Additive Hypotensive Effect Research Articles

QUERCETIN AS A POTENTIAL THERAPEUTIC AGENT IN HYPERTENSION COMPLICATED BY CONNECTIVE TISSUE DYSPLASIA

This article summarizes data on the effect of quercetin during the treatment of arterial hypertension, complicated by connective tissue dysplasia. Currently, numerous studies are being conducted to study the role of various genes in the development of arterial hypertension. One of the risk factors for hypertension, which remains insufficiently studied, is collagen pathology - undifferentiated connective tissue dysplasia (UND). The presence of connective tissue in all organs and systems, its common origin with mesenchyme, smooth muscle, blood, and lymph leads to dysplastic changes in any organ and system. Among the many metabolic agents in the treatment of hypertension in combination with DST, the bioflavonoid quercetin, which has a pronounced antioxidant effect, deserves the most attention. The use of water-soluble quercetin in the complex therapy of patients with hypertension in combination with DST reduces the frequency of recurrence of hypertensive crises in the post-hospital period, reduces the number of complications, leads to a decrease in blood stabilization, pressure, additional hypotensive effect.

Efficiency and safety of the fixed latanoprost/ dorzolamide combination in open-angle glaucoma hypotensive treatment

Purpose: to determine the efficacy and safety of fixed latanoprost/dorzolamide combination Dorzoprost in hypotensive treatment of primary open-angle glaucoma (POAG) patients previously treated with latanoprost.Material and methods. An observational study included 30 patients (37 eyes) with moderate and advanced POAG who had uncompensated elevated IOP receiving latanoprost monotherapy. During the screening visit, latanoprost was switched to Dorzoprost instilled once in the evening. The targets were IOP, visual acuity, MD and PSD perimetry indices, retinal nerve fiber layer thickness, minimum width of the neuroretinal rim, macula retinal nerve fiber layer thickness, and adverse events. The observation period lasted 12 weeks. IOP was measured at weeks 4 and 12.Results. After 4 weeks, a statistically significant decrease in IOP was noted, which remained stable at 12 weeks. The average additional IOP decrease of those treated with Dorzoprost was 17%. Statistically insignificant positive changes were registered in visual acuity, static perimetry and optical coherence tomography. By the end of the observation period, 6 cases revealed a decrease in the degree of conjunctival hyperemia, while all dry eye syndrome cases (5 patients) showed a decrease in the severity of the signs of the syndrome.Conclusion. Dorzoprost has a significant additive hypotensive effect and a favorable safety profile.

Additive Therapy for Advanced Stages of Glaucoma

Purpose of the study: to evaluate the efficacy and feasibility of using brimonidine 0.2 % in the additive therapy of patients with advanced stages of glaucoma. Materials and methods. There were 59 patients (77 eyes) with advanced stages of primary open-angle, glaucoma (POAG) aged 68 to 83 years in the study. Patients were randomized into 2 groups depending on the received antihypertensive therapy. The first group (I) included 32 people (41 eyes) who used a fixed combination of a prostaglandin analogue (APG) or a carbonic anhydrase inhibitor (CAI) with a beta-blocker (BB) for the treatment of POAG. The second group (II) consisted of 27 patients (36 eyes) who had the α2-adrenergic agonist brimonidine — S3 added to the previously available combination of APG or ICA with BB. The observation period was 6 months. Results. Application of brimonidine — SZ in the additive therapy of advanced stages of glaucoma led to an additional hypotensive effect. By the end of the observation period in the group of patients treated with brimonidine, intraocular pressure decreased by an additional 10 % from the initial level. A good hypotensive effect contributed to an increase in functional parameters. Analysis of the results of static automatic perimetry showed a positive trend in the mean deviation (MD) and standard deviation pattern (PSD), which may indicate a neuroprotective effect of the drug. All patients noted good tolerability of treatment. Throughout the observation period, patients maintained a high level of adherence and performance.

