Effects of enalaprilat on venoconstriction to norepinephrine: role of prostaglandins.
OBJECTIVE
Most patients with cardiovascular disease continue to receive both aspirin and an angiotensin-converting enzyme (ACE) inhibitor. This is despite the fact that ACE inhibition also inhibits the enzyme kininase II and leads to accumulation of bradykinin which increases prostaglandins. We hypothesized that in normal veins, vasodilator prostaglandins contribute significantly to ACE inhibitor dilation of norepinephrine-induced venoconstriction, and this would be blocked by cyclooxygenase inhibition.


METHODS
The study was performed using the in vivo dorsal hand vein technique for measuring vascular responses directly. Venoconstriction to norepinephrine infusions (0.5-1024 ng/min) was assessed in eight normal subjects (46+/-5 years, mean+/-S.E.M.) during coinfusion of saline in one hand (control) and enalaprilat (1000 microg/min) in the contralateral hand. On a second morning (7+/-1 days apart, mean+/-S.E.M., random order), the same procedure was repeated with indomethacin (3 microg/min) coinfusion in both hands.


RESULTS
Enalaprilat shifted the norepinephrine dose-response curve to the right (P=0.024) and increased the norepinephrine log ED(50) (dose required to cause 50% venoconstriction) from 1.70+/-0.08 to 2.31+/-0.11 log ng/min (P=0.001). Indomethacin shifted the norepinephrine dose-response curve to the left (P=0.018) and decreased the norepinephrine log ED(50) from 1.70+/-0.08 to 1.09+/-0.18 log ng/min (P=0.002). In the presence of indomethacin, enalaprilat caused only a small but significant increase in the norepinephrine log ED(50), from 1.09+/-0.18 to 1.29+/-0.18 log ng/min (P=0.041).


CONCLUSIONS
The results suggest that vasodilator prostaglandins contribute significantly to the attenuation of sympathetic venoconstriction by enalaprilat. This may have clinical relevance in patients receiving aspirin and ACE inhibitors in the setting of increased sympathetic activity.
Dzeka
T Nancy
TN
Department of Physiology, The University of Western Ontario and Lawson Health Research Institute, Ontario, London, Canada.
Townley
Richard
R
Arnold
J Malcolm O
JM
D000328:Adult; D000704:Analysis of Variance; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015773:Enalaprilat / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D006225:Hand / Q000098:blood supply; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000494:pharmacology*; D011453:Prostaglandins / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D014662:Vasoconstrictor Agents; D015773:Enalaprilat; D009638:Norepinephrine; D007213:Indomethacin