ABSTRACT
It is suggested that angiotensin II is involved in the pathogenesis of pulmonary hypertension and subsequent right ventricular hypertrophy; therefore, an angiotensin AT1 receptor antagonist could be beneficial for the treatment of this disease. We tested the effect of the new AT1 receptor antagonist olmesartan medoxomil on monocrotaline-induced pulmonary hypertension in rats. At 3 weeks after a single subcutaneous injection of monocrotaline (50 mg/kg), the lung/body weight ratio, the right ventricle/(left ventricle plus septum) weight ratio [RV/(LV+S)], and right ventricular systolic pressure were increased, indicating establishment of pulmonary hypertension and right ventricular hypertrophy. Oral administration of olmesartan medoxomil (2 or 5 mg/kg/day for 3 weeks) restored RV/(LV+S) and right ventricular systolic pressure, and a higher dose (5 mg/kg/day) improved the lung/body weight ratio. Pulmonary arteries isolated from monocrotaline-treated rats exhibited an increase in basal tone in the resting state, indicating that they had intrinsic tone. Three weeks of treatment with olmesartan decreased this intrinsic tone. These data suggest that long-term treatment with olmesartan has beneficial effects on monocrotaline-induced pulmonary hypertension and subsequent right ventricular hypertrophy.
Subject(s)
Antihypertensive Agents/pharmacology , Hypertension, Pulmonary/drug therapy , Hypertrophy, Right Ventricular/drug therapy , Imidazoles/pharmacology , Tetrazoles/pharmacology , Administration, Oral , Animals , Antihypertensive Agents/administration & dosage , Blood Pressure/drug effects , Body Weight/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Hemodynamics/drug effects , Hypertension, Pulmonary/chemically induced , Hypertrophy, Right Ventricular/chemically induced , Imidazoles/administration & dosage , Lung/drug effects , Lung/pathology , Male , Monocrotaline , Olmesartan Medoxomil , Pulmonary Artery/drug effects , Pulmonary Artery/pathology , Rats , Rats, Wistar , Tetrazoles/administration & dosage , Time FactorsABSTRACT
We evaluated the endothelial function of thoracic aortas and pulmonary arteries in a population of European wood mice (Apodemus sylvaticus), which exhibit hypercholesterolemia. According to the plasma cholesterol level, mice were divided into two groups: hypercholesterolemic (AHL, total plasma cholesterol 200-300 mg/dl) and normocholesterolemic (ANL, total plasma cholesterol <200 mg/dl). Acetylcholine (ACh) caused endothelium-dependent relaxation of precontracted aortas and pulmonary arteries. Relaxation of the pulmonary artery is completely dependent on nitric oxide. This relaxation was inhibited in AHL pulmonary arteries. On the other hand, part of the ACh-induced relaxation of the thoracic aorta was resistant to N(omega)-nitro-L-arginine (L-NNA). L-NNA-sensitive and -resistant relaxation to ACh were also inhibited in AHL aortas. Inhibition of endothelium-dependent relaxation of the aortas was correlated with total plasma cholesterol level. Endothelium-independent relaxation to sodium nitroprusside (SNP) was similar in AHL and ANL pulmonary arteries, but in the thoracic aorta of AHL mice, the sensitivity to SNP was slightly decreased, without a change in maximal response to SNP. No morphological change was observed in the aortas and the pulmonary arteries from AHL and ANL mice. Thus, AHL mice are valuable as a new experimental model to study the relation of hyperlipidemia to vascular disease since the endothelial function is impaired in these mild hyperlipidemic animals.
