Transforming growth factor-beta 1 inhibits postischemic increases in splanchnic vascular resistance.
Anesthesized male rabbits having a resting mean arterial pressure of 81 +/- 4 mm Hg and superior mesenteric artery blood flow of 91 +/- 7 mL min-1 were subjected to 60 min of splanchnic ischemia followed by 60 min of reperfusion. Upon reperfusion, mean arterial pressure fell. Splanchnic blood flow also decreased but not in parallel with blood pressure; consequently, vascular resistance was increased over the reperfusion period. This increase in splanchnic vascular resistance was not affected by intravenous t-PA (0.5 mg kg-1 + 5 mg kg-1 hr-1) for 30 min prior to and throughout the reperfusion period or by intravenous L-NAME (1 mg kg-1 x 2). However, intravenous infusions of TGF-beta (18 or 54 micrograms kg-1) at the time of reperfusion dose dependently attenuated the increases in vascular resistance (p < 0.05). This effect of TGF-beta was enhanced by coadministration of t-PA and inhibited by the coadministration of L-NAME. We propose that the effects of TGF-beta are ultimately mediated via nitric oxide release, and conclude that this may be useful therapy for the prevention of reperfusion-associated injury following surgery or as an adjunct to thrombolytic therapy.
Thomas
G R
GR
Department of Cardiovascular Research, Genentech Inc., South San Francisco, California 94080.
Thibodaux
H
H
D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D007422:Intestines / Q000098:blood supply / Q000187:drug effects / Q000293:injuries; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D012769:Shock / Q000503:physiopathology / Q000517:prevention & control; D013152:Splanchnic Circulation / Q000187:drug effects*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects
D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; D001120:Arginine; D010959:Tissue Plasminogen Activator; D019331:NG-Nitroarginine Methyl Ester