Pharmacodynamic Contribution to the Vasodilator Effect of Chronic AT(1) Receptor Blockade in SHR

-The present study investigated the pharmacodynamic contribution of AT(1) receptor blockade to the regional hemodynamic effects of long-term treatment with the AT(1) receptor antagonist candesartan cilexetil in adult spontaneously hypertensive rats (SHR). Blood pressure and Doppler flowmetry measurements were made during and after withdrawal of candesartan cilexetil, representing times of maximal and negligible blockade of AT(1) receptor-mediated vasoconstriction. There was marked renal, mesenteric, and hindquarter vasodilation in SHR treated for 4 weeks with candesartan cilexetil (2 mg/kg per day in drinking water, n=8) compared with vehicle (n=8). Blood pressure increased after withdrawal of candesartan cilexetil but was still reduced after 6 days, whereas regional flows and conductances did not reduce significantly compared with the last day of treatment. There was more prolonged inhibition of angiotensin (Ang) I-induced than Ang II-induced pressor responses after withdrawal of candesartan cilexetil, but these returned to control levels before blood pressure reached fully hypertensive levels. The renal and mesenteric vasoconstrictor effects of exogenously administered Ang I and Ang II returned to control levels just 2 days after withdrawal of candesartan cilexetil. Therefore, sustained inhibition of tonic Ang-mediated vasoconstriction caused by blockade of the AT(1) receptor is not the only factor contributing to the hemodynamic profile after long-term administration of candesartan cilexetil. In addition, compared with the vehicle group, blood pressures at maximum vasoconstriction and maximum vasodilation (an indirect measure of vascular hypertrophy) were significantly reduced in candesartan cilexetil-treated SHR on the last day of treatment, as was mesenteric media wall-to-lumen ratio in a separate group of similarly treated SHR. Collectively, these findings indicate that Ang-mediated vasoconstriction rapidly normalizes on withdrawal of AT(1) receptor blockade and that regression of vascular hypertrophy is important in determining blood pressure and hemodynamic status in candesartan cilexetil-treated SHR at this time.     

Cardioprotective Action of Perindopril versus Candesartan in Renovascular Hypertensive Rats

We investigated the effects of an angiotensin-converting enzyme inhibitor and an angiotensin II type 1 receptor blocker on cardiac hypertrophy in rats with renovascular hypertension. Renovascular hypertensive (Goldblatt) rats were surgically prepared from Wistar rats. Four weeks later, the rats showed a significant increase in blood pressure. At high doses, both the perindopril (1 mg/kg/day) and the candesartan (2 mg/kg/day) decreased the systolic pressure in these rats to the level of control Wistar rats. At low doses (perindopril 0.1 mg/kg/day and candesartan 0.1 mg/kg/day), these drugs lowered blood pressure to 85% of that in hypertensive rats. Echocardiographic and morphological studies revealed severe cardiac hypertrophy and fibrosis in untreated Goldblatt rats. High-dose treatment with both drugs suppressed the progression of hypertrophy and fibrosis. Also, low-dose perindopril prevented cardiac hypertrophy and fibrosis. In contrast, at the same levels of blood-pressure reduction, low-dose candesartan did not prevent cardiac fibrosis nor the upregulation of cardiac collagen types I and III mRNA observed in untreated Goldblatt rats. Atrial natriuretic peptide mRNA was up-regulated in untreated Goldblatt rats. These changes were significantly decreased by both doses of perindopril or the high dose of candesartan. Serum levels of angiotensin II and aldosterone were significantly higher in untreated Goldblatt rats. Both doses of perindopril inhibited activation of the renin-angiotensin system, whereas candesartan had weaker effects. In particular, serum aldosterone was 347 ± 20 pg/ml in low-dose perindopril versus 1796 ± 324 pg/ml in low-dose candesartan. These results suggest that there were no differences between the cardioprotective actions of perindopril and candesartan at high dosages. On the other hand, low-dose treatment with perindopril was more effective in preventing cardiac fibrosis than was low-dose treatment with candesartan, despite similar changes in blood pressure. It is possible that changes in aldosterone secretion are related to this difference.     

