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Sublingual nifedipine compared with intravenous hydrallazine in the acute treatment of severe hypertension in pregnancy: potential for use in rural practice

Jegasothy R, Paranthaman S

J Obstet Gynaecol Res, 1996 Feb;22(1):21-4.
PMID: 8624887

OBJECTIVES: The purposes of this study were to compare the efficacy of sublingual nifedipine with intravenous hydrallazine in the control of acute hypertension of pregnancy and to make a preliminary assessment whether sublingual nifedipine could be recommended for use by midwives faced with severe hypertension in pregnancy in a rural setting.
METHODS: Subjects were 200 consecutive patients admitted to Kuala Tereng-ganu General Hospital, Malaysia with severe hypertension in pregnancy between August 1989 and June 1990. Admission criteria were an ongoing viable pregnancy more than 28 weeks and diastolic blood pressure (DBP) more than 120 mmHg. The patients were randomly divided into 2 groups. In group I, sublingual nifedipine 5 mg was administered and repeated after 15 minutes if DBP > 120 mmHg; and in group II hydrallazine 5 mg was intravenously injected and repeated after 15 minutes if DBP > 120 mmHg. Both groups were put on hydrallazine infusion if DBP > 120 mmHg after 30 minutes. The Chi-square test was used for analysis with significance at p < 0.05.
RESULTS: There was no statistical difference in the efficacy of therapy for decreasing blood pressure between the 2 groups. The groups were comparable by age, parity, gestational age at presentation, birth weight of infants, incidence of postpartum haemorrhage and fetal distress. Caesarian section rates were similar. In the observational studies on nurses administering the drugs, no significant difficulties were observed.
CONCLUSION: Sublingual nifedipine was comparable to IV hydrallazine in the treatment of acute hypertension of pregnancy. Nurses were able to administer lingual nifedipine without difficulty.

Matched MeSH terms: Antihypertensive Agents/administration & dosage*
Fulltext The effects of Cicletanine, a new antihypertensive agent on insulin release in rat isolated pancreas by the perfusion technique

Mashori GR, Tariq AR, Shahimi MM, Suhaimi H

Singapore Med J, 1996 Jun;37(3):278-81.
PMID: 8942229

Treatment of hypertension has reduced the incidence of stroke, heart failure and renal failure. However, the incidence of coronary heart disease is not reduced to the same degree. Many of the drugs advocated as first-line drugs in the step-wise therapy have been shown to cause carbohydrate intolerance and it is an independent risk factor in the development of coronary heart disease. It is thus important to identify the antihypertensive drugs that may cause deterioration in glucose tolerance. Cicletanine, the first derivative of the furopyridines, is a new class of antihypertensive agents. It acts directly on vascular endothelium cells by increasing prostacyclin synthesis. It also decreases intracytosolic calcium levels in smooth muscles. The purpose of this study is to evaluate the effects of Cicletanine on insulin release in rat isolated pancreas by the perfusion technique adapted from Loubatieres and co-workers (1972). Doses used were based on therapeutic peak plasma concentration. Diazoxide was used as a positive control ie a known insulin suppressant. Cicletanine at 1/10 and equivalent therapeutic concentrations (0.5 microgram/mL and 5.0 micrograms/mL) did not suppress insulin release. However, at concentration exceeding 10X its therapeutic levels (50 micrograms/mL) it begins to suppress insulin release. In conclusion, Cicletanine did not inhibit insulin release at concentrations within the therapeutic range.

Matched MeSH terms: Antihypertensive Agents/administration & dosage
Application of similarity factor in development of controlled-release diltiazem tablet

Peh KK, Wong CF

Drug Dev Ind Pharm, 2000 Jul;26(7):723-30.
PMID: 10872090

Controlled-release grade hydroxypropylmethylcellulose (HPMC) or xanthan gum (XG) and microcrystalline cellulose (MCC) were employed to prepare controlled-release diltiazem hydrochloride tablets. The similarity factor f2 was used for dissolution profile comparison using Herbesser 90 SR as a reference product. Drug release could be sustained in a predictable manner by modifying the content of HPMC or XG. Moreover, the drug release profiles of tablets prepared using these matrix materials were not affected by pH and agitation rate. The f2 values showed that only one batch of tablets (of diltiazem HCl, HPMC or XG, and MCC in proportions of 3.0:3.0:4.0) was considered similar to that of the reference product, with values above 50. The unbiased similarity factor f2* values were not much different from the f2 values, ascribing to a small dissolution variance of the test and reference products. The amount of HPMC or XG incorporated to produce tablets with the desired dissolution profile could be determined from the curves of f2 versus polymer content. Hence, the f2 values can be applied as screening and optimization tools during development of controlled-release preparations.

