Influence of Hypersensitive C-Reactive Protein on the Effect of Continuous Antihypertensive Pharmacological Therapy.

ABSTRACT: Systemic chronic inflammation, represented by hypersensitive C-reactive protein (hsCRP), is an essential contributing factor to hypertension. However, the influence of hsCRP levels on the effect of antihypertensive pharmacological therapy remains unknown. We evaluated hsCRP levels in 3756 newly diagnosed, untreated hypertensive subjects. Participants were grouped by tertiles of hsCRP and were randomly treated with nitrendipine + captopril, nitrendipine + spironolactone hydrochlorothiazide + captopril, and hydrochlorothiazide + spironolactone. Blood pressure (BP) was recorded every 2 weeks. A multivariate mixed linear model was used to evaluate the impact of baseline hsCRP levels on the continuous antihypertensive effect. After 3, 6, 9, and 12 months of continuous antihypertensive treatment, no significant difference was observed in BP decline among the different hsCRP groups. We identified interactions between baseline hsCRP levels and follow-up time. After adjusting for conventional risk factors and the interactions between hsCRP and follow-up time, there was no significant association between baseline hsCRP level and antihypertensive effects at 0-6 months of follow-up. However, from 6 to 12 months, subjects with higher baseline hsCRP levels exhibited a more marked BP-lowering effect ( P < 0.001 at 9 months, P = 0.002 at 12 months). Overall, there exist interaction effects between baseline hsCRP levels and follow-up time. Individuals with higher baseline hsCRP levels may exhibit a better response to antihypertensive therapy.

Vasopressin-stimulated ORAI1 expression and store-operated Ca2+ entry in aortic smooth muscle cells.

Vascular calcification may result from stimulation of osteogenic signalling with upregulation of the transcription factors CBFA1, MSX2 and SOX9, as well as alkaline phosphatase (ALPL), which degrades and thus inactivates the calcification inhibitor pyrophosphate. Osteogenic signalling further involves upregulation of the Ca2+-channel ORAI1. The channel is activated by STIM1 and then accomplishes store-operated Ca2+ entry. ORAI1 and STIM1 are upregulated by the serum & glucocorticoid inducible kinase 1 (SGK1) which is critically important for osteogenic signalling. Stimulators of vascular calcification include vasopressin. The present study explored whether exposure of human aortic smooth muscle cells (HAoSMCs) to vasopressin upregulates ORAI1 and/or STIM1 expression, store-operated Ca2+ entry and osteogenic signalling. To this end, HAoSMCs were exposed to vasopressin (100 nM, 24 h) without or with additional exposure to ORAI1 blocker MRS1845 (10 µM) or SGK1 inhibitor GSK-650394 (1 µM). Transcript levels were measured using q-RT-PCR, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and store-operated Ca2+ entry from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, vasopressin enhanced the transcript levels of ORAI1 and STIM1, store-operated Ca2+ entry, as well as the transcript levels of CBFA1, MSX2, SOX9 and ALPL. The effect of vasopressin on store-operated Ca2+ entry as well as on transcript levels of CBFA1, MSX2, SOX9 and ALPL was virtually abrogated by MRS1845 and GSK-650394. In conclusion, vasopressin stimulates expression of ORAI1/STIM1, thus augmenting store-operated Ca2+ entry and osteogenic signalling. In HAoSMCs, vasopressin (VP) upregulates Ca2+ channel ORAI1 and its activator STIM1. VP upregulates store-operated Ca2+ entry (SOCE) and osteogenic signalling (OS). VP-induced SOCE, OS and Ca2+-deposition are disrupted by ORAI1 inhibitor MRS1845. VP-induced SOCE, OS and Ca2+-deposition are disrupted by SGK1 blocker GSK-650394. KEY MESSAGES: • In HAoSMCs, vasopressin (VP) upregulates Ca2+ channel ORAI1 and its activator STIM1. • VP upregulates store-operated Ca2+ entry (SOCE) and osteogenic signalling (OS). • VP-induced SOCE, OS and Ca2+-deposition are disrupted by ORAI1 inhibitor MRS1845. • VP-induced SOCE, OS and Ca2+-deposition are disrupted by SGK1 blocker GSK-650394.

