Neurally mediated cardiac effects of forskolin in conscious
dogs.
Iwase, Mitsunori, Yoshihiro Ishikawa, You-Tang Shen, Richard P.
Shannon, Naoki Sato, Pallab K. Ganguly, Toshiko Eki, Dorothy E.
Vatner, and Stephen F. Vatner.
Departments of Medicine, Harvard Medical School, Brigham &
Women's Hospital, Boston, MA 02115 and _The New England Regional
Primate Research Center, Southborough, MA 01772
APStracts 3:0222H, 1996.
Since 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 (LV) dP/dt increased by 96+/-7%,
p<0.05, in response to forskolin (50 nmol/kg/min) in normal dogs
and significantly less, by 52+/-14%, in VD dogs. Circulating
norepinephrine levels increased similarly in both groups (from 226+/
-18 pg/ml 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 norepinephrine levels
in both groups. Increases in heart rate in the presence of ganglionic
blockade (+54+/-6 beats/min) was 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 norepinephrine in response to forskolin.
Increases in LV dP/dt in response to NKH 477 (30 [mu]g/kg), a water
soluble forskolin derivative, was 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 also are mediated by neural mechanisms, and are
potentiated by the prevailing level of sympathetic tone.
Received 19 December 1995; accepted in final form 28 February
1996.
APS Manuscript Number H1182-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 June 96