Hypoxia-independent upregulation of placental hypoxia inducible factor-1α gene expression contributes to the pathogenesis of preeclampsia.

Accumulation of hypoxia inducible factor-1α (HIF-1α) is commonly an acute and beneficial response to hypoxia, whereas chronically elevated HIF-1α is associated with multiple disease conditions, including preeclampsia, a serious hypertensive disease of pregnancy. However, the molecular basis underlying the persistent elevation of placental HIF-1α in preeclampsia and its role in the pathogenesis of preeclampsia are poorly understood. Here we report that Hif-1α mRNA and HIF-1α protein were elevated in the placentas of pregnant mice infused with angiotensin II type I receptor agonistic autoantibody, a pathogenic factor in preeclampsia. Knockdown of placental Hif-1α mRNA by specific siRNA significantly attenuated hallmark features of preeclampsia induced by angiotensin II type I receptor agonistic autoantibody in pregnant mice, including hypertension, proteinuria, kidney damage, impaired placental vasculature, and elevated maternal circulating soluble fms-like tyrosine kinase-1 levels. Next, we discovered that Hif-1α mRNA levels and HIF-1α protein levels were induced in an independent preeclampsia model with infusion of the inflammatory cytokine tumor necrosis factor superfamily member 14 (LIGHT). SiRNA knockdown experiments also demonstrated that elevated HIF-1α contributed to LIGHT-induced preeclampsia features. Translational studies with human placentas showed that angiotensin II type I receptor agonistic autoantibody or LIGHT is capable of inducing HIF-1α in a hypoxia-independent manner. Moreover, increased HIF-1α was found to be responsible for angiotensin II type I receptor agonistic autoantibody or LIGHT-induced elevation of Flt-1 gene expression and production of soluble fms-like tyrosine kinase-1 in human villous explants. Overall, we demonstrated that hypoxia-independent stimulation of HIF-1α gene expression in the placenta is a common pathogenic mechanism promoting disease progression. Our findings reveal new insight to preeclampsia and highlight novel therapeutic possibilities for the disease.

Current status of dual Renin Angiotensin aldosterone system blockade for the treatment of cardiovascular diseases.

Clinical and experimental studies have shown that the initial suppression of angiotensin II after the administration of angiotensin-converting enzyme (ACE) inhibitors is later reversed and returns almost to pretreatment levels. This raised the hypothesis of the "escape phenomenon," which was strengthened by the discovery that angiotensin II can also be generated through non-ACEs. Therefore, the addition of angiotensin receptor blockers to ACE inhibitors would produce additional benefits by blocking all angiotensin II at the angiotensin II receptor type 1 level and in addition allowing angiotensin II to stimulate the unoccupied angiotensin II receptor type 2, causing additional vasodilation and antiremodeling effects. However, analysis of various studies including hypertension, heart failure, and renal disease has demonstrated that the gain is modest when combining ACE inhibitors, angiotensin receptor blockers, or the renin blocker aliskiren. In conclusion, on the basis of the results of this analysis, dual blockade of the renin-angiotensin-aldosterone system should not be used for the treatment of hypertension, heart failure, and renal disease, with perhaps the exception of diabetic nephropathy with albuminuria, until additional information is provided from ongoing studies.

Introducción: antagonistas de los receptores de la angiotensina II e insuficiencia cardíaca / No disponible

No disponible

Características farmacológicas de los ARA-II. ¿Son todos iguales? / Pharmacological properties of Angiotensin-II receptor antagonists. Do they all belong to the same class of drugs?