Cost-effectiveness of nitrendipine and hydrochlorothiazide or metoprolol to treat hypertension in rural community health centers in China.

OBJECTIVES: The objective of this article is to compare blood pressure (BP)-lowing effects of nitrendipine and hydrochlorothiazide and nitrendipine and metoprolol, and estimate the economic effect of these therapies on hypertension. METHODS: Outpatients (N = 793) 18-70 years of age with stage 2 or severe hypertension (SBP ≥ 160 mmHg and/or DBP ≥ 100 mmHg) were recruited from four randomly selected rural community health centers in Beijing and Jilin. After drug wash out, they were randomly divided into nitrendipine and hydrochlorothiazide group or nitrendipine and metoprolol group. The costs of drug treatment for hypertension were calculated and general estimation, whereas effectiveness was measured as a reduction in SBP and DBP at the end of a 24-week study period. RESULTS: Overall, 623 patients were eligible for the study and after a 24-week follow-up, SBP and DBP were 131.2/82.2 mmHg for the nitrendipine and hydrochlorothiazide group and 131.4/82.9 mmHg for the nitrendipine and metoprolol group and these were not significantly different (P = 0.7974 SBP and P = 0.1166 DBP). Comparing with nitrendipine and metoprolol, the cost of nitrendipine and hydrochlorothiazide was less, and its effectiveness was similar. The cost/effect ratio (US$/mmHg) was 1.4 for SBP and 2.8 for DBP for the nitrendipine and hydrochlorothiazide group, and 1.9 and 3.8 for the nitrendipine and metoprolol group's SBP and DBP values, respectively. The incremental cost per patient for achieving target BP was 5.1. Adverse events were mild or moderate and there were no differences between treatment groups. CONCLUSION: Treating hypertension with nitrendipine and hydrochlorothiazide was cost-effective than nitrendipine and metoprolol, and these data will allow more reasonable and efficient allocation of limited resources in low-income countries.

Is pomegranate juice a potential perpetrator of clinical drug-drug interactions? Review of the in vitro, preclinical and clinical evidence.

The area of fruit juice-drug interaction has received wide attention with numerous scientific and clinical investigations performed and reported for scores of drugs metabolized by CYP3A4/CYP2C9. While grapefruit juice has been extensively studied with respect to its drug-drug interaction potential, numerous other fruit juices such as cranberry juice, orange juice, grape juice, pineapple juice and pomegranate juice have also been investigated for its potential to show drug-drug interaction of any clinical relevance. This review focuses on establishing any relevance for clinical drug-drug interaction potential with pomegranate juice, which has been shown to produce therapeutic benefits over a wide range of disease areas. The review collates and evaluates relevant published in vitro, preclinical and clinical evidence of the potential of pomegranate juice to be a perpetrator in drug-drug interactions mediated by CYP3A4 and CYP2C9. In vitro and animal pharmacokinetic data support the possibility of CYP3A4/CYP2C9 inhibition by pomegranate juice; however, the human relevance for drug-drug interaction was not established based on the limited case studies.

Anti-arrhythmic and hemodynamic effects of oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine.

