Aliskiren monotherapy does not cause paradoxical blood pressure rises: meta-analysis of data from 8 clinical trials.

Angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and diuretics all cause reactive rises in plasma renin concentration, but particularly high levels have been reported with aliskiren. This prompted speculation that blockade of plasma renin activity with aliskiren could be overwhelmed, leading to paradoxical increases in blood pressure. This meta-analysis of data from 4877 patients from 8 randomized, double-blind, placebo- and/or active-controlled trials examined this hypothesis. The analysis focused on the incidence of paradoxical blood pressure increases above predefined thresholds, after > or =4 weeks of treatment with 300 mg of aliskiren, angiotensin receptor blockers (300 mg of irbesartan, 100 mg of losartan, or 320 mg of valsartan), 10 mg of ramipril, 25 mg of hydrochlorothiazide, or placebo. There were no significant differences in the frequency of increases in systolic (>10 mm Hg; P=0.30) or diastolic (>5 mm Hg; P=0.65) pressure among those treated with aliskiren (3.9% and 3.1%, respectively), angiotensin receptor blockers (4.0% and 3.7%), ramipril (5.7% and 2.6%), or hydrochlorothiazide (4.4% and 2.7%). Increases in blood pressure were considerably more frequent in the placebo group (12.6% and 11.4%; P<0.001). None of the 536 patients with plasma renin activity data who received 300 mg of aliskiren exhibited an increase in systolic pressure >10 mm Hg that was associated with an increase in plasma renin activity >0.1 ng/mL per hour. In conclusion, the incidence of blood pressure increases with aliskiren was similar to that during treatment with other antihypertensive drugs. Blood pressure rises on aliskiren treatment were not associated with increases in plasma renin activity. This meta-analysis found no evidence that aliskiren uniquely causes paradoxical rises in blood pressure.

Telmisartan: a different angiotensin II receptor blocker protecting a different population?

The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET()) showed that the angiotensin II receptor blocker (ARB) telmisartan was as protective as the reference-standard ramipril in a broad cross-section of patients at increased cardiovascular risk, but was better tolerated. Telmisartan has a unique profile among ARBs, with a high affinity for the angiotensin II type 1 receptor, a long duration of receptor binding, a high lipophilicity and a long plasma half life. This leads to sustained and powerful blood pressure lowering when compared with the first marketed ARBs, such as losartan and valsartan. Some pharmacological properties of telmisartan clearly distinguish it from other members of the ARB class and may contribute to the clinical effects seen with telmisartan. A class effect for ARBs cannot be assumed. To date, telmisartan is the only ARB that has been shown to reduce cardiovascular risk in at-risk cardiovascular patients.

Functional evidence that the central renin-angiotensin system plays a role in the pressor response induced by central injection of carbachol

We investigated the effects of losartan, an AT1-receptor blocker, and ramipril, a converting enzyme inhibitor, on the pressor response induced by angiotensin II (ANG II) and carbachol (a cholinergic receptor agonist). Male Holtzman rats (250-300 g) with a stainless steel cannula implanted into the lateral ventricle (LV) were used. The injection of losartan (50 nmol/1 &micro;l) into the LV blocked the pressor response induced by ANG II (12 ng/1 &micro;l) and carbachol (2 nmol/1 &micro;l). After injection of ANG II and carbachol into the LV, mean arterial pressure (MAP) increased to 31 &plusmn; 1 and 28 &plusmn; 2 mmHg, respectively. Previous injection of losartan abolished the increase in MAP induced by ANG II and carbachol into the LV (2 &plusmn; 1 and 5 &plusmn; 2 mmHg, respectively). The injection of ramipril (12 ng/1 &micro;l) prior to carbachol blocked the pressor effect of carbachol to 7 &plusmn; 3 mmHg. These results suggest an interaction between central cholinergic pathways and the angiotensinergic system in the regulation of arterial blood pressure

Reduced cortical renal GLUT1 expression induced by angiotensin-converting enzyme inhibition in diabetic spontaneously hypertensive rats