A comparative evaluation of the efficacy and safety of Latanoprost-Optic and Xalatan used as monotherapy and combined with Dorzolamide-Optic for primary open-angle glaucoma under clinical practice conditions

The number of ophthalmic antihypertensive drugs available in Russia is steadily increasing, which complicates the choice to be made by ophthalmologist practitioners. Purpose: to compare the efficacy and safety of the domestically produced drug Latanoprost-Optic with the original drug Xalatan used as monotherapy or combined with the domestic drug Dorzolamide-Optic in patients with primary open-angle glaucoma (POAG). Material and methods. 116 completed cases of patients aged 69.3 ± 5.7 with newly diagnosed POAG were retrospectively analyzed, whereby we assessed the efficacy, safety and tolerability of monotherapy with Latanoprost-Optic or Xalatan and their combinations with Dorzolamide-Optic. Results. Latanoprost-Optic efficacy is no worse than that of Xalatan as it reduces intraocular pressure (IOP) by 33.8%, and has a comparable safety and tolerability profile. More than 72% of patients rate the tolerability of treatment with LatanoprostOptic as very good or good. An additional hypotensive effect of Dorzolamide-Optic added to latanoprost is 2.6–2.8 mm Hg, or 13.2–14.4% and involves no significant effect on the safety profile and tolerability of therapy. Conclusion. Latanoprost-Optic can be considered as a more affordable alternative to the original drug. If the target IOP values cannot be achieved by latanoprost alone, its combination with DorzolamideOptic is recommended, especially for patients with chronic diseases of the respiratory system and the cardiovascular system.

Effect of Morning Exercise With or Without Breaks in Prolonged Sitting on Blood Pressure in Older Overweight/Obese Adults

Both exercise and breaks in prolonged sitting can reduce blood pressure (BP) in older overweight/obese adults. We investigated whether there is an additive hypotensive effect when exercise is combined with subsequent breaks in sitting. Sex differences and changes in plasma catecholamines as a potential candidate mechanism underlying BP responses were also examined. Sedentary older adults (n=67; 67±7 years; 31.2±4.1 kg/m2) completed 3 conditions in random order-sitting (SIT): uninterrupted sitting (8 hours, control); exercise+sitting (EX+SIT): sitting (1 hour), moderate-intensity walking (30 minutes), uninterrupted sitting (6.5 hours); exercise+breaks (EX+BR): sitting (1 hour), moderate-intensity walking (30 minutes), sitting interrupted every 30 minutes with 3 minutes of light-intensity walking (6.5 hours). Serial BP and plasma epinephrine/norepinephrine measurements occurred during 8 hours. The 8-hour average systolic and diastolic BP (mm Hg 95% CI) was lower in EX+SIT -3.4 (-4.5 to -2.3), -0.8 (-1.6 to -0.04), and EX+BR -5.1 (-6.2 to -4.0), -1.1 (-1.8 to -0.3), respectively, relative to SIT (all P <0.05). There was an additional reduction in average systolic BP of -1.7 (-2.8 to -0.6) in EX+BR relative to EX+SIT ( P=0.003). This additional reduction in systolic BP was driven by women -3.2 (-4.7 to -1.7; P<0.001 EX+BR versus EX+SIT). Average epinephrine decreased in EX+SIT and EX+BR in women (-13% to -12%) but increased in men (+12% to +23%), respectively, relative to SIT ( P<0.05). No differences in average norepinephrine were observed. Morning exercise reduces BP during a period of 8 hours in older overweight/obese adults compared with prolonged sitting. Combining exercise with regular breaks in sitting may be of more benefit for lowering BP in women than in men. Clinical Trial Registration- URL: https://www.anzctr.org.au . Unique identifier: ACTRN12614000737639.

The efficiency of monotherapy of patients with primary open-angle glaucoma with Bimatoprost 0.03 % (Bimoptic)

