Changes in α 1 -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 microM) 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 alpha(1)-adrenoceptor subtype(s) involved in the vascular NA-responses were characterized in normal rats using the alpha(1)-adrenoceptor subtype-selective antagonists 5-methylurapidil (5-MU; competitive alpha(1A)-adrenoceptor antagonist; 10(-8)-10(-6) M), BMY 7378 (competitive alpha(1D)-adrenoceptor antagonist; 10(-7)-10(-6) M) and chloroethylclonidine (CEC; irreversible alpha(1B)-adrenoceptor antagonist; 30 microM). In the pulmonary artery the pA(2) 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 pA(2) for BMY 7378 was 8.06, while 5-MU was less effective (pA(2) 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 (pA(2) 8.05). BMY 7378 had a lower pA(2) (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 alpha(1A)-adrenoceptors in small mesenteric arteries, by alpha(1D)-adrenoceptors in the thoracic aorta (with a contribution from alpha(1A)- and alpha(1B)-adrenoceptors) and by alpha(1D)- and alpha(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.

Ventricular Hypertrophy Plus Neurohumoral Activation Is Necessary to Alter the Cardiac β-Adrenoceptor System in Experimental Heart Failure

“…Because we had to use in the present study a new Wistar rat strain, we performed preliminary dose-finding experiments that revealed that 50 mg/kg body weight sc was an appropriate dose of MCT for this rat-strain with regard to survival and induction of right heart hypertrophy due to pulmonary hypertension and with regard to similarity to our previous studies, where we had used another rat strain and induced right heart hypertrophy with a single intraperitoneal (IP) injection of 60 mg MCT/kg body weight. 8,10,14 However, analogous to our previous studies, MCT-treated animals show, in general, significantly less weight gain than control animals; therefore, the MCT-treated rats had free supply to food, whereas control rats were restricted to the quantity of food consumed by the MCT-treated rats the previous day. 10,14 -15 All animals had free access to water.…”

“…11 Data from the literature and our own data show that a single injection of the pyrrolizidine alkaloid monocrotaline induces in rats within 14 days after application severe pulmonary hypertension, resulting first in development of right ventricular hypertrophy due to apparent pressure overload and then in right heart insufficiency accompanied by an increase in sympathetic nervous system activity. [7][8]10,[12][13][14] Thus, the monocrotaline rat model allows to investigate whether pressure overload evoked hypertrophy per se can induce the characteristic alterations in the cardiac ␤-adrenoceptor system seen in chronic heart failure, or whether those changes can only occur when hypertrophy is accompanied by neurohumoral activation. In order to study this, we assessed in monocrotaline-treated rats, ␤-adrenoceptor density and subtype distribution, G proteincoupled receptor kinase activity, neuronal noradrenaline transporter density and activity and plasma noradrenaline levels at two time-points after monocrotaline-treatment: one group (within 13 to 19 days after application) that had developed right ventricular hypertrophy but did not show signs of neurohumoral activation (no increase in plasma noradrenaline) and one group (within 21 to 28 days after application) that showed right ventricular hypertrophy and increased plasma noradrenaline levels (as index of neurohumoral activation).…”

Effects of Everolimus in Combination with Sildenafil in Monocrotaline-induced Pulmonary Hypertension in Rats

“…E1 after 3 weeks from injection of MCT, sildenafil (50 mg kg -1 ) and everolimus (1 mg kg -1 ) were administered rats orally for 21 days; SLD ? E3 after 3 weeks from injection of MCT, sildenafil (50 mg kg -1 ) and everolimus (3 mg kg -1 ) were administered rats orally for 21 days PH, it was observed that endothelium-dependent relaxation responses were significantly decreased compared to those in the control group owing to decreases in the production of NO secondarily to endothelial damage [15,16,26,34]. Ach relaxation responses in the treated groups, particularly the SLD ?…”

“…It causes pulmonary artery neomuscularisation, hyperplasia and hypertrophy of smooth muscle cells, inflammation, and endothelial damage as well as the obliteration of pulmonary vasculature and resultant right ventricular hypertrophy and failure [15,16].…”

Rhythmical contractions in pulmonary arteries of monocrotaline-induced pulmonary hypertensive rats

“…Changes in the contractile activity of the pulmonary artery in MCT-treated rats have also been demonstrated by several research groups; however, the data from the studies have been conflicting. While several studies have found attenuated constrictive responses to vasoconstrictors such as norepinephrine and 5-hydroxytryptamine in isolated pulmonary arteries from MCTtreated rats [5,25,38], others have demonstrated increased responsiveness [3,14,17,22,40]. It has also been reported that the main pulmonary artery from MCT-treated rats is depolarized [15,39], which is not attributable to the endothelial damage [15], and that the endothelial-denuded pulmonary artery from MCT-treated rats has active basal tone in the resting state [15,34].…”