Clinical trial design for assessing hypertension medications: are critical circadian chronopharmacological principles being taking into account?

INTRODUCTION: Clinical hypertension trials typically rely on homeostatic principles, including single time-of-day office blood pressure (BP) measurements (OBPM), rather than circadian chronopharmacological principles, including ambulatory monitoring (ABPM) done around-the-clock to derive the asleep systolic BP (SBP) mean and sleep-time relative SBP decline - jointly the strongest prognosticators of cardiovascular disease (CVD) risk and true definition of hypertension - to qualify participants and assess outcomes. AREAS COVERED: Eight chronopharmacological elements are indispensable for design and conduct of hypertension medication trials, mainly those on ingestion-time differences in effects, and also a means of rating quality of investigations. Accordingly, we highlight the findings and shortcomings of: (i) 155 such ingestion-time trials, 83.9% finding at-bedtime/evening treatment more beneficial than conventional upon-awakening/morning treatment; (ii) HOPE and ONTARGET CVD outcomes investigations assessing in the former add-on ramipril at-bedtime and in the latter telmisartan, ramipril, or both in combination in the morning; and (iii) pragmatic TIME CVD outcomes trial. EXPERT OPINION: Failure to incorporate chronopharmacological principals - including ABPM to derive asleep SBP and SBP dipping to qualify subjects as hypertensive and assess CVD risk - results in deficient study design, dubious findings, and unnecessary medical controversy at the expense of advances in patient care.

Evaluation of the efficacy of hydro-alcoholic extract of Evolvulus alsinoides L. for the treatment of primary hypertension - A randomized controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Evolvulus alsinoides L. (Sankhaholi) has been traditionally used in Unani (Greco-Arabic) medicine to treat diverse cardiovascular disorders. Notably, preclinical and clinical investigations have substantiated its remarkable potential as an antihypertensive agent. AIM OF THE STUDY: The aim of this study was to compare the efficacy of hydroalcoholic extract of Evolvulus alsinoides L. and ramipril in treating hypertension using a higher dose of the test drug within the recommended limit. MATERIALS AND METHODS: In this open-label randomized controlled trial, 57 participants (29 in the test group, 28 in the control group) completed the 42-day study. The test group received 630 mg of dried hydro-alcoholic extract of Evolvulus alsinoides L. in capsule form orally once daily, while the control group received 5 mg of Ramipril orally once daily. Participants in both groups were advised to adhere to the Dietary Approaches to Stop Hypertension (DASH) eating plan in terms of diet and lifestyle adjustments recommended by JNC-8. The primary outcome measures were changes in systolic and diastolic blood pressure as well as changes in plasma levels of hsCRP and IL6. Secondary outcome measures included changes in symptoms such as palpitations, giddiness, headaches, fatigue and shortness of breath. Headaches, palpitations, and giddiness were assessed using a customized Visual Analog Scale (VAS) graded as "none," "mild," "moderate," and "severe". Fatigue was assessed on a binary scale as either absent or present, and dyspnea was assessed using the modified Medical Research Council (mMRC) scale for breathlessness. Both primary and secondary outcomes were assessed at baseline and each follow-up visit (2nd week, 4th week, and 6th week) until the completion of the trial. RESULTS: At the end of the trial, the mean differences for the primary outcomes were as follows:SBP:-1.8895%CI:-4.82,1.05,p=0.203,d=0.33, DBP: -2.8395%CI:-4.67,-0.10,p=0.003,d=0.8, hsCRP: -1.4095%CI:-2.80,-0.003,p=0.49,d=0.53, and IL6: -88.6795%CI:-148.90,-28.43,p=0.005,d=0.78. No statistically significant differences were observed between the two groups for any of the secondary outcomes. CONCLUSIONS: Based on the preliminary results, it can be inferred that the hydro-alcoholic extract of Evolvulus alsinoides L. exhibits significant antihypertensive potential, comparable to that of ramipril. Furthermore, it appears that Evolvulus alsinoides L. may be more effective than ramipril in reducing the biochemical markers of inflammation associated with primary hypertension. However, additional research is required to validate these findings.

