ATP-binding cassette (ABC)-transporters, such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs) and breast cancer resistance protein (BCRP/ABCG2) transport numerous drugs thus regulating their absorption, distribution and excretion. Angiotensin receptor type 1 blockers (ARBs), used to treat hypertension and heart failure, are commonly administered in combination therapy. However, their interaction potential is not well studied and their effect on ABC-transporters remains elusive. The study therefore aimed to elucidate the effect of various ARBs (telmisartan, candesartan, candesartan-cilexetil, irbesartan, losartan, olmesartan, olmesartan-medoxomil, eprosartan) on ABC-transporter activity in vitro. P-gp inhibition was assessed by calcein assay, BCRP inhibition by pheophorbide A efflux assay, and MRP2 inhibition by a MRP2 PREDIVEZ Kit. Induction of P-gp, BCRP and MRP2 was assessed by real time reverse transcriptase polymerase chain reaction and for P-gp also in a functional assay. Telmisartan was identified as one of the most potent inhibitors of P-gp currently known (IC(50)=0.38+/-0.2 microM for murine P-gp) and it also inhibited human BCRP (IC(50)=16.9+/-8.1 microM) and human MRP2 (IC(50)=25.4+/-0.6 microM). Moreover, the prodrug candesartan-cilexetil, but not candesartan itself, significantly inhibited P-gp and BCRP activity. None of the compounds tested induced mRNA transcription of P-gp or BCRP but eprosartan and olmesartan induced MRP2 mRNA expression. In conclusion, telmisartan substantially differed from other ARBs with respect to its potential to inhibit ABC-transporters relevant for drug pharmacokinetics and tissue defense. These findings may explain the known interaction of telmisartan with digoxin and suggest that it may modulate the bioavailability of drugs whose absorption is restricted by P-gp and possibly also by BCRP or MRP2. Copyright (c) 2010 John Wiley & Sons, Ltd.

News stories: Adequate opioid-based pain relief is a human right Advancing treatment for chronic stable angina Tackling gastric cancer VTE prevention and treatment study launches in Europe Over 3000 emergency hospital admissions a year for children with diabetes Candesartan more effective in reducing blood pressure.

BACKGROUND: Although renin-angiotensin system (RAS) inhibitors have little demonstrable effect on mortality in patients with heart failure and preserved ejection fraction (HF-PEF), some trials have suggested a benefit with regard to reduction in HF hospitalization. METHODS AND RESULTS: Here, we systematically review and evaluate prospective clinical studies of RAS inhibitors enrolling patients with HF-PEF, including the 3 major trials of RAS inhibition (Candesartan in Patients with Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction [CHARM-Preserved], Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction [I-PRESERVE], and Perindopril in Elderly People with Chronic Heart Failure [PEP-CHF]). We also conducted a pooled analysis of 8021 patients in the 3 major randomized trials of RAS inhibition in HF-PEF (CHARM-Preserved, I-PRESERVE, and PEP-CHF) in fixed-effect models, finding no clear benefit with regard to all-cause mortality (odds ratio [OR] 1.03, 95% confidence interval [CI], 0.92-1.15; P=.62), or HF hospitalization (OR 0.90, 95% CI 0.80-1.02; P=.09). CONCLUSIONS: Although RAS inhibition may be valuable in the management of comorbidities related to HF-PEF, RAS inhibition in HF-PEF is not associated with consistent reduction in HF hospitalization or mortality in this emerging cohort.

