Chamber‐specific alterations of noradrenaline uptake (uptake₁) in right ventricles of monocrotaline‐treated rats

Abstract

1 In rats a single injection of the alkaloid monocrotaline (60 mg MCT kg 71 body weight, i.p.) caused right ventricular hypertrophy and heart failure. The aim of this study was to ®nd out whether, in these MCT-treated rats, the cardiac neuronal noradrenaline uptake (uptake 1 ) might undergo chamber-speci®c alterations. 6 We conclude that in MCT-treated rats with right ventricular hypertrophy and heart failure uptake 1 activity is chamber-speci®cally reduced possibly due to a decrease in carrier protein density.

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

“…[1][2][3][4][5][6] We and others have recently shown that the monocrotaline rat model of right heart failure exhibits alterations in myocardial ␤-adrenoceptors that resemble those in human heart failure: a decrease in ␤-adrenoceptors, a reduction in adenylyl cyclase, an increase in GRK, and a reduction in neuronal noradrenaline transporter. [7][8][9][10] These changes appear to occur predominately in right ventricles, and are therefore, well comparable with those observed in patients with primary pulmonary hypertension. 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.…”

“…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).…”

“…3 H]-Noradrenaline Transporter Activity (Uptake 1 ) 10 Nonspecific accumulation of radioactivity was determined by parallel incubation at 4°C. Specific uptake was defined as total uptake (37°C) minus nonspecific uptake (4°C).…”

Mechanical Load-Dependent Regulation of Gene Expression in Monocrotaline-Induced Right Ventricular Hypertrophy in the Rat

“…To prevent MCT-induced alterations of gene expression and contractile function from being modulated by differences in the nutritional state between groups, MCT rats had an unlimited food supply, whereas the amount of food given to control animals was restricted to the quantity consumed by MCT rats on the previous day. 12,14 All animal procedures were approved by the government committee for animal studies and carried out according to German laws regarding the care and use of laboratory animals.…”