Our previous studies have established cardio-protective effects of furnidipine and its active metabolites. We therefore decided to compare the influence of oral and intravenous administration of furnidipine, nifedipine, nitrendipine and nimodipine to examine their effects on hemodynamics and arrhythmias. Since dihydropyridines are oxidatively metabolized in the body and the oxidized metabolites are among the final products, we studied the influence of four oxidized dihydropyridines (oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine) on the same parameters. In vivo model of ischemia- and reperfusion-induced arrhythmias of rats was used. Dihydropyridines were administered 5 mg/kg orally (24 and 1 h before ischemia) or 5 µg/kg intravenously (10 min before ischemia). 20 mg/kg of the oxidized dihydropyridines was given orally (24 and 1 h before ischemia). The dihydropyridines exhibited significant anti-arrhythmic actions after both forms of administration but their influence on blood pressure was differential and contrasting and depended on route of administration. The oxidized dihydropyridines imparted strong protection against lethal arrhythmias while exerting differential influences on blood pressure with oxy nifedipine and oxy nisoldipine being hypertensive and oxy nitrendipine being most normotensive. The differential effects observed with the dihydropyridines after the two routes of administration lend strength to the hypothesis that their metabolites may have a significant role in mediating the actions of the parent drug. The strong anti-arrhythmic action of the oxidized dihydropyridines along with their differential effect on blood pressure could indicate their potential use as cardio-protective drugs in certain groups of patients.

Effect of pomegranate juice on intestinal transport and pharmacokinetics of nitrendipine in rats.

Pomegranate juice (PJ) is known to be a potent inhibitor of human cytochromes (CYP), particularly CYP2C9 and CYP3A4. The purpose of this study was to investigate the effect of oral PJ on the pharmacokinetics of nitrendipine (10 mg/kg) in rats. The effect of PJ was also investigated on the absorption kinetics of nitrendipine in rats using a single-pass intestinal perfusion model. There was a significant increase in effective permeability, absorption rate constant and fraction of drug absorbed in the pretreated group when compared with the control group, probably due to inhibition of the P-glycoprotein-mediated efflux of the drug by PJ. In comparison with control, PJ treatment significantly increased the area under the concentration-time curve of oral nitrendipine. The peak plasma concentration of nitrendipine was also significantly increased by PJ. However, elimination half-life of nitrendipine was not altered significantly in both PJ co-administered and pretreated groups. These results suggest that PJ inhibits the intestinal metabolism of nitrendipine without inhibiting the hepatic metabolism in rats. Therefore, the concomitant use of PJ, as food supplement, and nitrendipine should be avoided, although further clinical studies need to be undertaken in order to confirm this finding.

A potential calcium antagonist and its antihypertensive effects.

Imperatorin (Imp) as a hypotensive active ingredient, its hypotensive effect was evaluated in the SHRs, its calcium antagonism and affinity to L-type calcium channel was also confirmed. The results showed that the blood pressure was decreased in the SHRs treated with Imp, the aortic ring was relaxed with Imp, L-type calcium channel currents and intracellular calcium free ion rise was nearly disappeared when adding Imp. In addition, Imp displayed a chromatographic peak similar to nitrendipine and verapamil by the cell membrane chromatography, same results from protein-drug docking approaches. Hence, Imp target the L-type calcium channel, and may be used as a novel antihypertensive drug.

[Analysis of therapeutic effects of rural patients with hypertension by combination administration of low dosage of hydrochlorothiazide and nitrendipine].

OBJECTIVE: To evaluate the therapeutic effects of combination administration of hydrochlorothiazide and nitrendipine at low dosage in the treatment of rural hypertension patients. METHODS: By the method of cluster random sampling, 5292 primary hypertension patients from Fuxin, Liaoning Province were divided into health education group (control group) and drug intervention group in June 2006. The drug intervention group were treated with hydrochlorothiazide, nitrendipine and captopril by stepwise approach and we observe the antihypertensive effect of drug and the effect on the onset of stroke. RESULTS: The average follow-up time was 15 months. At last, 308 patients were lost to follow-up (the lost follow-up rate was 5.8 percent). The 4984 in cohort, including 2530 of intervention group and 2454 of control group, had examination of all indicators. Through health education and drug intervention, the average blood pressure in drug intervention group decreased by 16.1/9.4 mm Hg (1 mm Hg = 0.133 kPa) while the average blood pressure in control group decreased by 6.7/3.5 mm Hg. The control rate of blood pressure in drug intervention group was higher than control group (33.1% vs. 15.1%, P < 0.001). Through drug intervention, the morbidity risk of nonfatal stroke in drug intervention group decreased by 57.3% compared to control group, the total morbidity risk of stroke decreased by 59.4%. The results had significant statistical difference. And, the morbidity of severe hypopotassaemia (K(+) < 3.0 mmol/L) and diabetes mellitus had no significant statistical difference between two groups. CONCLUSIONS: The low-cost antihypertensive program based on thiazide had good antihypertensive effect, high safety and good cost-effect ratio. The program could be used in rural areas of China.