Development of blood pressure in spontaneously hypertensive rats after withdrawal of long-term treatment related to vascular structure

We have studied the effects of long-term treatment with different antihypertensive drugs on blood pressure and mesenteric resistance vessel structure of spontaneously hypertensive rats (SHR), both during treatment and after withdrawal of treatment. Young SHR were treated from 4 to 24 weeks with five different drugs: perindopril (1.5 mg/kg per day), captopril (60 mg/kg per day), hydralazine (25 mg/kg per day), isradipine (42 mg/kg per day) and metoprolol (130 mg/kg per day). At 24 weeks, 24-h mean blood pressures (MBP), measured invasively, were 121 mmHg (perindopril), 137 mmHg (captopril), 140 mmHg (hydralazine), 149 mmHg (isradipine) and 146 mmHg (metoprolol), compared to control values of 177 mmHg (SHR) and 132 mmHg (Wistar-Kyoto rats, WKY). Mesenteric resistance vessel structure, measured as media:lumen ratio (m:l), was also reduced to different extents: to WKY-level by perindopril (m:l = 4.4%), to midway between SHR- and WKY-levels by captopril, hydralazine and isradipine (m:l = 5.9%), and not at all by metoprolol (m:l = 6.8%). When treatment was discontinued, low MBP (ca 151 mmHg) persisted for 12 weeks in rats treated with the angiotensin converting enzyme inhibitors (perindopril and captopril), but rose rapidly in rats which had received the other treatments. At 3-12 weeks after withdrawal of treatment vascular structure was closely correlated with the blood pressure expected from the SHR- and WKY-control values, as were the left ventricle: body weight ratios. The results suggest that the ability of a drug to control vascular structure during treatment is not in itself a predictor of a persistent effect on blood pressure after withdrawal of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular effects of combination of perindopril, candesartan, and amlodipine in hypertensive rats

The combination therapy with ACE inhibitors, angiotensin II type 1 (AT(1)) receptor antagonists, or calcium channel antagonists may exert more beneficial effects on cardiovascular diseases than monotherapy. Perindopril, candesartan cilexetil, or amlodipine alone or the combination of low doses of each agent was administered orally to stroke-prone spontaneously hypertensive rats (SHRSP) for 4 weeks to compare the hypotensive or cardiovascular effects. Although perindopril (2 mg/kg), candesartan cilexetil (2 mg/kg), or amlodipine (3 mg/kg) alone caused comparable hypotensive effects in SHRSP, monotherapy with perindopril or candesartan decreased left ventricular (LV) weight; mRNA levels for atrial natriuretic factor, skeletal alpha-actin, and collagen types I and III; and aortic weight and platelet-derived growth factor-beta receptor tyrosine phosphorylation to a greater extent than monotherapy with amlodipine. Although monotherapy with a low dose (0.2 mg/kg) of perindopril or candesartan cilexetil did not significantly reduce the LV mRNA levels and aortic platelet-derived growth factor-beta receptor phosphorylation of the SHRSP, combination therapy at such a low dose normalized these parameters more potently than the use of amlodipine (3 mg/kg) alone. Although perindopril or candesartan cilexetil alone at 0.05 mg/kg did not decrease the blood pressure of the SHRSP, such a low dose of combination therapy decreased LV weight and atrial natriuretic factor mRNA levels of the SHRSP to a greater extent than amlodipine alone or amlodipine combined with perindopril or candesartan cilexetil. Our results provide evidence that suggests the combination of an ACE inhibitor and an AT(1) receptor antagonist may be more effective in the treatment of cardiac and vascular diseases than the combination of a calcium channel blocker with an ACE inhibitor or an AT(1) receptor antagonist or monotherapy with each agent.     

Comparative effects of candesartan and enalapril on augmented vasoconstrictive responses to endothelin-1 in coronary vessels of spontaneously hypertensive rats

