Iwase M, Ishikawa Y, Shen Y T, Shannon R P, Sato N, Ganguly P K, Eki T, Vatner D F, Vatner S F
Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston 02115, USA.
Am J Physiol. 1996 Oct;271(4 Pt 2):H1473-82. doi: 10.1152/ajpheart.1996.271.4.H1473.
Because major cardiovascular disease states are characterized by defects in adenylyl cyclase regulation, it becomes important to understand the mechanisms by which adenylyl cyclase activators affect inotropy and chronotropy in intact conscious animals. Accordingly, we examined the inotropic and chronotropic responses to forskolin in 11 normal conscious, chronically instrumented dogs and 3 dogs with ventricular denervation (VD). Left ventricular first derivative of pressure (LV dP/dt) increased by 96 +/- 7%, P < 0.05, in response to forskolin (50 nmol.kg-1.min-1) in normal dogs and by significantly less, 52 +/- 14%, in VD dogs. Circulating norepinephrine (NE) levels increased similarly in both groups (from 226 +/- 18 to 389 +/- 33 pg/ml in normal dogs, from 177 +/- 23 to 329 +/- 71 pg/ml in VD dogs). In the presence of ganglionic blockade, the increase in LV dP/dt in response to forskolin was reduced (+62 +/- 4%) in normal dogs but was unchanged in VD dogs (+52 +/- 12%). Ganglionic blockade abolished the increase in circulating NE levels in both groups. Increases in heart rate in the presence of ganglionic blockade (+54 +/- 6 beats/min) were less than in the presence of atropine alone (+92 +/- 10 beats/min). Notably, the LV dP/dt and heart rate responses to forskolin were further attenuated by beta-adrenergic receptor blockade in the presence and absence of ganglionic blockade. Morphine also attenuated the increases in both LV dP/dt and plasma NE in response to forskolin. Increases in LV dP/dt in response to NKH-477 (30 micrograms/kg), a water-soluble forskolin derivative, were similar before and after ganglionic blockade (+63 +/- 8 and +51 +/- 10%, respectively). However, in vitro experiments in LV sarcolemmal membrane preparations demonstrated that stimulation of adenylyl cyclase by forskolin and NKH-477 was not affected by beta-adrenergic receptor blockade. These results indicate that in conscious dogs, inotropic and chronotropic effects of forskolin are not only due to direct activation of adenylyl cyclase, but the effects also are mediated by neural mechanisms and potentiated by the prevailing level of sympathetic tone.
由于主要心血管疾病状态的特征是腺苷酸环化酶调节缺陷，因此了解腺苷酸环化酶激活剂影响完整清醒动物心肌收缩力和心率的机制变得很重要。因此，我们研究了11只正常清醒、长期植入仪器的犬和3只心室去神经支配（VD）犬对福斯高林的心肌收缩力和心率反应。正常犬对福斯高林（50 nmol·kg-1·min-1）的反应中，左心室压力一阶导数（LV dP/dt）增加了96±7%，P<0.05，而VD犬增加得明显较少，为52±14%。两组循环去甲肾上腺素（NE）水平的升高相似（正常犬从226±18 pg/ml升至389±33 pg/ml，VD犬从177±23 pg/ml升至329±71 pg/ml）。在存在神经节阻断的情况下，正常犬对福斯高林的LV dP/dt增加减少（+62±4%），而VD犬则无变化（+52±12%）。神经节阻断消除了两组循环NE水平的升高。在存在神经节阻断时心率的增加（+54±6次/分钟）小于仅使用阿托品时（+92±10次/分钟）。值得注意的是，在存在和不存在神经节阻断的情况下，β-肾上腺素能受体阻断均进一步减弱了对福斯高林的LV dP/dt和心率反应。吗啡也减弱了对福斯高林的LV dP/dt和血浆NE的增加。对水溶性福斯高林衍生物NKH-477（30 μg/kg）的反应中，神经节阻断前后LV dP/dt的增加相似（分别为+63±8%和+51±10%）。然而，在左心室肌膜制剂的体外实验表明，福斯高林和NKH-477对腺苷酸环化酶的刺激不受β-肾上腺素能受体阻断的影响。这些结果表明，在清醒犬中，福斯高林的心肌收缩力和心率作用不仅归因于腺苷酸环化酶的直接激活，而且这些作用还由神经机制介导，并受交感神经张力的主导水平增强。