Morbidity and mortality on combination versus monotherapy: a posthoc analysis of the Systolic Hypertension in Europe trial.

BACKGROUND: The current literature supports the immediate use of combinations of antihypertensive drugs in terms of ease of use and adherence, but the key issue whether combination therapy is more effective than monotherapy in the prevention of cardiovascular complications remains unproven. METHODS: We analysed the double-blind (median follow-up 2.0 years) and open follow-up (6.0 years) phases of the Systolic Hypertension in Europe trial. Patients were 60 years or more with an entry systolic/diastolic blood pressure (BP) of 160-219/less than 95 mmHg. Antihypertensive treatment started immediately after randomization in the active-treatment group, but only after completion of the double-blind trial in control patients. Treatment consisted of nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day). We adjusted our analyses for sex, age, history of cardiovascular complications, baseline systolic BP and previous antihypertensive treatment. RESULTS: During the double-blind trial, adding enalapril to nitrendipine (n = 515), compared with the equivalent combination of placebos (n = 559), decreased systolic BP by a further 9.5 mmHg and reduced all cardiovascular events by 51% (P = 0.0035) and heart failure by 66% (P = 0.032), with similar trends for stroke (-51%; P = 0.066) and cardiac events (-44%; P = 0.075). Over the whole duration of follow-up, combination therapy (n = 871), compared with nitrendipine monotherapy (n = 1552), decreased systolic BP by 3.1 mmHg and reduced total mortality (-32%; P = 0.023), with similar trends for all cardiovascular events (-23%; P = 0.081) and stroke (-42%; P = 0.054). CONCLUSION: Despite the limitations of a posthoc analysis, but congruent with the stronger BP reduction, our results suggest that combination therapy with nitrendipine plus enalapril might improve outcome over and beyond the benefits seen with nitrendipine monotherapy.

Solid self-emulsifying nitrendipine pellets: preparation and in vitro/in vivo evaluation.

Objective of this study is to develop and evaluate the new solid self-emulsifying (SE) pellets of poorly soluble nitrendipine (NTD). These pellets were prepared via extrusion/spheronization technique, using liquid SEDDS (NTD, Miglyol 812, Cremophor RH 40, Tween 80, and Transcutol P), adsorbents (silicon dioxide and crospovidone), microcrystalline cellulose and lactose. The resulting SE pellets with 30% liquid SEDDS exhibited uniform size (800-1000 microm) and round shape, droplet size distribution following self-emulsification was nearly same to the liquid SEDDS (72+/-16 nm and 64+/-12 nm). The in vitro release was similar for the two SE formulations (over 80% within 30 min), both significantly higher than the conventional tablets (only 35% within 30 min). The oral bioavailability was evaluated for the SE pellets, liquid SEDDS and conventional tablets in fasted beagle dogs. AUC of NTD from the SE pellets showed 1.6-fold greater than the conventional tablets and no significant difference compared with the liquid SEDDS. In conclusion, our studies illustrated that extrusion/spheronization technique could be a useful large-scale producing method to prepare the solid SE pellets from liquid SEDDS, which can improve oral absorption of NTD, nearly equivalent to the liquid SEDDS, but better in the formulation stability, drugs leakage and precipitation, etc.