Purpose: to evaluate the hypotensive effect and adverse reactions occurrence in patients with primary open angle glaucoma (POAG) who received Bimatoprost (Bimoptic Rompharm) monotherapy.Materials and methods. 46 patients (75 eyes) with stage I–III POAG were prescribed bimatoprost therapy. Of these, 16 patients (20 eyes) had newly diagnosed glaucoma, 15 patients (27 eyes) previously received treatment with prostaglandin analogs (APG — Latanoprost), and 15 patients (28 eyes) previously received treatment with a fixed combination (FC) composed of timolol B-blocker and brinzolamide carbonic anhydrase inhibitor. The reason for transferring the patient from therapy with APG and FC to monotherapy with Bimatoprost was insufficient hypotensive effect of APG/FC therapy, and the presence of dry eye syndrome of varying severity in most patients. The results were evaluated after 1, 4 and 12 weeks of Bimatoprost therapy. Results. A hypotensive effect of monotherapy with Bimatoprost was confirmed in patients with newly diagnosed POAG. An additional hypotensive effect was revealed when patients with POAG were transferred from APG and FC therapy to monotherapy with Bimatoprost. Adverse reactions: mild and moderate hyperaemia, periorbital manifestations such as skin pigmentation, deepening of upper eyelid folds, narrowing of the palpebral fissure (ptosis) were noted, respectively, in 8, 6.7, 1.3, 2.7, 2.7 % of cases respectively, but did not require a discontinuation of the therapy in any patient. Eyelash growth was noted by 3 patients (4 %). This effect was not considered to be a side effect, since none of the patients bothered. In 47 % of patients who had previously received APG and FC therapy and had dry eye syndrome of varying severity, objective and subjective positive changes relating to dry eye syndrome was noted. A positive dynamic of morphometric parameters of the optic nerve and cells of the retinal ganglion complex was revealed in patients of all groups of study.Conclusion. Monotherapy with Bimatoprost can be recommended as therapy of choice for patients with newly diagnosed glaucoma, and those previously receiving antihypertensive therapy with PGAs or fixed combinations (-blocker + carbonic anhydrase inhibitor) including those having dry eye syndrome of varying severity.

Novel Antihypertensive Prodrug from Grape Seed Proanthocyanidin Extract via Acid-Mediated Depolymerization in the Presence of Captopril: Synthesis, Process Optimization, and Metabolism in Rats.

Grape seed extract contains a high content of proanthocyanidins that can be depolymerized into C-4-substituted (epi)catechin derivatives in the presence of nucleophiles. However, the biological and medicinal values of depolymerization products have been rarely investigated. Recently, we developed a novel depolymerization product (-)-epicatechin-4β- S-captopril methyl ester (ECC) derived from the reaction of grape seed proanthocyanidin extract with captopril in the presence of acidified methanol. A central composite design was employed to select the most appropriate depolymerization temperature and time to obtain the target product ECC with a high yield. A total of 16 metabolites of ECC in rat urine, feces, and plasma were identified using liquid chromatography quadrupole time-of-flight tandem mass spectrometry. The in vivo results suggested that ECC could release captopril methyl ester and epicatechin, followed by the generation of further metabolites captopril and epicatechin sulfate conjugates. Therefore, ECC may be used as a potential prodrug with synergistic or additive hypotensive effects.

Restoration of autonomic balance and cortical and cerebral structures functions harmonization indicators by means of gamma-aminobutyric acid system modulation in patients with primary hypertension

The problem of arterial hypertension is getting more relevant because of the increasing of it prevalence both all over the world and inUkraine. Aim of the work was the investigation of psychoemotional disorders and vegetative homeostasis in patients with non-complicated forms of AH and their correction with the application of Passiflora incarnata extract as a part of the complex antihypertensive therapy. Materials and Methods. 73 patients of both sexes in active working age with AH stage II were examined. All patients were divided into 2 groups. Group 1 consisted of 35 patients with hypertension, who on the background of standard antihypertensive treatment were prescribed a plant remedy containing Passiflora incarnata extract – Alora® syrup (Nobelpharma Ilach Sanayi Wei Tidjaret A. Sh., Turkey) at a dose of 10 ml 3 times a day for 4 weeks. The 2 nd group was a control; it included 38 patients with hypertension treated only with antihypertensive therapy. pressure was measured with a manual mechanical tonometer at rest, according to the Unified clinical protocol of medical care Arterial hypertension. The psychoemotional state was investigated with the help of test questionnaire using the PHQ-90 Health Scale (maximum 27 points). To assess the state of autonomic regulation we used analysis of heart rate variability (HRV) values obtained with the IPEC-6-CARDIOPLUS FASAGRAF® device. Statistical processing was carried out using the Student's variation method. Results. The clinical study proves that using the medicine of Passiflora incarnata extract for patients with uncomplicated forms of hypertension during 4 weeks provides possibility to obtain an additional hypotensive effect against the background of using standard antihypertensive therapy as a demonstration of a wide range of Passiflora incarnata pharmacological activity. Conclusions. The implementation of the Рassiflora drug complex application are sympatholytic and vascular tone modifying effects, expressed positive dynamics in the psychoemotional state, manifested as anxiolytic and sedative actions, and optimization of the emotional state and degree of psychological tension in patients with AH.

