Neurally mediated cardiac effects of forskolin in conscious dogs

TY - JOUR

T1 - Neurally mediated cardiac effects of forskolin in conscious dogs

AU - Iwase, Mitsunori

AU - Ishikawa, Yoshihiro

AU - Shen, You Tang

AU - Shannon, Richard P.

AU - Sato, Naoki

AU - Ganguly, Pallab K.

AU - Eki, Toshiko

AU - Vatner, Dorothy E.

AU - Vatner, Stephen F.

PY - 1996/10

Y1 - 1996/10

N2 - 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 β-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 μg/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 β-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.

AB - 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 β-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 μg/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 β-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.

KW - chronotropic effect

KW - inotropic effect

KW - neural effects

KW - synergism

UR - https://www.scopus.com/pages/publications/0029861706

UR - https://www.scopus.com/pages/publications/0029861706#tab=citedBy

U2 - 10.1152/ajpheart.1996.271.4.h1473

DO - 10.1152/ajpheart.1996.271.4.h1473

M3 - Article

C2 - 8897942

SN - 0363-6135

VL - 271

SP - H1473-H1482

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

IS - 4 40-4

ER -