Analysis of therapeutic effects of rural patients with hypertension by combination administration of low dosage of hydrochlorothiazide and nitrendipine / 中华心血管病杂志

<p><b>OBJECTIVE</b>To evaluate the therapeutic effects of combination administration of hydrochlorothiazide and nitrendipine at low dosage in the treatment of rural hypertension patients.</p><p><b>METHODS</b>By the method of cluster random sampling, 5292 primary hypertension patients from Fuxin, Liaoning Province were divided into health education group (control group) and drug intervention group in June 2006. The drug intervention group were treated with hydrochlorothiazide, nitrendipine and captopril by stepwise approach and we observe the antihypertensive effect of drug and the effect on the onset of stroke.</p><p><b>RESULTS</b>The average follow-up time was 15 months. At last, 308 patients were lost to follow-up (the lost follow-up rate was 5.8 percent). The 4984 in cohort, including 2530 of intervention group and 2454 of control group, had examination of all indicators. Through health education and drug intervention, the average blood pressure in drug intervention group decreased by 16.1/9.4 mm Hg (1 mm Hg = 0.133 kPa) while the average blood pressure in control group decreased by 6.7/3.5 mm Hg. The control rate of blood pressure in drug intervention group was higher than control group (33.1% vs. 15.1%, P < 0.001). Through drug intervention, the morbidity risk of nonfatal stroke in drug intervention group decreased by 57.3% compared to control group, the total morbidity risk of stroke decreased by 59.4%. The results had significant statistical difference. And, the morbidity of severe hypopotassaemia (K(+) < 3.0 mmol/L) and diabetes mellitus had no significant statistical difference between two groups.</p><p><b>CONCLUSIONS</b>The low-cost antihypertensive program based on thiazide had good antihypertensive effect, high safety and good cost-effect ratio. The program could be used in rural areas of China.</p>

Eprosartan: a review of its use in hypertension.

Eprosartan is an angiotensin II receptor antagonist (angiotensin II receptor blocker [ARB]) used in the treatment of hypertension. In large, randomized trials, eprosartan (with or without hydrochlorothiazide [HCTZ]) demonstrated superior antihypertensive efficacy to that of placebo and, when administered at comparable dosage regimens, had similar blood pressure-lowering effects to enalapril. Eprosartan was generally well tolerated in clinical trials and had a lower incidence of persistent dry cough than enalapril. Eprosartan has a neutral effect on metabolic parameters, such as serum lipid levels and glucose homeostasis, and a low propensity for pharmacokinetic drug interactions. The use of eprosartan or other ARBs in combination with HCTZ tends to reverse the potassium loss associated with thiazide diuretics. Independent of its antihypertensive effects, eprosartan was associated with improved clinical outcomes (primary composite endpoint of all causes of mortality and all cardiovascular and cerebrovascular events, including all recurrent events) compared with nitrendipine in a randomized, secondary prevention trial in hypertensive patients with previous cerebrovascular events (MOSES trial). Eprosartan also reduced blood pressure and was associated with a modest improvement in cognitive function in a large observational study in patients > or =50 years of age with newly diagnosed hypertension (OSCAR study). In both of these trials, additional antihypertensive therapy, such as HCTZ, was permitted. Therefore, eprosartan is a useful treatment option in the management of a broad range of patients with hypertension, and its use with HCTZ provides a rational combination regimen.

Effect of metformin on weight gain during antihypertensive treatment with a beta-blocker in Chinese patients.

