(Circulation. 1997;95:2122-2129.)
© 1997 American Heart Association, Inc.
Articles |
`Cross Talk' Between Opioid Peptide and Adrenergic Receptor Signaling in Isolated Rat Heart
From the Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Md (S.P., R.-P.X., E.G.L.), and the Department of Medical Biochemistry, Ohio State University, Columbus (C.H., R.A.).
Correspondence to Edward G. Lakatta, MD, Chief, Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, 4940 Eastern Ave, Baltimore, MD 21224.
Background Cardiac myocyte sarcolemma contains both catecholamine and opioid peptide receptors (OPRs). Opioid peptides are coreleased with catecholamines from nerve terminals in the heart. We investigated whether OPR stimulation influences the effects of ß-adrenergic receptor (ß-AR) stimulation in the isolated, isovolumic rat heart and whether the mechanism of such an interaction involves both ß-AR subtypes or an alteration in ß-AR–mediated increase in cAMP.
Methods and Results Norepinephrine (NE,
10-7 mol/L) increased peak left
ventricular systolic pressure (LVSP) and cAMP more
than twofold compared with controls. The 
-OPR agonist
leucine-enkephalin (LE, 10-8 mol/L) markedly
inhibited the ß1-AR–induced positive inotropic effect
and increase in cAMP but alone had no effect on basal LVSP or basal
cAMP levels. The OPR antagonist naloxone
10-8 mol/L added to LE+NE perfusate
reversed the LE-induced decrease in cAMP and LVSP even though naloxone
alone had no effect on LVSP and cAMP levels. LE could not counteract
the twofold increase in LVSP produced by the nondegradable cAMP analog
CPTcAMP 2.3x10-5 mol/L or a high
concentration of forskolin (10-7 mol/L) but
did reverse the 173±11.8% and 135±13.6% increases in LVSP
stimulated by 10-8 and
0.5x10-8 mol/L forskolin, respectively. LE
inhibited cAMP production at all concentrations of forskolin
(10-7, 10-8, and
0.5x10-8 mol/L). Pertussis toxin (PTX)
pretreatment abolished LE effects on ß1-AR stimulation.
Zinterol 10-5 and
10-6 mol/L, a specific ß2-AR
agonist that elicits a cAMP-independent inotropic effect in rat heart,
caused 225±14% and 182±5% increases in LVSP that could not be
reversed by addition of LE.
Conclusions Potent, inhibitory "cross
talk" between -OPR and ß1-AR signaling pathways
occurs via a PTX-sensitive Gi/o protein involved in
adenylyl cyclase inhibition in rat heart.
Key Words: opioid peptides • receptors, adrenergic, beta • cAMP • proteins • rats
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