9C.09: TREATMENT WITH CANDESARTAN UNMASKS HIGHER URINARY NOREPINEPHRINE EXCRETION IN WHITE COAT HYPERTENSIVE PATIENTS COMPARED TO HEALTHY NORMOTENSIVE PARTICIPANTS.

OBJECTIVE: White coat hypertensive is a pre-hypertensive state that has been associated with increased sympathetic drive. The objective of the study was to compare the exposure of the kidney to sympathetic nerve activity using urinary normetanephrine (UNMN) as a marker of renal sympathetic exposure in white coat hypertensive (WCH) and healthy normotensive (HN) participants. DESIGN AND METHOD: This was a double-blind randomized placebo-controlled crossover study. WCH were included if office blood pressure was >140/80 mmHg and ambulatory blood pressure <135/85 mmHg and HN if OBP was <140/90 mmHg and ABP <135/85 mmHg Participants were randomized to receive either 16 mg of candesartan or a matched placebo for one week before study day. On the study day systemic and renal hemodynamics as well as plasma norepinephrine and urinary excretion of normetanephrine (measured by LC/MS-MS were measured after one hour of baseline, one hour of lower body negative pressure and one hour of recovery period. Excretion of UNMN was expressed as the total of UNMN excreted during these three hours (cumUNMN). Paired or unpaired t-test were used for comparison. RESULTS: 25 HN and 12 WCH participants were included in the study. Mean age (±standard deviation), BMI were respectively 31.0±10.5 years and 22.0 ± 2.2 Kg/m2 in HN and 40.7±17.8 years and 26.7 ± 6.3 Kg/m2 in WCH.Table 1 Baseline mean blood pressure, plasma noradrenaline and cumulated UNMN during placebo and candesartan(Figure is included in full-text article.)Mean blood pressure was higher during placebo and candesartan in WCH compared to HN. Cumulated UNMN was higher in both groups after candesartan treatment. Cumulated UNMN was higher in WCH than in HN only after candesartan treatment. CONCLUSIONS: Urinary excretion of normetanephrine is increased in WCH compared to HN when treated with candesartan. The increased excretion of uNMN when the renin angiotensin system is blocked might reflect an increased sensitivity of WCH to stress conditions such as orthostatic stress.

Candesartan cilexetil in children with hypertension or proteinuria: preliminary data

The angiotensin II receptor blockers irbesartan and losartan effectively reduce blood pressure and proteinuria in childhood. We were impressed by the neutral taste and the small size of the candesartan cilexetil tablets. This angiotensin II receptor blocker was used during 4 months in 17 pediatric patients (aged 0.5-16, median 4.5 years) with chronic arterial hypertension (n=6), overt proteinuria (n=2), or both (n=9). The initial candesartan dose of 0.23 (0.16-0.28) mg/kg body weight once daily (median and interquartile ranged) was doubled in ten patients [final dose 0.35 (0.22-0.47) mg/kg body weight]. No adverse clinical experiences were noted on candesartan. Candesartan increased plasma potassium by 0.3 (0.0-0.8) mmol/l (P<0.01). In children with arterial hypertension, blood pressure decreased by 9 (3-13)/9 (3-18) mmHg (P<0.01); in those with overt proteinuria the urinary albumin/creatinine ratio decreased by 279 (33-652) mg/mmol (P<0.05). In conclusion, in children candesartan reduces blood pressure and proteinuria with an excellent short-term tolerability profile.

