Alpha-1 adrenoceptor-mediated positive inotropic effect and inositol trisphosphate increase in mammalian heart.
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.
Scholz
J
J
Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, FRG.
Schaefer
B
B
Schmitz
W
W
Scholz
H
H
Steinfath
M
M
Lohse
M
M
Schwabe
U
U
Puurunen
J
J
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013268:Stimulation, Chemical; D013403:Sugar Phosphates / Q000378:metabolism*
D007295:Inositol Phosphates; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D013403:Sugar Phosphates; D010656:Phenylephrine; D015544:Inositol 1,4,5-Trisphosphate; D008094:Lithium; D002118:Calcium