Supplementation of antihypertensive drug regimen with vitamin E ameliorates alterations of primary haemodynamic parameters and total antioxidant capacity in ovariectomised rats.

OBJECTIVES: Ovariectomy induces heightened response to vasoconstrictors, alters vasorelaxation and consequently causes hypertension due to increased oxidative stress in rats. METHODS: This study evaluated the ameliorative effects of ramipril and vitamin E, on primary haemodynamic parameters and cardiac antioxidant defence status, in ovariectomised rats using 64 adult female rats of the Wistar strain randomly divided as follows: Control (sham); Ovariectomised (OVX); OVX plus Ramipril; OVX plus vitamin E; and OVX plus Ramipril plus vitamin E. RESULTS: The plasma level of oestrogen was significantly lower (p<0.05), in the ovariectomised rats compared with the sham. The systolic, diastolic and mean arterial blood pressure of ovariectomised rats increased significantly (p<0.05), but the alteration was significantly reduced by the administration of ramipril alone or in combination with vitamin E. Significant decrease (p<0.05) was observed in the serum level of nitric oxide in OVX group compared with Sham. Also, analysed markers of oxidative stress: Malondialdehyde (MDA) contents and hydrogen peroxide (H2O2) generated decreased significantly (p<0.05), but systemic antioxidants: reduced glutathione (GSH) contents; glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities increased significantly (p<0.05) in the ovariectomised rats treated with ramipril and vitamin E compared with untreated ovariectomised rats. The study concludes that alteration, in the primary haemodynamic parameters, associated with ovariectomy in rats is potently ameliorated by co-administration of the antihypertensive drug ramipril and vitamin E. CONCLUSIONS: The supplementation of antihypertensive regimen with antioxidants such as vitamin E in the treatment of hypertension is therefore justifiable especially in ovariectomised or hypogonadal patients.

Effect of ethanolic extract of Cyperus rotundus L. against isoprenaline induced cardiotoxicity.

Interruption of blood supply to the heart results in acute myocardial infarction (AMI), and further damages the heart muscles. Available drugs for the treatment MI have one or other side effects, and there is a need for development of better alternative drugs from herbal sources. Here, we evaluated cardioprotective effect of Cyperus rotundus on isoprenaline- induced myocardial infarction. Thirty five Wistar rats, aged 60-100 days with body wt. 150-200 g, pretreated with ethanolic extract of Cyperus rotundus L. (@ 250 and 500 mg/kg body wt.) orally before induction of myocardial necrosis by administrating isoprenaline (85 mg/kg, s.c.) on 19th and 20th day of the pretreatment period. The treated rats were examined for gross functioning of heart, heart weight/body wt. Ratio, and also observed histopathologically. Further, activities of various cardiac enzymes such as aspartate transaminase, alanine transaminase, creatinine kinase-myoglobulin, lactate dehydrogenase, and the gold marker troponin-I were also determined. The levels altered by isoproterenol were found to be restored significantly by the test extracts especially at higher dose. Biochemical observations viz., serum ALT (P <0.0001), AST (P <0.0001), creatine kinase-myoglobulin (CK-MB) (P <0.0001), LDH (P <0.0001) demonstrated significant cardioprotective activity of the ethanolic extract of C. rotundus (500 mg/kg body wt.), against isoprenaline induced myocardial infarction. These results were also substantiated by physical parameters and histopathological observations. All these results were comparable with that of two standard drugs metoprolol (10 mg/kg/day), ramipril (3 mg/kg/day) as well as polyherbal formulation Abana (50 mg/kg/day).

Renal antifibrotic effect of N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats.