BACKGROUND: The aim of this study was to compare the effect of angiotensin type-1 receptor blockade (ARB) on augmented vasoconstrictive response to endothelin-1 (ET-1) in coronary vessels of hypertensive hearts with angiotensin converting enzyme (ACE) inhibitor, candesartan cilexetil (CAN) or enalapril was administered for 3 weeks in spontaneously hypertensive rats (SHR). METHODS: We used SHR (9 to 12 weeks old, n = 18) and Wistar-Kyoto (WKY) rats (n = 6). Systolic blood pressure was measured once a week. Spontaneously hypertensive rats were divided into three groups. Enalapril malate (10 mg/day) or CAN (10 mg/day) was administered orally in each of six SHR in each group receiving treatment for 3 weeks. The control group (n = 6) received no treatment. At the end of this experiment, the hearts were isolated. Isolated hearts mounted on a Langendorff apparatus after weighing were then perfused with modified Krebs-Henseleit buffer at constant pressure (75 mm Hg). The coronary perfusion pressure and coronary flow were measured during perfusion of isolated hearts. Coronary vascular resistance (CVR; mm Hg/mL/min/100 g) was calculated. RESULTS: The ET-1 elicited increases in CVR dose-dependently in both normotensive and hypertensive rat hearts. However, the responses were significantly greater in SHR than in WKY rat. Chronic treatment with enalapril or candesartan inhibited the development of hypertension and cardiac hypertrophy equally in SHR. Augmented vasoconstrictive responses to ET-1 were significantly reduced in treated SHR. There was no difference in these effects between enalapril and candesartan. CONCLUSION: These findings suggest that both ACE inhibitors and ARB can equally inhibit augmented coronary vascular response to ET-1 in hypertensive hearts.     

Transient prehypertensive treatment in spontaneously hypertensive rats: a comparison of spironolactone and losartan regarding long-term blood pressure and target organ damage

OBJECTIVE: We previously demonstrated that when the renin-angiotensin system (RAS) is transiently blocked by an angiotensin receptor blocker (ARB) in young spontaneously hypertensive rats (SHR), this results in a prolonged blood pressure decrease and protection against target organ damage. Aldosterone is an essential hormone in the RAS, and contributes to pathologic remodeling. Thus, part of the protective effects of the ARB may be due to inhibition of aldosterone-mediated effects. To test this hypothesis, in young SHR, we compared the effectiveness of transient treatment with the mineralocorticoid receptor blocker spironolactone with those obtained by the ARB losartan. METHODS: SHR were transiently (i.e. between 4-8 weeks of age) treated with spironolactone (SHR-Spiro: 1 mg/kg per day), losartan (SHR-Los: 20 mg/kg per day) or saline. Rats were followed up until week 72 of age and cardiovascular parameters were repeatedly assessed by echocardiography, radiotelemetry of blood pressure and 24-h urine collection. End-point measurements included direct left ventricular contractility and relaxation, as well as cardiac and renal histomorphology. RESULTS: Transient spironolactone treatment reduced blood pressure up to 36 weeks of age and cardiac and renal collagen deposition and tubular atrophy up to 72 weeks of age compared to untreated SHR. Pulse pressure was higher in SHR-Spiro compared to SHR-Los. Cardiac hypertrophy, albuminuria and glomerulosclerosis were not attenuated in SHR-Spiro compared to untreated SHR up to 72 weeks of age, whereas the effects in SHR-Los were ameliorated. CONCLUSIONS: Although transient spironolactone treatment leads to prolonged blood pressure reduction and reduced collagen deposition, long-term organ protection only partially exists. Thus, transient spironolactone treatment is less effective than transient losartan treatment.     

Brief angiotensin converting enzyme inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term

Our study examines the long-term cardiovascular effects after a brief period of angiotensin converting enzyme (ACE) inhibitor treatment in young spontaneously hypertensive rats (SHR). SHR were treated with perindopril (3 mg/kg/day) by gavage from 2 to 6, from 6 to 10, or from 2 to 10 weeks of age. Systolic blood pressure was measured in the tail weekly until 25 weeks of age. Corresponding control groups received distilled water for the same periods. In each treatment group blood pressure was reduced significantly during treatment, rose when treatment stopped, but plateaued significantly below control SHR thereafter. This difference in blood pressure at 25 weeks of age was due to reduced total peripheral resistance as determined by microsphere methods, but plasma renin activity and angiotensin II concentrations were not different. Cardiac hypertrophy was also reduced in treated SHR. In a separate experiment, perindopril treatment from 6 to 10 weeks of age resulted in a significant reduction in the media/lumen ratios of mesenteric resistance vessels at 32 weeks of age. Concomitant administration of angiotensin II with perindopril from 6 to 10 weeks of age not only prevented the long-term effects on blood pressure seen with perindopril treatment alone but was associated with cardiovascular hypertrophy in excess of untreated control SHR. Finally, perindopril given for a shorter period (6 to 7 weeks) or later in life (20 to 24 weeks) had no significant long-term effects on blood pressure. These results demonstrate that a 4-week period of ACE inhibitor treatment in young SHR is sufficient to prevent the full expression of genetic hypertension and cardiovascular hypertrophy and that angiotensin II might be important in the development of hypertension in this model, its role in later life being less important.     

