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Therapeutic Advances in Cardiovascular... Jun 2009Stroke remains a common vascular event with high mortality and morbidity. After heart disease, stroke is the second leading cause of death worldwide in adult persons.... (Review)
Review
Stroke remains a common vascular event with high mortality and morbidity. After heart disease, stroke is the second leading cause of death worldwide in adult persons. Silent or subclinical stroke is likely to occur with even greater frequency than clinical stroke and increases the risk of subsequent cerebrovascular events. Hypertension is by far the single most important controllable risk factor for stroke. The relationship between blood pressure (BP) and stroke mortality is strong, linear, and continuous in subjects with levels of BP higher than 115/75 mm Hg. Blood pressure reduction by antihypertensive treatment is clearly efficacious in the prevention of stroke (both primary and secondary). Although meta-analyses suggest that BP reduction, per se, is the most important determinant for stroke risk reduction, the question is if specific classes of antihypertensive drugs offer special protection against stroke is still controversial. Some studies have suggested that angiotensin receptors blockers (ARBs) appear to offer additional protection against stroke. This has been hypothesized in studies in hypertensives, such as LIFE and SCOPE, and especially in the only comparative trial focused on secondary stroke prevention. In the MOSES trial, the comparison of eprosartan versus nitrendipine in patients with a previous stroke resulted, despite a similar BP reduction, in a significant reduction in the primary composite endpoint of total mortality plus cardiovascular and cerebrovascular events, including recurrent events. These results may suggest a blood pressure-independent effect of ARBs, which can be mediated through several mechanisms, including their ability to counteract other markers of target organ damage, but also through a direct neuroprotective effect.
Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Humans; Hypertension; Prognosis; Secondary Prevention; Stroke
PubMed: 19443514
DOI: 10.1177/1753944709104164 -
Effects of some antihypertensive drugs on the metabolism and pharmacokinetics of indapamide in rats.Journal of Pharmacy & Pharmaceutical... 2012Indapamide, a non-thiazide antihypertensive diuretic agent, has been widely coadministered with other classes of antihypertensive agents to reach target systolic blood...
PURPOSE
Indapamide, a non-thiazide antihypertensive diuretic agent, has been widely coadministered with other classes of antihypertensive agents to reach target systolic blood pressure. Indapamide is extensively metabolized by cytochromes P450. Interaction of indapamide and other antihypertensive drugs are unknown. We investigated the effects of other antihypertensive drugs on the metabolism and pharmacokinetics of indapamide in vitro and in vivo.
METHODS
Indapamide metabolism was studies in vitro using human liver microsomes pretreated with or without different concentrations of CYP-selective inhibitors and seven major antihypertensive drugs, felodipine, nifedipine, nitrendipine, telmisartan, irbesartan, valsartan and puerarin. Furthermore, the pharmacokinetics of indapamide was determined by HPLC-MS/MS to evaluate the effects of felodipine coadministered on the bioavailability of indapamide in rats in vivo.
RESULTS
The Km and Vmax of indapamide metabolism were 114.35 ± 3.47 μM and 23.13 ± 6.61 μmol/g/min. The metabolites of indapamide, hydroxyl-indapamide and dehydrogen-indapamide, were followed. CYP3A4 and CYP2C19 were involved in indapamide metabolism in human live microsomes. In addition, felodipine, nifedipine and nitrendipine significantly inhibited indapamide metabolism with the maximum inhibitory rates of 82.6%, 72% and 95%, respectively. Felodipine significantly elevated indapamide plasma concentration and prolonged its half-life.
CONCLUSIONS
Combination therapy of indapamide and felodipine might lead to the alteration of indapamide metabolism and pharmacokinetics. The consequence of such an interaction that may include increased effectiveness and side effect needs to be tudeis in human.
Topics: Animals; Antihypertensive Agents; Cytochrome P-450 Enzyme Inhibitors; Diuretics; Drug Interactions; Enzyme Inhibitors; Humans; Indapamide; Male; Microsomes, Liver; Rats; Rats, Sprague-Dawley
PubMed: 22579001
DOI: 10.18433/j3sk5v -
Drug Metabolism and Pharmacokinetics 2013Human carboxylesterase (CES) 1A and CES2, two major forms of human CES, dominate the pharmacokinetics of most prodrugs such as imidapril and irinotecan (CPT-11)....
