Effects of raloxifene on the renin–angiotensin–aldosterone system and blood pressure in hypertensive and normotensive osteoporotic postmenopausal women

Aim:   An increase in blood pressure after menopause has been documented. The renin–angiotensin–aldosterone system (RAAS) plays a central role in the regulation of blood pressure and in the pathophysiology of hypertension. This study investigated the effects of raloxifene, a selective estrogen receptor modulator, on components of the RAAS and blood pressure in hypertensive and normotensive osteoporotic postmenopausal women.
Methods:   A total of 41 hypertensive or normotensive postmenopausal women with osteoporosis or osteopenia were divided into four groups. Eleven hypertensive and eight normotensive women received raloxifene hydrochloride (60 mg/day) p.o. for 6 months, and 12 hypertensive and 10 normotensive women did not receive raloxifene hydrochloride for 6 months. In all of the hypertensive women, blood pressure had been controlled prior to the start of the study using a variety of antihypertensive drugs other than angiotensin-converting enzyme (ACE) inhibitors, angiotensin (Ang)II type 1 receptor antagonists or diuretics. Plasma renin activity (PRA), serum ACE activity, plasma AngI, AngII and aldosterone concentrations, and blood pressure were measured before and 6 months after the start of the study.
Results:   No significant changes in PRA, ACE activity, or the AngI, AngII or aldosterone levels were observed in any of the groups. In all the groups, blood pressure remained unchanged.
Conclusion:   Raloxifene may have no significant effect on the RAAS or blood pressure in hypertensive and normotensive osteoporotic postmenopausal women.     

Effects of long‐term transdermal hormone replacement therapy on the renin–angiotensin– aldosterone system,plasma bradykinin levels and blood pressure in normotensive postmenopausal women

Aim: This study was designed to investigate the effects of 24‐month long‐term transdermal hormone replacement therapy (HRT) on the circulating levels of components of the renin–angiotensin–aldosterone system (RAAS) and bradykinin, blood pressure (BP) and lipid profile in normotensive postmenopausal women (PMW). Methods: Twenty‐two normotensive PMW were randomized to receive transdermal HRT (continuous 17‐β estradiol patch at 36 µg/day plus cyclic oral medroxyprogesterone acetate 2.5 mg/day for 12 days/month) (n = 12) or control (n = 10). The plasma renin activity (PRA), serum angiotensin‐converting enzyme (ACE) activity, plasma angiotensin (Ang) I, Ang II, aldosterone, bradykinin, and BP were measured before, and 12 and 24 months after, the start of the HRT. Results: In the HRT group, the diastolic BP and mean BP were significantly decreased at 12 and 24 months (both P < 0.05) after the start of therapy, however, no significant change of the systolic BP was noted during the study period. No changes in the RAAS components or lipid profile were noted in either group. The plasma bradykinin levels were significantly reduced at 12 (P < 0.05) and 24 months (P < 0.01), while no changes were observed in the control group. Conclusion: More than 12 months of long‐term transdermal HRT kept diastolic BP, mean BP and plasma bradykinin levels decreased in normotensive PMW, without influencing any of the components of the RAAS. This therapy may allow optimal blood pressure control and prevent elevation of the cardiovascular risk.     

Effects of aldosterone and angiotensin II receptor blockade on cardiac angiotensinogen and angiotensin-converting enzyme 2 expression in Dahl salt-sensitive hypertensive rats

