Phorbol-12,13-dibutyrate-induced vasoconstriction in vivo: characterization of response in genetic hypertension.
To assess the role of protein kinase C (PKC) in the control of vessel tone in vivo in genetic hypertension, the vascular effects of phorbol-12,13-dibutyrate (PDBu), a PKC activator, was measured in the autoperfused hindlimb of reserpinized spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). PDBu infusion (1-3000 ng/kg/min) into the hindlimb elevated perfusion pressure in a dose-related manner. Vasoconstriction response characteristics (latency, T1/2 to peak effect, decay of effect) of PDBu were significantly longer (2- to 10-fold) than that produced by membrane receptor agonists; phenylephrine, SKF 89748, a lipophilic alpha-1 agonist, angiotensin II and 5-hydroxytryptamine. The tonic vasoconstriction induced by PDBu was not antagonized by prazosin, rauwolscine, cyproheptadine, [Sar1lle8]-angiotensin II but was inhibited reversibly by microbial PKC-inhibitors, K252a and staurosporine at concentrations (1.56-2.8 micrograms/kg/min) which did not block vasoconstriction by phenylephrine or 5-hydroxytryptamine. The EC50 for PDBu was identical in SHR and WKY. However, the maximal response to PDBu was significantly greater in SHR compared to WKY. Staurosporine lowered mean arterial pressure equally in SHR (20%) and WKY (17%) but reduced perfusion pressure in SHR (13%) to a slightly greater extent than in WKY (5%). Unlike the in vivo response, aortic rings removed from SHR were more sensitive to cumulative doses of PDBu than rings from WKY. It is concluded that PDBu-vasoconstriction in vivo is mediated largely through activation of PKC.(ABSTRACT TRUNCATED AT 250 WORDS)
Bilder
G E
GE
Rorer Central Research, King of Prussia, Pennsylvania.
Kasiewski
C J
CJ
Perrone
M H
MH
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012995:Solubility; D014661:Vasoconstriction / Q000187:drug effects*
D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C