Diabetes in spontaneously hypertensive rats is associated with cortical renal GLUT1 and GLUT2 overexpression. Our objective was to evaluate the effect of the angiotensin-converting enzyme blockade on cortical renal GLUT1 and GLUT2 expression, urinary albumin and urinary TGF-β1. Streptozotocin, 50 mg/kg, or citrate buffer (N = 16) was administered as a single injection into the tail vein in adult spontaneously hypertensive rats (~260 g). Thirty days later, these diabetic spontaneously hypertensive rats received ramipril by gavage: 0.01 mg·kg-1·day-1 (D0.01, N = 14), 1 mg·kg-1·day-1 (D1, N = 9) or water (D, N = 11) for 15 days. Albumin and TGF-β1 (24-h urine), direct arterial pressure, renal tissue angiotensin-converting enzyme activity (fluorometric assay), and GLUT1 and GLUT2 protein levels (Western blot, renal cortex) were determined. Glycemia and glycosuria were higher (P < 0.05) in the diabetic rats compared with controls, but similar between the diabetic groups. Diabetes in spontaneously hypertensive rats lowered renal tissue angiotensin-converting enzyme activity (40%), which was reduced further when higher ramipril doses were used. Diabetes associated with hypertension raised GLUT1 by 28% (P < 0.0001) and GLUT2 by 76% (P = 0.01), and both doses of ramipril equally reduced cortical GLUT1 (D vs D1 and vs D0.01, P ≤ 0.001). GLUT2 levels were reduced in D0.01 (P < 0.05 vs D). Diabetes increased urinary albumin and TGF-β1 urinary excretion, but the 15-day ramipril treatment (with either dose) did not reduce them. In conclusion, ramipril is effective in lowering renal tissue angiotensin-converting enzyme activity, as well as blocking cortical GLUT1 overexpression, which may be beneficial in arresting the development of diabetic nephropathy.

Myocardial fibrosis rather than hypertrophy induces diastolic dysfunction in renovascular hypertensive rats

The aim of the present study was to evaluate the-effect of interstitial fibrosis alone or associated with hypertrophy. on diastolic myocardial function in renovascular hypertensive rats. Myocardial function was evaluated in isolated papillary muscle from renovascular hypertensive Wistar rats (RHT, n = 14), renovascular hypertensive rats treated with the angiotensin converting enzyme inhibitor (ACEI) ramipril, 20 mg.kg(-1).day(-1) (RHT RAM, n = 14), and age-matched unoperated and untreated Wistar rats (CONT, n = 12). The ACEI treatment for 3 weeks allowed the regression of myocyte mass and the maintenance of interstitial fibrosis. Myocardial passive stiffness was analyzed by the resting tension - length relationship. The myocardial fibrosis was evaluated by measuring myocardial hydroxyproline (Hyp) concentration and by histological studies of the myocardium stained with hematoxylin and eosin or picrosirius red. Left ventricular weight was significantly higher in RHT (0.97 +/- 0.12 g) compared with CONT (0.66 +/- 0.06 g) and RHT RAM (0.69 +/- 0.14 g). The Hyp levels were 2.9 +/- 0.4, 3.4 +/- 0.3, and 3.8 +/- 0.4 mu g/mg of dry tissue for the CONT, RHT, and RHT RAM, respectively. Perivascular and interstitial fibrosis were observed in RHT and RHT RAM groups. There were lymphomononuclear inflammatory exudate and edema around arteries, involving adjacent myocytes in the RHT group. There was an increased passive stiffness in RHT and RHT RAM groups compared with the CONT group. In conclusion, our results indicate that the Impaired diastolic function in the renovascular hypertensive rats is related to interstitial fibrosis rather than to myocardial hypertrophy.

Alterations in myocardial collagen content affect rat papillary muscle function

We investigated the influence of myocardial collagen volume fraction (CVF, %) and hydroxyproline concentration (mu g/mg) on rat papillary muscle function. Collagen excess was obtained in 10 rats with unilateral renal ischemia for 5 wk followed by 3-wk treatment with ramipril (20 mg . kg(-1) . day(-1)) (RHTR rats; CVF = 3.83 +/- 0.80, hydroxyproline = 3.79 +/- 0.50). Collagen degradation was induced by double infusion of oxidized glutathione (GSSG rats; CVF 5 2.45 +/- 0.52, hydroxyproline = 2.85 +/- 0.18). Nine untreated rats were used as controls (CFV = 3.04 +/- 0.58, hydroxyproline = 3.21 +/- 0.30). Active stiffness (AS; g . cm(-2) . %L-max(-1)) and myocyte cross-sectional area (MA; mu m(2)) were increased in the GSSG rats compared with controls [AS 5.86 vs. 3.96 (P< 0.05); MA 363 +/- 59 vs. 305 +/- 28 (P< 0.05)]. In GSSG and RHTR groups the passive tension-length curves were shifted downwards, indicating decreased passive stiffness, and upwards, indicating increased passive stiffness, respectively. Decreased collagen content induced by GSSG is related to myocyte hypertrophy, decreased passive stiffness, and increased AS, and increased collagen concentration causes myocardial diastolic dysfunction with no effect on systolic function.