Matched MeSH terms: Antihypertensive Agents/administration & dosage*
Fulltext Choice of antihypertensive drug in the diabetic patient

Ong HT, Cheah JS

MedGenMed, 2005;7(2):74.
PMID: 16369452

The hypertensive patient with type 2 diabetes is especially at risk of adverse cardiovascular events. The United Kingdom Prospective Diabetes Study (UKPDS) and Hypertension Optimal Treatment (HOT) studies suggested that treatment to a lower target blood pressure resulted in better prevention of clinical disease in these patients. Most trials comparing antihypertensive drugs have shown only minimal differences between the various agents. The evidence from the trials suggests that diuretics, beta-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and the angiotensin-receptor antagonists (ARBs) will all successfully reduce adverse clinical events. The largest of the comparative hypertensive drug trials, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), demonstrated that a diuretic has a better hypotensive effect, and was more successful in preventing many aspects of cardiovascular disease compared with CCBs and ACE inhibitors. The importance of good blood pressure control and the general equivalence of antihypertensive drugs were again shown in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, which compared an ARB with a CCB. Choice of antihypertensive agent should be individualized and guided by the presence of concomitant clinical disease and the need to protect any specific target organ system in the diabetic hypertensive. Diuretics, being potent hypotensive drugs with clearly demonstrated clinical benefit, should form part of the antihypertensive regimen of most diabetic hypertensives. ACE inhibitors and ARBs are especially useful in preventing nephropathy. Most patients will require a combination of antihypertensive drugs to achieve tight blood pressure control of under 130/80 mm Hg in the diabetic hypertensive. The clinician should concentrate on seeking this lower target blood pressure rather than be excessively concerned about which is the best antihypertensive agent.

Matched MeSH terms: Antihypertensive Agents/administration & dosage*
The application of glucose biosensor in studying the effects of insulin and anti-hypertensive drugs towards glucose level in brain striatum

Ahmad F, Yusof AP, Bainbridge M, Ab Ghani S

Biosens Bioelectron, 2008 Jul 15;23(12):1862-8.
PMID: 18440218 DOI: 10.1016/j.bios.2008.03.006

The mechanisms involving insulin and anti-hypertensive drugs regulation for in vivo cerebral glucose metabolism are not well-understood. This might be due to lack of direct means of measuring cerebral glucose. It is known that the continuous delivery of glucose to the brain is critical for its normal metabolic function. In this study, we report the effect of insulin and anti-hypertensive drugs on glucose level in the striatum of rats. The rats were divided into two groups, i.e. hyperglycemia (14.8+/-0.3mM plasma glucose) and diabetic (10.8+/-0.2mM plasma glucose). A custom-built glucose microsensor was implanted at coordinates A/P 1.0 from bregma, M/L +2.5 and D/V -5.0 (from dura) in the striatum. The amperometric response obtained at +0.23 V vs. Ag|AgCl corresponded to the glucose level in striatum. By varying the concentrations of protaminc zinc insulin infused into the rats, striatum glucose level was found to remain constant throughout, i.e. 9.8+/-0.1 and 4.7+/-0.1mM for hyperglycemic rats and for diabetic rats, respectively. However, infusion of valsartan and felodipine has lowered the striatum glucose level significantly. These findings agreed with the hypothesis that suggested striatum glucose uptake do not depend on insulin but is clearly dependant on anti-hypertensive drugs administration.

Matched MeSH terms: Antihypertensive Agents/administration & dosage*
Fulltext An Asian regional analysis of cost-effectiveness of early irbesartan treatment versus conventional antihypertensive, late amlodipine, and late irbesartan treatments in patients with type 2 diabetes, hypertension, and nephropathy

Annemans L, Demarteau N, Hu S, Lee TJ, Morad Z, Supaporn T, et al.

