increases in heart rate. Nitrendipine is almost equivalent in hypotensive effect to propranolol, but nitrendipine increases plasma renin activity after exertion and may produce transient tachycardia. However, nitrendipine does not cause unwanted metabolic effects.

Administration, Oral↗

PubMed1983

[3H]nitrendipine receptors in skeletal muscle.

The richest source of receptors for the organic calcium channel blocker [3H]nitrendipine in muscle is the transverse tubule membrane. The tubular membrane preparation binds [3H]nitrendipine with a high affinity and has a very high number of [3H]nitrendipine binding sites. For example, for the transverse tubule membrane preparation from rabbit muscle, the dissociation constant of the nitrendipine-receptor complex is 1.8 +/- 0.3 nM and the maximum binding capacity Bmax = 50 +/- 6 pmol/mg of protein. Similar results have been found with a membrane preparation from frog muscle. The dissociation constant found at equilibrium is near that determined from the ratio of rate constants for association (kappa 1) and dissociation (kappa-1). Binding of [3H] nitrendipine is pH-dependent and reveals the presence of an essential ionizable group with a pK of 5.4 on the nitrendipine receptor. The binding is destroyed by proteases showing that the receptor is a protein. Three different classes of Ca2+ channel blockers inhibit [3H]nitrendipine to its specific site. (i) The dihydropyridine analogs of nitrendipine which are competitive inhibitors of [3H]nitrendipine. These molecules form tight complexes with the nitrendipine receptor with dissociation constants between 1.4 and 4.0 nM. (ii) Other antiarrhythmic molecules like verapamil, amiodarone, bepridil, and F13004 which are noncompetitive inhibitors of [3H]nitrendipine binding with dissociation constants between 0.2 and 1 microM. (iii) Divalent cations like Ni2+, Co2+, Mn2+, or Ca2+ which are noncompetitive inhibitors of [3H]nitrendipine binding with the following rank order of potency: Ni+ (K0.5 = 1.8 mM) greater than Co2+ (K0.5 = 2.7 mM) greater than Mn2+ (K0.5 = 4.8 mM) greater than Ca2+ (K0.5 = 65 mM).

Animals↗

PubMed1984

Direct photoaffinity labeling of the high affinity nitrendipine-binding site in subcellular membrane fractions isolated from canine myocardium.

[3H]Nitrendipine and high intensity ultraviolet irradiation have been used to photoaffinity label the protein component of the high affinity nitrendipine-binding site in subcellular membrane fractions from canine cardiac muscle. Irradiation of isolated cardiac membranes in the presence of [3H]nitrendipine resulted in the covalent labeling of a protein component that migrated on sodium dodecyl sulfate-polyacrylamide gels with an apparent molecular weight of 32,000. Incorporation of [3H]nitrendipine did not occur in the absence of irradiation. The photoaffinity labeling of the 32,000-Da protein by [3H]nitrendipine was inhibited by excess unlabeled nitrendipine, nifedipine, or verapamil. EDTA, ATP, and La3+, which are known to reduce high affinity nitrendipine binding, also inhibited the photoaffinity labeling of this membrane protein by [3H]nitrendipine. The 32,000-Da [3H]nitrendipine-labeled protein was found to be enriched in the ryanodine-sensitive fraction of cardiac sarcoplasmic reticulum and absent from the ryanodine-insensitive fraction of cardiac sarcoplasmic reticulum which is known to lack high affinity nitrendipine binding. Therefore, the 32,000-Da photoaffinity-labeled [3H]nitrendipine-binding protein exhibits properties identical to those expected for the protein component of the high affinity nitrendipine-binding site in isolated cardiac membranes.

Affinity Labels↗

PubMed1996

Antihypertensive efficacy and orthostatic tolerance of bunazosin vs nitrendipine: a multicentre double-blind randomized controlled study.

A multicentre double-blind randomized controlled study was conducted in 358 patients with mild to moderate essential hypertension. The goal was to compare the antihypertensive efficacy, tolerability, and in particular postural hypotension of the alpha 1-adrenoreceptor blocker bunazosin with the calcium channel blocker nitrendipine. Both treatment groups had comparable baseline blood pressure (BP) values, namely diastolic BP (DBP) of 103.8 +/- 5.6 mm Hg in the bunazosin group, and 103.4 +/- 6.0 mm Hg in the nitrendipine group, respectively. Baseline systolic BPs (SBP) were 149.7 +/- 14.4 mm Hg (bunazosin) and 149.2 +/- 14.3 mm Hg (nitrendipine). After 12 weeks of therapy, reduction of DBP (-6.1 +/- 11.7 mm Hg on bunazosin vs -6.9 +/- 9.9 mm Hg on nitrendipine; P = n.s.), and SBP (-4.4 +/- 14.3 mm Hg on bunazosin vs -7.0 +/- 14.4 mm Hg on nitrendipine; P = n.s.) was similar in both groups. During a provocative orthostatic tolerance test after the first dose, the incidence of prae-collapses (ie termination of the test due to orthostatic complaints) was higher on bunazosin (17 vs 2; P < 0.05) but orthostatic dysregulation symptoms (symptom score 1.37 on bunazosin vs 0.95 on nitrendipine; n.s.) and collapses (four on bunazosin vs one on nitrendipine; n.s.) occurred to a similar extent in both treatment groups. Three and 9 weeks after treatment, no increased susceptibility to orthostatic stress compared to baseline could be found in either group. Under daily life conditions, the frequency of orthostatic dysregulation was identical in both groups (0.8%). Bunazosin, however, was far better tolerated with 43.8% of the patients complaining of adverse events as opposed to 63.6% on nitrendipine (P < 0.001). The rate of early discontinuations due to adverse events was only 1.3% on bunazosin compared to 13.6% on nitrendipine (P < 0.001). In conclusion, bunazosin has a similar antihypertensive efficacy as nitrendipine. Despite an initially higher susceptibility to orthostatic stress under a provocative manoeuver, bunazosin evoked the same low incidence of orthostatic dysregulation symptoms as nitrendipine under daily life conditions, but was significantly better tolerated than nitrendipine.

Adrenergic alpha-Antagonists↗

PubMed2005

In vivo evaluation of two novel controlled-release nitrendipine formulations.

The objective of this work is to assess two novel controlled-release nitrendipine formulations, i.e., sustained-release nitrendipine microspheres having solid dispersion structure and a novel pH-dependent gradient-release delivery system for nitrendipine in healthy male volunteers, which were prepared by current authors. Domestic commercial nitrendipine tablets and Baypress nitrendipine tablets were employed as reference formulations. In a randomized, single-dose, fasting-state, crossover study design with a 1-week washout period, each subject received a 40-mg nitrendipine formulation. Plasma samples were collected over a 25-hour period after oral administration and were analyzed by a validated method using high performance liquid chromatography with ultraviolet detection. Pharmacokinetic parameters were determined using a noncompartmental analysis. The results provided evidence that the time to maximum plasma concentration of two novel controlled-release nitrendipine formulations were statistically significant prolonged in comparison with that of Baypress nitrendipine tablets. The relative bioavailabilities of test formulations were intensively improved compared with the domestic nitrendipine tablets, while the ratio is in a range of 80-120% in comparison with Baypress nitrendipine tablets. It is concluded that the two types of controlled-release systems are feasible for improving the dissolution rate of nitrendipine and obtaining a long-acting in vivo as well.

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