The effects of Bay K 8644 on myocardial relaxation and cAMP levels in perfused rat heart: role of sympathetic neurotransmitter release.
Bay K 8644 typifies a number of drugs known to act directly on voltage-dependent calcium channels to increase calcium current. Such effects probably underly the drug's positive inotropic action and smooth muscle stimulation. Although the effects of this compound on myocardial contractility have been extensively described, its action upon myocardial relaxation is not well established. Either no changes or a prolongation in ventricular relaxation have been mentioned. On the other hand, during the course of other experiments performed in our laboratory with the perfused rat heart (unpublished results), we observed that Bay K 8644 elicits a moderate but consistent relaxant effect. The present work was undertaken in an attempt to clarify the effect of Bay K 8644 upon myocardial relaxation. Evidence will be presented showing that in the perfused rat heart, the positive inotropic action of Bay K 8644 occurs together with a prolongation of the contraction time (TTP) without changes in time to half relaxation (t 1/2). However, an enhancement of ventricular relaxation was detected by the proportional greater increase in maximal velocity of relaxation (-T) with respect to maximal velocity of contraction (+T) and the shortening of the time constant of relaxation (tau). These actions occur associated with a significant increase in cAMP levels and phospholamban phosphorylation. Either the relaxant effect as well as the increments in cAMP and phospholamban phosphorylation were abolished when the hearts were depleted of norepinephrine by previous treatment with reserpine. Depletion of norepinephrine stores also decreases the positive inotropic effect of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)
Mundiña
C
C
Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Medicas, Universidad Nacional de La Plata, Argentina.
Vittone
L
L
Chiappe de Cingolani
G
G
Mattiazzi
A
A
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis*; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000242:Cyclic AMP; D009638:Norepinephrine