The Effect Of Inorganic Nitrate And Exercise On Blood Pressure In Pre-and Hypertension Subjects.

Dietary supplementation of inorganic nitrate (NO-3) reduces blood pressure (BP) in normal and hypertensive subjects. An acute bout of exercise also reduces BP in many normotensive and in most hypertensive individuals. The possible additive hypotensive effect of NO-3 plus exercise has not been investigated in pre- and hypertensives. PURPOSE: To assess whether intake of NO-3 followed by maximal exercise may potentiate the hypotensive effect of both procedures. METHODS: Ten pre- or hypertensive subjects participated in a randomized double-blind study one week apart. (7 men, 3 women) (BP ≥ 120/80mmHg) (Systolic Blood Pressure SBP/Diastolic Blood Pressure DBP). Subjects arrived in the fasting condition and without medications and ingested either a fruit and vegetables juice containing 25O g of NO-3 (8 mmol/L of NO-3) (N) or nitrate depleted juice (P). After 90 minutes post supplementation, they performed a MAXCAP-T treadmill test. BP was obtained 10 minutes post arrival (BP1), 90 minutes post dietary supplementation (BP2), immediately Post MAXCAP-T (BP3), 10 minutes after MAXCAP-T(BP4), and 150 minutes post MAXCAP-T (BP5). Statistics anova, paired t test, t test two groups. RESULTS: After ingestion of N, SBP and DBP were reduced by 11 and 6 mmHg, respectively. Meanwhile, after P, SBP decreased 3 mmHg while DBP did not change. Following MAXCAP-T, SBP increased less after N than P (26 vs 31 mmHg, P <0.05). DBP decreased 2 and increased 5 mmHg with N and P, respectively (P <0.05). Ten minutes after MAXCAP-T, SBP was 20 and 11 mmHg lower than BP1 for N and P respectively (P< 0.05). The difference between N and P was significant (P <0.05). DBP was reduced 10 mmHg with N with no changes in P. After 150 minutes of MAXCAP-T, SBP was 24 and 16 mmHg lower than BP1 for N and P, respectively (p < 0.05). Meanwhile, DBP was 8 mmHg lower than BP1 for N without significant changes for P. CONCLUSIONS: Ingestion of inorganic nitrate decreased SBP and DBP before exercise and prevented increases in SBP and DBP immediately after acute maximal exercise. The combination of NO-3 and exercise resulted in greater decreases in BP in pre- and hypertensive patients as compared with P.

Abstract 10036: Olmesartan Improves Not Only Vascular Endothelial Dysfunction but Cardiac Diastolic Dysfunction in Hypertensive Heart Failure With Preserved Ejection Fraction - ORION Study