Human carboxylesterase (CES) 1A and CES2, two major forms of human CES, dominate the pharmacokinetics of most prodrugs such as imidapril and irinotecan (CPT-11). Antihypertensive drugs are often prescribed for clinical therapy concurrently with others. Moreover, two or more antihypertensive drugs are ubiquitously combined. The influences of antihypertensive drugs on the activity of CES remain undefined. In the present study, the inhibitory effects of 17 antihypertensive drugs on the CES1A1 and CES2 activities were evaluated. Imidapril and CPT-11 were used as substrates and cultured with liver microsomes in vitro. The imidapril hydrolase activities by recombinant CES1A1 and human liver microsomes (HLM) were intensely inhibited by telmisartan and nitrendipine (K(i) = 0.49 ± 0.09 and 1.12 ± 0.39 µM for CES1A1, 1.69 ± 0.17 µM and 1.24 ± 0.27 µM for HLM, respectively). However, other drugs did not exert strong inhibition. The enzyme hydrolase activity of recombinant CES2 was substantially inhibited by diltiazem and verapamil (K(i) = 0.25 ± 0.02 and 3.84 ± 0.99 µM, respectively). Hence, diltiazem, verapamil, nitrendipine and telmisartan may attenuate the drug efficacy of catalyzed prodrugs by changing the activities of CES1A1 and CES2.
Topics: Antihypertensive Agents; Benzimidazoles; Benzoates; Carboxylesterase; Diltiazem; Drug Interactions; Humans; Imidazolidines; Liver; Nitrendipine; Telmisartan; Verapamil
PubMed: 23648675
DOI: 10.2133/dmpk.dmpk-12-rg-143 -
Indian Journal of Pharmaceutical... Sep 2008A mucoadhesive drug delivery system for systemic delivery of nitrendipine, a calcium channel blocker through buccal route was formulated. Mucoadhesive polymers like...
A mucoadhesive drug delivery system for systemic delivery of nitrendipine, a calcium channel blocker through buccal route was formulated. Mucoadhesive polymers like hydroxypropylmethylcellulose K-100, hydroxypropylcellulose, sodium carboxymethylcellulose, sodium alginate, polyvinyl alcohol, polyvinyl pyrrolidone K-30 and carbopol-934P were used for film fabrication. The films were evaluated for their weight, thickness, percentage moisture absorbed and lost, surface pH, folding endurance, drug content uniformity, In vitro residence time, In vitro release and ex vivo permeation. Based on the evaluation of these results, it was concluded that buccal films made of hydroxylpropylcellulose and sodium carboxymethylcellulose (5±2% w/v; F-4), which showed moderate drug release (50% w/w at the end of 2 h) and satisfactory film characteristics could be selected as the best among the formulations studied.
PubMed: 21394260
DOI: 10.4103/0250-474X.45402 -
The Journal of Biological Chemistry Feb 1991There is evidence that myocardial injury, as would occur on post-ischemic reperfusion, may be caused by the generation of oxygen radicals, as well as by the induction of...