Inflammation plays a major role in pathological conditions leading to cardiovascular events. Administration of lipopolysaccharide to animals decreases arterial blood flow, in contrast to the dilatations that occur in microvessels. The purpose of the present study was to determine whether or not lipopolysaccharide, in vivo, evokes arterial constriction and if so the underlying mechanisms. Rabbits were anaesthetized, blood pressure monitored and femoral artery diameter continuously recorded with an echotracking device. Lipopolysaccharide induced leucopenia, thrombocytopenia, acidosis and a progressive hypotension with a decrease in femoral artery diameter (-30.7+/-2.4 % after 3h) and an increase in arterial rigidity. Three hours after lipopolysaccharide administration, the arterial dilatations to acetylcholine, arachidonic acid and iloprost were inhibited while that to sodium nitroprusside was not altered; the constrictions to norepinephrine, angiotensin II, U46619 (thromboxane analogue) and serotonin were not modified. Under control conditions endothelin-1 produced an endothelin ETB dependent dilatation, reversed after lipopolysaccharide to an endothelin ETA dependent constriction. The thromboxane TP receptor antagonist S 18886 partially blocked the constriction; the angiotensin AT1 receptor antagonist candesartan prevented it. S 18886 normalized the impaired dilatations to acetylcholine, antagonists of 5-HT-receptors partially restored them while candesartan was ineffective. Antagonists of the endothelin or the histamine receptors had no effect. The present data show that lipopolysaccharide- induced inflammation causes 1) a strong constriction of the femoral artery in which activation of both thromboxane and angiotensin AT1 receptors are involved 2) a reduction of the endothelium- dependent dilatation to acetylcholine attributed to the activation of thromboxane TP receptors.

ABSTRACT: BACKGROUND: Cerebral ischemia results in the middle cerebral artery wall (MCA), in increased expression of cerebrovascular endothelin and angiotensin receptors and activation of the mitogen-activated protein kinase (MAPK) pathway, reduced local cerebral blood flow and increased levels of pro-inflammatory mediators in the infarct region. In this study, we hypothesise that inhibition of the cerebrovascular inflammatory reaction with a specific MEK1/2 inhibitor (U0126) to block transcription or a combined receptor blockade will reduce infarct size and improve neurological score. METHODS: Rats were subjected to a 2 hours middle cerebral artery occlusion (MCAO) followed by reperfusion for 48 hours. Two groups of treated animals were studied; (i) intraperitoneal administration of a specific MEK1/2 inhibitor (U0126) starting at 0, 6, or 12 hours after the occlusion, and (ii) specific double receptor antagonism (combination of the angiotensin AT1 receptor inhibitor Candesartan and the endothelin ETA receptor antagonist ZD1611), given immediately after occlusion. The middle cerebral arteries, microvessels and brain tissue were harvested; the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and phosphorylated ERK1/2, p38 and JNK were analysed with immunohistochemistry. RESULTS: We observed an infarct volume of 25 +/- 2% and reduced neurological function at 2 days after MCAO followed by 48 hours of recirculation. Immunohistochemistry revealed enhanced expression of TNF-alpha, IL-1beta, IL-6 and iNOS, as well as elevated levels of phosphorylated ERK1/2 in the smooth muscle cells of the ischemic MCA and in the associated intracerebral microvessels. U0126 given intraperitoneal at zero or 6 hours after the ischemic event, but not at 12 hours, reduced the infarct volume (11.7 +/- 2.% and 15 +/- 3%, respectively), normalized pERK1/2 and prevented elevation of expression of TNF-alpha, IL-1beta , IL-6 and iNOS. The combined inhibition of angiotensin AT1 and endothelin ETA receptors decreased the brain damaged (12.3 +/- 3; P<0.05) but only slightly reduced the MCAO induced enhanced expression of iNOS and cytokines CONCLUSION: The present study shows that the elevated vascular expression of TNF-alpha, IL-1beta, IL-6 and iNOS is associated with the microvasculature following focal ischemia is transcriptionally regulated via the MEK/ERK pathway.

AbstractObjective Hypertensive patients are at increased risk of developing diabetes. Accumulating evidence suggests a close relation between metabolic disturbance and increased arterial stiffness. Here, we examined the association between pulse pressure (PP) and the risk of new-onset diabetes in high-risk Japanese hypertensive patients. Research Design and Methods The CASE-J trial examined the effects of candesartan and amlodipine on the incidence of cardiovascular events in 4,728 high-risk Japanese hypertensive patients. In the present study, we analyzed the relationship between PP at baseline and new-onset diabetes in 2,685 patients without diabetes at baseline (male, 1,471; mean age, 63.7 years; mean BMI, 24.8 kg/m(2)) as a subanalysis of the CASE-J trial. Results During 3.3 +/- 0.8 years of follow-up, 97 patients (3.6%) developed diabetes. In multiple Cox regression analysis, PP was an independent predictor for new-onset diabetes (hazard ratio per 1 SD increase 1.44, 95% CI 1.15-1.79), as were male sex, body mass index and additional use of diuretics, whereas age and heart rate were not. Plots of hazard ratios for new-onset diabetes considering both systolic and diastolic blood pressure (DBP) revealed that a higher PP with a lower DBP, indicating that the increased PP was largely due to increased arterial stiffness, was strongly associated with the risk of new-onset diabetes. Conclusion PP is an independent predictor of new-onset diabetes in high-risk Japanese hypertensive patients. Increased arterial stiffness may be involved in the development of diabetes.