Functional evidence that the central renin-angiotensin system plays a role in the pressor response induced by central injection of carbachol

We investigated the effects of losartan, an AT 1-receptor blocker, and ramipril, a converting enzyme inhibitor, on the pressor response induced by angiotensin II (ANG II) and carbachol (a cholinergic receptor agonist). Male Holtzman rats (250-300 g) with a stainless steel cannula implanted into the lateral ventricle (LV) were used. The injection of losartan (50 nmol/l μl) into the LV blocked the pressor response induced by ANG II (12 ng/l μl) and carbachol (2 nmol/l μl). After injection of ANG II and carbachol into the LV, mean arterial pressure (MAP) increased to 31 ± 1 and 28 ± 2 mmHg, respectively. Previous injection of losartan abolished the increase in MAP induced by ANG II and carbachol into the LV (2 ± 1 and 5 ± 2 mmHg, respectively). The injection of ramipril (12 ng/l μl) prior to carbachol blocked the pressor effect of carbachol to 7 ± 3 mmHg. These results suggest an interaction between central cholinergic pathways and the angiotensinergic system in the regulation of arterial blood pressure.

The effect of non-antihypertensive doses of angiotensin converting enzyme inhibitor on myocardial necrosis and hypertrophy in young rats with renovascular hypertension

In renovascular hypertensive rats, low doses of angiotensin converting enzyme (ACE) inhibitors have been found to prevent myocardial hypertrophy independent of blood pressure level. This finding would suggest humoral rather than mechanical control of myocyte growth. The aim of this study was to examine the effect of nonantihypertensive doses of ACE inhibitor on myocardial hypertrophy and necrosis in hypertensive rats. Renovascular hypertension (RHT) was induced in four-week-old Wistar rats. Twenty-eight animals were treated for four weeks with three doses of ramipril (0.01, 0.1 or 1.0 mg/kg/day, which are unable to lower blood pressure. Fourteen animals were not treated (RHT group). A sham operated, age/sex-matched group was used as control (n=10). Myocardial histology was analysed in 3 μm thick sections of the ventricle stained with either haematoxylin-eosin, reticulin silver stain or Masson's trichrome. There was a significant correlation between systolic blood pressure and left ventricular to body weight ratio in both sets of animals: untreated plus controls and ramipril-treated rats. ACE inhibition prevented myocyte and perivascular necrosis and fibrosis in a dose-dependent manner. We conclude that myocardial hypertrophy in rats with renovascular hypertension is directly related to arterial pressure, and that this relationship is not affected by nonantihypertensive doses of ACE inhibitor. Myocardial necrosis/fibrosis and coronary artery damage induced by angiotensin II are prevented by ACE inhibitor in a dose-dependent manner, despite the presence of arterial hypertension.

The effect of non-antihypertensive doses of angiotensin converting enzyme inhibitor on myocardial necrosis and hypertrophy in young rats with renovascular hypertension

In renovascular hypertensive rats, low doses of angiotensin converting enzyme (ACE) inhibitors have been found to prevent myocardial hypertrophy independent of blood pressure level. This finding would suggest humoral rather than mechanical control of myocyte growth. The aim of this study was to examine the effect of nonantihypertensive doses of ACE inhibitor on myocardial hypertrophy and necrosis in hypertensive rats. Renovascular hypertension (RHT) was induced in four-week-old Wistar rats. Twenty-eight animals were treated for four weeks with three doses of ramipril (0.01, 0.1 or 1. 0 mg/kg/day, which are unable to lower blood pressure. Fourteen animals were not treated (RHT group). A sham operated, age/sex-matched group was used as control (n = 10). Myocardial histology was analysed in 3 microm thick sections of the ventricle stained with either haematoxylin-eosin, reticulin silver stain or Masson's trichrome. There was a significant correlation between systolic blood pressure and left ventricular to body weight ratio in both sets of animals: untreated plus controls and ramipril-treated rats. ACE inhibition prevented myocyte and perivascular necrosis and fibrosis in a dose-dependent manner. We conclude that myocardial hypertrophy in rats with renovascular hypertension is directly related to arterial pressure, and that this relationship is not affected by nonantihypertensive doses of ACE inhibitor. Myocardial necrosis/fibrosis and coronary artery damage induced by angiotensin II are prevented by ACE inhibitor in a dose-dependent manner, despite the presence of arterial hypertension.