BACKGROUND: Overweight and obesity are associated with cardiovascular disease (CVD). This study was designed to investigate whether combined use of nitrendipine and atenolol has any effect on body weight (BW) and whether metformin can prevent antihypertensive medication-induced weight gain and has any effect on blood glucose (BG). METHODS: Included in the present study were 94 hypertensive patients with a body mass index (BMI) > or =25 kg/m(2), of whom 45 patients were treated with nitrendipine plus atenolol (N/A group), and the remaining 49 patients were treated with nitrendipine, atenolol, and metformin (N/A/M group). The mean follow-up duration was 14 months. BW and glucose tolerance were measured. RESULTS: In N/A group, BW and fasting BG significantly increased from 73.5 +/- 9.6 kg to 74.2 +/- 9.7 kg (P < 0.05) and from 94.2 +/- 10.5 mg/dl to 97.9 +/- 11.3 mg/dl (P < 0.01), respectively, whereas postprandial BG did not change significantly. In N/A/M group, BW slightly decreased from 72.7 +/- 10.1 kg to 72.3 +/- 10.2 kg (P = 0.30), and fasting BG did not change significantly (93.5 +/- 10.4 mg/dl vs. 92.7 +/- 10.2 mg/dl, P = 0.59), whereas 2-h postprandial BG significantly decreased from 133.7 +/- 30.5 mg/dl to 124.0 +/- 29.6 mg/dl (P < 0.05). Furthermore, a significant difference was observed in difference value of BW before and after treatment between the two groups (0.7 (95% confidence interval, 0.1-1.3) kg in N/A group vs. -0.4 (95% confidence interval, -1.3 to 0.4) kg in N/A/M group, P < 0.05). CONCLUSIONS: Combination therapy of nitrendipine and atenolol may significantly increase BW and fasting BG in overweight or obese patients with hypertension. Metformin may prevent BW gain and improve BG levels in hypertensive patients who received combination therapy of nitrendipine and atenolol.

Effectiveness and tolerability of fixed-dose combination enalapril plus nitrendipine in hypertensive patients: results of the 3-month observational, post-marketing, multicentre, prospective CENIT study.

BACKGROUND AND OBJECTIVE: Monotherapy with any class of antihypertensive drug effectively controls blood pressure (BP) in only about 50% of patients. Consequently, the majority of patients with hypertension require combined therapy with two or more medications. This study aimed to evaluate the effectiveness (systolic BP [SBP]/diastolic BP [DBP] control) and tolerability of the fixed-dose combination enalapril/nitrendipine 10 mg/20 mg administered as a single daily dose in hypertensive patients. METHODS: This was a post-authorization, multicentre, prospective, observational study conducted in primary care with a 3-month follow-up. Patients throughout Spain with uncontrolled hypertension (> or =140/90 mmHg for patients without diabetes mellitus, or > or =130/85 mmHg for patients with diabetes) on monotherapy or with any combination other than enalapril + nitrendipine, or who were unable to tolerate their previous antihypertensive therapy, were recruited. Change from previous to study treatment was according to usual clinical practice. BP was measured once after 5 minutes of rest in the sitting position. Therapeutic response was defined as follows: 'controlled' meant controlled BP (<140/90 mmHg for nondiabetic patients, or <130/85 mmHg for diabetic patients); 'response' meant controlled BP, or a decrease in SBP of > or =20 mmHg and in DBP of > or =10 mmHg. The main laboratory test parameters were documented at baseline and after 3 months. Patients aged >65 years, with diabetes, with isolated systolic hypertension (ISH; SBP > or =140 mmHg for patients without diabetes, SBP > or =130 mmHg for patients with diabetes) and who were obese (body mass index [BMI] > or =30 kg/m2) were analysed separately. RESULTS: Of 6537 patients included, 5010 and 6354 patients were assessed in effectiveness and tolerability analyses, respectively. In the tolerability analysis population, there were 3023 men (47.6%) and 3321 women (52.4%). The mean (+/- SD) age of the tolerability analysis group was 62.8 (+/- 10.7) years. A total of 71.1% of the patients presented at least one clinical cardiovascular risk factor other than hypertension, with the most frequent being dyslipidaemia (42.3%), obesity (29.2%) and diabetes (23.9%). After 3 months of treatment, SBP and DBP showed mean (+/- SD) decreases of 26.5 (+/- 14.4) mmHg and 14.9 (+/- 9.0) mmHg, respectively, and 73.0% of patients responded to treatment while 40.9% achieved BP control (70.8%/36.1% in 2658 patients aged >65 years; 61.7%/46.8% in 1521 patients with diabetes; 55.3%/44.2% in 731 patients with ISH; 72.0%/36.4% in 1762 obese patients). Adverse events were reported in 10.8% of patients (n = 689). During the follow-up period, ten patients died and seven patients had serious adverse events; in no case was a causal relationship attributed to the study product. CONCLUSIONS: The rate of SBP/DBP control achieved demonstrates the effectiveness of the fixed-dose enalapril/nitrendipine 10 mg/20 mg combination administered as a single daily dose in patients with essential hypertension not adequately controlled with monotherapy or with any combination other than enalapril + nitrendipine. The proportion and type of adverse events reported were as expected and have already been described for both components of the enalapril/nitrendipine 10 mg/20 mg combination. These results confirm the effectiveness of a strategy based on a fixed-dose enalapril/nitrendipine 10 mg/20 mg combination in reducing BP and achieving BP control goals.