Introduction: The optimal treatment for heart failure (HF) with preserved left ventricular (LV) ejection fraction (EF) (HFpEF) has not been established. Using an experimental model of HFpEF, we previously reported a novel mechanism underlying reversal of endothelial dysfunction and HFpEF by AT1 receptor blocker (ARB). By performing this study (ORION: OlmesaRtan Improvement endothelial functiON with hypertension study), we examined the effects of ARB on hypertensive HFpEF patients, focusing on reactive oxygen species (ROS). Methods and Results: We examined prospectively 20 hypertensive HFpEF patients, taking any renin-angiotensin system inhibitors, switched to appreciable amounts of highly-selective ARB; olmesartan (average dosage amounts: 22.9 mg/day) for 3 months. Despite no additive hypotensive effects of olmesartan, endothelial dysfunction assessed by fingertrip digital reactive hyperemia (RH) peripheral arterial tonometry using Endo-PAT2000 was significantly reversed (RH-index; 1.57±0.34 to 1.87±0.50, P=0.034), accompanied by significant reduction of serum derivatives of reactive oxidative metabolites levels, novel biomarker of ROS (362.8±13.7 to 302.1±9.4 unit called the Carratelli unit [U.CARR], P=0.001). Olmesartan treatments significantly improved cardiac diastolic function evaluated by the ratio of early transmitral flow velocity to tissue doppler early diastolic mitral annular velocity (15.4 to 11.0, P&lt;0.001) but not LVEF and LV anterior wall thickness in echocardiography, and decreased plasma B-type natriuretic peptide levels (214.9 to 191.4, P&lt;0.05) in HFpEF patients. Additionaly, olmesartan significantly increased plasma superoxide dismutase activity (2.39±0.73 to 3.06±0.78 U/mL, P=0.02) and adiponectin levels (2.66±1.55 to 4.12±1.99 μg/mL, P&lt;0.05), but not affect plasma nitrates and nitrites (NO3-/NO2-) levels (53.2±28.1 to 62.9±28.4 μmol/L). Conclusions: These data suggested that strong AT1 receptor blockade by olmesartan restored not only endothelial dysfunction but cardiac diastolic dysfunction in HFpEF beyond hypotensive effects. Increased in SOD activities and adiponectin levels, but not nitric oxide levels, might contribute to these beneficial effects of olmesartan.

Efficacy and safety of pneumatic trabeculoplasty versus timolol added to latanoprost in primary open angle glaucoma.

To compare the safety and short-term additive hypotensive effect of pneumatic trabeculoplasty (PNT) versus timolol among patients receiving topical latanoprost for primary open angle glaucoma (POAG). This study prospectively evaluated 30 eyes of 30 patients with POAG receiving latanoprost monotherapy. We randomly assigned 15 eyes to PNT plus latanoprost (Group A), and 15 eyes to latanoprost/timolol fixed combination therapy (Group B). PNT treatment was performed at days 0, 7, and 90. Follow-up visits occurred at day 1, week 1, and months 1 and 3. Compared to baseline values, both treatments significantly lowered IOP (p ≤ 0.001).The mean IOP for Group A was 21.13 ± 1.6 mmHg at baseline and 18.7 ± 1.5 mmHg at three months (p ≤ 0.001). For Group B, mean IOP was 20.8 ± 1.9 mmHg at baseline and 18.9 ± 0.8 mmHg at three months (p ≤ 0.001). Transient conjunctival hyperaemia, the only adverse effect occurring after PNT, was observed in all patients in Group A. The additive IOP-lowering effect of PNT was similar to timolol in patients with POAG receiving latanoprost.

Reduced Cardiac Contractile Force Due to Sympathovagal Dysfunction Mediates the Additive Hypotensive Effects of Limited-Access Regimens of Ethanol and Clonidine in Spontaneously Hypertensive Rats

Our previous attempts to investigate the long-term hemodynamic interaction between ethanol and clonidine in telemetered spontaneously hypertensive rats (SHRs) were hampered by the lack of a sustained hypotensive response to continuous clonidine exposure. This limitation was circumvented when we adopted a limited-access clonidine (8:30 AM-4:30 PM) paradigm in a recent study. The latter paradigm was employed here to evaluate the ethanol-clonidine interaction and possible roles of myocardial function and autonomic control in this interaction. Changes in blood pressure (BP), heart rate, maximum rate of rise in BP wave (+dP/dt(max)), and spectral cardiovascular autonomic profiles were measured by radiotelemetry in pair-fed SHRs receiving clonidine (150 μg/kg/day), ethanol [2.5% (w/v)], or their combination during the day for 12 weeks. Ethanol or clonidine elicited long-term decreases in BP, and their combination caused additive hypotensive response. Significant reductions in +dP/dt(max) were observed upon concurrent treatment with ethanol and clonidine, in contrast to no effect for individual treatment. In addition, the combined treatment increased the high-frequency (HF) spectral band of interbeat interval (IBI-HF(nu), 0.75-3 Hz) and decreased low-frequency (IBI-LF(nu), 0.2-0.75 Hz) bands and IBI(LF/HF) ratios. Clonidine-evoked reductions in plasma and urine norepinephrine and BP-LF spectral power (measure of vasomotor sympathetic tone) were not affected by ethanol. In conclusion, concurrent treatment with ethanol and clonidine shifts the sympathovagal balance toward parasympathetic dominance and elicits exaggerated hypotension as a result of a reduction in cardiac contractile force.