BACKGROUND AND AIM: Diabetic nephropathy is the main cause of end-stage renal disease. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a physiological tetrapeptide hydrolyzed by the angiotensin-converting enzyme (ACE), has antifibrotic effects in the cardiovascular system and in the kidney in experimental models of hypertension, heart failure and renal disease. The aim of the study was to evaluate the effect of Ac-SDKP in diabetic nephropathy and the potential additive effect of Ac-SDKP, when compared to ACE inhibitors alone, on the development of renal fibrosis. METHOD: Diabetes was induced in 28 Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin. Control rats (n = 10) received only buffer solution. An ACE inhibitor (ramipril, 3 mg/kg/day) was administered to 11 diabetic rats. After 2 months, Ac-SDKP (1 mg/kg/day) was administered by osmotic minipumps for 8 weeks to 7 diabetic rats and to 6 diabetic rats treated with ramipril. Osmotic minipumps delivered saline solution in the corresponding sham-treated rats (diabetic rats, n = 10, and ramipril-treated diabetic rats, n = 5). RESULTS: Diabetic rats showed a significant increase in blood glucose level, urinary albumin excretion and renal fibrosis, and a reduction of glomerular nephrin expression with respect to control rats. Ac-SDKP administration significantly reduced renal fibrosis in diabetic rats, without significantly reducing urinary albumin excretion. Ramipril treatment caused a significant decrease in albuminuria and renal fibrosis and restored glomerular nephrin expression. Administration of Ac-SDKP, in addition to ramipril, further reduced renal fibrosis with respect to ramipril alone, while it did not improve the antiproteinuric effect of ramipril. CONCLUSION: Ac-SDKP administration reduces renal fibrosis in diabetic nephropathy. Addition of Ac-SDKP to ACE inhibition therapy improves the reduction of renal fibrosis with respect to ACE inhibition alone, suggesting a beneficial effect of this pharmacological association in diabetic nephropathy.

Comparative effect of Ocimum sanctum, Commiphora mukul, folic acid and ramipril on lipid peroxidation in experimentally-induced hyperlipidemia.

Treatment with C. mukul and O. sanctum, showed a significant decrease in cholesterol and triglyceride levels respectively. O. sanctum also significantly increased serum HDL-cholesterol compared to control. Serum MDA levels were significantly reduced in all the treated groups compared to control suggesting that each of the drugs under study were effective in their free radical scavenging action. Erythrocyte SOD activity was increased in all the treatment groups with C. mukul showing the maximum effect followed by O. sanctum, folic acid and ramipril. The erythrocyte CAT activity was significantly increased in all the drug treated groups with maximum increase seen in O. sanctum and ramipril treated groups, whereas lesser effects were observed with C. mukul and folic acid groups. Thus, the indigenous drugs, C. mukul and O. sanctum had beneficial effect on hypercholesterolemic rabbit model, both in terms of lipid profile as well as antioxidant potential. Ocimum sanctum was found to be the most promising of all the drugs. Moreover, it could be hypothesized that these plant products along with folic acid and ramipril can be explored for synergistic effect for treatment for hypercholesterolemic conditions.

Effects of zofenopril and ramipril on cough reflex responses in anesthetized and awake rabbits.

Cough is the most common symptom reported by patients in a primary care setting and is one of the most frequent secondary effects recorded during treatment with angiotensin-converting enzyme (ACE) inhibitors. The aim of the current study was to analyze potential differences in cough induction between 2 structurally different ACE inhibitors, namely zofenopril, which has a sulphydryl moiety, and ramipril, which has a carboxyl moiety. The cough reflex was induced by chemical (citric acid) and/or mechanical stimulation of the tracheobronchial tree in awake and anesthetized rabbits. Intravenous injection of the active compounds of the 2 ACE inhibitors, zofenoprilat (288 nmol/kg) and ramiprilat (129 nmol/kg), caused similar hypotensive effects in anesthetized rabbits. None of the studied cough-related variables changed in response to ACE inhibitor administration, with the exception of the number of coughs. Ramiprilat, but not zofenoprilat, increased the cough response induced by both mechanical and chemical stimulation (1 mol/L citric acid aerosol) of the tracheobronchial tree. In awake animals, zofenoprilat- or vehicle-treated rabbits did not show any significant changes in the number of coughs induced by 1 mol/L citric acid aerosol compared to their respective basal values (from 15.2 ± 2.3 to 13.1 ± 1.3 and from 16.1 ± 4.9 to 15.8 ± 4.3, respectively). Conversely, ramiprilat resulted in a significant increase in the number of coughs (from 21.1 ± 2.6 to 34.9 ± 3.5; P < .01). These findings confirm that there are differences in the cough potentiation effect induced by different ACE inhibitors. The low rate of cough seen with zofenoprilat may be related to its ability to induce a lower accumulation of bradykinin and prostaglandins at the lung level.