Angiotensin receptor blockers and secondary stroke prevention: the MOSES study.

Hypertension control is critical to prevent stroke. With several clinical trials conducted over the last decade, it seems that the use of an angiotensin-modulating antihypertensive agent conveys benefits beyond blood pressure reduction. Currently, there is evidence supporting the use of either an angiotensin receptor blocker or an angiotensin-converting enzyme inhibitor in the primary-prevention context. However, in the secondary prevention of stroke, the choice of agent is less clear. There is evidence that intensive blood pressure reduction with a combination of an angiotensin-converting enzyme inhibitor and a diuretic can reduce stroke recurrence, but do angiotensin receptor blockers have the same ability? The Morbidity and Mortality after Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) trial endeavors to answer this question and strives to demonstrate the benefit of angiotensin receptor blockers in the secondary prevention of stroke.

The effect of penetration enhancers on permeation kinetics of nitrendipine in two different skin models.

The purpose of this research was to evaluate the effect of penetration enhancers on permeation kinetics of nitrendipine (NTP) through two different skin models. The permeation profile and related kinetics parameters such as activity parameter, diffusion parameter, lag time, relative activity parameter and relative diffusion parameter of NTP was determined in presence of some novel and widely accepted permeation enhancers. Among all the more pronounced enhancing effect was obtained with oleic acid (OA) as it presented the highest permeability coefficient. The enhancement was found to be increased in the following order: Dimethyl sulphoxide (DMSO)

Calcium entry inhibition during resuscitation from shock attenuates inflammatory lung injury.

Trauma and hemorrhagic shock (T/HS) induce a systemic inflammatory response syndrome (SIRS). Neutrophils (polymorphonuclear leukocytes [PMN]) and other cells involved in acute lung injury (ALI) are activated by Ca2+ entry. Thus, inhibiting Ca2+ entry might attenuate post-traumatic lung injury. Inhibiting voltage-operated (L-type) Ca2+ channels during shock could cause cardiovascular collapse, but PMN are "nonexcitable" cells, lack L-type channels, and mobilize Ca2+ via nonspecific channels. We previously showed that PMN Ca2+ entry requires sphingosine 1-phosphate synthesis by sphingosine kinase and that both sphingosine kinase inhibition and blockade of nonspecific channels attenuate ALI when begun before shock. Pretreatment for clinical injuries, however, is impractical. Therefore, we now studied whether Ca2+ entry inhibition that begun during resuscitation from T/HS could attenuate SIRS and ALI without causing hemodynamic compromise. Male Sprague-Dawley rats underwent laparotomy and fixed-pressure shock (mean arterial pressure, 35 +/- 5 mmHg; 90 min). Sphingosine kinase inhibition or nonspecific Ca2+ channel inhibition was begun after resuscitation with 10% of shed blood. We then studied in vivo PMN activation and associated lung injury in the presence or absence of Ca2+ entry inhibition. Neither treatment worsened shock. Each treatment decreased CD11b expression, respiratory burst, PMN p38 MAP-kinase phosphorylation, PMN sequestration, and lung capillary leak in vivo. The similar results seen with two different forms of inhibition strengthen the conclusion that the biological effects seen were specific for calcium entry inhibition. Ca2+ entry inhibition is a candidate therapy for management of lung injury after shock.