BACKGROUND: We previously reported that a high-sodium diet activates the local renin-angiotensin-aldosterone system (RAAS) in cardiovascular tissues of Dahl salt-sensitive hypertensive (DS) rats. Angiotensin-converting enzyme 2 (ACE2) is a novel regulator of blood pressure (BP) and cardiac function. The effect of blockade of aldosterone or angiotensin II (Ang II) on cardiac angiotensinogen and ACE2 in DS rats is unknown. METHODS: The BP, plasma renin activity (PRA), plasma aldosterone concentration (PAC), heart weight, endothelium-dependent relaxation (EDR), and messenger RNA (mRNA) levels of collagen III, angiotensinogen, ACE, and ACE2 in the heart were measured in DS rats and in Dahl salt-resistant (DR) rats fed high or low salt diets. The rats were treated orally with or without eplerenone (100 mg/kg/d), candesartan (10 mg/kg/d), or both drugs combined for 8 weeks. RESULTS: A high salt diet increased BP (140%), heart/body weight (132%), and collagen III mRNA levels (146%) and decreased PRA and PAC concomitant with increased expression of cardiac angiotensinogen mRNA and decreased mRNA levels of ACE2 in DS rats. Eplerenone or candesartan significantly decreased the systolic BP from 240 +/- 5 mm Hg to 164 +/- 4 mm Hg or to 172 +/- 10 mm Hg, respectively (P < .05). Eplerenone or candesartan partially improved heart/body weight and cardiac fibrosis, improved EDR and decreased cardiac ACE and angiotensinogen mRNA levels in DS rats. Candesartan increased ACE2 mRNA levels in the heart. Combination therapy normalized BP and further improved cardiac hypertrophy, fibrosis, and EDR. CONCLUSIONS: In DS rats, blockade of aldosterone or Ang II protects cardiac hypertrophy and fibrosis by inactivation of the local RAAS in the heart.     

Hormone replacement therapy increases plasma level of angiotensin II in postmenopausal hypertensive women

The renin-angiotensin-aldosterone system plays a major role in the pathogenesis of hypertension by enhancing the production or the activity of angiotensin II (ANG II). We evaluated the effects of hormone replacement therapy (HRT) on the renin-angiotensin-aldosterone system and on bradykinin in postmenopausal women (PMW) who were hypertensive or normotensive. Subjects included 28 PMW whose elevated blood pressure (BP) was well controlled on antihypertensive agents excluding diuretics, angiotensin-converting enzyme (ACE) inhibitors, and ANG II receptor antagonists. As controls, we evaluated 16 normotensive PMW. All subjects received oral HRT daily for 6 months. The plasma levels of angiotensin I (ANG I), ANG II, and bradykinin as well as plasma renin activity (PRA) showed a significant increase in HRT in the hypertensive group, but not in the normotensive group. The serum ACE activity showed a significant decrease in both groups, but the plasma level of aldosterone was unchanged. Despite the decrease in serum ACE activity, there was an increase in the plasma ANG II level. Hormone replacement therapy increased the level of ANG II in the hypertensive women, but their BP was unaffected. The increase in plasma bradykinin level may maintain homeostasis in the presence of an increase in plasma ANG II, which is a risk factor for cardiovascular disease. Hormone replacement therapy was associated with a decrease in serum ACE and an increase in plasma bradykinin in hypertensive PMW. Accordingly, the protective effect of HRT against cardiovascular disease in PMW can be provided by a decrease in ACE activity and an increase in bradykinin.     

Different effects of transdermal and oral hormone replacement therapy on the renin-angiotensin system, plasma bradykinin level, and blood pressure of normotensive postmenopausal women

BACKGROUND: This study compared the efficacy of transdermally administered estradiol with that of orally administered conjugated equine estrogens (CEE) on the renin-angiotensin system, plasma bradykinin level, and blood pressure (BP) in normotensive postmenopausal women (PMW). METHODS: A total of 38 normotensive PMW were randomly assigned to two groups. The transdermal hormone replacement therapy (HRT) group consisted of 19 women treated with a continuous transdermal estradiol patch (36 microg/day) plus cyclic oral medroxyprogesterone acetate (MPA; 2.5 mg/day for 12 days) for 12 months. The oral HRT group consisted of 19 women who received continuous oral CEE (0.625 mg/day) plus cyclic oral MPA (2.5 mg/day for 12 days) for 12 months. Plasma renin activity (PRA), serum angiotensin-converting enzyme (ACE) activity, plasma angiotensin (Ang) I, Ang II, and bradykinin concentrations, and BP were measured before and 12 months after the start of HRT. RESULTS: Transdermal HRT significantly decreased both diastolic and mean BP and concomitantly reduced bradykinin levels (all P < .05). However, no significant changes in PRA, ACE activity, Ang I, or Ang II levels were observed. The BP remained unchanged in the oral HRT group, but the PRA, Ang I, Ang II, and bradykinin levels had significantly increased and ACE activity had significantly decreased (all P < .05) at 12 months after the start of HRT. CONCLUSIONS: Transdermal HRT decreased BP in normotensive PMW without influencing Ang II, whereas oral HRT increased Ang II without altering BP. Transdermal HRT may be more beneficial than oral HRT with regard to BP and Ang II levels.     