Los antagonistas de los receptores AT1 de la angiotensina II (ARA-II) son un grupo de fármacos que antagonizan las acciones que la angiotensina II (A-II) ejerce por mediación de éstos, independientemente de cuál sea su vía de síntesis. En presencia de un ARA-II, la A-II estimula los receptores AT2, produciendo diversas acciones que contrarrestan aquellas mediadas por los receptores AT1. Los ARA-II han demostrado ser fármacos antihipertensivos efectivos y seguros y, además, ejercen efectos beneficiosos independientes de su acción antihipertensiva en pacientes con insuficiencia cardiaca, diabetes mellitus tipo 2 y nefropatías. Sin embargo, existen diferencias en la estructura química, la afinidad receptiva y las propiedades farmacodinámicas y farmacocinéticas de estos fármacos. De hecho, recientemente se ha demostrado que los ARA-II ejercen acciones no relacionadas con el bloqueo de los receptores AT1 y que, por tanto, son características de cada uno de estos fármacos. En este artículo comparamos el mecanismo de acción, las acciones, las características farmacocinéticas y las reacciones adversas de los 7 ARA-II comercializados (candesartán, eprosartán, irbesartán, losartán, olmesartán, telmisartán y valsartán). Existen diferencias farmacológicas entre los ARA-II que sugieren que no podemos hablar de un efecto de clase. Sin embargo, aún no disponemos de ensayos clínicos adecuadamente diseñados que comparen sus efectos a largo plazo (AU)

Angiotensin-II receptor antagonists or blockers (ARBs) form a class of drugs that block angiotensin-II AT1 receptors and, thereby, any action of angiotensin II mediated by these receptors, irrespective of how the angiotensin II originates. In the presence of an ARB, angiotensin II can still activate AT2 receptors, thereby inducing actions that counteract some of the effects mediated by AT1 receptor stimulation. ARBs have been shown to be effective and safe antihypertensive drugs. However, their beneficial effects in patients with heart failure, type-2 diabetes and renal insufficiency extend beyond reducing blood pressure. There are differences between ARBs in chemical structure, receptor affinity, and pharmacodynamic and pharmacokinetic properties. Moreover, each ARB induces specific characteristic additional effects that are not associated with AT1-receptor blockade. This article provides a comparison of the mechanisms of action, the main pharmacodynamic and pharmacokinetic properties, the side effects, and the drug interactions of the seven currently available ARBs (i.e., candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan). Although no adequate clinical trials have been carried out to compare the long-term effects of the different ARBs, sufficient pharmacological differences are known to exist between the various drugs to suggest that they may not all belong to a single class (AU)

ARA-II en la insuficiencia cardiaca con función sistólica normal. ¿Dónde estamos y adónde vamos? / ARBs for heart failure with normal systolic function. Where are we and where are we going?

La insuficiencia cardiaca (IC) con función sistólica conservada se caracteriza por una alteración en el llenado ventricular que acontece durante la diástole debido a un defecto de elasticidad y/o distensibilidad. Más de una tercera parte de todas las IC lo son por disfunción diastólica, cuyo sustrato anatómico es, en una importante proporción de casos, la hipertrofia ventricular izquierda, estrechamente relacionada con la hipertensión arterial crónica. El tratamiento con fármacos que bloquean el sistema renina-angiotensina-aldosterona, además de controlar la presión arterial, ha demostrado mejorar la capacidad funcional de estos pacientes. Además, existen evidencias de que estos compuestos son eficaces para reducir tanto la masa ventricular como la fibrosis miocárdica. Los resultados del estudio CHARM Preservado indican que el tratamiento con candesartán es de utilidad clínica para el tratamiento de estos pacientes al limitar el riesgo de hospitalizaciones y debe tenerse en cuenta al plantear la estrategia terapéutica de este patrón fisiopatológico de la IC (AU)

Heart failure with normal systolic function is characterized by abnormal ventricular filling during diastole due to poor elasticity or distensibility. More than a third of all cases of heart failure result from diastolic dysfunction. In a significant number of cases, the underlying anatomical defect is left ventricular hypertrophy, which is closely related to chronic arterial hypertension. Drugs that block the renin-angiotensinaldosterone system not only control blood pressure, but have also been shown to improve functional capacity in these patients. Moreover, there is evidence that this group of compounds is effective in reducing both left ventricular mass and myocardial fibrosis. The results of the CHARMPreserved trial showed that treatment with candesartan can reduce the hospitalization rate in these patients. These findings should be taken into account in planning treatment for patients with this pathophysiological form of heart failure (AU)