The additive effect of dorzolamide hydrochloride (Trusopt) and a morning dose of bimatoprost (Lumigan) on intraocular pressure and retrobulbar blood flow in patients with primary open-angle glaucoma

AimsTo assess the additive effect of dorzolamide hydrochloride 2% on the diurnal intraocular pressure (IOP) curve and retrobulbar haemodynamics in patients with primary open-angle glaucoma (POAG) treated with morning-dosed bimatoprost...

Polytherapy with two or more antihypertensive drugs to lower blood pressure in elderly Ontarians. Room for improvement

Although guidelines now recommend polytherapy to achieve blood pressure targets, little is know about which antihypertensive drugs are combined in clinical practice. To examine current practices for the coprescribing of antihypertensive agents. A population-based cohort study was performed using linked administrative databases on all Ontario residents 66 years of age or older who were newly treated for hypertension between July 1, 1994, and March 31, 2002, and did not have diabetes or other relevant comorbidities. All patients were followed for two years to determine which antihypertensives were prescribed concurrently. Of the 166,018 patients in the described cohort, 1819 (1%) were prescribed a combination therapy tablet as their first-line therapy. The number of patients prescribed antihypertensive polytherapy within the first two years of diagnosis increased from 2071 (21%) of the 9825 hypertensive patients starting treatment in the second half of 1994 to 2578 (37%) of the 6988 hypertensive patients beginning treatment in the first quarter of 2002 (P<0.0001). Overall, 11,003 (27%) of polytherapy prescriptions were for drugs without additive hypotensive effects when combined and this proportion did not change over time. Although there has been an increase in the use of polytherapy in elderly hypertensive patients without comorbidities in Ontario over the past decade, more than one-quarter of the two drugs prescribed together have not been proven to have additive hypotensive effects. Because this likely contributes to suboptimal blood pressure control rates, future guidelines and educational programs should devote increased attention to the choice of optimal polytherapy combinations.

Efficacy of Combination Antihypertensive Therapy with Low-Dose Indapamide: Assessment by Blood Pressure Self-Monitoring at Home

We examined the effects of the addition of low-dose indapamide to antihypertensive drugs of other classes, as well as its duration of action, using blood pressure (BP) self-monitoring at home. Seventy-six patients undergoing monotherapy with a calcium channel blocker (CCB), angiotensin converting-enzyme inhibitor (ACEI), or angiotensin AT1-receptor blocker (ARB), but had an average morning home systolic BP (SBP) > or =135 mmHg or diastolic BP (DBP) > or =85 mmHg, were studied. Indapamide (1 mg) was added to their existing treatment once daily for 4 weeks. The additional hypotensive effects of indapamide were evaluated by casual and home BPs, and the results were compared among the three groups of subjects classified according to their initial drug treatment classes. The morning/evening (M/E) ratio of BP reduction was calculated to assess the duration of the effect. Overall, indapamide significantly (P < 0.001) lowered morning home BP (147 +/- 12/87 +/- 9 mmHg to 135 +/- 12/81 +/- 9 mmHg), evening home BP (138 +/- 15/79 +/- 10 mmHg to 126 +/- 12/73 +/- 9 mmHg), and casual BP (145 +/- 21/86 +/- 14 mmHg to 136 +/- 17/81 +/- 13 mmHg). All groups showed significant indapamide-induced home SBP/DBP decreases, whereas only the ACEI and ARB groups, but not the CCB group, showed a home pulse pressure (PP) reduction. Evening SBP and PP decreases were significantly greater in the ARB group than in the CCB group. The mean M/E ratio with indapamide was 0.95 for SBP and 0.85 for DBP. Low-dose indapamide used in combination can provide additional anti-hypertensive efficacy lasting for 24 h. The added effect of indapamide may be more prominent on ARBs than on CCBs.