Ramipril-like activity of Spondias mombin linn against no-flow ischemia and isoproterenol-induced cardiotoxicity in rat heart.

The cardioprotective property of Spondias mombin (SM) was investigated and compared with that of the ACE inhibitor, ramipril. Alterations to markers of myocardial injury and indices of antioxidant capacity by isoproterenol (ISP) intoxication were significantly corrected in groups treated with SM. The inflammatory index was increased by 24% in ISP-intoxicated group compared with control (P < 0.001) but reduced in the groups administered ISP and treated with 100 or 250 mg/kg SM by 17% (P < 0.001) and 11% (P < 0.05) respectively. Serum lactate dehydrogenase activity and cholesterol level which were significantly increased in ISP-intoxicated group compared with control were reduced in groups administered ISP and treated with SM. Serum phosphate levels in groups administered ISP and treated with SM were significantly lower than values obtained for the ISP-intoxicated group (P < 0.001). Tissue catalase and superoxide dismutase activities as well as glutathione level were significantly increased in groups administered ISP and treated with SM compared to ISP-intoxicated group while MDA and nitrite levels were decreased. Disruption in the structure of cardiac myofibrils by ISP intoxication was reduced by treatment with SM. Comparable results were obtained for ramipril. These results are indicative of the potent cardioprotective property of SM.

Kidney flow and function in hypertension: protective effects of pycnogenol in hypertensive participants--a controlled study.

This study evaluated the effects of Pycnogenol as an adjunct to angiotensin-converting enzyme (ACE)-inhibitor ramipril treatment of hypertensive patients presenting with early signs of renal function problems. One group of 26 patients was medicated with 10 mg ramipril per day only; a second group of 29 patients took Pycnogenol in addition to the ACE inhibitor over a period of 6 months. At trial end, a lowered systolic and diastolic blood pressure was found in both groups, with a significant further reduction of diastolic pressure in the group given Pycnogenol in addition to ramipril. The major aim of this study was the investigation of kidney-protective effects of Pycnogenol. Urinary albumin decreased from 87 +/- 23 to 64 +/- 16 mg/d with ramipril only. Additional Pycnogenol lowered albumin significantly better from 91 +/- 25 to 39 +/- 13 mg/day (P < .05). In both groups, serum creatinine was lowered; however, only in the combination treatment group did the effect reached statistical significance. In both groups, CRP levels decreased from 2.1 to 1.8 with ramipril and from 2.2 to 1.1 with the ramipril-Pycnogenol combination; the latter reached statistical significance. Kidney cortical flow velocity was investigated by Doppler color duplex ultrasonography. Both systolic and diastolic flow velocities increased significantly after 6 months medication with ramipril. The addition of Pycnogenol to the regimen statistically significantly further enhanced kidney cortical flow velocities, by 8% for diastolic flow and 12% for systolic flow, relative to values found for the group taking ramipril only. The protective effects of Pycnogenol for initial kidney damage found in this study warrant further research with a larger number of patients and over a longer period of time.

[Effects and mechanism of ShenQi compound recipe on inflammation maker in GK rats].

