Enhanced in vivo alpha1- and alpha2-adrenoceptor-mediated venoconstriction with indomethacin in humans.
Vasodilator prostaglandins are released in vitro from endothelium during adrenergic stimulation. We hypothesized that indomethacin would block this production in vivo and increase venoconstriction to alpha1- and alpha2-stimulation but not to the nonadrenergic agonist PGF2alpha. Hand vein distension was measured in 24 normal subjects (23.0 +/- 0.5 yr) during local infusions of phenylephrine (8-12,000 ng/min), clonidine (3-7,000 ng/min), or PGF2alpha (1-2,048 ng/min) plus indomethacin (3 microg/min) versus saline on two separate days. Dose-dependent venoconstriction to phenylephrine occurred in all subjects, with a parallel shift to the left with indomethacin (P = 0. 003) and a decrease in the phenylephrine 50% effective dose (1,009 vs. 241 ng/min, geometric means, P = 0.012). Venoconstriction to clonidine was more variable, with most subjects eliciting a biphasic response (initial venoconstriction followed by attenuation). With indomethacin, the dose-response curve was displaced up and to the left (P = 0.005), and peak venoconstriction was increased (51.1 +/- 6.8 vs. 27.2 +/- 5.3% of control, P = 0.018) without a biphasic response. In all subjects, PGF2alpha elicited dose-dependent venoconstriction that was not altered by indomethacin. Thus venous alpha1- and alpha2-stimulation results in release of vasodilator prostaglandins that antagonize the venoconstrictor response. This modulates the sympathetic response of venous smooth muscle and may be important in diseases with endothelial dysfunction.
Callow
I D
ID
University of Western Ontario, London, Ontario, Canada N6A 5C1.
Campisi
P
P
Lambert
M L
ML
Feng
Q
Q
Arnold
J M
JM
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000328:Adult; D003000:Clonidine / Q000008:administration & dosage / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010656:Phenylephrine / Q000008:administration & dosage / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects*
D000316:Adrenergic alpha-Agonists; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D010656:Phenylephrine; D015237:Dinoprost; D003000:Clonidine; D007213:Indomethacin