There is evidence that myocardial injury, as would occur on post-ischemic reperfusion, may be caused by the generation of oxygen radicals, as well as by the induction of intracellular calcium overload; however, the relationship between these two mechanisms of injury is not known. To test the hypothesis that oxidants and oxygen radicals can cause cardiac myocyte injury and intracellular calcium overload, isolated adult rat ventricular myocytes were exposed to H2O2 (1-10 mM) and Fe3(+)-nitrilotriacetate. EPR measurements confirmed the production of the highly reactive .OH radical by this system. The oxygen radical generating system initially caused a transient augmentation of twitch amplitude in single field stimulated myocytes. This was followed by contractile oscillations occurring during the twitch prior to full cell relaxation, and spontaneous mechanical oscillations occurring between electrically stimulated contractions. Eventually, cells became inexcitable and abruptly underwent contracture. In the presence of lower bathing calcium concentrations, these oxidant-induced alterations were prevented or delayed. However, cells exposed to the radical generating system in the absence of extracellular calcium still eventually underwent contracture but stimulated contractions or mechanical oscillations were not seen. Measurements in single myocytes loaded with the fluorescent probe of intracellular calcium, Indo-1, demonstrated a rise in both systolic and diastolic fluorescence ratio, as well as oscillations and widening of the fluorescence transient, suggestive of cellular calcium loading, following exposure to the radical generating system. Injured myocytes did not take up trypan blue dye. Contractile dysfunction and calcium channel blocker, nitrendipine. NMR measurements of cellular [ATP] demonstrated that these alterations in cellular calcium preceded the depletion of ATP. Subsequent depletion of ATP was accompanied by the appearance of increased concentrations of sugar phosphates indicative of a block in glycolysis and ATP depletion correlated with cellular rigor. Thus, oxygen free radicals can cause cardiac myocyte injury with contractile abnormalities which occur due to myocyte calcium loading. The mechanism of oxidant-induced calcium loading is not due to nonspecific membrane damage, or energy depletion, but rather due to increased calcium influx through voltage gated calcium channels. This early calcium overload state as well as oxidant induced block of glycolysis result in cellular energy depletion and cell death with the induction of contracture.
Topics: Adenosine Triphosphate; Animals; Calcium; Electric Stimulation; Electron Spin Resonance Spectroscopy; Ferric Compounds; Free Radicals; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydroxides; Hydroxyl Radical; Kinetics; Magnetic Resonance Spectroscopy; Male; Myocardial Contraction; Myocardium; Nitrilotriacetic Acid; Rats; Rats, Inbred Strains
PubMed: 1846625
DOI: No ID Found -
The Journal of Biological Chemistry Oct 1985The effects of short term stimulation of beta-adrenergic receptors and elevations in intracellular cyclic AMP on nitrendipine-sensitive voltage-dependent Ca2+ channels...
The effects of short term stimulation of beta-adrenergic receptors and elevations in intracellular cyclic AMP on nitrendipine-sensitive voltage-dependent Ca2+ channels of skeletal muscle cells in vitro has been studied using both the 45Ca2+ flux technique and [3H] nitrendipine-binding experiments. Isoproterenol increased the nitrendipine-sensitive 45Ca2+ influx under depolarizing conditions. The effects of isoproterenol were additive to those of depolarization and were antagonized by alprenolol. Half-maximal inhibition of 45Ca2+ influx induced both by depolarization and by isoproterenol occurred at a nitrendipine concentration of 1 nM. Treatments that resulted in an increased level of intracellular cyclic AMP, such as treatment with 1-methyl-3-isobutylxanthine, theophylline, dibutyryl cyclic AMP, or 8-bromocyclic AMP also resulted in an increased rate of 45Ca2+ entry via nitrendipine-sensitive Ca2+ channel. In contrast, long term treatment of myotubes in culture with isoproterenol and other compounds that increased intracellular cyclic AMP led to a large increase in the number of nitrendipine receptors. This increase was accompanied by a 4-10-fold decrease in the affinity of the receptors for nitrendipine. Alprenolol inhibited the long term effects of isoproterenol. In vivo treatment of 7-day-old chicks with reserpine and alprenolol produced a decrease in the number of skeletal muscle nitrendipine receptors. This decrease in receptor number was accompanied by an increase in the affinity of nitrendipine for its receptor by a factor of 4 to 5. These effects on the nitrendipine receptor were prevented by simultaneous injection of isoproterenol. The results are discussed in relation to the role of beta-adrenergic receptors and intracellular cyclic AMP in the regulation of skeletal muscle Ca2+ channels.