Antihypertensive contribution of sodium depletion and the sympathetic axis during chronic angiotensin II converting enzyme inhibition

The known physiological adaptation of cardiovascular sensitivity to variations in angiotensin II (Ang II) levels would predict that the blood pressure (BP)-lowering effect of Ang II inhibition might be at least partly counterbalanced by enhanced Ang II reactivity. Therefore, factors other than Ang II inhibition per se may contribute to the antihypertensive mechanisms of angiotensin converting enzyme (ACE) inhibitors. In order to further investigate this, the body sodium-blood volume state as well as the pressor reactivity to infused Ang II or norepinephrine (NE) were assessed in 12 normal subjects and 16 patients with essential hypertension given a placebo, and after 6 weeks of intervention with enalapril (20-40 mg/day). Enalapril produced in both groups similar falls in plasma ACE activity (P less than 0.0001) and upright plasma aldosterone (P less than 0.01), and a rise in plasma renin activity (PRA; P less than 0.05). BP decreased from 156/107 +/- 3/2 (mean +/- s.e.m.) to 142/94 +/- 5/3 mmHg (P less than 0.001) in the hypertensives and from 118/84 +/- 4/2 to 111/73 +/- 4/3 mmHg (P less than 0.01) in the normal subjects. In the hypertensive patients only, the Ang II pressor reactivity relative to Ang II plasma levels during Ang II infusion was increased (P less than 0.01), while the NE pressor reactivity relative to NE plasma levels during NE infusion (P less than 0.01) as well as the exchangeable body sodium (-5%, P less than 0.001) were reduced significantly. Blood and plasma volume, levels of plasma atrial natriuretic factor and catecholamines, and the heart rate and its response to isoproterenol were unchanged in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adrenal and circulating renin-angiotensin system in stroke-prone hypertensive rats.

The plasma and adrenal renin-angiotensin system in stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats were examined in animals at 5, 11, 18, and 25 weeks of age. Plasma active renin was significantly increased in 18- and 25-week-old SHRSP with impaired renal function, whereas there was no difference in the plasma prorenin level or renal renin content between the two strains at all ages examined. Thus, the rate of activation of prorenin seems to be enhanced in the kidney of SHRSP with malignant hypertension. Adrenal renin contents were severalfold higher in SHRSP than WKY rats at all ages. However, adrenal angiotensin peptides were not increased in SHRSP aged 5 and 11 weeks. In 18-week-old SHRSP, adrenal angiotensin II (Ang II) and III (Ang III) levels were fourfold and 1.8-fold higher, respectively, than in WKY rats, accompanied by 1.5-fold higher plasma aldosterone. Increased adrenal angiotensin and plasma aldosterone were also found in 25-week-old SHRSP. Zonal distribution studies indicated that the elevated Ang II and III in SHRSP were derived mainly from the capsular tissue (the zona glomerulosa). To examine the contribution of circulating angiotensin to the adrenal angiotensin content, effects of bilateral nephrectomy on adrenal angiotensin and renin were examined in 18-week-old rats. At 24 hours after nephrectomy, plasma angiotensin, prorenin, and active renin were decreased to almost negligible concentrations. Conversely, in both adrenal capsular and decapsular tissues of SHRSP and WKY rats, neither angiotensin nor renin was significantly decreased after nephrectomy. These results suggest that the increase in adrenal capsular Ang II contents in SHRSP may be partly due to an enhanced local production of Ang II.     