Value Health, 2008 May-Jun;11(3):354-64.
PMID: 17888064 DOI: 10.1111/j.1524-4733.2007.00250.x

OBJECTIVE: The prevalence of type 2 diabetes, often leading to diabetic nephropathy, has increased globally, especially in Asia. Irbesartan treatment delays the progression of kidney disease at the early (microalbuminuria) and late (proteinuria) stages of nephropathy in hypertensive type 2 diabetics. This treatment has proven to be cost-effective in Western countries. This study assessed the cost-effectiveness of early irbesartan treatment in Asian settings.
METHODS: An existing lifetime model was reprogrammed in Microsoft Excel to compare irbesartan started at an early stage to irbesartan or amlodipine started at a late stage, and standard treatments from a health-care perspective in China, Malaysia, Thailand, South Korea, and Taiwan. The main effectiveness parameters were incidences of end-stage renal disease, time in dialysis, and life expectancy. All costs were converted to 2004 US$ using official purchasing power parity. Local data were obtained for costs, transplantation,dialysis, and mortality rates. Probabilities regarding disease progression after treatment with the investigated drugs were extracted from two published clinical trials. A probabilistic sensitivity analysis was performed.
RESULTS: Early use of irbesartan yielded the largest clinical and economic benefits reducing need for dialysis by 61% to 63% versus the standard treatment, total costs by 9% (Thailand) to 42% (Taiwan), and increasing life expectancy by 0.31 to 0.48 years. Early irbesartan had a 66% (Thailand) to 95% (Taiwan) probability of being dominant over late irbesartan.
CONCLUSION: Although the absolute results varied in different settings, reflecting differences in epidemiology, management, and costs, early irbesartan treatment was a cost-effective alternative in the Asian settings.

Matched MeSH terms: Antihypertensive Agents/administration & dosage
Characterization of the possible mechanisms underlying the hypotensive and spasmogenic effects of Loranthus ferrugineus methanolic extract

Ameer OZ, Salman IM, Siddiqui MJ, Yam MF, Sriramaneni RN, Sadikun A, et al.

Am J Chin Med, 2009;37(5):991-1008.
PMID: 19885958

In the present study, L. ferrugineus methanol extract (LFME) was evaluated for its blood pressure lowering effect in anesthetized normotensive Sprague Dawley (SD) rats and its spasmogenic effect in isolated guinea pig ileum. The possible mechanism(s) of action were also investigated. LFME was obtained by Soxhlet extraction. The rats were fasted overnight and anesthetized with sodium pentobarbitone (60 mg/kg i.p.). LFME was administered in i.v. boluses in the concentrations of 25, 50, 100 and 200 mg/kg respectively, with concomitant monitoring of mean arterial pressure (MAP). It was found that LFME dose-dependently reduced MAP. An i.v. bolus injection of atropine significantly decreased the blood pressure lowering effect of LFME. Similarly, L-NAME (Nomega-nitro-L-arginine methyl ester) significantly lowered both the MAP and the action duration. Conversely, no significant change in MAP was seen following i.v. injections of neostigmine, hexamethonium, prazosin and propranolol. LFME also produced a dose-dependent contractile effect in guinea pig ileum. This contraction was significantly reduced in atropine pre-incubated tissue segments, yet it was significantly enhanced in the presence of neostigmine. No appreciable change in the ability of LFME to contract guinea pig ileum was seen in the presence of hexamethonium. Accordingly, it can be postulated that LFME possesses a marked hypotensive effect that can be attributed to stimulation of muscarinic receptors and/or stimulation of nitric oxide (NO) release. Moreover, LFME retains a considerable spasmogenic action due to its cholinergic properties. The hypotensive and spasmogenic effects of LFME justify its traditional uses.

Matched MeSH terms: Antihypertensive Agents/administration & dosage
Real-life safety and effectiveness of amlodipine/valsartan combination in the treatment of hypertension

Chazova IE, Dongre N, Vigdorchik AV

Adv Ther, 2011 Feb;28(2):134-49.
PMID: 21240661 DOI: 10.1007/s12325-010-0099-1

The aim of our study was to evaluate the safety and effectiveness of the free combination of amlodipine/valsartan in patients with arterial hypertension in a real-life setting.