An 82-year-old woman was admitted to the hospital with dyspnea and fatigue. She had been given amlodipine, furosemide, candesartan, pravastatin and roxatidine acetate for two months in an other hospital. Chest CT showed patchy consolidations throughout the entire lungs. We suspected drug-induced pneumonia, and treated her with prednisolone under mechanical ventilation. The pulmonary consolidations eventually improved, but on the 15th hospital day the patient developed thrombocytopenia and disseminated intravascular coagulation (DIC). Heparin flushes had been performed since the first hospital day. After these were stopped, her platelet count became normal and the patient recovered from DIC. The clinical course, and the fact that testing for heparin-induced thrombocytopenia (HIT) antibodies was positive, supported the diagnosis of HIT and DIC. We report a rare case of HIT and DIC during treatment for drug-induced pneumonia.

Angiotensin II (Ang II) is a major regulator of steroidogenesis in adrenocortical cells, and is also an effective inducer of cytokine and growth factor synthesis in several cell types. In microarray analysis of H295R human adrenocortical cells, the mRNA of brain-derived neurotrophic factor (BDNF), a neurotrophin widely expressed in the nervous system, was one of the most up-regulated genes by Ang II. The aim of the present study was the analysis of the Ang II-induced BDNF expression and BDNF-induced effects in adrenocortical cells. Real-time PCR studies have shown that BDNF is expressed in H295R and rat adrenal glomerulosa cells. In H295R cells, the kinetics of Ang II-induced BDNF expression was faster than that of aldosterone synthase (CYP11B2). Inhibition of calmodulin kinase by KN93 did not significantly affect the Ang II-induced stimulation of BDNF expression, suggesting that it occurs by a different mechanism from the CYP11B2-response. Ang II also caused candesartan-sensitive, type-1 Ang II receptor-mediated stimulation of BDNF gene expression in primary rat glomerulosa cells. In rat adrenal cortex, BDNF protein was localized to the subcapsular region. Ang II increased BDNF protein levels both in human and rat cells, and BDNF secretion of H295R cells. Ang II also increased type-1 Ang II receptor-mediated BDNF expression in vivo in furosemide-treated rats. In rat glomerulosa cells, BDNF induced tropomyosin-related kinase B receptor-mediated stimulation of EGR1 and TrkB expression. These data demonstrate that Ang II stimulates BDNF expression in human and rat adrenocortical cells, and BDNF may have a local regulatory function in adrenal glomerulosa cells.

Abstract Tonin is a serine proteinase of the kallikrein family able to produce angiotensin II directly from angiotensinogen. In order to clarify the importance of this enzyme for the central nervous control of the cardiovascular system, we have generated transgenic mice, TGM(rTon), which express rat tonin in astrocytes. These mice present high levels of tonin mRNA and activity specifically in the brain. As a consequence, TGM(rTon) develop increased blood pressure and water intake. Lisinopril, an ACE inhibitor, is less hypotensive for transgenic mice than for control animals. The AT(1) receptor antagonist candesartan equally lowers blood pressure in transgenic and in control mice. Plasma angiotensin II, but not angiotensin I, is increased in TGM(rTon) as compared to the wild type suggesting a release of the peptide from the brain into the circulation. However, AT(1) receptors are desensitized in this transgenic model as shown by a blunted pressor response to intravenous application of angiotensin II. In conclusion, tonin in the brain may represent an alternative pathway to generate angiotensin II with effects on the cardiovascular system.

