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Abstract-Treatment of rats with monocrotaline (MCT) leads to pulmonary hypertension, right ventricular (RV) hypertrophy, and finally to RV heart failure. This is associated with characteristic changes in right ventricular ␤-adrenoceptors (␤-AR), neuronal noradrenaline transporter (NAT) density and activity (uptake 1 ), and G proteincoupled receptor kinase (GRK) activity. This study aimed to find out factors that determine ␤-AR, uptake 1 , and GRK changes. Thus, 6-week-old rats were treated with 50 mg/kg MCT subcutaneous or 0.9% saline. Within 13 to 19 days after MCT application (group A), RV weight (222Ϯ6 versus 147Ϯ5 mg) and RV/left ventricular (LV) weight ratio (0.42Ϯ0.01 versus 0.29Ϯ0.01) were significantly increased, whereas plasma noradrenaline, RV ␤-AR density, RV NAT density and activity, and RV GRK activity were not significantly altered. Twenty-one to twenty-eight days after MCT (group B), however, not only RV weight (316Ϯ4 versus 148Ϯ2 mg) and RV/LV weight ratio (0.61Ϯ0.01 versus 0.3Ϯ0.01) were markedly increased but also plasma noradrenaline (645Ϯ63 versus 278Ϯ18 pg/mL); now, RV ␤-AR density ( 32 P]-rhodopsin in cpm) significantly increased. LV parameters of MCT-treated rats were only marginally different from control LV. We conclude that in MCT-treated rats ventricular hypertrophy per se is not sufficient to cause characteristic alterations in the myocardial ␤-AR system often seen in heart failure; only if ventricular hypertrophy is associated with neurohumoral activation ␤-ARs are downregulated and GRK activity is increased. Key Words: monocrotaline Ⅲ right heart hypertrophy Ⅲ neurohumoral activation Ⅲ ␤-adrenoceptor Ⅲ G protein-coupled receptor kinase I n human heart failure, there are characteristic alterations in the cardiac ␤-adrenoceptor system: selective downregulation of ␤ 1 -adrenoceptors with little or no change in ␤ 2 -adrenoceptors, reduced adenylyl cyclase activity, increased G protein-coupled receptor kinases (GRKs) activity, and reduced neuronal noradrenaline transporter. [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. 7-10 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. [7][8]10,[12][13][14] Thus, the monocrotaline rat model allows to investigate whether pressure overload evoked hy...

, and on contractile force in left ventricular strips of the rat heart. For comparison, eects of prostanoids on InsP-formation and contractile force were determined in rat thoracic aorta, a classical TP-receptor containing tissue. 2 Prostanoid increased InsP-formation and rate of protein synthesis in neonatal as well as adult rat cardiomyocytes; the order of potency was in neonatal (PGF 2a 4PGD 2 5PGE 2 5U 466194PGE 1 ) and adult (PGF 2a 4PGD 2 5PGE 2 4U 46619) rat cardiomyocytes well comparable. Moreover, in electrically driven left ventricular strips PGF 2a caused positive inotropic eects (pD 2 7.5) whereas U 46619 (up to 1 mM) was uneective. 3 In contrast, in rat thoracic aorta U 46619 was about 100 times more potent than PGF 2a in increasing InsP-formation and contractile force. 4 The TP-receptor antagonist SQ 29548 only weakly antagonized prostanoid-induced increases in rate of protein synthesis (pK B about 6) in rat cardiomyocytes but was very potent (pK B about 8 ± 9) in antagonizing prostanoid-induced increases in InsP-formation and contractile force in rat aorta. 5 We conclude that, in cardiomyocytes of neonatal and adult rats, the prostanoid-receptor mediating increases in InsP-formation and rate of protein synthesis is a FP-receptor. Moreover, stimulation of these cardiac FP-receptors can mediate increases in contractile force.

In isolated ventricular cardiomyocytes from rats, beta1-adrenoceptor stimulation attenuates the hypertrophic response evoked by alpha1-adrenoceptor stimulation.

1 Muscarinic receptors (M-receptors) in the mammalian heart are predominantly of the M 2 -subtype. The aim of this study was to ®nd out whether there might exist an additional myocardial non-M 2 -receptor. 2 For this purpose, we assessed, in adult rat isolated ventricular cardiomyocytes, carbacholinduced [ 3 H]-inositol phosphate (IP) formation, and its inhibition by M-receptor antagonists. 3 Carbachol (10 77 ± 10 73 mol l 71 ) increased IP-formation (maximal increase: 14+3% above basal, n=6). This increase was signi®cantly enhanced by pretreatment with pertussis toxin (PTX, 250 ng ml 71 for 20 h): maximal increase was 31+5%, pEC 50 -value was 5.08+0.33 (n=6). 4 In PTX-pretreated cardiomyocytes 100 mmol l 71 carbachol-induced IP-formation was inhibited by atropine (pK i -value: 8.89+0.10) and by the M 3 -receptor antagonist darifenacin (pK i -value: 8.67+0.23) but was not signi®cantly a ected by the M 1 -receptor antagonist pirenzepine (1 mmol l 71 ) or the M 2 -receptor antagonists AF-DX 116 and himbacine (1 mmol l 71 ). 5 In conclusion, in adult rat cardiomyocytes there exists an additional, non-M 2 -receptor, that is coupled to activation of the phospholipase C/IP 3 -pathway; this receptor is very likely of the M 3 -subtype.