Renal GLUT1 reduction depends on angiotensin-converting enzyme inhibition in diabetic hypertensive rats

Aims: Angiotensin-converting enzyme (ACE) inhibitors are used in diabetic kidney disease to reduce systemic/intra-glomerular pressure. The objective of this study was to investigate whether reducing blood pressure (BP) could modulate renal glucose transporter expression, and urinary markers of diabetic nephropathy in diabetic hypertensive rats treated with ramipril or amlodipine. Main methods: Diabetes was induced in spontaneously-hypertensive rats (~210 g) by streptozotocin (50 mg/kg). Thirty days later, animals received ramipril 15 μg/kg/day (R, n =10), or amlodipine 10 mg/kg/day (A, n= 8,) or water (C, n = 10) by gavage. After 30-day treatment, body weight, glycaemia, urinary albumin and TGF-β1 (enzyme-linked immunosorbent assay) and BP (tail-cuff pressure method) were evaluated. Kidneys were removed for evaluation of renal cortex glucose transporters (Western blotting) and renal tissue ACE activity (fluorometric assay). Key findings: After treatments, body weight (p = 0.77) and glycaemia (p = 0.22) were similar among the groups. Systolic BP was similarly reduced (p < 0.001) in A and R vs. C (172.4 ± 3.2; 186.7 ± 3.7 and 202.2 ± 4.3 mm Hg; respectively). ACE activity (C: 0.903 ± 0.086; A: 0.654 ± 0.025, and R: 0.389 ± 0.057 mU/mg), albuminuria (C: 264.8 ± 15.4; A: 140.8 ± 13.5 and R: 102.8 ± 6.7 mg/24 h), and renal cortex GLUT1 content (C: 46.81 ± 4.54; A: 40.30 ± 5.39 and R: 26.89 ± 0.79 AU) decreased only in R (p < 0.001, p < 0.05 and p < 0.001; respectively). Significance:We concluded that the blockade of the renin–angiotensin systemwith ramipril reduced earlymarkers of diabetic nephropathy, a phenomenon that cannot be specifically related to decreased BP levels.

Cost-effectiveness of pharmacogenetic testing to predict treatment response to angiotensin-converting enzyme inhibitor

OBJECTIVE: This study aimed to assess the potential cost-effectiveness of testing patients with nephropathies for the I/D polymorphism before starting angiotensin-converting enzyme (ACE) inhibitor therapy, using a 3-year time horizon and a healthcare perspective. METHODS: We used a combination of a decision analysis and Markov modeling technique to evaluate the potential economic value of this pharmacogenetic test by preventing unfavorable treatment in patients with nephropathies. The estimation of the predictive value of the I/D polymorphism is based on a systematic review showing that DD carriers tend to respond well to ACE inhibitors, while II carriers seem not to benefit adequately from this treatment. Data on the ACE inhibitor effectiveness in nephropathy were derived from the REIN (Ramipril Efficacy in Nephropathy) trial. We calculated the number of patients with end-stage renal disease (ESRD) prevented and the differences in the incremental costs and incremental effect expressed as life-years free of ESRD. A probabilistic sensitivity analysis was conducted to determine the robustness of the results. RESULTS: Compared with unselective treatment, testing patients for their ACE genotype could save 12 patients per 1000 from developing ESRD during the 3 years covered by the model. As the mean net cost savings was euro 356,000 per 1000 patient-years, and 9 life-years free of ESRD were gained, selective treatment seems to be dominant. CONCLUSION: The study suggests that genetic testing of the I/D polymorphism in patients with nephropathy before initiating ACE therapy will most likely be cost-effective, even if the risk for II carriers to develop ESRD when treated with ACE inhibitors is only 1.4% higher than for DD carriers. Further studies, however, are required to corroborate the difference in treatment response between ACE genotypes, before genetic testing can be justified in clinical practice.

Taste acceptability of pulverized brand-name and generic drugs containing amlodipine or candesartan.

Trials with pulverized brand-name antihypertensive drugs suggest that, from the perspective of taste acceptability, crushed candesartan, chlortalidon, hydrochlorothiazide, lercanidipine and lisinopril should be preferred to pulverized amlodipine, atenolol, bisoprolol, enalapril, irbesartan, losartan, ramipril, telmisartan and valsartan. Brand-name antihypertensive drugs and the corresponding generic medicines have never been compared with respect to their taste acceptability. We therefore investigated among healthy health care workers the taste acceptability of a pulverized 1 mg-test dose of the brand-name and two generics containing either the dihydropyridine calcium-channel blocker amlodipine (Norvasc(®), Amlodipin-Mepha(®) and Amlodipin Pfizer(®)) or the angiotensin receptor antagonist candesartan (Atacand(®), Cansartan-Mepha(®) and Pemzek(®)). For this purpose, a smiley-face scale depicting four degrees of pleasure was used. Between November and December 2013, the taste test was performed among 19 nurses (15 female and 4 male subjects) and 12 physicians (5 female and 7 male subjects) aged between 25 and 49 years. Pulverized brand-names and generics containing either amlodipine or candesartan did not differ with respect to their taste acceptability.

