Dissociation of phosphoinositide hydrolysis and positive inotropic effect of histamine mediated by H1-receptors in guinea-pig left atria.
The present study was undertaken to determine whether the phosphoinositide hydrolysis is responsible for the positive inotropic effect of histamine in guinea-pig left atria. Histamine induced hydrolysis of phosphoinositides and a positive inotropic effect in a concentration-dependent manner. These effects were antagonized by chlorpheniramine (0.1 mumol/l) but not by cimetidine (10 mumol/l). At a concentration of 1 mumol/l histamine produced a dual-component positive inotropic response composed of an initial increasing phase and a second and late developing, greater positive inotropic phase. Histamine (10 mumol/l) caused a gradual increase in the formation of [3H]inositol trisphosphate (IP3) and a significant increase in the [3H]IP3 level was detected 10 min after the stimulation. Thus, the increase in IP3 did not precede the increase in force of contraction. The phospholipase C inhibitors 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (100 mumol/l) and neomycin (100 mumol/l) significantly reduced the histamine-induced [3H]inositol monophosphate accumulation. However, pretreatment with the phospholipase C inhibitors did not affect the positive inotropic effect of histamine, either in its extent or in its pattern. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) (100 nmol/l) and phorbol-12,13-dibutyrate (PDBu) (100 nmol/l) also significantly inhibited the phosphoinositide hydrolysis induced by histamine. The inhibitory effect of the phorbol esters on the phosphoinositide response was completely abolished in the presence of 10 mumol/l 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), a protein kinase C inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
Hattori
Y
Y
Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan.
Endou
M
M
Shirota
M
M
Kanno
M
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D002219:Carbamates / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006632:Histamine / Q000502:physiology*; D006868:Hydrolysis; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology; D018021:Lithium Chloride; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D009355:Neomycin / Q000494:pharmacology; D048448:Phenylcarbamates; D010703:Phorbol Esters / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000502:physiology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D002219:Carbamates; D002712:Chlorides; D007546:Isoquinolines; D048448:Phenylcarbamates; D010703:Phorbol Esters; D010716:Phosphatidylinositols; D010879:Piperazines; D011969:Receptors, Histamine H1; C025508:2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate; D006632:Histamine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D008094:Lithium; D010738:Type C Phospholipases; D018021:Lithium Chloride; D009355:Neomycin