Matched MeSH terms: Antihypertensive Agents/administration & dosage
Antihypertensive and cardiovascular effects of catechin-rich oil palm (Elaeis guineensis) leaf extract in nitric oxide-deficient rats

Jaffri JM, Mohamed S, Rohimi N, Ahmad IN, Noordin MM, Manap YA

J Med Food, 2011 Jul-Aug;14(7-8):775-83.
PMID: 21631357 DOI: 10.1089/jmf.2010.1170

Oil palm (Elaeis guineensis) leaf extract (OPLE) possesses good ex vivo vasodilation and antioxidant properties. This study evaluated the catechin-rich OPLE antioxidant, antihypertensive, and cardiovascular effects in normal and nitric oxide (NO)-deficient hypertensive rats. OPLE was administered orally (500 mg/kg of body weight/day) to normotensive Wistar rats and N(ω)-nitro-L-arginine methyl ester (L-NAME)-induced NO-deficient hypertensive rats. OPLE significantly (P

Matched MeSH terms: Antihypertensive Agents/administration & dosage*
Fulltext Oral nifedipine versus intravenous labetalol for acute blood pressure control in hypertensive emergencies of pregnancy: a randomised trial

Raheem IA, Saaid R, Omar SZ, Tan PC

BJOG, 2012 Jan;119(1):78-85.
PMID: 21985500 DOI: 10.1111/j.1471-0528.2011.03151.x

To compare oral nifedipine with intravenous labetalol in their rapidity to control hypertensive emergencies of pregnancy.

Matched MeSH terms: Antihypertensive Agents/administration & dosage*
Fulltext Controlled release and angiotensin-converting enzyme inhibition properties of an antihypertensive drug based on a perindopril erbumine-layered double hydroxide nanocomposite

Hussein Al Ali SH, Al-Qubaisi M, Hussein MZ, Ismail M, Zainal Z, Hakim MN

Int J Nanomedicine, 2012;7:2129-41.
PMID: 22619549 DOI: 10.2147/IJN.S30461

The intercalation of perindopril erbumine into Zn/Al-NO(3)-layered double hydroxide resulted in the formation of a host-guest type of material. By virtue of the ion-exchange properties of layered double hydroxide, perindopril erbumine was released in a sustained manner. Therefore, this intercalated material can be used as a controlled-release formulation.

Matched MeSH terms: Antihypertensive Agents/administration & dosage*
Fulltext Honey supplementation in spontaneously hypertensive rats elicits antihypertensive effect via amelioration of renal oxidative stress

Erejuwa OO, Sulaiman SA, Ab Wahab MS, Sirajudeen KN, Salleh S, Gurtu S

Oxid Med Cell Longev, 2012;2012:374037.
PMID: 22315654 DOI: 10.1155/2012/374037

Oxidative stress is implicated in the pathogenesis and/or maintenance of elevated blood pressure in hypertension. This study investigated the effect of honey on elevated systolic blood pressure (SBP) in spontaneously hypertensive rats (SHR). It also evaluated the effect of honey on the amelioration of oxidative stress in the kidney of SHR as a possible mechanism of its antihypertensive effect. SHR and Wistar Kyoto (WKY) rats were randomly divided into 2 groups and administered distilled water or honey by oral gavage once daily for 12 weeks. The control SHR had significantly higher SBP and renal malondialdehyde (MDA) levels than did control WKY. The mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione S-transferase (GST) were significantly downregulated while total antioxidant status (TAS) and activities of GST and catalase (CAT) were higher in the kidney of control SHR. Honey supplementation significantly reduced SBP and MDA levels in SHR. Honey significantly reduced the activities of GST and CAT while it moderately but insignificantly upregulated the Nrf2 mRNA expression level in the kidney of SHR. These results indicate that Nrf2 expression is impaired in the kidney of SHR. Honey supplementation considerably reduces elevated SBP via amelioration of oxidative stress in the kidney of SHR.

Matched MeSH terms: Antihypertensive Agents/administration & dosage*
Fulltext Effect of Clonidine (an antihypertensive drug) treatment on oxidative stress markers in the heart of spontaneously hypertensive rats