AT1 receptor blockade is superior to conventional triple therapy in protecting against end-organ damage in Cyp1a1-Ren-2 transgenic rats with inducible hypertension

OBJECTIVE: In the present study we compared the effects of treatment with the AT1 receptor antagonist candesartan and of 'triple therapy' (hydralazine, hydrochlorothiazide, reserpine) on the course of blood pressure, cardiac hypertrophy and angiotensin II concentrations after induction of hypertension in transgenic rats with inducible expression of the mouse renin gene (Cyp1a1-Ren-2 rats). METHODS: Hypertension was induced in Cyp1a1-Ren-2 rats through dietary administration of the natural xenobiotic indole-3-carbinol (I3C, 0.3%) for 4 days. Starting on the day before administration of I3C, rats were treated either with candesartan or received triple therapy for 9 days. Systolic blood pressure was measured in conscious animals. Rats were decapitated and angiotensin II levels in plasma and in whole kidney and left ventricular tissues were determined by radioimmunoassay. RESULTS: Administration of I3C resulted in the development of severe hypertension and cardiac hypertrophy that was accompanied by marked elevations of plasma and tissue angiotensin II concentrations. Candesartan treatment prevented the development of hypertension and cardiac hypertrophy and was associated with a reduction of tissue angiotensin II concentrations. In contrast, triple therapy, despite maintaining systolic blood pressure in the normotensive range, did not prevent the development of cardiac hypertrophy and tissue angiotensin II augmentations. CONCLUSIONS: Our findings indicate that hypertension in Cyp1a1-Ren-2 rats is a clearly angiotensin II-dependent model of hypertension with elevated circulating and tissue angiotensin II concentrations, and that antihypertensive treatment with AT1 receptor blockade is superior to conventional triple therapy in effective protection against hypertension-induced end-organ damage in this rat model.     

Role of tissue angiotensin II in myocardial remodelling induced by mechanical stress

In an in vivo study, spontaneously hypertensive rats (SHR) were treated with an angiotensin II (Ang II) type 1 receptor antagonist of candesartan or hydralazine. Untreated SHR progressively developed severe hypertension, and treatment with candesartan or hydralazine decreased blood pressure. Candesartan reduced left ventricular (LV) weight, LV wall thickness, transverse myocyte diameter, the relative amount of V3 myosin heavy chain, and interstitial fibrosis, while treatment with hydralazine slightly prevented an increase in LV wall thickness, but did not exert a significant reduction on other parameters. In an in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes. Stretching cardiomyocytes activated second messengers such as protein kinase C, Raf-1 kinase, and mitogen-activated protein (MAP) kinase, increasing protein synthesis, enhancing endothelin (ET)-1 release, activating the Na+/H+ ion exchanger. Moreover, pretreatment with candesartan diminished an increase in phenylalanine incorporation, MAP kinase activity, and c-fos gene expression induced by the stretching of cardiomyocytes. This suggests that the cardiac renin-angiotensin system is linked to the formation of pressure-overload hypertrophy and that Ang II increases the growth of cardiomyocytes by an autocrine mechanism. Finally, we examined the signalling pathways leading to MAP kinase activation both in cardiac myocytes and in cardiac fibroblasts. Ang II-evoked signal transduction pathways differed between cell types. In cardiac fibroblasts, Ang II activated MAP kinase through a pathway including the Gbetagamma subunit of Gi protein, Src, Shc, Grb2, and Ras, while Gq and protein kinase C were important in cardiac myocytes.     

Angiotensin II type 1 receptor blocker prevents atrial structural remodeling in rats with hypertension induced by chronic nitric oxide inhibition.