Tonic stimulation of renin gene expression by nitric oxide is counteracted by tonic inhibition through angiotensin II.

This study was designed to examine the possible involvement of prostaglandins and nitric oxide (NO) in the renin stimulatory effect of angiotensin II (AngII) antagonists. To this end, plasma renin activities (PRAs) and renal renin mRNA levels were assayed in rats that were treated with the Ang-converting enzyme inhibitor ramipril or with the AngII AT1-receptor antagonist losartan. Ramipril and losartan increased PRA values from 7.5 +/- 1.6 to 86 +/- 6 and 78 +/- 22 ng of AngI per h per ml and renin mRNA levels from 112 +/- 9% to 391 +/- 20% and 317 +/- 10%, respectively. Inhibition of prostaglandin formation with indomethacin did not influence basal or ramipril-affected PRA. Basal renin mRNA levels also were unchanged by indomethacin, while increases in renin mRNA levels after ramipril treatment were slightly reduced by indomethacin. Inhibition of NO synthase by nitro-L-arginine methyl ester (L-NAME) reduced PRA values to 3.2 +/- 0.9, 34 +/- 13, and 12.1 +/- 2.7 ng of AngI per h per ml in control, ramipril-treated, and losartan-treated animals, respectively. Renin mRNA levels were reduced to 77 +/- 14% under basal conditions and ramipril- and losartan-induced increases in renin mRNA levels were completely blunted after addition of L-NAME. The AngII antagonists, furthermore, induced an upstream recruitment of renin-expressing cells in the renal afferent arterioles, which was also blunted by L-NAME. These findings suggest that renin mRNA levels are tonically increased by NO and that the action of NO is counteracted by AngII.

Benefits of ACE inhibitors with tissue-active levels in the cardiac-compromised patient

Angiotensin converting enzyme inhibitors (ACEI) have been proven beneficial to the cardiac-compromised patient, but whether there is an advantage associated with using a tissue-active or systemically-active ACEI is debatable. An investigation into the clinical benefits of tissue ACEI for veterinary patients was undertaken by comparing enalapril with ramipril. Results obtained concluded that although there is much evidence to prove that tissue ACEIs are superior over systemic ACEIs at the cellular level, this does not correlate in the clinical sense. Both enalapril and ramipril provided similar clinical benefits to the cardiac-compromised patient.

Paediatric drug development:reformulation, in vitro, genomic and in vivo evaluation

Angiotensin converting enzyme (ACE) inhibitors lisinopril and ramipril were selected from EMA/480197/2010 and the potassium-sparing diuretic spironolactone was selected from the NHS specials list for November 2011 drug tariff with the view to produce oral liquid formulations providing dosage forms targeting paediatrics. Lisinopril, ramipril and spironolactone were chosen for their interaction with transporter proteins in the small intestine. Formulation limitations such as poor solubility or pH sensitivity needed consideration. Lisinopril was formulated without extensive development as drug and excipients were water soluble. Ramipril and spironolactone are both insoluble in water and strategies combating this were employed. Ramipril was successfully solubilised using low concentrations of acetic acid in a co-solvent system and also via complexation with hydroxypropyl-β-cyclodextrin. A ramipril suspension was produced to take formulation development in a third direction. Spironolactone dosages were too high for solubilisation techniques to be effective so suspensions were developed. A buffer controlled pH for the sensitive drug whilst a precisely balanced surfactant and suspending agent mix provided excellent physical stability. Characterisation, stability profiling and permeability assessment were performed following formulation development. The formulation process highlighted current shortcomings in techniques for taste assessment of pharmaceutical preparations resulting in early stage research into a novel in vitro cell based assay. The formulations developed in the initial phase of the research were used as model formulations investigating microarray application in an in vitro-in vivo correlation for carrier mediated drug absorption. Caco-2 cells were assessed following transport studies for changes in genetic expression of the ATP-binding cassette and solute carrier transporter superfamilies. Findings of which were compared to in vitro and in vivo permeability findings. It was not possible to ascertain a correlation between in vivo drug absorption and the expression of individual genes or even gene families, however there was a correlation (R2 = 0.9934) between the total number of genes with significantly changed expression levels and the predicted human absorption.