A NEW FAMILY WITH DEXAMETHASONE-SUPPRESSIBLE HYPERALDOSTERONISM: ALDOSTERONE UNRESPONSIVENESS TO ANGIOTENSIN II

A family with nine siblings in which three siblings have been shown to have dexamethasone-suppressible hyperaldosteronism was studied. All three showed no significant changes of plasma aldosterone during angiotensin II infusion at incremental rates under baseline conditions. After dexamethasone administration (2 mg/d for 4 weeks) plasma renin activity (PRA) rose to normal-supranormal range, while plasma and urinary aldosterone were maintained at low-normal levels. No restoration of aldosterone response to angiotensin II was observed on dexamethasone. Two other siblings were found to be hypertensive with normal baseline data; however, both showed plasma aldosterone hyperresponsiveness to ACTH. In the four normotensive siblings aldosterone response to ACTH was normal. The family pedigree was consistent with autosomal dominant transmission of the disorder. HLA typing showed haplotype A3 Bw35 in all five hypertensive sibs and in one normotensive. In conclusion, low aldosterone compared to PRA, and plasma aldosterone unresponsiveness to angiotensin II infusion before and during dexamethasone, show functional impairment, at least temporary, of the zona glomerulosa. These findings support the hypothesis that aldosterone may be derived from the zona fasciculata in this disorder.     

Plasma levels of prorenin and Renin in blacks and whites: their relative abundance and associations with plasma aldosterone concentration

BackgroundAll renin arises from prorenin. The proportion of renin relative to prorenin could influence overall renin-angiotensin-aldosterone activity. We sought to determine whether prorenin levels were related to extracellular volume, as reflected by the levels of plasma renin activity (PRA), and to aldosterone.MethodsWe analyzed plasma levels of prorenin, renin, and aldosterone, as well as their interactions, in 129 young blacks and whites.ResultsBlacks had lower plasma renin concentration (PRC) and PRA, but had prorenin levels similar to whites (69 pg/ml in blacks vs. 62 pg/ml in whites, P = 0.41). As a result, the renin-to-total renin ratio was significantly lower in blacks (11.5% in blacks as compared to 19.8% in whites; P = 0.0001). Because prorenin also resides in tissues including the adrenal where it can bind to a specific receptor to generate angiotensin II, we examined the relationship of prorenin levels to plasma aldosterone concentrations (PAC). While a positive association between PRC and PAC was found in both blacks and whites, PAC was positively related to prorenin in whites (P = 0.04) but negatively in blacks, an observation that we hypothesize was due to reduced prorenin-to-renin conversion in blacks.ConclusionsWe observed a disproportionately high level of prorenin in blacks. These high circulating prorenin levels however do not result in greater adrenal angiotensin II and aldosterone production in healthy young blacks.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.83.     

Nisoldipine--effects on the renin-angiotensin-aldosterone system and catecholamines. Studies in normotensive and hypertensive subjects

We have studied the effects of nisoldipine, a new calcium channel antagonist, on the renin-angiotensin-aldosterone system and on plasma catecholamines in 10 healthy volunteers and in 29 patients with primary essential hypertension. Of these 29 patients, thirteen had normal renin hypertension (NRH), and sixteen had low renin hypertension (LRH). Eight healthy volunteers received placebo. Short-term (24 h) effects were measured in all subjects and long-term (up to 6 months) effects of 10-40 mg nisoldipine daily were monitored in the 29 hypertensive patients. Plasma renin activity (PRA) increased slightly, although this rise was not statistically significant, 1 h after the first dose of nisoldipine in both normotensive subjects and hypertensive patients. After 2 h PRA had returned to the pre-treatment level. No change in PRA was observed after administration of placebo. Plasma angiotensin II (AII) levels showed considerable variation after nisoldipine administration. Plasma aldosterone levels decreased despite the increase in PRA and AII concentrations. However, no concomitant reduction in urinary aldosterone excretion was observed. Plasma noradrenaline levels increased slightly 2-4 h after administration of nisoldipine, and decreased again thereafter, but no changes in plasma adrenaline levels were seen. Nisoldipine had no long-term effects on the renin-angiotensin-aldosterone system or on serum catecholamine levels.     