Telmisartan shows antihypertensive and several pleiotropic effects that interact with metabolic pathways. In the present study we tested the hypothesis that telmisartan prevents adipogenesis in vitro and weight gain in vivo through activation of peroxisome proliferator-activated receptor (PPAR)-delta-dependent pathways in several tissues. In vitro, telmisartan significantly upregulated PPAR-delta expression in 3T3-L1 preadipocytes in a time- and dose-dependent manner. Other than enhancing PPAR-delta expression by 68.2+/-17.3% and PPAR-delta activity by 102.0+/-9.0%, telmisartan also upregulated PPAR-gamma expression, whereas neither candesartan nor losartan affected PPAR-delta expression. In vivo, long-term administration of telmisartan significantly reduced visceral fat and prevented high-fat diet-induced obesity in wild-type mice and hypertensive rats but not in PPAR-delta knockout mice. Administration of telmisartan did not influence food intake in mice. Telmisartan influenced several lipolytic and energy uncoupling related proteins (UCPs) and enhanced phosphorylated protein kinase A and hormone sensitive lipase but reduced perilipin expression and finally inhibited adipogenesis in 3T3-L1 preadipocytes. Telmisartan-associated reduction of adipogenesis in preadipocytes was significantly blocked after PPAR-delta gene knockout. Chronic telmisartan treatment upregulated the expressions of protein kinase A, hormone-sensitive lipase, and uncoupling protein 1 but reduced perilipin expression in adipose tissue and increased uncoupling protein 2 and 3 expression in skeletal muscle in wild-type mice but not in PPAR-delta knockout mice. We conclude that telmisartan prevents adipogenesis and weight gain through activation of PPAR-delta-dependent lipolytic pathways and energy uncoupling in several tissues.

Objective: The aim of this study was to elucidate the effect of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activating angiotensin receptor blocker (ARB) telmisartan and the non-PPAR-gamma activating ARB valsartan and candesartan on mycophenolic acid (MPA) pharmacokinetics in renal transplant recipients. Methods: Recipients (n = 10 each group) were randomly given either 40 mg of telmisartan, 80 mg of valsartan or 8 mg of candesartan cilexetil for at least 6 months, and no ARB. Blood was sampled a year after transplantation. Results: Dose-adjusted maximum and trough plasma concentration of MPA co-administered with telmisartan were the lowest in all groups. The mean dose-adjusted area under the concentration curve from 0 to 12 h (AUC(0-12)) and AUC(0-6) of MPA co-administered with telmisartan were significantly lower than that without ARB (98 vs. 138 ng.h/mL/mg, P = 0.0353 and 63 vs. 96 ng.h/mL/mg, P = 0.0305). Coadministration of valsartan and candesartan did not alter MPA pharmacokinetics. The AUC ratio of MPA glucuronide (MPAG)/MPA co-administered with telmisartan was higher than that without ARBs, but not significantly (14.2 vs. 9.1). The mean maximum and minimum plasma concentrations of telmisartan (40 mg) after oral administration were 84 and 15 ng/mL, respectively, and that of valsartan (80 mg) 2220 and 441 ng/mL, respectively. Plasma concentrations of candesartan in most transplant patients were not observed 19 h after oral administration of candesartan cilexeil (8 mg). Conclusions: The degree of drug interaction between MPA and telmisartan was significantly greater than that between MPA and valsartan or candesartan. Uridine diphosphate-glucuronosyltransferase (UGT) 1A9 has been identified as a PPAR-gamma target gene. UGT induction by telmisartan might stimulate MPA glucuronidation. A combination of telmisartan and mycophenolate mofetil might require periodic monitoring of MPA.

This study has evaluated whether candesartan prevent the recurrence of atrial fibrillation (AF) and decrease type III procollagen-N-peptide (PIIINP) levels. A total of 153 patients with AF were enrolled in this study. Three groups of patients were compared; candesartan group was treated with candesartan plus bepridil (n=52); and carvedilol group with carvedilol plus bepridil (n=51); and bepridil group with bepridil alone (n=50). The primary end point was length of time to the recurrence of AF and all patients were ultimately followed-up for 730 days. Serum levels of the biomarkers were measured at baseline and after 24 months. Maintenance of sinus rhythm was achieved in 25 (50%) patients in bepridil group, 37 (73%) in candesartan group, and 34 (67%) in carvedilol group, giving a bepridil group / candesartan group hazard ratio of 0.36 (95% CI 0.21 to 0.63; P = 0.03). Candesartan significantly decreased PIIINP levels at 24 months than at baseline in sinus rhythm group (0.57+/-0.02 u/ml versus 0.64+/-0.05 u/ml, P=0.04) and did not decrease PIIINP levels in the recurrence group. In conclusions, PIIINP might be related to the possibility of the atrial fibrosis for AF. However, further studies are needed to clarify the relationship between PIIINP and AF.