OBJECTIVE: To explore the effects and mechanism of ShenQi Compound Recipe on inflammation maker of type 2 diabetes mellitus in GK rats. METHODS: Rats were ranodmly divided into Model group, Ramipril group (positive control, 1 mg/kg x d), SQCR low dosage (0.72 g/kg x d), SQCR high dosage group (2.88 g/kg x d) and Wistar control group. Each group was administrated correspondent substance respectively for 32 days. Determined C-reactive protein (CRP) by ELISA and tumour necrosis factor (TNF)-alpha by radioimmunassay. The mRNA expression of nuclear factor (NF)-kappaB p65 in aorta was determined by real time RT-PCR, and activation of it using immunohistochemistry staining. RESULTS: Concentrations of CRP and TNF-alpha in serum and the expression of mRNA and activation of NF-kappaB were all decreased in SQCR low and high dosage groups compared with model group (P < 0.05 or P < 0.01). CONCLUSION: These results suggest that SQCR can decrease the level of inflammation maker in serum, which may be resulted from reducing the mRNA expression and activation of NF-kappaB.

Angiotensin II inhibition reduces stress sensitivity of hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats.

Angiotensin II type 1 (AT(1)) receptors are expressed within organs of the hypothalamo-pituitary-adrenal (HPA) axis and seem to be important for its stress responsiveness. Secretion of CRH, ACTH, and corticosterone (CORT) is increased by stimulation of AT(1) receptors. In the present study, we tested whether a blockade of the angiotensin II system attenuates the HPA axis reactivity in spontaneously hypertensive rats. Spontaneously hypertensive rats were treated with candesartan (2 mg/kg), ramipril (1 mg/kg), or mibefradil (12 mg/kg) for 5 wk. In addition to baseline levels, CORT and ACTH responses to injection of CRH (100 microg/kg) were monitored over 4 h. mRNA of CRH, proopiomelanocortin, AT(1A), AT(1B), and AT(2) receptors was quantified by real-time PCR. All treatments induced equivalent reductions of blood pressure and had no effect on baseline levels of CORT and ACTH. However, both candesartan and ramipril significantly reduced CRH-stimulated plasma levels of ACTH (-26 and -15%) and CORT (-36 and -18%) and lowered hypothalamic CRH mRNA (-25 and -29%). Mibefradil did not affect any of these parameters. Gene expression of AT(1A), AT(1B), and AT(2) receptors within the HPA axis was not altered by any drug. We show for the first time that antihypertensive treatment by inhibition of AT(1) receptors or angiotensin-converting enzyme attenuates HPA axis reactivity independently of blood pressure reduction. This action is solely evident after CRH stimulation but not under baseline conditions. Both a reduced pituitary sensitivity to CRH and a down-regulation of hypothalamic CRH expression have the potential to reduce HPA axis activity during chronic AT(1) blockade or angiotensin-converting enzyme inhibition.

Cardioprotective activity of alcoholic extract of Tinospora cordifolia in ischemia-reperfusion induced myocardial infarction in rats.

It has been suggested that the beneficial effects of reperfusing the myocardium might be in part reversed by the occurrence of reperfusion injury. Oxidative stress was suggested to be implicating in the pathogenesis of ischemia-reperfusion (I/R) injury. Many antioxidative plants were shown to be cardioprotective in experimental models of myocardial ischemia-reperfusion (I/R) injury. The present study was designed to investigate the effects of pretreatment with alcoholic extract of Tinospora cordifolia in an in vivo rat model. The model adopted was that of surgically-induced myocardial ischemia, performed by means of left anterior descending coronary artery occlusion (LAD) for 30 min followed by reperfusion for another 4 h. Infarct size was measured by using the staining agent TTC (2,3,5-triphenyl tetrazolium chloride). Lipid peroxide levels in serum and in heart tissue were estimated spectrophotometrically by the methods developed by Yagi and Ohkawa et al. respectively. A lead II electrocardiogram was monitored at various intervals throughout the experiment. A dose dependent reduction in infarct size and in lipid peroxide levels of serum and heart tissue were observed with the prior treatment of T. cordifolia with various doses for 7 d compared to control animals. Hence, the present study suggests the cardioprotective activity of T. cordifolia in limiting ischemia-reperfusion induced myocardial infarction.

Vasopeptidase inhibitor omapatrilat induces profound insulin sensitization and increases myocardial glucose uptake in Zucker fatty rats: Studies comparing a vasopeptidase inhibitor, angiotensin-converting enzyme inhibitor, and angiotensin II type I receptor blocker.