Nik Yusoff NS, Mustapha Z, Govindasamy C, Sirajudeen KN

Oxid Med Cell Longev, 2013;2013:927214.
PMID: 23766863 DOI: 10.1155/2013/927214

Hypertension is a risk factor for several cardiovascular diseases and oxidative stress suggested to be involved in the pathophysiology. Antihypertensive drug Clonidine action in ameliorating oxidative stress was not well studied. Therefore, this study investigate the effect of Clonidine on oxidative stress markers and nitric oxide (NO) in SHR and nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME) administered SHR. Male rats were divided into four groups [SHR, SHR+Clonidine (SHR-C), SHR+L-NAME, SHR+Clonidine+L-NAME(SHRC+L-NAME)]. Rats (SHRC) were administered with Clonidine (0.5 mg kg(-1) day(-1)) from 4 weeks to 28 weeks in drinking water and L-NAME (25 mg kg(-1) day(-1)) from 16 weeks to 28 weeks to SHRC+L-NAME. Systolic blood pressure (SBP) was measured. At the end of 28 weeks, all rats were sacrificed and in their heart homogenate, oxidative stress parameters and NO was assessed. Clonidine treatment significantly enhanced the total antioxidant status (TAS) (P < 0.001) and reduced the thibarbituric acid reactive substances (TBARS) (P < 0.001) and protein carbonyl content (PCO) (P < 0.05). These data suggest that oxidative stress is involved in the hypertensive organ damage and Clonidine not only lowers the SBP but also ameliorated the oxidative stress in the heart of SHR and SHR+L-NAME.

Matched MeSH terms: Antihypertensive Agents/administration & dosage
Hydralazine administration activates sympathetic preganglionic neurons whose activity mobilizes glucose and increases cardiovascular function

Parker LM, Damanhuri HA, Fletcher SP, Goodchild AK

Brain Res, 2015 Apr 16;1604:25-34.
PMID: 25662772 DOI: 10.1016/j.brainres.2015.01.049

Hypotensive drugs have been used to identify central neurons that mediate compensatory baroreceptor reflex responses. Such drugs also increase blood glucose. Our aim was to identify the neurochemical phenotypes of sympathetic preganglionic neurons (SPN) and adrenal chromaffin cells activated following hydralazine (HDZ; 10mg/kg) administration in rats, and utilize this and SPN target organ destination to ascribe their function as cardiovascular or glucose regulating. Blood glucose was measured and adrenal chromaffin cell activation was assessed using c-Fos immunoreactivity (-ir) and phosphorylation of tyrosine hydroxylase, respectively. The activation and neurochemical phenotype of SPN innervating the adrenal glands and celiac ganglia were determined using the retrograde tracer cholera toxin B subunit, in combination with in situ hybridization and immunohistochemistry. Blood glucose was elevated at multiple time points following HDZ administration but little evidence of chromaffin cell activation was seen suggesting non-adrenal mechanisms contribute to the sustained hyperglycemia. 16±0.1% of T4-T11 SPN contained c-Fos and of these: 24.3±1.4% projected to adrenal glands and 29±5.5% projected to celiac ganglia with the rest innervating other targets. 62.8±1.4% of SPN innervating adrenal glands were activated and 29.9±3.3% expressed PPE mRNA whereas 53.2±8.6% of SPN innervating celiac ganglia were activated and 31.2±8.8% expressed PPE mRNA. CART-ir SPN innervating each target were also activated and did not co-express PPE mRNA. Neurochemical coding reveals that HDZ administration activates both PPE+SPN, whose activity increase glucose mobilization causing hyperglycemia, as well as CART+SPN whose activity drive vasomotor responses mediated by baroreceptor unloading to raise vascular tone and heart rate.

Matched MeSH terms: Antihypertensive Agents/administration & dosage*
Combination therapy in hypertension: an Asia-Pacific consensus viewpoint

Abdul Rahman AR, Reyes EB, Sritara P, Pancholia A, Van Phuoc D, Tomlinson B

Curr Med Res Opin, 2015 May;31(5):865-74.
PMID: 25707364 DOI: 10.1185/03007995.2015.1020368

Hypertension incurs a significant healthcare burden in Asia-Pacific countries, which have suboptimal rates of blood pressure (BP) treatment and control. A consensus meeting of hypertension experts from the Asia-Pacific region convened in Hanoi, Vietnam, in April 2013. The principal objectives were to discuss the growing problem of hypertension in the Asia-Pacific region, and to develop consensus recommendations to promote standards of care across the region. A particular focus was recommendations for combination therapy, since it is known that most patients with hypertension will require two or more antihypertensive drugs to achieve BP control, and also that combinations of drugs with complementary mechanisms of action achieve BP targets more effectively than monotherapy. The expert panel reviewed guidelines for hypertension management from the USA and Europe, as well as individual Asia-Pacific countries, and devised a treatment matrix/guide, in which they propose the preferred combination therapy regimens for patients with hypertension, both with and without compelling indications. This report summarizes key recommendations from the group, including recommended antihypertensive combinations for specific patient populations. These strategies generally entail initiating therapy with free drug combinations, starting with the lowest available dosage, followed by treatment with single-pill combinations once the BP target has been achieved. A single reference for the whole Asia-Pacific region may contribute to increased consistency of treatment and greater proportions of patients achieving BP control, and hence reducing hypertension-related morbidity and mortality.