PURPOSE: To investigate the effects of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II antagonist against retinal ischemia-reperfusion injury in the rat retina. METHODS: Retinal ischemia was induced by increasing intraocular pressure to 130 mmHg. Rats were treated with an ACE inhibitor (captopril), an angiotensin II type 1 receptor (AT1-R) antagonist (candesartan), an AT2-R antagonist (PD123319), bradykinin, or a bradykinin B2 receptor antagonist (icatibant). At 7 days after the ischemia, retinal damage was evaluated. Immunohistochemistry and image analysis were used to measure changes in the levels of reactive oxygen species (ROS) and the localization of AT1-R. Dark-adapted full-field electroretinography (ERG) was also performed. RESULTS: Pretreatment with captopril or candesartan significantly inhibited the ischemic injury of the inner retina. However, PD123319, bradykinin or icatibant did not reduce the ischemic damage. In control retinas, retinal vessels were positive for AT1-R. In contrast, 12 h after ischemia, immunohistochemical analysis detected numerous AT1-R positive cells in the inner retina in vehicle-treated rats. After the ischemia, production of ROS was detected in retinal cells. However, pretreatment with captopril or candesartan suppressed the production of ROS. On the seventh postoperative day, the amplitudes of the ERG b-waves were significantly lower in the vehicle group than in the groups pretreated with captopril or candesartan. Conclusions: The present findings demonstrate that ischemic damage promotes the expression of AT1-R in the inner retina. Both the ACE inhibitor and AT1-R antagonist examined block the stimulation of AT1-R and attenuate subsequent ischemic damage in the rat retina.

BACKGROUND: The goal of this study was to test the hypothesis that intrarenal Ang II has a proinflammatory effect leading to renal damage and dysfunction in Dahl S rats on high Na intake. METHODS: Forty-six 7-to 8-week old Dahl S or R/Rapp strain rats were maintained for 5 weeks on high sodium (8%) with or without candesartan cilexetil in daily doses of 10-15 mg/kg/day. Arterial catheters were implanted at day 28. RESULTS: By day 35 in the high Na S + candesartan rats, renal tissue Ang II concentration, renal monocytes/macrophages, TNFalpha, and MCP-1 significantly decreased. Plasma Ang II remained at very low levels in all groups. Reduced renal damage in candesartan-treated Dahl S rats was demonstrated by marked decreases in urinary protein excretion and renal glomerular and interstitial damage. After 5 weeks of high Na, compared to high Na Dahl S rats, arterial pressure was unchanged in candesartan S rats, but creatinine clearance was increased. CONCLUSIONS: Therefore, candesartan reduced renal tissue Ang II, renal damage, infiltration of immune cells, cytokines, chemokines, and improved renal hemodynamics. These data suggest that intrarenal Ang II plays an important role in causing renal inflammation which leads to renal cortical damage, proteinuria, and decreases in renal hemodynamics.

BACKGROUND: Few antihypertensive drugs are available in appropriate formulations for infants. METHOD: We investigated candesartan cilexetil liquid suspension in a 4-week, randomized double-blind dose-ranging study followed by a 1-year open-label treatment phase (NCT00244621). The drug was administered at 0.05, 0.2 or 0.4 mg/kg per day in 93 hypertensive children aged 1-5 years, of whom 74 had underlying renal disorders. RESULTS: A single-dose pharmacokinetic profile was obtained in 10 patients. At 4 weeks, SBP declined dose dependently by 6, 9 and 12 mmHg in the three dose groups (P = 0.01), and DBP by 5, 8 and 11 mmHg (P = 0.03). During the 1-year follow-up, responder rates (both SBP and DBP < 95th percentile) ranged from 48.2 to 54.1%. Candesartan lowered the blood pressure regardless of age, sex, BMI or cause of hypertension. The pharmacokinetic profile was independent of age, sex and weight, and was similar to that in older children and adults. In participants with proteinuric renal disease (urinary albumin/creatinine ratio >30 mg/g), a 57% median decline in albumin/creatinine ratio was observed at 4 weeks, which was dose related (P = 0.007) and persisted with long-term administration. There were no notable electrocardiographic or laboratory abnormalities. A mild decline in estimated glomerular filtration rate observed at 4 weeks was not progressive with long-term dosing. Candesartan was generally well tolerated; two patients withdrew for adverse events (fatigue and worsening glomerulopathy). One patient died, probably from acute-on-chronic renal failure. CONCLUSION: Candesartan cilexetil dose-dependently decreases blood pressure and albuminuria in hypertensive infants and is generally well tolerated.

