Molecular mechanism by which cyclic amp regulates myocardial contractility Page: 19 of 153
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(Drummond et al_., 1969; Drummond and Hemmings, 1973; Kukovetz et al.,
1975; Ones and 0ye, 1975; Posner et^ al_., 1965). A second-messenger
hypothesis (Sutherland et^ aj_., 1968; Epstein et al_., 1971) involves a
sequence of events connecting the appearance of the e-agonist with the
eventual increase in contractility: a) catecholamine diffusion to the
vicinity of the cell membrane; b) binding to the e-receptor; c) activation
of adenyl cyclase; d) elevation of cyclic AMP concentration; e)
diffusion of cyclic AMP to its sites of action: f) modification of some
aspect(s) of excitation-contraction coupling; g) enhancement of
systolic calcium concentration; and h) greater contractile strength
(Tsien, 1977). Drummond et al. (1966) found that the level of cyclic
AMP in cardiac cells increased by nine-fold within 1 sec after
epinephrine administration.
Attempts have been made to see if cyclic AMP can produce the same
physiological responses in cardiac tissues that catecholamines do.
Exposure of a perfused heart to cyclic AMP did not increase twitch
tension (Rail and West, 1963; Robison et_ al_., 1965). Reasoning that
this lack of effectiveness might be due to a slow entry of cyclic AMP
into heart ceils, other investigators turned to acyl substituted
derivatives, such as N^,2^-0-dibutyryl cyclic AMP (DBcAMP), in the
hope that the lipophilic side chains would facilitate movement across
the cell membrane (Posternak et aj^., 1962) or provide temporary
protection against degradation by phosphodiesterase (Henion et^ al_., 1967).
It is now generally agreed that DBcAMP does give adrenaline-like
effects in increasing the strength of contraction (Skeleton et al_., 1970;
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Bidlack, J. M. Molecular mechanism by which cyclic amp regulates myocardial contractility, report, January 1, 1979; United States. (https://digital.library.unt.edu/ark:/67531/metadc1085147/m1/19/: accessed July 17, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.