Changes in α₁-adrenergic vascular reactivity in monocrotaline-treated rats

Abstract.

In rats, injection of monocrotaline (MCT) causes pulmonary hypertension that leads to right ventricular failure. The aim of the present study was to characterize the responses of various vessels (the pulmonary artery, the thoracic aorta and small mesenteric arteries) to noradrenaline (NA; 10^–10–10^–5 M) and carbachol (10 µM) in MCT-treated rats. For this purpose 6-week-old male Wistar rats (n=13) were treated with 60 mg/kg MCT i.p. After 4–6 weeks the rats were killed and the heart, lungs and vessels removed and compared with those from age-matched saline-treated control rats (n=47). First, the α₁-adrenoceptor subtype(s) involved in the vascular NA-responses were characterized in normal rats using the α₁-adrenoceptor subtype-selective antagonists 5-methylurapidil (5-MU; competitive α_1A-adrenoceptor antagonist; 10^–8–10^–6 M), BMY 7378 (competitive α_1D-adrenoceptor antagonist; 10^–7–10^–6 M) and chloroethylclonidine (CEC; irreversible α_1B-adrenoceptor antagonist; 30 µM). In the pulmonary artery the pA₂ for BMY 7378 was 7.93, while that for 5-MU could not be calculated. CEC suppressed the NA-induced contraction significantly. In the thoracic aorta, the pA₂ for BMY 7378 was 8.06, while 5-MU was less effective (pA₂ 7.31). CEC again suppressed the NA-induced contraction significantly. In mesenteric arteries, CEC was ineffective whereas 5-MU induced a significant, rightwards shift of the concentration/response curve for NA (pA₂ 8.05). BMY 7378 had a lower pA₂ (6.6). MCT-treated rats developed an increased right ventricular pressure, obliteration of pulmonary vessels and inflammatory lung infiltration. In the pulmonary artery, but not in the thoracic aorta or mesenteric artery of MCT-treated rats NA-induced contraction was attenuated. In addition, carbachol-induced relaxation was reduced in the pulmonary and mesenteric arteries.

In conclusion, NA-induced contraction is mediated predominantly by α_1A-adrenoceptors in small mesenteric arteries, by α_1D-adrenoceptors in the thoracic aorta (with a contribution from α_1A- and α_1B-adrenoceptors) and by α_1D- and α_1B-adrenoceptors in pulmonary arteries. MCT leads to reduced NA-responsiveness exclusively in the pulmonary artery that does not, however, account for the development of pulmonary hypertension, and to a more generalized endothelial dysfunction which may contribute to the pathogenesis of pulmonary hypertension in this model.