In rat mesenteric arteries we have recently found that perivascular adipose tissue (PVAT) promoted vasoconstriction to perivascular neuronal activation (by electrical field stimulation, EFS) through generation of superoxide. In this study, we examined the role of adipocyte-generated angiotensin II in PVAT-mediated potentiation of contraction to nerve stimulation. In rat mesenteric PVAT, the presence of angiotesinogen and angiotensin I-converting enzyme (ACE) mRNA was confirmed by RT-PCR. Immunohistochemical staining showed the presence of angiotensin II in mesenteric PVAT. In rat mesenteric arteries, treatment of the vessels with an ACE inhibitor (enalaprilat) or angiotensin II type 1 receptor antagonist (candesartan) reduced PVAT-mediated potentiation of EFS-induced contraction. Exogenously applied angiotensin II enhanced EFS-induced contraction in arteries without PVAT, but not in the arteries with intact PVAT. Chronic treatment with an ACE inhibitor quinapril (14 days) lowered blood pressure and alleviated the potentiation effects of PVAT in EFS-induced contraction. Mesenteric arteries from quinapril-treated group now exhibited the potentiation response to exogenously applied angiotensin II in arteries with intact PVAT to a comparable level as in arteries with PVAT removed. Treatment with hydralazine reduced blood pressure to the same level as quinapril treatment, but did not affect PVAT-associated potentiation of vasoconstriction to EFS and the response to exogenously applied angiotensin II in PVAT-intact arteries. These results showed that adipocyte-derived angiotensin II is critically involved in PVAT-mediated potentiation of EFS-evoked contraction in rat mesenteric arteries.

Diabetes is associated with an activated renal renin-angiotensin-aldosterone system (RAAS) and it was shown that streptozotocin (STZ)-induced diabetic rats had increased whole kidney protein levels of the epithelial sodium channel subunits (alpha-, beta- and gamma-ENaC). However, the role of the RAAS on the regional, i.e., cortical versus medullary, regulation of ENaC is unclear. Male Sprague-Dawley rats were injected with STZ (intravenous, 65 mg/kg.bw, n=12/group). After 14 days, half of them received drinking water with candesartan (2 mg/kg.bw/day), an angiotensin-II type-1 receptor (AT1R) antagonist, for one week. In the medulla, i.e., inner stripe of the outer medulla (ISOM), base and/or tip of the inner medulla, immunoblotting revealed increased protein abundances of alpha1 Na-K-ATPase and ENaC subunits with diabetes (200-600% of controls), which were not reversed by candesartan. In fact, candesartan increased all ENaC subunits and alpha1 Na-K-ATPase in the ISOM and/or base in control rats. In contrast, in the cortex, diabetes did not increase these proteins. However, candesartan reduced cortical beta- and gamma-ENaC regardless of diabetic state. In summary, diabetes-induced increases in ENaC were seen preferentially in the medulla. These changes appeared to be due to a mechanism clearly distinct from AT1R activation, because they were not abolished by candesartan. In fact, candesartan treatment tended to increase some of these medullary proteins, perhaps in compensation for increased NaCl load. In contrast, cortical beta- and gamma-ENaC were reduced by candesartan regardless of diabetic state suggesting their regulation by AT1R at this site; however this did not appear to be a site of diabetes-induced ENaC up-regulation.