Efficacy of Combination Antihypertensive Therapy with Low-Dose Indapamide: Assessment by Blood Pressure Self-Monitoring at Home

We examined the effects of the addition of low-dose indapamide to antihypertensive drugs of other classes, as well as its duration of action, using blood pressure (BP) self-monitoring at home. Seventy-six patients undergoing monotherapy with a calcium channel blocker (CCB), angiotensin converting-enzyme inhibitor (ACEI), or angiotensin AT1-receptor blocker (ARB), but had an average morning home systolic BP (SBP) ≥ 135 mmHg or diastolic BP (DBP) ≥ 85 mmHg, were studied. Indapamide (1 mg) was added to their existing treatment once daily for 4 weeks. The additional hypotensive effects of indapamide were evaluated by casual and home BPs, and the results were compared among the three groups of subjects classified according to their initial drug treatment classes. The morning/evening (M/E) ratio of BP reduction was calculated to assess the duration of the effect. Overall, indapamide significantly (P < 0.001) lowered morning home BP (147 ± 12/87 ± 9 mmHg to 135 ± 12/81 ± 9 mmHg), evening home BP (138 ± 15/79 ± 10 mmHg to 126 ± 12/73 ± 9 mmHg), and casual BP (145 ± 21/86 ± 14 mmHg to 136 ± 17/81 ± 13 mmHg). All groupsshowed significant indapamide-induced home SBP/DBP decreases, whereas only the ACEI and ARB groups, but not the CCB group, showed a home pulse pressure (PP) reduction. Evening SBP and PP decreases were significantly greater in the ARB group than in the CCB group. The mean M/E ratio with indapamide was 0.95 for SBP and 0.85 for DBP. Low-dose indapamide used in combination can provide additional anti-hypertensive efficacy lasting for 24 h. The added effect of indapamide may be more prominent on ARBs than on CCBs.

Effects of bunazosin hydrochloride on ciliary muscle constriction and matrix metalloproteinase activities.

To clarify the mechanism by which bunazosin hydrochloride (BZ), a selective alpha1-adrenoceptor antagonist, increases uveoscleral outflow. The effects of BZ on matrix metalloproteinase (MMP) activities in cultured monkey ciliary muscle cells, and on phenylephrine hydrochloride-induced constriction in bovine ciliary muscles, were examined. Also, the possible additive ocular hypotensive effects of BZ and latanoprost (LP) were evaluated in ocular normotensive monkeys. Although BZ at 10 to 10 M did not increase MMP-2, -3, and -9 activities in the culture medium of ciliary muscle cells, BZ at 10 to 10 M inhibited phenylephrine hydrochloride-induced constriction in ciliary muscles. The maximal reduction in intraocular pressure of concomitant administration of BZ and LP was greater than that of BZ alone and tended to be greater than that of LP alone. These findings, in normotensive monkeys, indicate that the mechanism whereby BZ increases uveoscleral outflow is independent of an effect on MMPs and is partly due to relaxation of the ciliary muscle. This effect is different from that of LP, which might help to explain the finding that topical concomitant administration of BZ and LP increased AUC(0-6h) value (IOP reduction) to 201% and 145% of BZ and LP given alone, respectively.

Additive Beneficial Effects of the Combination of a Calcium Channel Blocker and an Angiotensin Blocker on a Hypertensive Rat-Heart Failure Model