Protective effect of melatonin on Ca2+ homeostasis and contractility in acute cholecystitis.

Impaired Ca2+ homeostasis and smooth muscle contractility co-exist in acute cholecystitis (AC) leading to gallbladder dysfunction. There is no pharmacological treatment for this pathological condition. Our aim was to evaluate the effects of melatonin treatment on Ca2+ signaling pathways and contractility altered by cholecystitis. [Ca2+]i was determined by epifluorescence microscopy in fura-2 loaded isolated gallbladder smooth muscle cells, and isometric tension was recorded from gallbladder muscle strips. Malondialdehyde (MDA) and reduced glutathione (GSH) contents were determined by spectrophotometry and cycloxygenase-2 (COX-2) expression was quantified by western blot. Melatonin was tested in two experimental groups, one of which underwent common bile duct ligation for 2 days and another that was later de-ligated for 2 days. Inflammation-induced impairment of Ca2+ responses to cholecystokinin and caffeine were recovered by melatonin treatment (30 mg/kg). This treatment also ameliorated the detrimental effects of AC on Ca2+ influx through both L-type and capacitative Ca2+ channels, and it was effective in preserving the pharmacological phenotype of these channels. Despite its effects on Ca2+ homeostasis, melatonin did not improve contractility. After de-ligation, Ca2+ influx and contractility were still impaired, but both were recovered by melatonin. These effects of melatonin were associated to a reduction of MDA levels, an increase in GSH content and a decrease in COX-2 expression. These findings indicate that melatonin restores Ca2+ homeostasis during AC and resolves inflammation. In addition, this indoleamine helps in the subsequent recovery of functionality.

Effects of angiotensin II blockade on inflammation-induced alterations of pharmacokinetics and pharmacodynamics of calcium channel blockers.

BACKGROUND AND PURPOSE: Inflammation elevates plasma verapamil concentrations but diminishes pharmacological response. Angiotensin II is a pro-inflammatory mediator. We examined the effect of angiotensin II receptor blockade on the pharmacokinetics and pharmacodynamics of verapamil, as well as the binding properties and amounts of its target protein in calcium channels, in a rat model of inflammation. EXPERIMENTAL APPROACH: We used 4 groups of male Sprague-Dawley rats (220-280 g): inflamed-placebo, inflamed-treated, control-placebo and control-treated. Inflammation as pre-adjuvant arthritis was induced by injecting Mycobacterium butyricum on day 0. From day 6 to 12, 30 mg kg(-1) oral valsartan or placebo was administered twice daily. On day 12, a single oral dose of 25 mg kg(-1) verapamil was administered and prolongation of the PR interval measured and plasma samples collected for verapamil and nor-verapamil analysis. The amounts of the target protein Ca(v)1.2 subunit of L-type calcium channels in heart was measured by Western blotting and ligand binding with (3)H-nitrendipine. KEY RESULTS: Inflammation reduced effects of verapamil, although plasma drug concentrations were increased. This was associated with a reduction in ligand binding capacity and amount of the calcium channel target protein in heart extracts. Valsartan significantly reversed the down-regulating effect of inflammation on verapamil's effects on the PR interval, and the lower level of protein binding and the decreased target protein. CONCLUSIONS AND IMPLICATIONS: Reduced responses to calcium channel blockers in inflammatory conditions appeared to be due to a reduced amount of target protein that was reversed by the angiotensin II antagonist, valsartan.