Matched MeSH terms: Antihypertensive Agents/administration & dosage
Fulltext Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive rats

Jaarin K, Foong WD, Yeoh MH, Kamarul ZY, Qodriyah HM, Azman A, et al.

Clinics (Sao Paulo), 2015 Nov;70(11):751-7.
PMID: 26602523 DOI: 10.6061/clinics/2015(11)07

This study was conducted to determine whether the blood pressure-lowering effect of Nigella sativa might be mediated by its effects on nitric oxide, angiotensin-converting enzyme, heme oxygenase and oxidative stress markers.

Matched MeSH terms: Antihypertensive Agents/administration & dosage
Role of adenosine receptors in resveratrol-induced intraocular pressure lowering in rats with steroid-induced ocular hypertension

Razali N, Agarwal R, Agarwal P, Kumar S, Tripathy M, Vasudevan S, et al.

Clin Exp Ophthalmol, 2015 Jan-Feb;43(1):54-66.
PMID: 24995479 DOI: 10.1111/ceo.12375

BACKGROUND: Steroid-induced ocular hypertension is currently treated in the same way as primary open-angle glaucoma. However, the treatment is often suboptimal and is associated with adverse effects. We evaluated the oculohypotensive effects of topical trans-resveratrol in rats with steroid-induced ocular hypertension and involvement of adenosine receptors (AR) in intraocular pressure (IOP) lowering effect of trans-resveratrol.
METHODS: The oculohypotensive effect of unilateral single-drop application of various concentrations of trans-resveratrol was first studied in oculonormotensive rats. Concentration with maximum effect was similarly studied in rats with steroid-induced ocular hypertension. Involvement of AR was studied by observing the alterations of IOP in response to trans-resveratrol after pretreating animals with AR subtype-specific antagonists. Additionally, we used computational methods, including 3D modelling, 3D structure generation and protein-ligand interaction, to determine the AR-trans-resveratrol interaction.
RESULTS: All concentrations of trans-resveratrol produced significant IOP reduction in normotensive rat eyes. Maximum mean IOP reduction of 15.1% was achieved with trans-resveratrol 0.2%. In oculohypertensive rats, trans-resveratrol 0.2% produced peak IOP reduction of 25.2%. Pretreatment with A₁ antagonist abolished the oculohypotensive effect of trans-resveratrol. Pretreatment with A₃ and A₂A AR antagonists produced significant IOP reduction in both treated and control eyes, which was further augmented by trans-resveratrol application in treated eyes. Computational studies showed that trans-resveratrol has highest affinity for A₂B and A₁, followed by A2A and A₃ AR.
CONCLUSION: Topically applied trans-resveratrol reduces IOP in rats with steroid-induced ocular hypertension. Trans-resveratrol-induced oculohypotension involves its agonistic activity at the A₁ AR.
KEYWORDS: adenosine receptors; docking simulation; intraocular pressure; resveratrol; topical

Matched MeSH terms: Antihypertensive Agents/administration & dosage*
Fulltext Blood-pressure and cholesterol lowering in persons without cardiovascular disease

Yusuf S, Lonn E, Pais P, Bosch J, López-Jaramillo P, Zhu J, et al.

N Engl J Med, 2016 May 26;374(21):2032-43.
PMID: 27039945 DOI: 10.1056/NEJMoa1600177

BACKGROUND: Elevated blood pressure and elevated low-density lipoprotein (LDL) cholesterol increase the risk of cardiovascular disease. Lowering both should reduce the risk of cardiovascular events substantially.
METHODS: In a trial with 2-by-2 factorial design, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to rosuvastatin (10 mg per day) or placebo and to candesartan (16 mg per day) plus hydrochlorothiazide (12.5 mg per day) or placebo. In the analyses reported here, we compared the 3180 participants assigned to combined therapy (with rosuvastatin and the two antihypertensive agents) with the 3168 participants assigned to dual placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included heart failure, cardiac arrest, or revascularization. The median follow-up was 5.6 years.
RESULTS: The decrease in the LDL cholesterol level was 33.7 mg per deciliter (0.87 mmol per liter) greater in the combined-therapy group than in the dual-placebo group, and the decrease in systolic blood pressure was 6.2 mm Hg greater with combined therapy than with dual placebo. The first coprimary outcome occurred in 113 participants (3.6%) in the combined-therapy group and in 157 (5.0%) in the dual-placebo group (hazard ratio, 0.71; 95% confidence interval [CI], 0.56 to 0.90; P=0.005). The second coprimary outcome occurred in 136 participants (4.3%) and 187 participants (5.9%), respectively (hazard ratio, 0.72; 95% CI, 0.57 to 0.89; P=0.003). Muscle weakness and dizziness were more common in the combined-therapy group than in the dual-placebo group, but the overall rate of discontinuation of the trial regimen was similar in the two groups.
CONCLUSIONS: The combination of rosuvastatin (10 mg per day), candesartan (16 mg per day), and hydrochlorothiazide (12.5 mg per day) was associated with a significantly lower rate of cardiovascular events than dual placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.).
Note: Malaysia is a study site (Author: Yusoff K)