BACKGROUND: ACE inhibitors (ACEIs) improve insulin resistance and prevent type 2 diabetes, possibly mediated by inhibition of bradykinin (BK) degradation. The vasopeptidase inhibitor omapatrilat (OMA) raises BK to a greater extent than ACEIs by dual enzyme inhibition, whereas its insulin-sensitizing effects and mechanisms have not been investigated. METHODS AND RESULTS: We compared the insulin-sensitizing effects of OMA, ramipril (an ACEI), losartan (an angiotensin II type 1 receptor blocker), and placebo by 2-step euglycemic hyperinsulinemic clamp in insulin-resistant Zucker fatty rats (n=6 to 7 in each group). OMA resulted in a lower rate of endogenous glucose production than placebo at baseline (35+/-5 versus 54+/-4 mmol x kg(-1) x min(-1), P<0.01), greater suppression of endogenous glucose production by low-dose insulin (73+/-11% versus 27+/-18%, P<0.05), and greater glucose disposal at high-dose insulin (135+/-5 versus 92+/-4 mmol x kg(-1) x min(-1), P<0.01). Ramipril tended to improve insulin sensitivity, but losartan did not. OMA significantly increased 2-deoxyglucose uptake by myocardium, fat, and skeletal muscle. Ramipril increased 2-deoxyglucose uptake only by some skeletal muscles, but losartan did not. The insulin-sensitizing effects of OMA were blocked significantly by HOE-140 (a BK, B2 receptor antagonist) and NG-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor) in all tissues except myocardium. CONCLUSIONS: OMA induces profound insulin sensitization and increases myocardial glucose uptake in Zucker fatty rats. This effect is greater than that of ramipril and probably occurs at least in part via stimulation of the B2 receptor. OMA has the potential for greater type 2 diabetes prevention than ACEI.

Ramipril treatment alters Ca(2+) and K(+) channels in small mesenteric arteries from Wistar-Kyoto and spontaneously hypertensive rats.

Numerous studies have emphasized the important role of altered Ca(2+) channel function in hypertension. We previously showed that Ca(2+) currents measured in myocytes isolated from both Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) small mesenteric arteries closely correlated with systolic blood pressure (BP) during normal development. The purpose of the present experiments was to determine whether antihypertensive therapy with an angiotensin converting enzyme inhibitor normalizes Ca(2+) channel function in SHR myocytes along with BP. Ramipril (3.5 mg/kg/day) was added to the drinking water of 12-week-old male WKY and SHR for 8 weeks. Segments of small mesenteric arteries were used for isometric contraction studies, and for isolation of myocytes for measurement of Ca(2+) and K(+) currents (I(Ca) and I(K)) by patch clamp methods. Ramipril treatment decreased systolic pressure in WKY and SHR, decreased heart weight and heart weight-to-body weight ratio in SHR, and decreased body weight in WKY. Maximum contractile responses to Bay k 8644 in SMA from ramipril-treated SHR were smaller compared to untreated SHR (10% +/- 2% v 55% +/- 7% of the response to 120 mmol/L KCl). The smaller responses in WKY were not affected by ramipril treatment (11% +/- 4% v 8% +/- 3%). Contractile responses to 10 mmol/L tetraethylammonium (TEA) were not different in untreated versus ramipril-treated SHR (65% +/- 6% v 82% +/- 8%) but were increased in treated WKY (4% +/- 1% v 35% +/- 9%). Ramipril treatment decreased peak I(Ca) and equalized the voltage-dependence of I(Ca) activation between SHR and WKY. The I(K) measured from holding potentials of -60 and -20 mV were significantly smaller in treated SHR and WKY compared to their untreated counterparts, as was the component of I(K) measured in the presence of 100 nmol/L iberiotoxin. These results show that ramipril treatment decreases arterial pressure and Ca(2+) channel function in SHR as expected but unexpectedly also decreases I(K) in both WKY and SHR. These results suggest that angiotensin may have a BP independent effect on ion channel function in arterial smooth muscle.

