Altered prostacyclin synthesis by aortae from hepatic portal vein-constricted rats: evidence for effects on protein kinase C and calcium.
To investigate the mechanisms causing reduced systemic vascular reactivity to vasoconstrictor agents in portal hypertension, we studied receptor- and signal-transduction-linked PGI2 (a vasodilator) synthesis (measured as 6-oxo-PGF1 alpha by radioimmunoassay) in the aorta (ex vivo) of portal vein-constricted rats. PGI2 synthesis was stimulated by adrenaline (via heterogeneous alpha-adrenoceptors), phorbol ester dibutyrate (a protein kinase C activator), arachidonic acid (the substrate for PGI2 synthesis) and the Ca2+ ionophore A23187 (A23187) and thapsigargin (both of which elevate intracellular Ca2+, which in turn elicits the release of arachidonic acid). The release of PGI2 by the aortae of rats with portal hypertension in comparison to sham-operated controls was: 1) enhanced in response to adrenaline, 2) reduced in response to phorbol ester dibutyrate, A23187 and thapsigargin and 3) unchanged in response to arichidonic acid. These data indicate that in aortae from rats with experimental portal hypertension: i) there are no changes in the enzymes involved in PGI2 synthesis (cyclooxygenase, PGI2 synthase), ii) there is a specific increase in adrenoceptor-linked PGI2 synthesis in aortae which may contribute to arterial vasodilation in this experimental model and 3) the diminished response of PGI2 synthesis to A23187, phorbol ester dibutyrate and thapsigargin indicates that there is a generalised attenuation of protein kinase C activator activity and of Ca2+. Since Ca2+ is a key component of excitation-contraction coupling and protein kinase C activator has been implicated in mediating this event, attenuation of these systems may also explain, at least in part, the known reduced vasoactivity of aortae from rats with portal hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
Jeremy
J Y
JY
University Department of Chemical Pathology and Human Metabolism, Royal Free Hospital and School of Medicine, University of London, UK.
Mikhailidis
D P
DP
Karatapanis
S
S
Harry
D
D
Burroughs
A K
AK
McIntyre
N
N
Stansby
G
G
Jacobs
M
M
McCormick
A
A
D000818:Animals; D001011:Aorta / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D004837:Epinephrine / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis*; D006975:Hypertension, Portal / Q000378:metabolism*; D008026:Ligation; D008099:Liver / Q000098:blood supply; D008102:Liver Circulation; D008297:Male; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011169:Portal Vein; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin
D013729:Terpenes; D015240:Phorbol 12,13-Dibutyrate; D000001:Calcimycin; D019284:Thapsigargin; D011464:Epoprostenol; D011493:Protein Kinase C; D002118:Calcium; D004837:Epinephrine