Prenatal exposure to angiotensin II increases blood pressure and decreases salt sensitivity in rats

Renin angiotensin aldosterone system (RAAS) plays an essential role in the homeostatic control of arterial blood pressure, perfusion of tissues, and control of extracellular fluid. Its components are highly expressed in the developing kidney, general vasculature, brain, and heart. A modified intrauterine environment alters mechanisms controlling blood pressure (BP) and can lead to hypertension in the adult offspring and developmentally programmed RAAS can be involved in this process. There are very little data about the effects of increased angiotensin II (Ang II) concentrations during pregnancy on in utero development of the fetus. In our study, we administered Ang II to pregnant female rats via osmotic mini-pumps and evaluated the postnatal development and BP control in the offspring. To estimate possible developmental changes in sensitivity to salt, we exposed the offspring to a diet with increased salt content and measured plasma aldosterone levels and plasma renin activity. Increased Ang II during pregnancy raised BP in the offspring; however, salt sensitivity was decreased in comparison to controls. Relative weight of the left ventricle was decreased in the offspring prenatally exposed to Ang II, while relative kidney weight was reduced only in female offspring. Prenatal treatment led to increased aldosterone levels and decreased plasma renin activity, suggesting a complex physiological response. Our results suggest that conditions leading to upregulation of RAAS during pregnancy can influence the cardiovascular system of the fetus and have a long-term impact on the offspring’s health.     

Blunted aldosterone responsiveness to angiotensin II in normotensive subjects with familial predisposition to essential hypertension

The responsiveness of plasma aldosterone to an angiotensin (Ang) II infusion was assessed in normotensive young men, nine without and 13 with a family history of essential hypertension, after 7 days of low (mean urinary sodium 12 +/- 10 mmol/24 h) and 7 days of high (269 +/- 92 mmol/day) sodium intake. Under both conditions, the two study groups did not differ in body weight, arterial pressure, heart rate, plasma or urinary sodium and potassium or plasma renin, aldosterone or Ang II levels. However, after both dietary periods, the relationship between plasma aldosterone and plasma Ang II concentrations had shifted significantly (P less than 0.01) to the right in predisposed compared to non-predisposed subjects. The sodium-related changes in adrenocortical sensitivity to Ang II were similar in the two groups. The pressor response to Ang II did not differ between the two groups of subjects. These findings suggest that, in addition to the known cardiovascular abnormalities of sympathetic, renal and ion transport mechanisms, a fourth area of disturbance involving the response of plasma aldosterone to Ang II may be present in normotensive subjects with familial predisposition to essential hypertension.     

Nocturnal diastolic blood pressure decline is associated with higher 25-hydroxyvitamin D level and standing plasma renin activity in a hypertensive population

Patients with nondipper hypertension are known to carry a high risk of cardiovascular complications. Vitamin D deficiency is associated with hypertension. Because vitamin D deficiency activates the renin–angiotensin–aldosterone system (RAAS), we hypothesized that this vitamin would interact with the RAAS to influence blood pressure (BP) in nondipper hypertensive patients. We performed a cross-sectional analysis of 1,007 outpatients with hypertension (HTN). Dipper and nondipper patterns were detected, and the two groups were matched for clinical, laboratory, 25-hydroxyvitamin D (25OHD) levels, and ambulatory blood pressure recording. Plasma renin activity (PRA), angiotensin II, and plasma aldosterone concentration (PAC) were assessed in 174 patients treated with calcium channel blockers or no medication. The mean 25OHD concentration in the entire study population was 12.3ng/dL, and the prevalence of vitamin D deficiency was 87.0%. Dipper and nondipper HTN were noted in 187 patients (24.6%) and 573 patients (75.4%). 25OHD levels were similar between nondipper and dipper HTN groups. Forward stepwise logistic regression analysis showed that BMI and age were independent predictors of nondipper HTN. Neither 25OHD levels nor RAAS components were included in the model. In correlation analyses, nocturnal decline of diastolic BP was positively associated with 25OHD levels and standing PRA (r = 0.152 p = 0.045, r = 0.165 p = 0.038, respectively). The present study showed that vitamin D deficiency was astonishingly prevalent in hypertensive subjects residing in Xinjiang, China. There may be a weakly association of nocturnal DBP decline with 25OHD levels and standing PRA levels. We found no association between vitamin D deficiency and nondipper HTN.     

