Evidence for the involvement of protein kinase C in acidic pH-induced contraction in spontaneously hypertensive rat aorta.
This study was performed to test the hypothesis that activation of protein kinase C (PKC) is a mechanism underlying the acidic pH-induced contraction (APIC) in spontaneously hypertensive rat (SHR) aorta. Changing pH of the bathing solution from 7.4 to 6.5 induced a marked contraction of SHR aorta. PKC inhibitors, GF109203X and calphostin C markedly inhibited the APIC selectively, without having a marked effect on the KCl-induced contraction. Inhibitors of mitogen-activated protein kinase kinase, U0126 and PD98059 mildly but significantly attenuated the APIC. However, at the similar concentrations both U0126 and PD98059 inhibited the KCl-induced contraction in a manner similar to that observed in APIC. D-609, an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC) markedly inhibited the APIC and the extent of inhibition by this compound was similar to that shown by PKC inhibitors. Whereas, U-73122 and propranolol, inhibitors of phosphatidylinositol-specific PLC and phosphatidate phosphohydrolase, respectively, had no affect on the APIC. A tyrosine kinase inhibitor, tyrphostin 23 and GF109203X inhibited the APIC in an additive manner, and together they abolished the contractile response. From all these results, it is suggested that a significant component of the contraction observed in response to acidosis in SHR aorta is dependent upon the activation of PKC that seems to be the downstream event of the activation of PC-PLC. Furthermore, PKC- and tyrosine kinase-dependent pathways underlying the APIC are independent of each other.
Rohra
Dileep Kumar
DK
Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. dileep.rohra@aku.edu
Yamakuni
Tohru
T
Ito
Saiko
S
Saito
Shin-Ya
SY
Ohizumi
Yasushi
Y
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D004357:Drug Synergism; D004963:Estrenes / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D009636:Norbornanes; D010711:Phosphatidate Phosphatase / Q000037:antagonists & inhibitors / Q000494:pharmacology; D043265:Phosphatidylinositol Diacylglycerol-Lyase / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011189:Potassium Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
D001952:Bridged-Ring Compounds; D002070:Butadienes; D004963:Estrenes; D005419:Flavonoids; D007211:Indoles; D008301:Maleimides; D009281:Naphthalenes; D009570:Nitriles; D009636:Norbornanes; D011760:Pyrrolidinones; D013859:Thiocarbamates; D013871:Thiones; D020032:Tyrphostins; C113580:U 0126; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C046498:tricyclodecane-9-yl-xanthogenate; D011189:Potassium Chloride; D011433:Propranolol; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D010711:Phosphatidate Phosphatase; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C; D043265:Phosphatidylinositol Diacylglycerol-Lyase; C058819:calphostin C; C070515:bisindolylmaleimide I; C060641:tyrphostin A23; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one