Despite data suggesting that angiotensin-receptor blockers (ARBs) are associated with increased risk to the fetus, there has been an increasing exposure of ARBs in pregnancy. We report a case report regarding a woman, who accidentally was treated with Candesartan during the first 22 weeks of pregnancy. At 22 weeks of gestation the fetal kidneys were oedematous with very little amniotic fluid. The prognosis for the fetus was considered poor. Five weeks after discontinuation of Candesartan normal quantities of amnionic fluid and a visible fetal bladder was registered. After delivery at week 31, creatinine clearance, diuresis and urine examination of the neonate were within normal limits. Ultrasound examinations of the kidneys showed bilaterally marked calices, small cysts and parenchymal increased echogenety at one week with complete sonographic normalization at 6 weeks. However, experimental studies raise the question of potential long-term adverse effects, including renal dysfunction and arterial hypertension in adulthood.

Background and purpose: Angiotensin type 2 receptor (AT(2) receptor) stimulation evokes vasodilator effects in vitro and in vivo that oppose the vasoconstrictor effects of angiotensin type 1 receptors (AT(1) receptors). Recently, a novel non-peptide AT(2) receptor agonist, Compound 21, was described, which exhibited high AT(2) receptor selectivity. Experimental approach: Functional cardiovascular effects of the drug candidate Compound 21 were assessed, using mouse isolated aorta and rat mesenteric arteries in vitro and in conscious spontaneously hypertensive rats (SHR). Key results: Compound 21 evoked dose-dependent vasorelaxations in aortic and mesenteric vessels, abolished by the AT(2) receptor antagonist, PD123319. In vivo, Compound 21 administered alone, at doses ranging from 50 to 1000 ng.kg(-1).min(-1) over 4 h did not decrease blood pressure in conscious normotensive Wistar-Kyoto rats or SHR. However, when given in combination with the AT(1) receptor antagonist, candesartan, Compound 21 (300 ng.kg(-1).min(-1)) lowered blood pressure in SHR only. Further analysis in separate groups of conscious SHR revealed that, at a sixfold lower dose, Compound 21 (50 ng.kg(-1).min(-1)) still evoked a significant depressor response in adult SHR ( approximately 30 mmHg) when combined with different doses of candesartan (0.01 or 0.1 mg.kg(-1)). Moreover, the Compound 21-evoked depressor effect was abolished when co-infused (50 microg.kg(-1).min(-1) for 2 h) with the AT(2) receptor antagonist PD123319. Conclusion and implications: Collectively, our results indicate that acute administration of Compound 21 evoked blood pressure reductions via AT(2) receptor stimulation. Thus Compound 21 can be considered an excellent drug candidate for further study of AT(2) receptor function in cardiovascular disease.

This study examined the role of the renin-angiotensin-aldosterone system (RAAS) in mediating cardiovascular and renal damage in SHR given salt-excess. Since the circulating RAAS is inhibited in this model, it permits examination of the role of local tissue RAASs in mediating this injury. To this end, male 8-week SHR rats were divided into 7 groups. The control group (C) received normal NaCl (0.6%) diet. All other groups were given 8% NaCl chow. In addition, Group 2 was given placebo, Group 3 the mineralocorticoid receptor blocker eplerenone (100/mg/day), Group 4 received the ACE-I, quinapril (3 mg/kg/day), Group 5 an ARB candesartan (10 mg/kg/day), and Groups 6 and 7 were given eplerenone and either quinapril or candesartan. The treatments lasted 8 weeks. Compared with controls, mean arterial pressure (MAP), renal blood flow (RBF), coronary flow reserve (CFR), minimal coronary vascular resistance (MCVR), diastolic time constant (tau), and maximal rate of ventricular pressure fall (-dP/dT) were all adversely affected by salt-loading. Left ventricular mass and fibrosis as well as proteinuria were also markedly increased by salt overload. Eplerenone induced only slight changes, whereas quinapril and candesartan normalized all indices except MAP. Combination therapy also normalized all indices, including MAP. These data suggest that: (1) cardiovascular and renal damage induced by salt-excess in the SHR were not pressure dependent; (2) mineralocorticoids were only marginally involved in this model; and (3) local tissue generation of AII may be, at least in part, responsible for the other adverse effects. Key words: ventricular function, salt excess, angiotensin convering enzyme inhibitor, angiotensin II receptor blockade.