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

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

CHARMed - the effects of candesartan in heart failure

The Candesartan in Heart failure: Assessment of Reduction in Mortality and mortality (CHARM) programme has already shown that candesartan is an effective alternative to angiotensin-converting enzyme (ACE) inhibitors (CHARM-Alternative), that additional benefits can be achieved by adding candesartan to ACE inhibitors (CHARM-Added), and that in patients with a preserved cardiac output there are reduced hospital admissions (CHARM-Preserved). Further recent analysis of the CHARM programme has shown that of the cardiovascular deaths, the benefit of candesartan was due to a reduction in sudden death and progressive heart failure, and that these reductions were observed in the -Alternative and -Added but not -Preserved components. Combination of the CHAR M-Alternative and -Added trials confirmed this reduction of cardiovascular deaths, and also demonstrated that candesartan reduced hospital admissions. There were also improvements in the New York Heart Association functional class of heart failure in the -Alternative and -Added, but not -Preserved, components of CHARM. The benefits of candesartan in heart failure are maintained in the presence of an ACE inhibitor and P-blocker. So far, all of the findings with candesartan in the CHARM programme have been favourable/CHARMed, although the beneficial effects in patients with a preserved cardiac output are limited.

Reversal of cardiovascular remodelling with candesart

Cardiovascular remodelling, defined as ventricular and vascular hypertrophy together with fibrosis, characterises hypertension following inhibition of the production of the endogenous vasodilator, nitric oxide (NO). This study has determined whether the cardiovascular remodelling following chronic NO synthase inhibition can e reversed by administration of the selective angiotensin II AT(1)-receptor antagonist, candesartan. Male Wistar rats were treated with L-nitroarginine methyl ester (L-NAME, 400 mg/l in drinking water) for eight weeks and with candesartan cilexetil (2 mg/kg/day by oral gavage) for the last four weeks. L-NAME-treated rats became hypertensive with systolic blood pressure increasing from 110 +/- 4 mmHg (control) to 170 +/- 10 mmHg. Rats developed left ventricular hypertrophy (control 1.70 +/- 0.06; L-NAME 2.10 +/- 0.04 mg/kg body wt) with markedly increased deposition of perivascular and interstitial collagen. Candesartan returned blood pressure, left ventricular weights and collagen deposition to control values. Echo cardiographic assessment showed concentric hypertrophy with an increased fractional shortening; this was reversed by candesartan treatment. Heart failure was not evident. In the isolated Langendorff heart, diastolic stiffness increased in L-NAME-treated rats while the rate of increase in pressure (+dP/dt) increased after eight weeks only; candesartan reduced collagen deposition and normalised +dP/dt. In isolated left ventricular papillary muscles, the potency (negative log EC50) of noradrenaline as a positive inotropic compound was unchanged, (control 6.56 +/- 0.14); maximal increase in force before ectopic beats was reduced from 5.0 +/- 0.4 mN to 2.0 +/- 0.2 mN. Noradrenaline potency as a vasoconstrictor in thoracic aortic rings was unchanged, but maximal contraction was markedly reduced from 25.2 +/- 2.0 mN to 3.0 +/- 0.3 mN; this was partially reversed by candesartan treatment. Thus, chronic inhibition of NO production with L-NAME induces hypertension, hypertrophy and fibrosis with increased toxicity and significant decreases in vascular responses to noradrenaline. These changes were at least partially reversible by treatment with candesartan, implying a significant role of AT(1)-receptors in L-NAME-induced cardiovascular changes.

Angiotensin II receptor blockade prevents acute renal sodium retention induced by low levels of orthostatic stress.