Relationships between left ventricular mass and the renin-angiotensin system,catecholamines, insulin and leptin

OBJECTIVES: Several neurohormonal systems have been suggested to stimulate myocardial cell growth, and thus take part in the development of left ventricular (LV) hypertrophy. We studied associations between LV mass and markers of the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system, glucose homeostasis and leptin. DESIGN: A total of 115 hypertensive patients with LV hypertrophy and two age- and gender-matched control groups consisting of 38 hypertensive patients without LV hypertrophy and 38 normotensive subjects were included. We examined determinants of the RAAS, plasma levels and 24-h urinary excretions of noradrenaline and adrenaline, plasma proinsulin, insulin, glucose, leptin and LV mass by echocardiography. RESULTS: Plasma renin activity (PRA) and serum aldosterone were higher (both P < 0.001) in the LV hypertrophy group than in patients without LV hypertrophy and normotensive subjects (1.0 +/- 0.8, 0.2 +/- 0.2 and 0.2 +/- 0.2 ng mL(-1) h(-1), and 327 +/- 126, 269 +/- 146 and 221 +/- 80 pmol L(-1), respectively). PRA and aldosterone both related (P < 0.001) to LV mass index (r = 0.44 and 0.27, respectively). Catecholamine levels and excretions were similar in all three groups and did not relate to LV mass index. Proinsulin, insulin and leptin levels were all elevated in the hypertensive patients (P < 0.01), but proinsulin, insulin, insulin sensitivity (by the homeostasis model assessment) and leptin did not relate to LV geometry, when indexed for body size. CONCLUSIONS: Plasma renin activity and serum aldosterone levels are elevated in hypertensive LV hypertrophy and relate to LV mass index. In addition to blood pressure, activation of the RAAS may be an important nonhaemodynamic mechanism in the control of LV hypertrophy.     

New roles for renin and prorenin in heart failure and cardiorenal crosstalk

The renin-angiotensin-aldosterone-system (RAAS) plays a central role in the pathophysiology of heart failure and cardiorenal interaction. Drugs interfering in the RAAS form the pillars in treatment of heart failure and cardiorenal syndrome. Although RAAS inhibitors improve prognosis, heart failure–associated morbidity and mortality remain high, especially in the presence of kidney disease. The effect of RAAS blockade may be limited due to the loss of an inhibitory feedback of angiotensin II on renin production. The subsequent increase in prorenin and renin may activate several alternative pathways. These include the recently discovered (pro-) renin receptor, angiotensin II escape via chymase and cathepsin, and the formation of various angiotensin subforms upstream from the blockade, including angiotensin 1–7, angiotensin III, and angiotensin IV. Recently, the direct renin inhibitor aliskiren has been proven effective in reducing plasma renin activity (PRA) and appears to provide additional (tissue) RAAS blockade on top of angiotensin-converting enzyme and angiotensin receptor blockers, underscoring the important role of renin, even (or more so) under adequate RAAS blockade. Reducing PRA however occurs at the expense of an increase plasma renin concentration (PRC). PRC may exert direct effects independent of PRA through the recently discovered (pro-) renin receptor. Additional novel possibilities to interfere in the RAAS, for instance using vitamin D receptor activation, as well as the increased knowledge on alternative pathways, have revived the question on how ideal RAAS-guided therapy should be implemented. Renin and prorenin are pivotal since these are at the base of all of these pathways.     