Sistema renina angiotensina en la nefropatía diabética / Renin-angiotensin system in diabetic nephropathy

La importancia atribuida al SRA en el desarrollo y progresión de la nefropatíadiabética se confirma con las evidencias recientes que demuestran que se puedeprevenir el desarrollo de nefropatía en los pacientes diabéticos mediante la intervenciónterapéutica con bloqueantes del SRA. Por ello, es necesaria la promociónde programas preventivos para la detección de microalbuminuria, desde las fasestempranas de la diabetes, que deben de incluir un adecuado control tensional,glucémico y lipídico. Si se detecta microalbuminuria, la administración de un bloqueantedel SRA, aún en presencia de cifras tensionales clásicamente consideradascomo normales puede prevenir la progresión a nefropatía diabética

The importance of the renin angiotensin system (RAS) in the development andprogression of the diabetic nephropathy is confirmed with the recent demonstrationthat the development of nephropathy in the diabetic patients can be avoidedby blockers of the RAS. For that reason, the promotion of preventive programsfor the detection of microalbuminuria, from the early phases of thediabetes is needed. Control of blood pressure, of glucose and lipids are needed.If microalbuminuria is present, the administration of a blocker of RAS, even inthe presence of normal blood pressure can prevent the progression to diabeticnephropathy. The main objective to prevent the development and progressionof nephropathy in the diabetic patients, as well as the cardiovascular risk, is astrict control of the PA

[Long-term effects of TCV116 on cardiac function changes after myocardial infarction].

OBJECTIVE: To investigate the long-term effects of TCV116 (candesartan cilexetil) on cardiac function changes after myocardial infarction. METHODS: Myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in rats. One week after the surgical performance,the surviving rats were randomly assigned to the following treatment groups: (1) MI rats with no therapy; (2) MI rats treated with TCV116 2 mg/kg per day; (3) Sham-operated control and (4) Sham-operated rats treated with TCV116 2 mg/kg per day. At 22 weeks, left ventricular function and cardiac histomorphometric parameters were measured, mRNA expression of cardiac genes such as beta myosin heavy chain, B-type natriuretic peptide, transforming growth factor beta1, collagen I and III quantified, and survival rates calculated. RESULTS: Treatment with TCV116 significantly improved LV function, suppressed mRNA expression of cardiac genes,and extended the survival period compared with MI rats with no therapy (P<0.05). CONCLUSION: Treatment with long-term angiotensin II type 1 receptor blocker may improve LV function and prolong the survival of rats after MI.

Angiotensin II type 2 receptor gene transfer elicits cardioprotective effects in an angiotensin II infusion rat model of hypertension.

The role of the angiotensin II type 2 receptor (AT2R) in cardiovascular physiology remains elusive. We have developed an in vivo lentiviral vector-mediated gene transfer system to study the physiological functions of the AT2R. Our objectives in this study were to determine whether the AT2R influences cardiac hypertrophy and myocardial and perivascular fibrosis in a nongenetic rat model of hypertension. Lentiviral vector containing the AT2R or saline was injected intracardially in 5-day-old Sprague-Dawley rats. This resulted in a persistent overexpression of the AT2R in cardiac tissues. At 15 wk of age, animals were infused with either 200 ng x kg(-1) x min(-1) of angiotensin II or saline by implantation of a 4-wk osmotic minipump. This resulted in an increase in blood pressure (BP) that reached maximal by 2 wk of treatment and was associated with a 123% increase in left ventricular wall thickness (LVWT) and a 129% increase in heart weight to body weight ratios (HW/BW). In addition, the increase in cardiac hypertrophy was associated with a 300% and 158% increase in myocardial and perivascular fibrosis, respectively. Cardiac transduction of the AT2R resulted in an 85% attenuation of LVWT, 91% attenuation of HW/BW, and a 43% decrease in myocardial fibrosis induced by angiotensin infusion. These improvements in cardiac pathology were observed in the absence of attenuation of high BP. Thus our observations indicate that long-term expression of the AT2R in the heart attenuates cardiac hypertrophy and fibrosis in a nongenetic rat model of hypertension.