BACKGROUND: Depending on its magnitude, lower body negative pressure (LBNP) has been shown to induce a progressive activation of neurohormonal, renal tubular, and renal hemodynamic responses, thereby mimicking the renal responses observed in clinical conditions characterized by a low effective arterial volume such as congestive heart failure. Our objective was to evaluate the impact of angiotensin II receptor blockade with candesartan on the renal hemodynamic and urinary excretory responses to a progressive orthostatic stress in normal subjects. METHODS: Twenty healthy men were submitted to three levels of LBNP (0, -10, and -20 mbar or 0, -7.5, and -15 mm Hg) for 1 hour according to a crossover design with a minimum of 2 days between each level of LBNP. Ten subjects were randomly allocated to receive a placebo and ten others were treated with candesartan 16 mg orally for 10 days before and during the three levels of LBNP. Systemic and renal hemodynamics, renal sodium excretions, and the hormonal response were measured hourly before, during, and for 2 hours after LBNP. RESULTS: During placebo, LBNP induced no change in systemic and renal hemodynamics, but sodium excretion decreased dose dependently with higher levels of LBNP. At -20 mbar, cumulative 3-hour sodium balance was negative at -2.3 +/- 2.3 mmol (mean +/- SEM). With candesartan, mean blood pressure decreased (76 +/- 1 mm Hg vs. 83 +/- 3 mm Hg, candesartan vs. placebo, P < 0.05) and renal plasma flow increased (858 +/- 52 mL/min vs. 639 +/- 36 mL/min, candesartan vs. placebo, P < 0.05). Glomerular filtration rate (GFR) was not significantly higher with candesartan (127 +/- 7 mL/min in placebo vs. 144 +/- 12 mL/min in candesartan). No significant decrease in sodium and water excretion was found during LBNP in candesartan-treated subjects. At -20 mbar, the 3-hour cumulative sodium excretion was + 4.6 +/- 1.4 mmol in the candesartan group (P= 0.02 vs. placebo). CONCLUSION: Selective blockade of angiotensin II type 1 (AT1) receptors with candesartan increases renal blood flow and prevents the antinatriuresis during sustained lower body negative pressure despite a modest decrease in blood pressure. These results thus provide interesting insights into potential benefits of AT1 receptor blockade in sodium-retaining states such as congestive heart failure.

Comparative angiotensin II receptor blockade in healthy volunteers: the importance of dosing.

OBJECTIVES: We have reported previously that 80 mg valsartan and 50 mg losartan provide less receptor blockade than 150 mg irbesartan in normotensive subjects. In this study we investigated the importance of drug dosing in mediating these differences by comparing the AT(1)-receptor blockade induced by 3 doses of valsartan with that obtained with 3 other antagonists at given doses. METHODS: Valsartan (80, 160, and 320 mg), 50 mg losartan, 150 mg irbesartan, and 8 mg candesartan were administered to 24 healthy subjects in a randomized, open-label, 3-period crossover study. All doses were given once daily for 8 days. The angiotensin II receptor blockade was assessed with two techniques, the reactive rise in plasma renin activity and an in vitro radioreceptor binding assay that quantified the displacement of angiotensin II by the blocking agents. Measurements were obtained before and 4 and 24 hours after drug intake on days 1 and 8. RESULTS: At 4 and 24 hours, valsartan induced a dose-dependent "blockade" of AT(1) receptors. Compared with other antagonists, 80 mg valsartan and 50 mg losartan had a comparable profile. The 160-mg and 320-mg doses of valsartan blocked AT(1) receptors at 4 hours by 80%, which was similar to the effect of 150 mg irbesartan. At trough, however, the valsartan-induced blockade was slightly less than that obtained with irbesartan. With use of plasma renin activity as a marker of receptor blockade, on day 8, 160 mg valsartan was equivalent to 150 mg irbesartan and 8 mg candesartan. CONCLUSIONS: These results show that the differences in angiotensin II receptor blockade observed with the various AT(1) antagonists are explained mainly by differences in dosing. When 160-mg or 320-mg doses were investigated, the effects of valsartan hardly differed from those obtained with recommended doses of irbesartan and candesartan.

Comparative vascular and renal tubular effects of angiotensin II receptor blockers combined with a thiazide diuretic in humans.