Effects of conjugated oestrogen and droloxifene on the renin-angiotensin system, blood pressure and renal blood flow in postmenopausal women

OBJECTIVE: The aim of this study was to evaluate the effect of conjugated equine oestrogen (CEE), and droloxifene, a selective oestrogen receptor modulator (SERM) on individual components of renin-angiotensin-aldosterone (RAAS) and blood pressure (BP) in postmenopausal women. DESIGN AND PATIENTS: Twenty-one normotensive (NT) and 10 hypertensive (HT) postmenopausal women received either CEE (0.625 mg/day) or droloxifene (60 mg/day) for 6 weeks and, after a 4-week washout, were restudied on the alternate medication. MEASUREMENTS: Hormones of the RAAS and supine BP were measured prior to and at the end of each drug treatment in all subjects. In a subgroup of the NT (n = 10), 24 h ambulatory BP was performed and renal blood flow was determined by PAH clearance both basally and in response to 45-min angiotensin II (Ang II) infusion (3 ng/kg/min). RESULTS: CEE significantly increased angiotensinogen, decreased active renin and angiotensin-converting enzyme (ACE), and maintained plasma immunoreactive (ir) angiotensin I (Ang I) levels compared to baseline. With droloxifene, angiotensinogen, active renin and Ang I remained unchanged. Both CEE and droloxifene significantly increased plasma ir-Ang II levels (pmol/l) in NT (baseline: 25.7 +/- 2.5, CEE: 36.6 +/- 3.4, droloxifene: 33.3 +/- 3.1, P < 0.002) and HT women (baseline: 17.9 +/- 2.3, CEE: 27.9 +/- 3.2, droloxifene: 25.9 +/- 4.9, P < 0.005). Renal blood flow was lower on CEE (P = 0.02) compared with baseline. Systemic BP (supine and 24-h ambulatory) was unchanged during both treatments. CONCLUSION: This study demonstrates higher circulating levels of ir-Ang II with CEE and droloxifene.     

Failure of renin suppression by angiotensin II in hypertension

Angiotensin II was infused at rates varying from 0.1 to 10 ng/kg per minute into 49 subjects with hypertension and 26 normotensive subjects and changes in blood pressure, plasma angiotensin II, and plasma renin activity (PRA) were determined after 20 and 30 minutes at each dose. Similar dose-related increases in angiotensin II and blood pressure occurred with a threshold of 1 ng/kg per minute in the normotensive and hypertensive subjects. Whereas angiotensin II induced a significant, dose-related decrement in renin activity in the normotensive subjects, with a threshold of 1.0 ng/kg per minute, no significant change in renin activity occurred in either the normal-renin or high-renin hypertensive subjects. In a separate study, nine normotensive and six hypertensive sodium-restricted subjects were given a converting enzyme inhibitor, SQ 20881, 30 microgram/kg. Despite a significantly greater fall in blood pressure (P less than 0.006) and angiotensin II concentration (P less than 0.045) in the hypertensive subjects, they did not have a greater rise in plasma renin activity. We conclude that angiotensin II reduces renin release in normal man at infusion rates that yield plasma angiotensin II levels within the physiological range but has a strikingly reduced influence on renin release in hypertension. In high-renin hypertension due to renal artery stenosis or nephrosclerosis, renin release is presumed to be relatively autonomous because of a dominant, intrarenal mechanism. The mechanism in normal-renin essential hypertension is not clear, but the abnormality could well be related to the pathogenesis of the hypertension.     

