© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Effects of enalaprilat on venoconstriction to norepinephrine: role of prostaglandins
aDepartments of Physiology and Pharmacology, The University of Western Ontario and Lawson Health Research Institute, London, Ontario, Canada
bDepartment of Medicine, The University of Western Ontario and Lawson Health Research Institute, London, Ontario, Canada
malcolm.arnold{at}lhsc.on.ca
* Corresponding author. London Health Sciences Centre, Victoria Campus, Room S226A, 375 South Street, London, Ontario, Canada N6A 4G5. Tel.: +1-519-667-6650; fax: +1-519-667-6526.
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 µg/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 µg/min) coinfusion in both hands. Results: Enalaprilat shifted the norepinephrine dose–response curve to the right (P = 0.024) and increased the norepinephrine log ED50 (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 ED50 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 ED50, 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.
KEYWORDS Clinical; Vasculature; Organism; Pharmacology