Mechanism of the negative lusitropic effect of [alpha]1
-adrenoceptor stimulation in cat papillary muscles.
Vila-Petroff, Mart[acute]in, Gustavo N. P[acute]erez, Bernardo
Alvarez, Horacio E. Cingolani, and Alicia Mattiazzi.
Centro de Investigaciones Cardiovasculares, Universidad Nacional de
La Plata, 60 y 120, 1900 La Plata, Argentina
APStracts 2:0360H, 1995.
The present experiments were designed to explore the mechanisms by
which [alpha]1-adrenoceptor stimulation affect myocardial relaxation
in feline myocardium. In papillary muscles contracting isometrically
at 0.2 Hz, 10[mu]M phenylephrine + 1[mu]M atenolol (n=8) produced a
negative lusitropic effect. This effect was detected by the
prolongation of half relaxation time (t1/2) by 30 +/- 10 %
(p<0.05) and the proportional smaller increase in maximal
velocity of relaxation (-) than in maximal velocity of contraction
(+) which significantly increased the ratio +/-. A similar increase
in contractility produced by increasing extracellular calcium, failed
to significantly change t1/2 and +/-, which further emphasizes that
the negative lusitropic effect observed was independent of positive
inotropy. Phenylephrine-induced negative lusitropic effect was
significantly inhibited by two protein kinase C inhibitors,
staurosporine (0.1[mu]M) and chelerythrine chloride (10[mu]M).
Phenylephrine in the presence of atenolol also increased
intracellular pH (pHi), measured by the pH sensitive fluorescent dye
2'-7'-bis (2-carboxymethyl)-5, 6-carboxy fluorescein (BCECF), by 0.18
+/- 0.05 pH units (P<0.05, n=4). This intracellular alkalosis as
well as the negative lusitropic effect of phenylephrine were both
prevented by ethylisopropylamiloride (EIPA, 10[mu]M), an inhibitor of
the Na+-H+ exchanger. In chemically skinned trabeculae perfused at
constant pH, phenylephrine in the presence of a [beta]-blocker,
failed to significantly change calcium myofilament sensitivity and
maximal tension. These results indicate that an increase in pHi, due
to an enhancement of Na+-H+ exchanger possibly mediated by PKC
activation, may fully account for the negative lusitropic effect of
[alpha]1-adrenoceptor stimulation. It is suggested that an alkalosis
-sensitive mechanism, such as an increase in myofilament
responsiveness to calcium, mediates the negative lusitropic effect of
[alpha]1-adrenoceptor stimulation. This is consistent with the lack
of effect of phenylephrine on skinned trabeculae perfused at constant
pH.
Received 1 February 1995; accepted in final form 8 August 1995.
APS Manuscript Number H92-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 24 August 1995.