Hypertension
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Comparative Study
Ambrisentan and tadalafil synergistically relax endothelin-induced contraction of rat pulmonary arteries.
Endothelin receptor antagonists and phosphodiesterase type 5 inhibitors are used to treat pulmonary arterial hypertension. We tested the hypothesis that a selective endothelin type A receptor antagonist (ambrisentan) and a phosphodiesterase type 5 inhibitor (tadalafil) may act synergistically to relax endothelin-constricted pulmonary arteries. Rat isolated intrapulmonary arterial rings contracted with 8 nmol/L endothelin-1 were relaxed by 10 nmol/L ambrisentan and 30 nmol/L tadalafil alone by 26±3% and 21±1%, respectively, whereas both drugs in combination acted synergistically to relax arterial rings by 83±6%. ⋯ Denudation of endothelium from pulmonary arterial rings abolished the vasodilator response to 30 nmol/L tadalafil and the synergistic vasorelaxant effect of tadalafil with ambrisentan. In the presence of 1 μmol/L BQ-788, a selective endothelin type B receptor antagonist, the vasorelaxant effects of 10 nmol/L ambrisentan and 30 nmol/L tadalafil were additive but not synergistic. These data can be interpreted to suggest that ambrisentan and tadalafil synergistically inhibit endothelin-1-induced constriction of rat intrapulmonary arteries and that endothelin type B receptors in endothelium are necessary to enable a synergistic vasorelaxant effect of the drug combination.
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Resistant hypertension is defined as uncontrolled office blood pressure, despite the use of ≥3 antihypertensive drugs. Ambulatory blood pressure monitoring (ABPM) is mandatory to diagnose 2 different groups, those with true and white-coat resistant hypertension. Patients are found to change categories between controlled/uncontrolled ambulatory pressures without changing their office blood pressures. ⋯ In the third and fourth ABPMs, 74% and 79% of patients sustained the diagnosis. In multivariate regression, a daytime systolic blood pressure ≤115 mm Hg in the confirmatory ABPM triplicated the chance of white-coat resistant hypertension status persistence after 1 year. In conclusion, a confirmatory ABPM is necessary after 3 months of the first white-coat-resistant hypertension diagnosis, and the procedure should be repeated at 6-month intervals, except in patients with daytime systolic blood pressure ≤115 mm Hg, in whom it may be repeated annually.
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Comparative Study
Glycogen phosphorylase isoenzyme BB plasma concentration is elevated in pregnancy and preterm preeclampsia.
Glycogen phosphorylase is a key enzyme in glycogenolysis. Released with myocardial ischemia, blood concentration of glycogen phosphorylase isoenzyme BB (GPBB) is a marker of acute coronary syndromes. Pregnancy imposes metabolic stress, and preeclampsia is associated with cardiac complications. ⋯ GPBB was detected in the placenta and was less abundant in preterm preeclampsia than in preterm delivery cases (P<0.01). There is physiological elevation of plasma GPBB concentration during pregnancy; an increase in maternal plasma GPBB is a novel phenotype of preterm preeclampsia. It is strongly suggested that these changes are attributed to GPBB of placental origin.
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Right ventricular (RV) failure (RVF) is the main cause of death in patients with pulmonary artery hypertension (PAH). Sildenafil, a phosphodiesterase type 5 inhibitor, was approved recently for treatment of PAH patients. However, the mechanisms underlying RV contractile malfunction and the benefits of sildenafil on RV function are not well understood. ⋯ In conclusion, PAH-induced increase in RV afterload causes severe T-tubule remodeling and Ca(2+) handling dysfunction in RV myocytes, leading to RV contractile failure. Sildenafil prevents and partially reverses ultrastructural, molecular, and functional remodeling of failing RV myocytes. Reversal of pathological T-tubule remodeling, although incomplete, is achievable without the regression of RV hypertrophy.
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Microsomal prostaglandin E synthase 1 (mPGES-1) is a cytokine-inducible enzyme responsible for generation of prostaglandin E(2) (PGE(2)) during the inflammatory response. In the present study, we investigated the role of mPGES-1 in the development of chronic renal failure in mice with 5/6 nephrectomy (Nx). After 4 weeks of Nx, wild-type mice with renal mass reduction exhibited increased blood urea nitrogen, plasma creatinine and phosphorus concentrations, and defective urine concentrating capability, all of which were significantly attenuated by mPGES-1 deletion. ⋯ Paradoxically, the Nx knockout mice developed worsened anemia, accompanied by impaired erythropoietin synthesis. The coinduction of mPGES-1 and cyclooxygenase 2 but not cyclooxygenase 1 mRNA expressions, along with increased PGE(2) synthesis, was demonstrated in the remnant kidney of wild-type mice. mPGES-1 deletion remarkably reduced renal PGE(2) content and urinary PGE(2) excretion after renal ablation but had a limited effect on the baseline PGE(2) production. We conclude that mPGES-1 deletion ameliorates chronic renal failure in the mouse model of renal mass reduction, and mPGES-1 deletion paradoxically exacerbates anemia in this model likely via suppression of erythropoietin synthesis.