Modulation of the beta-adrenergic response in cultured rat heart cells. I. Beta-adrenergic supersensitivity is induced by lactate via a phospholipase A2 and 15-lipoxygenase involving pathway.
Incubation of rocker-cultured neonatal rat heart cells with 3 mM L(+)-lactate led to a sharp increase in the sensitivity of cardiomyocytes to the beta-adrenergic agonist isoprenaline, as measured by their chronotropic response. This effect was accompanied by a reduction in the arachidonic acid content of the total phospholipids. The phospholipase A2-activator melittin as well as free arachidonic acid induced this supersensitivity to the same degree. On the other hand, the L(+)-lactate-evoked supersensitivity could be blocked by the phospholipase A2 inhibitors mepacrine and n-bromophenacyl-bromide, suggesting an involvement of phospholipase A2 in the process of beta-adrenergic sensitization. The sensitizing action of arachidonic acid was blocked by the lipoxygenase inhibitors esculetin and nordihydroguaiaretic acid, but not by the cyclo-oxygenase inhibitor indomethacin. Supersensitivity was likewise evoked by 15-S-hydroxyeicosatetraenoic acid (15-S-HETE), but not by 5-S-HPETE or 5-S-HETE. These findings suggest that the phospholipase A2-15-lipoxygenase pathway plays a role in the induction of beta-adrenergic supersensitivity in the cultured cardiomyocytes and point to a new physiological role of the lipoxygenase product 15-S-HETE.
Wallukat
G
G
Central Institute for Cardiovascular Research, Academy of Sciences, Berlin-Buch, Germany.
Nemecz
G
G
Farkas
T
T
Kuehn
H
H
Wollenberger
A
A
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured / Q000187:drug effects; D002909:Chronobiology Phenomena; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology*; D007773:Lactates / Q000494:pharmacology; D015289:Leukotrienes / Q000494:pharmacology; D008555:Melitten / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D011457:Prostaglandins D / Q000494:pharmacology*; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D000098:Acetophenones; D001095:Arachidonic Acids; D006893:Hydroxyeicosatetraenoic Acids; D007773:Lactates; D015289:Leukotrienes; D011457:Prostaglandins D; D011943:Receptors, Adrenergic, beta; D008555:Melitten; D016718:Arachidonic Acid; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C025348:arachidonic acid 5-hydroperoxide; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine; D007545:Isoproterenol; C006821:4-bromophenacyl bromide