Involvement of the renin-angiotensin system in endogenous central histamine-induced reversal of critical haemorrhagic hypotension in rats.

The study was undertaken to examine the involvement of the renin-angiotensin system in the reversal by endogenous central histamine of critical haemorrhagic hypotension in anaesthetised Wistar rats. Histamine N-methyltransferase inhibitor metoprine (20 microg) administered intracerebroventricularly at 5 min of critical hypotension 20-25 mmHg produced increases in histamine concentrations as measured 20 min after treatment in the hypothalamus (581.33 +/- 63.23 vs. 488.26 +/- 56.34 ng/g of wet tissue; P < 0.01) and medulla oblongata (53.42 +/- 14.65 vs. 34.68 +/- 13.52 ng/g of wet tissue; P < 0.05). That was accompanied by 34.7% higher plasma angiotensin II concentration in comparison to the control group. Metoprine produced dose-dependent (5-20 microg) rises in mean arterial pressure (MAP) and heart rate, which were significantly higher than those in normotensive animals. The resuscitating action of metoprine (20 microg) was associated with rises in renal, mesenteric and hindquarters blood flows, and a 100% survival at 2 h after treatment, while in the saline-treated group, all the animals died within 30 min. Angiotensin type 1 (AT(1)) receptor antagonist ZD 7155 (0.5 mg/kg; iv) decreased regional vascular resistance and inhibited metoprine-induced increase in MAP, whereas AT(2) receptor blocker PD 123319 (10 mg/kg; i.v.) had no effect. Angiotensin-converting enzyme inhibitor captopril (30 mg/kg; i.v.) reduced the increase in plasma angiotensin II level and the haemodynamic effects of metoprine. Neither capropril, nor angiotensin receptor antagonists influence the survival at 2 h after treatment. In conclusion, the renin-angiotensin system is involved in central histamine-induced resuscitating action in rats.

Losartan and atenolol on hypertension induced by adenosine receptor blockade.

1. The prolonged infusion of 1,3-dipropyl-8-sulfophenylxanthine (DPSPX), a non-selective antagonist of adenosine receptors, induces hypertension, an increase in plasma renin activity and morphological cardiovascular changes. 2. The aim of this work was to evaluate the effects of losartan, a selective AT1 receptor antagonist, and atenolol, a beta-adrenoceptor antagonist, on DPSPX-induced hypertension. 3. Male Wistar rats (250-300 g, n = 4-6) were treated for 1 or 4 weeks with: saline i.p.; DPSPX (90 microg kg(-1) h(-1)) i.p.; losartan (15 mg kg(-1) day(-1)) p.o.; atenolol (25 mg kg(-1) day(-1)) p.o.; DPSPX (90 microg kg(-1) h(-1)) i.p. + losartan (15 mg kg(-1) day(-1)) p.o.; DPSPX (90 microg kg(-1) h(-1)) i.p. + atenolol (25 mg kg(-1) day(-1)) p.o. Blood pressure was measured by the 'tail-cuff' method in conscious animals. Fragments of the mesenteric and tail arteries were processed for morphological study and the mean diameter of the vascular smooth muscle cells was determined. 4. DPSPX increased blood pressure. Losartan and atenolol prevented this rise but had no effect on blood pressure of control rats. DPSPX-treated groups showed hypertrophy of the vascular smooth muscle cells and proliferation of subintimal cells. Losartan but not atenolol prevented these changes. Losartan had no effect on the vascular morphology of control rats, while treatment with atenolol for 4 weeks induced hypertrophy of the vascular smooth muscle cells. 5. Both losartan and atenolol counteract the development of DPSPX-induced hypertension but only losartan prevents the alterations in vascular morphology.