The present study was undertaken to examine the effects of a calcium channel blocker, azelnidipine (1 mg/kg/day), an angiotensin converting enzyme (ACE) inhibitor, temocapril (10 mg/kg/day), an angiotensin II type 1 (AT1) receptor blocker (ARB), olmesartan (5 mg/kg/day), and their combination on Dahl salt-sensitive rats (DS rats) developing heart failure with preserved systolic function. DS rats were fed a high-salt diet (8% NaCl) from 7 weeks of age and progressively developed hypertension. Although monotherapy with azelnidipine lowered the blood pressure of DS rats to a greater extent than monotherapy with temocapril or olmesartan, the three drugs had similar effects on cardiac hypertrophy, cardiac fibrosis, the expressions of brain natriuretic peptide, transforming growth factor-beta1, collagen I, collagen III and monocyte chemoattractant protein-1 mRNA (as estimated by Northern blot analysis), and cardiac diastolic dysfunction (as estimated by echocardiography). These results show that ACE and AT1 receptor, as well as hypertension, are involved in the development of heart failure with preserved systolic function in DS rats. The combination of azelnidipine with olmesartan or temocapril produced no additive hypotensive effect in DS rats and no additive effect on cardiac hypertrophy or gene expressions. However, the combination therapy prolonged the survival rate of DS rats more than azelnidipine (p <0.01) or temocapril alone (p <0.05), and this additive beneficial effect by the combination therapy was associated with a greater reduction of cardiac fibrosis, urinary albumin excretion and serum creatinine. Our results thus showed that the combination of a calcium channel blocker with an ARB or an ACE inhibitor had additive preventive effects on a rat model of hypertensive heart failure with preserved systolic function. Thus, combination therapy with these agents seems to be a useful therapeutic strategy for the prevention of hypertensive heart failure.

Augmented sympathetic neural response to simulated obstructive apnoea in human heart failure.

Sleep apnoea in heart failure increases mortality risk, possibly as a result of greater activation of the sympathetic nervous system. In healthy subjects, simulated central apnoeas (holding breath) and obstructive apnoeas (Mueller manoeuvres) increase muscle sympathetic activity equally, primarily through chemoreceptor stimulation. In heart failure, however, Mueller manoeuvres cause greater reductions in blood pressure than breath holds. We hypothesized that in heart failure, the summation of arterial baroreceptor unloading and chemoreceptor stimulation would increase sympathetic activity more during obstructive than central apnoeas. Healthy human subjects and heart failure patients (seven of each) performed 15-s breath holds and 15-s Mueller manoeuvres. Breath holds evoked a progressive increase in muscle sympathetic nerve activity in both groups, but had no effect on blood pressure. In healthy subjects, breath holds and Mueller manoeuvres caused equal peaks in sympathetic activity. In contrast, in heart failure patients, Mueller manoeuvres caused a progressive decrease in blood pressure (P < 0.05) and greater increases in sympathetic activity than breath holds (P < 0.01). In heart failure, simulated obstructive apnoea elicits greater increases in sympathetic activity than simulated central apnoea, due to its additional hypotensive effect. These present findings offer novel insight into the potential role of sleep apnoea in augmenting sympathetic activity and accelerating disease progression in heart failure.

Augmented sympathetic neural response to simulated obstructive apnoea in human heart failure

Sleep apnoea in heart failure increases mortality risk, possibly as a result of greater activation of the sympathetic nervous system. In healthy subjects, simulated central apnoeas (holding breath) and obstructive apnoeas (Mueller manoeuvres) increase muscle sympathetic activity equally, primarily through chemoreceptor stimulation. In heart failure, however, Mueller manoeuvres cause greater reductions in blood pressure than breath holds. We hypothesized that in heart failure, the summation of arterial baroreceptor unloading and chemoreceptor stimulation would increase sympathetic activity more during obstructive than central apnoeas. Healthy human subjects and heart failure patients (seven of each) performed 15-s breath holds and 15-s Mueller manoeuvres. Breath holds evoked a progressive increase in muscle sympathetic nerve activity in both groups, but had no effect on blood pressure. In healthy subjects, breath holds and Mueller manoeuvres caused equal peaks in sympathetic activity. In contrast, in heart failure patients, Mueller manoeuvres caused a progressive decrease in blood pressure (P&lt;0.05) and greater increases in sympathetic activity than breath holds (P&lt;0.01). In heart failure, simulated obstructive apnoea elicits greater increases in sympathetic activity than simulated central apnoea, due to its additional hypotensive effect. These present findings offer novel insight into the potential role of sleep apnoea in augmenting sympathetic activity and accelerating disease progression in heart failure.