Abstract
The positive inotropic effect of the alpha-1 adrenoceptor agonist
phenylephrine was accompanied by a concentration-dependent increase
in inositol trisphosphate (IP3) in electrically driven left auricles
isolated from rat hearts. Further analysis of the myocardial phosphoinositide
pathway revealed an additional increase in inositol phosphate and
inositol bisphosphate with a concomitant decrease in phosphatidylinositol
phosphate and phosphatidylinositol bisphosphate. The decrease in
phosphatidylinositol bisphosphate and increase in IP3 preceded the
increase in force of contraction. All effects were antagonized by
the alpha-1 adrenoceptor antagonist prazosin. For comparison the
effects of the beta adrenoceptor agonist isoprenaline were studied.
Isoprenaline produced a positive inotropic effect similar to that
of phenylephrine but all phosphoinositide products remained unaffected.
The influence of lithium and calcium ions were studied systematically.
The stimulatory effect of phenylephrine on inositol phosphates was
lithium-dependent. Without lithium phenylephrine did not detectably
affect the phosphoinositide turnover. Phenylephrine caused a maximal
increase in inositol phosphate, inositol bisphospate and IP3 at 10
mmol/l of lithium. Lithium itself had a concentration-dependent positive
inotropic effect. However, lithium did not enhance the positive inotropic
effect of phenylephrine. Variation of the extracellular concentration
of calcium did not influence the stimulatory effect of phenylephrine
on inositol phosphates indicating that inositol phosphate turnover
does not require the presence of extracellular calcium. It is concluded
that the stimulation of myocardial phosphoinositide breakdown generating
an increased IP3 turnover may be involved in the mechanism(s) whereby
alpha-1 adrenoceptor stimulation exerts an increase in myocardial
force of contraction.
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