Combined angiotensin II receptor antagonism and angiotensin-converting enzyme inhibition further attenuates postinfarction left ventricular remodeling.

BACKGROUND: ACE inhibition (ACEI) attenuates post-myocardial infarction (MI) LV remodeling, but the effects of angiotensin II type 1 receptor (AT(1)) antagonism alone or in combination with ACEI are unclear. Accordingly, we investigated the effects of AT(1) antagonism, ACEI, and their combination in a well-characterized ovine postinfarction model. METHODS AND RESULTS: Beginning 2 days after transmural anteroapical MI, 62 sheep were treated with 1 of 5 treatment regimens: no therapy (control, n=12), standard-dose ACEI (sACEI; ramipril 10 mg/d, n=14), high-dose ACEI (hACEI; ramipril 20 mg/d, n=8), AT(1) blockade (losartan 50 mg/d, n=13), and combination therapy with sACEI+AT(1) blockade (CT; ramipril 10 mg/d+losartan 50 mg/d, n=15). MRI was performed before and 8 weeks after MI to quantify changes in LV end-diastolic and end-systolic volume indices (DeltaEDVI, DeltaESVI) and ejection fraction (DeltaEF). Change in regional percent intramyocardial circumferential shortening in noninfarcted segments adjacent to the infarct (Adj Delta%S) was measured by tagged MRI. CT resulted in the most marked blunting of LV remodeling: DeltaESVI (+1.0+/-0.4, +0.7+/-0.4, +0.6+/-0.3, +0.9+/-0.5, and +0.4+/-0.2* mL/kg); DeltaEDVI (+0.9+/-0.4, +0.7+/-0.5, +0.6+/-0.5, +0.9+/-0.5, and +0.4+/-0.3 mL/kg); DeltaEF (-24+/-7, -18+/-6, -14+/-7, -18+/-10, and -11+/-9* %); and Adj Delta%S (-8+/-4, -7+/-3, -5+/-3, -5+/-3, and -2+/-3* %) for Control, sACEI, hACEI, AT(1) blockade, and CT, respectively (*P<0.04 versus sACEI, AT(1) blockade, and control; P<0.05 versus control; P<0.002 versus AT(1) blockade and control). EDVI and ESVI at 8 weeks after MI were smallest with CT (P<0.02 versus all). CONCLUSIONS: Combination therapy with sACEI+AT(1) blockade shows promise in attenuating postinfarction LV remodeling but was not clearly superior to hACEI in the present study.

Low-dose ramipril treatment improves relaxation and calcium cycling after established cardiac hypertrophy.

Rapid cooling contractures were used in this study to test whether low-dose ramipril improves sarcoplasmic reticulum (SR) Ca(2+) uptake and Na(+)/Ca(2+) exchanger function in isolated hypertrophied rat myocytes. Compensated cardiac hypertrophy was induced by abdominal aortic constriction for 5 wk followed by administration of ramipril (50 microg x kg(-1) x day(-1)) or vehicle for 4 wk. Myocyte cell length and cell width were significantly (P < 0.05) increased in both hypertrophied groups (+/-ramipril). Myocytes were loaded with indo 1, and relaxation was investigated after rapid cooling. Hypertrophied myocyte relaxation in Na(+)-free/Ca(2+)-free solution was 63% slower (P < 0.01) and the fall in intracellular Ca(2+) was 60% slower (P < 0.05) than the relaxation of control cells. After ramipril treatment both relaxation and the decline in intracellular Ca(2+) returned to control rates through improved SR Ca(2+)-ATPase function. Relaxation in caffeine showed no change after hypertrophy; however, after ramipril treatment the time to 50% relaxation in caffeine decreased by 30% (P < 0.05). The improvement in Ca(2+) extrusion across the sarcolemmal membrane occurred independently of changes in Na(+)/Ca(2+) exchanger mRNA and protein abundance. These data demonstrate that ramipril improves both SR-dependent and non-SR-dependent calcium cycling after established cardiac hypertrophy. However, the improvements in function are independent of transcriptional activation and likely to involve altered intracellular ion concentrations.

