Leineweber Kirsten, Brandt Katja, Wludyka Beate, Beilfuss Anja, Pönicke Klaus, Heinroth-Hoffmann Ingrid, Brodde Otto-Erich
Institute of Pharmacology, Martin-Luther-University of Halle-Wittenberg, Halle, Germany.
Circ Res. 2002 Nov 29;91(11):1056-62. doi: 10.1161/01.res.0000045088.59360.b7.
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 beta-adrenoceptors (beta-AR), neuronal noradrenaline transporter (NAT) density and activity (uptake1), and G protein-coupled receptor kinase (GRK) activity. This study aimed to find out factors that determine beta-AR, uptake1, 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 (222+/-6 versus 147+/-5 mg) and RV/left ventricular (LV) weight ratio (0.42+/-0.01 versus 0.29+/-0.01) were significantly increased, whereas plasma noradrenaline, RV beta-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 (316+/-4 versus 148+/-2 mg) and RV/LV weight ratio (0.61+/-0.01 versus 0.3+/-0.01) were markedly increased but also plasma noradrenaline (645+/-63 versus 278+/-18 pg/mL); now, RV beta-AR density (13.4+/-1.3 versus 26.5+/-1.1 fmol/mg protein), RV NAT density (50.9+/-11.3 versus 79.6+/-2.9 fmol/mg protein), and RV NAT activity (65.4+/-7.4 versus 111.8+/-15.9 pmol [3H]-NA/mg tissue slices/15 min) were significantly decreased and RV-membrane GRK activity (100+/-15 versus 67+/-6 [32P]-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 beta-AR system often seen in heart failure; only if ventricular hypertrophy is associated with neurohumoral activation beta-ARs are downregulated and GRK activity is increased.
用野百合碱（MCT）处理大鼠会导致肺动脉高压、右心室（RV）肥厚，最终导致右心衰竭。这与右心室β-肾上腺素能受体（β-AR）、神经元去甲肾上腺素转运体（NAT）密度和活性（摄取1）以及G蛋白偶联受体激酶（GRK）活性的特征性变化有关。本研究旨在找出决定β-AR、摄取1和GRK变化的因素。因此，对6周龄大鼠皮下注射50 mg/kg MCT或0.9%生理盐水。在应用MCT后的13至19天内（A组），右心室重量（222±6对147±5 mg）和右心室/左心室（LV）重量比（0.42±0.01对0.29±0.01）显著增加，而血浆去甲肾上腺素、右心室β-AR密度、右心室NAT密度和活性以及右心室GRK活性没有显著改变。然而，在MCT处理后的21至28天（B组），不仅右心室重量（316±4对148±2 mg）和右心室/左心室重量比（0.61±0.01对0.3±0.01）显著增加，而且血浆去甲肾上腺素（645±63对278±18 pg/mL）也增加；此时，右心室β-AR密度（13.4±1.3对26.5±1.1 fmol/mg蛋白）、右心室NAT密度（50.9±11.3对79.6±2.9 fmol/mg蛋白）和右心室NAT活性（65.4±7.4对111.8±15.9 pmol [3H]-NA/mg组织切片/15分钟）显著降低，右心室膜GRK活性（100±15对67±6 [32P]-视紫红质cpm）显著增加。MCT处理大鼠的左心室参数与对照左心室仅略有不同。我们得出结论，在MCT处理的大鼠中，心室肥厚本身不足以引起心力衰竭中常见的心肌β-AR系统的特征性改变；只有当心室肥厚与神经体液激活相关时，β-AR才会下调，GRK活性才会增加。