Matched MeSH terms: Antihypertensive Agents/administration & dosage*
Fulltext Blood-pressure lowering in intermediate-risk persons without cardiovascular disease

Lonn EM, Bosch J, López-Jaramillo P, Zhu J, Liu L, Pais P, et al.

N Engl J Med, 2016 May 26;374(21):2009-20.
PMID: 27041480 DOI: 10.1056/NEJMoa1600175

BACKGROUND: Antihypertensive therapy reduces the risk of cardiovascular events among high-risk persons and among those with a systolic blood pressure of 160 mm Hg or higher, but its role in persons at intermediate risk and with lower blood pressure is unclear.
METHODS: In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to receive either candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; the second coprimary outcome additionally included resuscitated cardiac arrest, heart failure, and revascularization. The median follow-up was 5.6 years.
RESULTS: The mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg; the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatment group than in the placebo group. The first coprimary outcome occurred in 260 participants (4.1%) in the active-treatment group and in 279 (4.4%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40); the second coprimary outcome occurred in 312 participants (4.9%) and 328 participants (5.2%), respectively (hazard ratio, 0.95; 95% CI, 0.81 to 1.11; P=0.51). In one of the three prespecified hypothesis-based subgroups, participants in the subgroup for the upper third of systolic blood pressure (>143.5 mm Hg) who were in the active-treatment group had significantly lower rates of the first and second coprimary outcomes than those in the placebo group; effects were neutral in the middle and lower thirds (P=0.02 and P=0.009, respectively, for trend in the two outcomes).
CONCLUSIONS: Therapy with candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day was not associated with a lower rate of major cardiovascular events than placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.).
Note: Malaysia is a study site (Author: Yusoff K)

Matched MeSH terms: Antihypertensive Agents/administration & dosage*
Fulltext Sodium nitrite exerts an antihypertensive effect and improves endothelial function through activation of eNOS in the SHR

Ling WC, Murugan DD, Lau YS, Vanhoutte PM, Mustafa MR

Sci Rep, 2016 09 12;6:33048.
PMID: 27616322 DOI: 10.1038/srep33048

Sodium nitrite (NaNO2) induces relaxation in isolated arteries partly through an endothelium-dependent mechanism involving NO-eNOS-sGC-cGMP pathway. The present study was designed to investigate the effect of chronic NaNO2 administration on arterial systolic blood pressure (SBP) and vascular function in hypertensive rats. NaNO2 (150 mg L-1) was given in drinking water for four weeks to spontaneously (SHR) and Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) treated hypertensive SD rats. Arterial SBP and vascular function in isolated aortae were studied. Total plasma nitrate/nitrite and vascular cyclic guanosine monophosphate (cGMP) levels were measured using commercially available assay kits. Vascular nitric oxide (NO) levels were evaluated by DAF-FM fluorescence while the proteins involved in endothelial nitric oxide synthase (eNOS) activation was determined by Western blotting. NaNO2 treatment reduced SBP, improved the impaired endothelium-dependent relaxation, increased plasma total nitrate/nitrite level and vascular tissue NO and cGMP levels in SHR. Furthermore, increased presence of phosphorylated eNOS and Hsp-90 was observed in NaNO2-treated SHR. The beneficial effect of nitrite treatment was not observed in L-NAME treated hypertensive SD rats. The present study provides evidence that chronic treatment of genetically hypertensive rats with NaNO2 improves endothelium-dependent relaxation in addition to its antihypertensive effect, partly through mechanisms involving activation of eNOS.

Matched MeSH terms: Antihypertensive Agents/administration & dosage*

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