The prevalence of atrial fibrillation (AF) increases in patients with hypertension. Angiotensin II is involved in structural atrial remodeling, which contributes to the onset and maintenance of AF in paced animal models. We investigated the role of angiotensin II in atrial structural remodeling in rats with hypertension. Ten-week-old male Wistar-Kyoto rats were randomly divided into 4 groups: a control group (no treatment), an Nomega-nitro-L-arginine methyl ester (L-NAME) group (administered L-NAME, an inhibitor of nitric oxide synthase, 1 g/l in drinking water), an L-NAME+candesartan group (L-NAME plus candesartan-an angiotensin II receptor blocker (ARB)-at 0.1 mg/kg/day), and an L-NAME + hydralazine group (L-NAME plus hydralazine at 120 mg/l in drinking water). Eight weeks after treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (197 +/- 12 vs.138 +/- 5 mmHg, p < 0.05). Candesartan or hydralazine with L-NAME reduced systolic blood pressure to baseline. Chronic inhibition of NO synthesis increased the extent of fibrosis and transforming growth factor-beta expression in atrial tissue, and both of these effects were prevented by candesartan, but not by hydralazine. Cardiac hypertrophy and dysfunction were induced in the L-NAME group, and these effects were also prevented by candesartan, but not by hydralazine. In contrast, the decrease in thrombomodulin expression in the atrial endocardium in hypertensive rats was restored by candesartan and hydralazine. The ARB prevented atrial structural remodeling, a possible contributing factor for the development of AF, in the hearts of rats with hypertension induced by long-term inhibition of NO synthesis.     

Hemodynamic and hormonal effects of the angiotensin II antagonist, candesartan cilexetil, in patients with congestive heart failure

Candesartan cilexetil is a newly synthesized, specific angiotensin II type 1 receptor antagonist. Candesartan cilexetil is a prodrug, and is converted to its active form, candesartan, by the enzyme esterase at the time of intestinal absorption. We conducted a single-dose study to evaluate the effect of candesartan cilexetil on cardiac hemodynamics and hormone response in 13 patients with congestive heart failure. Mean blood pressure did not show any significant change in the patients receiving either 2 or 8 mg. Pulmonary capillary wedge pressure was reduced by 34.9% in the patients given 8 mg of candesartan cilexetil. The cardiac index did not show any significant changes. Total peripheral vascular resistance was reduced in the patients receiving 2 or 8 mg from 1 h after administration, and the tendency to decrease continued until 8 h after administration. Plasma atrial natriuretic peptide levels were reduced by 15.5% 2 h after dosing with 8 mg of candesartan cilexetil. Plasma brain natriuretic peptide levels decreased slightly after dosing with candesartan cilexetil. Administration of candesartan cilexetil reduces cardiac preload and afterload and is expected to be useful for the treatment of congestive heart failure.     

Candesartan cilexetil in hypertension: effects of six weeks' treatment on haemodynamics, baroreceptor sensitivity and the renin-angiotensin-aldosterone system

The effects of the angiotensin II receptor blocker candesartan cilexetil on systemic and forearm haemodynamics and baroreceptor sensitivity were evaluated in this randomized, placebo-controlled, double-blind, crossover study. After a 4-week placebo run-in period, 22 patients with essential hypertension (diastolic blood pressure 100-114 mmHg) were randomized to receive either candesartan cilexetil 16 mg or placebo once daily for 6 weeks. At the end of each period, 24 h after the last dose, invasive haemodynamic assessments were performed. Simultaneously, the plasma renin activity and plasma concentrations of angiotensin II, aldosterone and catecholamines were measured. Compared to placebo, candesartan cilexetil significantly reduced mean arterial pressure by 8 mmHg (95% CI: 2.6; 12.3), while cardiac output, stroke volume and heart rate were unchanged. Forearm vascular resistance was reduced by 1 mmHg*ml     

Vascular remodeling and improvement of coronary reserve after hydralazine treatment in spontaneously hypertensive rats

