Differential effect of cytochrome P-450 omega-hydroxylase inhibition on O2-induced constriction of arterioles in SHR with early and established hypertension.
OBJECTIVE
To determine whether two structurally and mechanistically different inhibitors of cytochrome P-450 omega-hydroxylase would alter the enhanced vasoconstrictor response to elevated PO2 in arterioles of spontaneously hypertensive rats (SHR). Cytochrome P-450 omega-hydroxylases, which catalyze the formation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid from arachidonic acid, have been proposed to serve as microvascular O2 sensors.


METHODS
Arteriolar diameters were measured in the in situ cremaster muscle of 4- to 6- and 12- to 16-week-old SHR and normotensive Wistar-Kyoto (WKY) controls during superfusion with physiological salt solution (PSS) equilibrated with 0% O2 and 21% O2 before and after P-450 enzyme inhibition.


RESULTS
The P-450 omega-hydroxylase inhibitors 17-octadecynoic acid (17-ODYA) and N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS) significantly reduced O2-induced constriction of arterioles of 12- to 16-week-old SHR and WKY and eliminated the difference in the response between the two groups. In contrast, both enzyme inhibitors attenuated the O2-induced constriction of arterioles in the younger WKY, but not in the 4- to 6-week-old SHR.


CONCLUSIONS
These results support the hypothesis that cytochrome P-450 4A may act as an O2 sensor in the skeletal muscle microcirculation and suggest that 20-hydroxyeicosatetraenoic acid plays an important role in the enhanced response to elevated PO2 in the SHR with established hypertension. Other mechanisms seem to contribute to the enhanced sensitivity of arterioles to elevated PO2 in young SHR during the early development of hypertension.
Kunert
M P
MP
Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Roman
R J
RJ
Falck
J R
JR
Lombard
J H
JH
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010100:Oxygen / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D013450:Sulfones / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D000577:Amides; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D013450:Sulfones; C047008:17-octadecynoic acid; D003577:Cytochrome P-450 Enzyme System; C117975:DDMS; D006899:Mixed Function Oxygenases; C409986:cytochrome P-450 omega-hydroxylase; D010100:Oxygen