OBJECTIVE: The goal of this study was to investigate whether angiotensin II receptor blockers (ARBs) induce a comparable blockade of AT1 receptors in the vasculature and in the kidney when the renin-angiotensin system is activated by a thiazide diuretic. METHOD: Thirty individuals participated in this randomized, controlled, single-blind study. The blood pressure and renal hemodynamic and tubular responses to a 1-h infusion of exogenous angiotensin II (Ang II 3 ng/kg per min) were investigated before and 24 h after a 7-day administration of either irbesartan 300 mg alone or in association with 12.5 or 25 mg hydrochlorothiazide (HCTZ). Irbesartan 300/25 mg was also compared with losartan 100 mg, valsartan 160 mg, and olmesartan 20 mg all in association with 25 mg HCTZ. Each participant received two treatments with a 1-week washout period between treatments. RESULTS: The blood pressure response to Ang II was blocked by more than 90% with irbesartan alone or in association with HCTZ and with olmesartan/HCTZ and by nearly 60% with valsartan/HCTZ and losartan/HCTZ (P < 0.05). In the kidney, Ang II reduced renal plasma flow by 36% at baseline (P < 0.001). Irbesartan +/- HCTZ and olmesartan/HCTZ blocked the renal hemodynamic response to Ang II nearly completely, whereas valsartan/HCTZ and losartan/HCTZ only blunted this effect by 34 and 45%, respectively. At the tubular level, Ang II significantly reduced urinary volume (-84%) and urinary sodium excretion (-65%) (P < 0.01). These tubular effects of Ang II were only partially blunted by the administration of ARBs. CONCLUSION: These data demonstrate that ARBs prescribed at their recommended doses do not block renal tubular AT1 receptors as effectively as vascular receptors do. This observation may account for the need of higher doses of ARB for renal protection. Moreover, our results confirm that there are significant differences between ARBs in their capacity to induce a sustained vascular and tubular blockade of Ang II receptors.

Connexin40 regulates renin production and blood pressure.

Renin secretion is regulated by coordinated signaling between the various cells of the juxtaglomerular apparatus. The renin-secreting cells (RSC), which play a major role in the control of blood pressure, are coupled to each other and to endothelial cells by Connexin40 (Cx40)-containing channels. In this study, we show that Cx40 knockout (Cx40-/-) mice, but not their heterozygous littermates, are hypertensive due to the increase in the number of RSC, renin biosynthesis, and plasma renin. Treatment with the angiotensin II receptor AT1 antagonist candesartan or the angiotensin II-converting enzyme inhibitor ramipril reduced the blood pressure of the Cx40-/- mice to the same levels seen in wild-type (WT) mice. The elevated blood pressure of the knockout mice was not affected by clipping one renal artery (2K1C, renin-dependent model of hypertension) or after a high salt diet. Under these conditions, however, Cx40-/- mice showed an altered production and release of renin. The renin mRNA ratio between the clipped and the non-clipped kidney was lower in the knockout than in the WT 2K1C mice. This indicates that the response to a change in blood pressure was altered. The RSC of the Cx40-/- mice did not have a compensatory increase in the levels of either Cx43 or Cx37. Our data show that renin secretion is dependent on Cx40 and suggest the Cx40-/- mice may be a genetic model of renin-dependent hypertension.

Increased Expression of Renal Cyclooxygenase-2 and Neuronal Nitric Oxide Synthase in Hypertensive Cx40-Deficient Mice.

Cx40-deficient mice (Cx40-/-) are hypertensive due to increased renin secretion. We evaluated the renal expression of neuronal nitric oxide synthase (nNOS) and cyclooxygenases COX-1 and COX-2, three macula densa enzymes. The levels of nNOS were increased in kidneys of Cx40-/- mice, as well as in those of wild-type (WT) mice subjected to the two-kidney one-clip model of hypertension. In contrast, the levels of COX-2 expression were only increased in the hypoperfused kidney of Cx40-/- mice. Treatment with indomethacin lowered blood pressure and renin mRNA in Cx40-/- mice without affecting renin levels, indicating that changes in COX-2 do not cause the altered secretion of renin. Suppression of NOS activity by N(G)-nitro-L-arginine methyl ester (L-NAME) decreased renin levels in Cx40-/- animals, indicating that NO regulates renin expression in the absence of Cx40. Treatment with candesartan normalized blood pressure in Cx40-/- mice, and decreased the levels of both COX-2 and nNOS. After a treatment combining candesartan and L-NAME, the blood pressure of Cx40-/- mice was higher than that of WT mice, showing that NO may counterbalance the vasoconstrictor effects of angiotensin II in Cx40-/- mice. These data document that renal COX-2 and nNOS are differentially regulated due to the elevation of renin-dependent blood pressure in mice lacking Cx40.