The purpose of these studies was to evaluate cardiovascular structural and functional changes in a model of hypertension-induced myocardial hypertrophy in which vasodilator therapy decreased blood pressure to normal levels. Thus, we determined the separate contributions of hypertension and hypertrophy on myocardial and coronary vascular function and structure. Twelve-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with and without 12 weeks of vasodilator antihypertensive treatment (hydralazine) were studied using an isolated perfused rat heart model. Hydralazine treatment normalized blood pressure in SHR but did not cause regression of cardiac hypertrophy (heart weight to body weight ratio of SHR + hydralazine 4.33 +/- 0.098 vs. SHR 4.66 +/- 0.091; WKY 3.21 +/- 0.092 and WKY + hydralazine 3.38 +/- 0.152; mean +/- SEM). Coronary flow reserve, elicited by adenosine vasodilation in the perfused heart, was decreased in SHR (29%) compared with WKY (105%) and WKY + hydralazine (100%) and was significantly improved in SHR + hydralazine (75%). Morphometric evaluation of perfusion-fixed coronary arteries and arterioles (30-400 microns diameter) demonstrated a significant increase in the slope of the regression line comparing the square root of medial area versus outer diameter in SHR (0.444) compared with WKY (0.335) and WKY + hydralazine (0.336, p less than 0.05). Blood vessels from SHR + hydralazine were not different from control (0.338). Cardiac oxygen consumption was decreased in SHR (10.9 +/- 0.74 mumols oxygen/min/g/60 mm Hg left ventricular pressure) compared with WKY (22.4 +/- 1.47) and WKY + hydralazine (23.4 +/- 1.90; p less than 0.01), while SHR + hydralazine was intermediate (16.0 +/- 1.60). These studies suggest that significant alterations in myocardial and coronary vascular structure and function occur in hypertension-induced cardiac hypertrophy. The coronary vasculature is responsive to blood pressure, independent of cardiac hypertrophy, although moderate coronary deficits do remain after chronic antihypertensive therapy.     

Effect on atrial natriuretic peptides of chronic treatment with alpha-methyldopa and hydralazine in spontaneously hypertensive rats

The present study was designed to examine the effect of antihypertensive therapy on plasma and atrial concentration of atrial natriuretic peptides (ANP) in spontaneously hypertensive rats (SHR) by using alpha-methyldopa and hydralazine. Methyldopa and hydralazine treatment reduced blood pressure (P less than .05, P less than .05, respectively); however, ventricular weight was reduced by methyldopa (P less than .05) but not by hydralazine. Plasma ANP concentration in untreated SHR was higher than that observed in Wistar-Kyoto rats (WKY). Methyldopa treatment decreased plasma ANP concentration, but hydralazine treatment did not. Moreover, plasma ANP concentration and ventricular weight were positively correlated in untreated and treated SHR. The left atrial ANP concentration in untreated SHR was lower than that observed in WKY. Methyldopa treatment increased left atrial ANP concentration, but hydralazine treatment did not. These results suggest that the ANP release from the left atrium is chronically stimulated in adult SHR, and that a decrease in plasma ANP concentration by methyldopa treatment is, in part, associated with the decline of ANP release from the heart due to the reductions of blood pressure and cardiac hypertrophy.     

The effect duration of candesartan cilexetil once daily, in comparison with enalapril once daily, in patients with mild to moderate hypertension

OBJECTIVE: To determine the antihypertensive efficacy, effect duration and safety of the angiotensin II type 1 receptor blocker candesartan cilexetil and the angiotensin converting enzyme inhibitor enalapril once daily in patients with mild to moderate hypertension. METHODS: A multicenter, randomised, double-blind parallel group study was performed in Finland, France, the Netherlands, Spain and Sweden. Three-hundred-and-ninety-five men and women in the age range 20-80 years with primary hypertension were randomised to an 8-week double-blind treatment period with either candesartan cilexetil 8-16 mg or enalapril 10-20 mg once daily, with forced dose titration after 4 weeks. Non-invasive ambulatory blood pressure was measured for 36 h at baseline and after 8 weeks. The primary efficacy variable was the change in mean diastolic and systolic ambulatory blood pressure 22-24 h post-dose. RESULTS: There was a significant difference in the adjusted mean difference for the change from baseline to week 8 between candesartan cilexetil and enalapril 22-24 h post-dose by -3.5 mmHg (95% confidence interval, CI: -6.8 to -0.3 mmHg; p < 0.032) in ambulatory systolic blood pressure and -3.0 mmHg (95% CI: -5.1 to -0.8 mmHg; p < 0.008) in ambulatory diastolic blood pressure. There was a significant difference in adjusted mean daytime ambulatory blood pressure 24-36 h post-dose by -4.2 mmHg (95% CI: -6.8 to -1.6 mmHg; p < 0.002)/-3.5 mmHg (95% CI: -5.1 to -1.8 mmHg; p < 0.001). Both drugs were generally well tolerated. CONCLUSION: The results of the present study suggest that advantages may be attributed to the use of candesartan cilexetil, as compared to enalapril in the treatment of patients with essential hypertension. In comparison with enalapril 20 mg, candesartan cilexetil 16 mg more effectively lowered blood pressure at trough and in particular on the day following the day after the last dose.     

