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Allahdadi KJ, Cherng TW, Pai H, Silva AQ, Walker BR, Nelin LD, Kanagy NL. Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia. Am J Physiol Heart Circ Physiol 295: H434-H440, 2008. First published May 30, 2008 doi:10.1152/ajpheart.91477.2007.-We have reported that eucapnic intermittent hypoxia (E-IH) causes systemic hypertension, elevates plasma endothelin 1 (ET-1) levels, and augments vascular reactivity to ET-1 and that a nonspecific ET-1 receptor antagonist acutely lowers blood pressure in E-IH-exposed rats. However, the effect of chronic ET-1 receptor inhibition has not been evaluated, and the ET receptor subtype mediating the vascular effects has not been established. We hypothesized that E-IH causes systemic hypertension through the increased ET-1 activation of vascular ET type A (ETA) receptors. We found that mean arterial pressure (MAP) increased after 14 days of 7 h/day E-IH exposure (109 Ϯ 2 to 137 Ϯ 4 mmHg; P Ͻ 0.005) but did not change in sham-exposed rats. The ETA receptor antagonist BQ-123 (10 to 1,000 nmol/kg iv) acutely decreased MAP dose dependently in conscious E-IH but not sham rats, and continuous infusion of BQ-123 (100 nmol ⅐ kg Ϫ1 ⅐ day Ϫ1 sc for 14 days) prevented E-IHinduced increases in MAP. ET-1-induced constriction was augmented in small mesenteric arteries from rats exposed 14 days to E-IH compared with those from sham rats. Constriction was blocked by the ETA receptor antagonist BQ-123 (10 M) but not by the ET type B (ET B) receptor antagonist BQ-788 (100 M). ETA receptor mRNA content was greater in renal medulla and coronary arteries from E-IH rats. ETB receptor mRNA was not different in any tissues examined, whereas ET-1 mRNA was increased in the heart and in the renal medulla. Thus augmented ET-1-dependent vasoconstriction via vascular ETA receptors appears to elevate blood pressure in E-IHexposed rats. sleep apnea; BQ-123; BQ-788; mitochondrial ribonucleic acid OBSTRUCTIVE SLEEP APNEA is characterized by repeated upper airway obstruction during sleep and affects between 5% and 20% of the population (32). This syndrome of sleep-disordered breathing leads to episodic hypoxia and sleep deprivation. Recent epidemiological studies reveal that sleep apnea and other forms of sleep-disordered breathing increase the risk for hypertension and associated metabolic disorders (24). However, the mechanisms whereby sleep apnea and the associated eucapnic intermittent hypoxia (E-IH) cause systemic hypertension remain incompletely understood. Recent studies show that patients with sleep apnea have increased circulating levels of endothelin (ET)-1 (29, 42), a potent vasoconstrictor and mitogenic peptide implicated in the development of many forms of arterial hypertension (1). Furthermore, the synthesis of ET-1 is increased by hypoxia, shear stress, oxidative stress, and catecholamines, which are elevated in E-IH-exposed rats and sleep apnea (42, 47). We have previously described that both blood pressure and plasma ET-1 levels are incre...

Obesity, the metabolic syndrome, diabetes and cardiometabolic risk are increasing at epidemic rates worldwide. Without interventions, the healthcare ramifications and costs of this epidemic will be astronomical. Current available treatment modalities have demonstrated limited effectiveness to deal with this metabolic epidemic. A novel metabolic pathway, the endocannabinoid system, plays a significant and direct role in appetite regulation, glucose homeostasis and lipid metabolism. Activation of the endocannabinoid system increases hunger and decreases satiety, and promotes insulin resistance and lipogenesis. Studies indicate that the endocannabinoid system is chronically activated in abdominal obesity and Type 2 diabetes. Additionally, blockade of the endocannabiniod receptor type-1 improves multiple cardiometabolic parameters and may represent a potential mechanism to combat obesity, metabolic syndrome, diabetes and other cardiometabolic risks. Rimonabant, a novel agent, blocks the endocannabinoid-receptor type 1, and results in weight loss, decreases in abdominal adiposity, improvement in glucose and lipid homeostasis and decreases components of the metabolic syndrome. It is the first therapeutic agent that inhibits the endocannabiniod system and improves multiple cardiometabolic parameters.

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