Analysis of thromboxane receptor-mediated responses in the feline pulmonary vascular bed.
OBJECTIVE
Current evidence suggests that thromboxane plays a role in pathophysiologic processes in the lung. Efforts to find effective, specific therapy to modify these effects have led to the development of a new class of thromboxane receptor blockers. This present investigation examined the selectivity and duration of the inhibitory effects of one of these novel agents in the pulmonary vascular bed of anesthetized cats.


METHODS
Prospective, randomized, controlled study with repeated measures.


METHODS
University research laboratory.


METHODS
Twenty-nine adult cats obtained from the Tulane University School of Medicine vivarium.


METHODS
The effects of GR32191, a thromboxane receptor antagonist, were investigated under constant-flow conditions in the intact-chest cat, using a triple-lumen, 6-Fr, balloon perfusion catheter that was placed by means of fluoroscopic guidance. Data were analyzed using a paired or unpaired t-test or analysis of variance. A p < .05 was considered statistically significant.


RESULTS
Aortic, left atrial, and left lobar arterial pressures were measured. After administration of GR32191 (0.25 and 1.0 mg/kg iv), pulmonary vasoconstrictor responses to U46619, a thromboxane mimic, were significantly decreased. Blockade was overcome with higher doses of the thromboxane mimic. GR32191 was without significant effect on the responses to prostaglandin (PG) D2, PGF2 alpha, serotonin, the calcium-channel agonist BAY K8644, or norepinephrine. Additionally, GR32191 did not alter baseline vascular pressures. Responses to U46619 returned to 50% of control value 90 mins after administration of 0.25 mg/kg of U46619. Responses to GR32191 returned to 50% of control value 180 mins after administration of 1.0 mg/kg of GR32191. These data suggest that GR32191 selectively blocks thromboxane A2 receptor-mediated responses in a competitive and reversible manner in the pulmonary vascular bed of the cat.


CONCLUSIONS
These results are consistent with the hypothesis that discrete thromboxane A2 receptors, unrelated to receptors activated by PGF2 alpha or PGD2, are present in the feline pulmonary vascular bed. Specific thromboxane receptor antagonists, such as GR32191, could be useful therapeutic agents in the treatment of pulmonary hypertensive and thromboembolic disorders.
Kaye
A D
AD
Department of Anesthesiology, Tulane University Medical Center, New Orleans, LA 70112-2699.
Nossaman
B D
BD
Ibrahim
I N
IN
DeWitt
B J
BJ
Feng
C J
CJ
Kadowitz
P J
PJ
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002415:Cats; D015237:Dinoprost / Q000494:pharmacology; D006538:Heptanoic Acids / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011446:Prospective Studies; D015230:Prostaglandin D2 / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000502:physiology*; D011897:Random Allocation; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D001713:Biphenyl Compounds; D006538:Heptanoic Acids; D017482:Receptors, Thromboxane; D012701:Serotonin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D015237:Dinoprost; C060013:vapiprost; D015230:Prostaglandin D2; D009638:Norepinephrine