A new approach to assessing antihypertensive therapy: effect of treatment on pulse pressure. Candesartan cilexetil in Hypertension Ambulatory Measurement of Blood Pressure (CHAMP) Study Investigators

BACKGROUND: A high pulse pressure is an independent cardiovascular risk factor. It has therefore been suggested that antihypertensive treatment should not only reduce systolic blood pressure (SBP) and diastolic blood pressure (DBP), but should also decrease pulse pressure (SBP minus DBP). In a previous analysis, we showed that two angiotensin II type 1 (AT1)-receptor blockers, candesartan cilexetil and losartan, differed in their effects in reducing SBP and DBP. OBJECTIVE: To compare the efficacy of candesartan cilexetil and losartan according to a new approach--their effect on pulse pressure--and to describe the dose-effect relationship for SBP, DBP and pulse pressure, in a placebo-controlled study. METHODS: After a 4-week placebo run-in period, 268 patients with mild-to-moderate hypertension were allocated randomly to groups to receive placebo, candesartan cilexetil (8 mg once daily) or losartan (50 mg once daily), for 4 weeks. The doses were then doubled to 16 and 100 mg, respectively, for the final 4 weeks of the study. Clinic blood pressure was measured 24 and 48 h after each dose of drug or placebo, and ambulatory blood pressure was monitored from 0 to 36 h after each dose, at baseline and after 4 and 8 weeks of treatment. RESULTS: Candesartan cilexetil decreased ambulatory pulse pressure significantly (P < 0.05) more than did losartan during both daytime and night-time, and over the 24 h period after the previous dose. A different dose-effect relationship on SBP, DBP and pulse pressure was observed. The duration of action of candesartan cilexetil was greater than that of losartan. After a missed dose (i.e. approximately 24-36 h after the previous dose), mean ambulatory pulse pressure values after 4 and 8 weeks of treatment with candesartan cilexetil were lower than those observed with losartan (P < 0.005). Clinic pulse pressure measurements were consistent with these ambulatory measurements. CONCLUSIONS: AT1 -receptor blockers differ both in their ability to reduce pulse pressure and in their duration of effect, candesartan cilexetil having a greater and more sustained effect than losartan. Different dose-effect relationships on SBP, DBP or pulse pressure were observed. Further prospective studies based on pulse pressure are needed to analyse the mechanism of reduction of pulse pressure and to determine its prognostic value.     

Pharmacologic properties of candesartan cilexetil--possible mechanisms of long-acting antihypertensive action

Candesartan cilexetil has shown potent and long-lasting antihypertensive effects in clinical trials and in several animal models of hypertension. In spontaneously hypertensive rats, the duration of the antihypertensive effect of candesartan cilexetil was compared to those of losartan, valsartan, eprosartan, and irbesartan at the same degree of maximal blood pressure reduction. A single oral dose of candesartan cilexetil at 0.3 mg/kg reduced maximal blood pressure by about 25 mm Hg, and the antihypertensive effect of candesartan cilexetil lasted the longest, continuing for more than 1 week, without an effect on circadian rhythm. In a rabbit aortic preparation, candesartan, active form of candesartan cilexetil, decreased the maximal contractile response of angiotensin II. This inhibitory mode was different from that of other angiotensin II-receptor antagonists, and showed a shift to the right in the angiotensin II-induced contraction curve and/or a small depression of the maximal response. In kinetic studies using bovine adrenal cortical membrane and tritiated candesartan, both receptor association and dissociation were found to be slow. The dissociation rate of tritiated candesartan binding (t1/2 = 66 min) was five times slower than that of radiolabelled angiotensin II binding (t1/2 = 12 min). The insurmountable inhibition of candesartan in vascular contraction is the result of its tight binding and slow dissociation from angiotensin II AT1 receptors. These characteristics are related to the potency and long duration of action in candesartan cilexetil.     