Plasma renin and prorenin (inactive renin) in diabetes mellitus: effects of intravenous furosemide

PRA, active renin, and prorenin were measured in 32 normotensive diabetic patients and 14 normal subjects of similar ages before and after iv injection of 40 mg furosemide. The majority of the diabetic patients had normal PRA and active renin levels before and after furosemide, but in 4 normal subjects and 5 diabetic patients PRA did not rise after furosemide treatment to at least 0.25 ng angiotensin I/(L.s) as previously found in 90% of normal subjects. Two thirds of the diabetic patients had higher plasma prorenin levels than the normal subjects. Four of the 5 diabetic patients whose PRA failed to rise to the usual level after furosemide treatment attained a plasma prorenin level higher than any normal subject, suggesting that furosemide stimulated synthesis and secretion of prorenin, but that conversion of prorenin to active renin was impaired. These 5 diabetic patients also had higher plasma creatinine and potassium levels as well as an increased frequency of albuminuria compared with the other diabetic patients. In contrast, the 4 normal subjects whose PRA failed to reach the usual level after furosemide treatment had low unresponsive prorenin levels, indicating that furosemide did not evoke the expected increase in prorenin or renin synthesis. We conclude that the inability of some diabetic patients to increase PRA after furosemide treatment is not dependent on failure of renin synthesis, but reflects an impairment of the normal processing of prorenin, leading to high levels of prorenin in plasma.     

Pharmacological Demonstration of the Additive Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Antagonism in Sodium Depleted Healthy Subjects

A blockade of the hemodynamic and tissue effects of angiotensin II (Ang II) more complete than that presently achieved with usual daily doses of angiotensin converting enzyme (ACE) inhibitors or type 1 Ang II receptor antagonists has potential advantages and risks. Therefore, it is worthwhile to investigate the biological and the hemodynamic effects of the simultaneous blockade of the renin-angiotensin system (RAS) at the two sites where it can be currently achieved, ACE and type 1 Ang II receptors. To investigate this issue, 2 double-blind randomized crossover studies were performed in a model of mild sodium depletion in normotensive volunteers. They ingested single oral doses of captopril 50 mg, losartan 50 mg, their combination or matched placebos, and in a second study, single oral doses of enalapril 10 mg, enalapril 20 mg and the combination of losartan 50 mg with enalapril 10 mg. The combination captopril 50 mg and losartan 50 mg had additive effects on blood pressure fall and renin release in sodium-depleted normotensive subjects. When compared to enalapril 10 mg and the doubling of its dose, the combination of losartan 50 mg and enalapril 10 mg significantly increased both the area under the time curve of mean blood pressure fall and plasma active renin levels. It did not further decrease plasma aldosterone levels. The conclusion is that a more complete blockade of the RAS can be achieved by concomitant administration of an type 1 Ang 11 receptor antagonist and an ACE inhibitor.     

Long-term effects of telmisartan on blood pressure, the renin-angiotensin-aldosterone system, and lipids in hypertensive patients

We prospectively evaluated long-term (12 months) effects of telmisartan on blood pressure (BP), circulating renin-anigiotensin-aldosterone levels, and lipids in hypertensive patients. There were 13 men and 11 women, 59 ± 8.7 years of age (mean ± SEM), with untreated essential hypertension. The 20-60 mg doses of telmisartan were administered once daily in the morning until BP130/85 was obtained. Blood pressure and plasma renin activity, plasma angiotensin (Ang) I and Ang II, serum angiotensin-converting enzyme (ACE) activity, plasma aldosterone concentration, plasma human atrial natriuretic peptide (hANP) concentration, and serum lipids were obtained 6 and 12 months after starting telmisartan administration. Systolic and diastolic BP were significantly (P < 0.001, P < 0.001) decreased from 162 ± 3.3 and 97.7 ± 2.1 mmHg to 128 ± 3.8 and 79.6 ± 2.0 mmHg after 12 months of treatment, respectively. Plasma Ang I and Ang II were unchanged at 12 months. Plasma renin activity and serum ACE activity were significantly (P < 0.001, P < 0.05) increased and plasma aldosterone concentration was unchanged during the study period. Total cholesterol levels were unchanged, but serum triglycerides levels were significantly decreased at 12 months (P < 0.01). Plasma hANP showed no significant alteration throughout the 12-month period. In hypertensive patients, telmisartan is a beneficial antihypertensive drug that also lowers serum triglycerides.