[Clinical study of the month. The HOPE study, a two-by-two factorial clinical trial with contrasted results]. / L'étude clinique du mois. L'étude HOPE, un essai clinique bicéphale aux résultats contrastés.

The results of the HOPE ("Heart Outcomes Prevention Evaluation") study, recently published in the New England Journal of Medicine, demonstrated a highly significant cardiovascular protection by an angiotensin converting enzyme inhibitor, ramipril at a dose of 10 mg/day, after a mean follow-up of 4.5 years, but not of vitamin E supplements at a dose of 400 UI/day in high-risk patients (> 55 years old) who had evidence of vascular disease (secondary prevention) or combined diabetes mellitus and another cardiovascular risk factor (primary prevention).

Regulation of renin gene expression in kidneys of eNOS- and nNOS-deficient mice.

Our study aimed to assess the roles of nitric oxide derived from endothelium NO-synthase (eNOS) and macula densa neuronal NO-synthase (nNOS) in the regulation of renal renin expression. For this purpose renin mRNA levels and renin content were determined in kidneys of wild-type (wt), nNOS-deficient (nNOS-/-), and eNOS-deficient (eNOS-/-) mice, in which the renin system was suppressed by feeding a high-salt diet (NaCl 4%), or was stimulated by feeding a low-salt (NaCl 0.02%) diet together with the converting-enzyme inhibitor ramipril (10 mg kg(-1) day(-1)). In all mouse strains, renin mRNA levels were inversely related to the rate of sodium intake. In eNOS-/- mice renin mRNA levels and renal renin content were 50% lower than in wt mice at each level of salt intake, whilst in nNOS-/- mice renin expression was not different from wt controls. Administration of the general NO-synthase inhibitor nitro-L-arginine methyl ester (L-NAME, 50 mg kg(-1) day(-1)) to mice kept on the low-salt/ramipril regimen caused a decrease of renal renin mRNA levels in wt and nNOS-/- mice, but not in eNOS-/- mice. These observations suggest that neither eNOS nor nNOS is essential for up- or downregulation of renin expression. eNOS-derived NO appears to enhance renin expression, whereas nNOS-derived NO does not.

Angiotensin converting enzyme inhibition and calcium antagonism attenuate streptozotocin-diabetes-associated mesenteric vascular hypertrophy independently of their hypotensive action.

OBJECTIVES: To investigate the relative roles of angiotensin II, bradykinin, and calcium-dependent pathways in the genesis of mesenteric vascular hypertrophy in experimental diabetes. DESIGN: Streptozotocin-induced diabetic Sprague-Dawley rats were randomly allocated to these treatments for 24 weeks: no treatment; ramipril at a hypotensive dose; ramipril plus the bradykinin type 2 receptor blocker icatibant; icatibant alone; ramipril at a low dose; the angiotensin II type 1 receptor antagonist, valsartan; the dihydropyridine calcium antagonist, lacidipine; and the nondihydropyridine calcium antagonist mibefradil. METHODS: Systolic blood pressure was serially measured every 4 weeks by tail-cuff plethysmography. We assessed the vascular architecture in sections of mesenteric arteries obtained after in-vivo perfusion, which were stained with an antibody to alpha-smooth muscle actin. RESULTS: Both blood pressure and the mesenteric arterial wall: lumen ratio were reduced by administration of ramipril, at the high dose, either alone or in combination with icatibant, and also by valsartan. Treatment either with the low dose of ramipril or with the calcium antagonists lacidipine and mibefradil was associated with a decrease in the wall : lumen ratio of the mesenteric arteries without influencing blood pressure. CONCLUSIONS: These findings demonstrate that blockade both of angiotensin II-dependent and of calcium-dependent pathways attenuates mesenteric vascular hypertrophy in experimental diabetes. Furthermore, the antitrophic effects of these antihypertensive agents may be independent of their hypotensive effects.