Different effects of antihypertensive agents on cardiac and vascular hypertrophy in the transgenic rat line TGR(mRen2)27.

The hypertensive transgenic rat model TGR(mRen2)27 has been used to investigate the development of cardiac and vascular hypertrophy in response to two different drug regimes. Cardiac hypertrophy was shown to be related to age and gender with the copy number of mouse renin transgenes having an additive effect. A similar observation was noted for hypertrophy in the vasculature, which was assessed using flow cytometry cell cycle DNA analysis of aortic vascular smooth muscle cells. Chronic treatment from weaning with equihypotensive doses of perindopril (2 mg/kg/day) or hydralazine and hydrochlorothiazide (4 mg/day of each) prevented the development of cardiac hypertrophy. Perindopril treatment also effectively prevented the development of vascular hypertrophy; however, treatment with hydralazine and hydrochlorothiazide was not as effective despite equivalent blood pressure reduction. These studies have demonstrated the presence of marked vascular and cardiac hypertrophy in the hypertensive transgenic TGR(mRen2)27 model of hypertension. Furthermore, these results provide new evidence to support the role of a locally activated renin angiotensin system in the blood vessel wall, which is involved in the pathogenesis of vascular hypertrophy in this transgenic rat model.     

Persistent improvement of cardiovascular risk factors in spontaneously hypertensive rats following early short-term captopril treatment

This study was designed to determine whether an improvement in cardiovascular risk factors persists in spontaneously hypertensive rats (SHR) following withdrawal of angiotensin converting enzyme inhibitor (ACE-I) treatment. SHR were given deionized drinking water or captopril solution from four to sixteen weeks of age. At twelve weeks of age, rats from each group were instrumented with radiotelemetry devices for continuous monitoring of blood pressure. Mean arterial blood pressure was significantly lower in captopril-treated SHR during treatment (92+/-2 vs 147+/-1 mm Hg), and at twelve weeks after treatment withdrawal (131+/-2 vs 158+/-2 mm Hg). In addition, proteinuria, renal vascular resistance, plasma triglyceride levels, fasting glucose levels, post-prandial insulin levels, and heart weights were significantly reduced in the treated SHR compared to control SHR, at time-points between three to seven months after captopril withdrawal. Our findings indicate that short-term administration of an ACE-I during the developmental phase of hypertension in the SHR results in a long-term overall improvement of cardiovascular risk factors.     

The Antihypertensive Effect and Tolerability of Candesartan Cilexetil, a New Generation Angiotensin II Antagonist, in Comparison with Losartan

This multicentre study compared the antihypertensive effect and tolerability of the novel angiotensin II antagonist candesartan cilexetil with those of losartan and placebo. Men and women aged 20-80 years, with primary hypertension and sitting diastolic blood pressure (DBP) 95-114 mm Hg after a 4-week placebo run-in period, were randomized to once daily double-blind treatment with candesartan cilexetil 8 mg (n = 82), candesartan cilexetil 16 mg (n = 84), losartan 50 mg (n = 83) or placebo (n = 85) for 8 weeks. Blood pressure was measured 6 and 24 h after dose, i.e. at peak and trough. Differences between treatments were analysed by analysis of covariance, and the primary effect variable was reduction in trough sitting DBP. Compared with placebo treatment, trough DBP was significantly reduced by a mean (95% CI) of 8.9 (6.0; 11.8) mm Hg with 8 mg and 10.3 (7.4; 13.2) mm Hg with 16 mg candesartan cilexetil. The 8 mg dose was as effective as losartan 50 mg, while 16 mg candesartan cilexetil was significantly more effective, with a difference between treatments of 3.7 (0.8; 6.7) mm Hg (p = 0.013). The placebo corrected trough/peak ratio was 0.9-1.1 with candesartan cilexetil and 0.7 with losartan. Candesartan cilexetil was similarly well tolerated as placebo. In conclusion, candesartan cilexetil 8 mg or 16 mg once daily is an effective and well tolerated antihypertensive treatment. Candesartan cilexetil 16 mg is significantly more effective than losartan 50 mg once daily.