Topics: 1-Methyl-3-isobutylxanthine; 8-Bromo Cyclic Adenosine Monophosphate; Adrenergic beta-Agonists; Alprenolol; Animals; Bucladesine; Calcium; Calcium Channels; Cell Membrane; Cells, Cultured; Chick Embryo; Cyclic AMP; Ion Channels; Isoproterenol; Muscles; Nifedipine; Nitrendipine; Receptors, Nicotinic; Reserpine; Theophylline
PubMed: 2414273
DOI: No ID Found -
British Journal of Pharmacology Apr 19921. The ability of BRL 38227 and nitrendipine to affect muscarinic agonist and histamine-stimulated [3H]-inositol phosphate accumulation in slices of bovine tracheal... (Comparative Study)
Comparative Study
1. The ability of BRL 38227 and nitrendipine to affect muscarinic agonist and histamine-stimulated [3H]-inositol phosphate accumulation in slices of bovine tracheal smooth muscle has been studied and compared with the established inhibitory effects of isoprenaline on this pathway. 2. Pre-addition of BRL 38227 (5 microM), nitrendipine (1 microM) or isoprenaline (10 microM) significantly inhibited the subsequent inositol phosphate response to histamine at all concentrations studied (10- 1000 microM). BRL 38227 and nitrendipine also significantly inhibited the [3H]-inositol phosphate response to low (1 microM), but not high (100 microM) concentrations of carbachol. Isoprenaline had no effect at any concentration of carbachol studied. 3. Nitrendipine (IC50 = 95 nM) and BRL 38227 (IC50 = 322 nM) caused concentration-related inhibitions of the inositol phosphate response to histamine (100 microM). Similar maximal inhibitions were caused by each agent (55-58%). Inhibitory effect of BRL 38227 was reduced in potency (IC50 = 5.5 microM), but not magnitude, in the presence of glibenclamide (0.5 microM). 4. Time-course studies comparing the effects of BRL 38227 addition 15 min before, and 10 min after histamine challenge showed that for pre-addition a distinct (less than 2 min) lag occurred following histamine addition before the inhibitory effect of BRL 38227 was manifest. In contrast, when BRL 38227 was added 10 min after histamine, an inhibitory effect was immediately apparent. 5. Further evidence for an initial, 'protected' phase of inositol phosphate accumulation was provided by the finding that BRL 38227 pre-addition had no effect on the early (0-300 s) time-course of inositol 1,4,5-trisphosphate mass accumulation. 6. The inhibitory effect of BRL 38227, but not that of nitrendipine or isoprenaline, on histaminestimulated [3H]-inositol phosphate accumulation was completely prevented in the presence of an elevated extracellular K+ (65 mM) concentration. 7. The results demonstrate that membrane hyperpolarization, and/or blockade of voltage-operated Ca2"-channels can regulate agonist-stimulated phosphoinositide metabolism in airway smooth muscle. The possible contribution of this regulatory mechanism to the relaxant properties of these agents is discussed.
Topics: Animals; Benzopyrans; Carbachol; Cattle; Cromakalim; Histamine; In Vitro Techniques; Isoproterenol; Muscle, Smooth; Nitrendipine; Parasympatholytics; Phosphatidylinositols; Pyrroles; Trachea
PubMed: 1324062
DOI: 10.1111/j.1476-5381.1992.tb09091.x -
Hypertension Research : Official... Nov 2000The present study was designed to evaluate the effects of an ACE inhibitor, lisinopril, and a calcium antagonist, nitrendipine, on urinary albumin excretion (UAE) and... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The present study was designed to evaluate the effects of an ACE inhibitor, lisinopril, and a calcium antagonist, nitrendipine, on urinary albumin excretion (UAE) and renal function in mild to moderate essential hypertensive patients with microalbuminuria. After the 4-week drug-free period, 17 patients were randomly divided into two groups. The first group (group 1: n=8) received lisinopril 10-20 mg daily for 8 weeks followed by nitrendipine 5-10 mg daily for another 8 weeks. The second group (group 2: n=9) received nitrendipine 5-10 mg daily for 8 weeks followed by lisinopril 10-20 mg daily for another 8 weeks. The mean blood pressure (MBP) significantly decreased in a similar manner in both groups. UAE significantly decreased after 8 weeks of treatment with lisinopril in group 1 and after 8 weeks of subsequent treatment with lisinopril in group 2. On the other hand, UAE was not altered by treatment with nitrendipine. The changes in UAE were significantly correlated with changes in MBP after 8 weeks of treatment with nitrendipine, but not after 8 weeks of treatment with lisinopril. No significant changes in creatinine clearance, urinary excretion of sodium or urinary N-acetyl-beta-D-glucosaminide were observed by any treatment in either group. These results suggest that lisinopril, not nitrendipine, reduces UAE in essential hypertensive patients with microalbuminuria independently of its effective antihypertensive properties.
Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Female; Humans; Hypertension; Kidney; Lisinopril; Male; Middle Aged; Nitrendipine; Severity of Illness Index
PubMed: 11131273
DOI: 10.1291/hypres.23.607 -
Proceedings of the National Academy of... Jun 1982[3H]Nitrendipine binds with high affinity to brain membranes with a drug specificity indicating association with sites mediating the pharmacologic actions of...
[3H]Nitrendipine binds with high affinity to brain membranes with a drug specificity indicating association with sites mediating the pharmacologic actions of dihydropyridine slow-calcium-channel antagonist drugs. In brain membranes, [3H]nitrendipine binding is absolutely dependent on the presence of calcium ions. Interactions of cation with [3H]nitrendipine binding sites correlate with their physiologic actions at voltage-dependent calcium channels. Ions such as strontium and barium, which mimic calcium physiologically, share the action of calcium in enhancing [3H]nitrendipine binding. Ions such as lanthanum an cobalt, which block the effects of calcium, can inhibit [3H]nitrendipine binding and block the stimulating actions of calcium. The ability to monitor the influence of ions on an agonist-antagonist continuum at [3H]nitrendipine binding sites provides a molecular probe to explore the regulation of cellular function by calcium and other cations.
Topics: Animals; Brain; Brain Mapping; Calcium; Cations, Divalent; Guinea Pigs; Ion Channels; Kinetics; Male; Nifedipine; Nitrendipine; Pyridines; Rats; Tissue Distribution
PubMed: 6285357
DOI: 10.1073/pnas.79.11.3656 -
Proceedings of the National Academy of... May 1986Antibodies with high affinity and specificity for the 1,4-dihydropyridine Ca2+-channel blockers have been produced in rabbits by immunization with...
Antibodies with high affinity and specificity for the 1,4-dihydropyridine Ca2+-channel blockers have been produced in rabbits by immunization with dihydropyridine-protein conjugates. Anti-dihydropyridine antibodies were found to specifically bind [3H]nitrendipine, [3H]-nimodipine, [3H]nisoldipine, and [3H]PN 200-110 (all 1,4-dihydropyridine Ca2+-channel blockers) with high affinity, while [3H]verapamil, [3H]diltiazem, and [3H]trifluoperazine were not recognized. The average dissociation constant of the [3H]nitrendipine-antibody complex was 0.06 (+/- 0.02) X 10(-9) M for an antiserum studied in detail and ranged from 0.01 to 0.24 X 10(-9) M for all antisera. Inhibition of [3H]nitrendipine binding was specific for the 1,4-dihydropyridine Ca2+-channel modifiers and the concentrations required for half-maximal inhibition ranged between 0.25 and 0.90 nM. Structurally unrelated Ca2+-channel blockers, calmodulin antagonists, inactive metabolites of nitrendipine, and UV-inactivated nisoldipine did not modify [3H]nitrendipine binding to the anti-dihydropyridine antibodies. Dihydropyridines without a bulky substituent in the 4-position of the heterocycle were able to displace [3H]nitrendipine binding, but the concentrations required for half-maximal inhibition were greater than 800 nM. In summary, anti-dihydropyridine antibodies have been shown to have high affinity and specificity for the 1,4-dihydropyridine Ca2+-channel blockers and to exhibit dihydropyridine binding properties similar to the membrane receptor for the 1,4-dihydropyridine Ca2+-channel blockers.
Topics: Animals; Antibodies; Antibody Specificity; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Nifedipine; Nitrendipine; Pyridines; Rabbits; Receptors, Nicotinic; Structure-Activity Relationship; Tritium
PubMed: 3010317
DOI: 10.1073/pnas.83.9.2792