Activation of protein kinase C as a modulator of potentiated UK-14304-induced contractions in dog mesenteric artery and vein.
We assessed the role of protein kinase C (PKC) in the mechanism responsible for the potentiation of UK-14304-induced contractions produced when isolated dog mesenteric vascular rings were pretreated with threshold concentrations of 12-O-tetradecanoyl-phorbol-13-acetate (TPA), KCl, or endothelin-1 (ET-1). In dog mesenteric artery. UK-14304 produced a biphasic concentration-response curve in the presence of TPA, KCl, or ET-1, with the curve portion at lower concentrations being alpha 2-adrenoceptor dependent and the portion at higher concentrations being alpha 1-adrenoceptor dependent. Calphostin C (10(-6)M), a PKC inhibitor, abolished amplified UK-14304-induced contraction in the TPA-pretreated tissues. In the KCl- and ET-1-pretreated tissues. 10(-6)M calphostin C antagonized amplified UK-14304-induced contractions by approximately 20% in both parts of the concentration-response curve. In contrast, in dog mesenteric vein, amplified UK-14304-induced contractions by TPA, KCl, and ET-1 were entirely dependent on alpha 2-adrenoceptors. Calphostin C (10(-6)M), which in control experiments had no effect on KCl-induced contraction and antagonized responses to TPA by 60.1%, inhibited UK-14304-induced contraction by 18.3%. Amplified UK-14304-induced contraction was antagonized by 10(-6)M calphostin C by 21.8% in KCl-precontracted tissues, 58.1% in ET-1-precontracted tissues, and 66.3% in TPA-precontracted tissues. In the ET-1- and TPA-pretreated dog mesenteric veins, 10(-6)M calphostin C decreased maximal tensions of enhanced UK-14304-induced contractions to the same level as the UK-14304-induced maximal tension inhibited by 10(-6)M calphostin C in untreated dog mesenteric vein. Therefore, TPA can be a precontracting agent that amplifies UK-14304-induced contractions through PKC activation in both dog mesenteric artery and vein. PKC predominantly mediates the contraction amplification mechanisms after exposure to ET-1 in dog mesenteric vein and does not play a major role in the amplification of UK-14304-induced contraction by KCl in both dog mesenteric artery and vein. These data show that a common mechanism need not underlie amplification of adrenergic responses in mesenteric artery and vein.
Shimamoto
H
H
Department of Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Shimamoto
Y
Y
Kwan
C Y
CY
Daniel
E E
EE
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000068438:Brimonidine Tartrate; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D008642:Mesenteric Veins / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D011810:Quinoxalines / Q000494:pharmacology*; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
D000316:Adrenergic alpha-Agonists; D009281:Naphthalenes; D011810:Quinoxalines; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D000068438:Brimonidine Tartrate; D011189:Potassium Chloride; D011493:Protein Kinase C; C058819:calphostin C