ENHANCED IN-VIVO ALPHA(1)-ADRENOCEPTOR-MEDIATED AND ALPHA(2)-ADRENOCEPTOR-MEDIATED VENOCONSTRICTION WITH INDOMETHACIN IN HUMANS

Vasodilator prostaglandins are released in vitro from endothelium duri ng adrenergic stimulation. We hypothesized that indomethacin would blo ck this production in vivo and increase venoconstriction to alpha(1)- and alpha(2)-stimulation but not to the nonadrenergic agonist PGF(2 al pha). Hand vein distension was measured in 24 normal subjects (23.0 +/ - 0.5 yr) during local infusions of phenylephrine (8-12,000 ng/min), c lonidine (3-7,000 ng/min), or PGF(2 alpha) (1-2,048 ng/min) plus indom ethacin (3 mu g/min) versus saline on two separate days. Dose-dependen t venoconstriction to phenylephrine occurred in all subjects, with a p arallel shift to the left with indomethacin (P = 0.003) and a decrease in the phenylephrine 50% effective dose (1,009 vs. 241 ng/min, geomet ric means, P = 0.012). Venoconstriction to clonidine was more variable , with most subjects eliciting a biphasic response (initial venoconstr iction followed by attenuation). With indomethacin, the dose-response curve was displaced up and to the left (P = 0.005), and peak venoconst riction was increased (51.1 +/- 6.8 vs. 27.2 +/- 5.3% of control, P = 0.018) without a biphasic response. In all subjects, PGF(2 alpha) elic ited dose-dependent venoconstriction that was not altered by indometha cin. Thus venous alpha(1)- and alpha(2)-stimulation results in release of vasodilator prostaglandins that antagonize the venoconstrictor res ponse. This modulates the sympathetic response of venous smooth muscle and may be important in diseases with endothelial dysfunction.