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Analysis of thromboxane receptor-mediated responses in the feline pulmonary vascular bed
A D Kaye1, B D Nossaman, I N Ibrahim
1Department of Anesthesiology, Tulane University Medical Center, New Orleans, LA 70112-2699.
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.
Design:
Prospective, randomized, controlled study with repeated measures.
Setting:
University research laboratory.
Subjects:
Twenty-nine adult cats obtained from the Tulane University School of Medicine vivarium.
Interventions:
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.
Measurements And Main 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.
Insights
GR32191, a novel thromboxane receptor antagonist, selectively blocked pulmonary vasoconstriction in cats. This agent demonstrated competitive and reversible blockade, suggesting potential therapeutic use for pulmonary hypertensive and thromboembolic disorders.
Area of Science:
- Pulmonary vascular pharmacology
- Cardiovascular research
Background:
- Thromboxane (TX) plays a role in lung pathophysiology.
- Novel thromboxane receptor antagonists are being developed for therapeutic intervention.
Purpose of the Study:
- To investigate the selectivity and duration of action of GR32191, a thromboxane receptor antagonist, in the feline pulmonary vascular bed.
- To assess the potential of GR32191 as a therapeutic agent for pulmonary hypertensive and thromboembolic disorders.
Main Methods:
- Prospective, randomized, controlled study with repeated measures in anesthetized cats.
- GR32191 administered intravenously under constant-flow conditions.
- Pulmonary vasoconstrictor responses to U46619 (thromboxane mimic) and other agents were measured.
Main Results:
- GR32191 significantly decreased pulmonary vasoconstrictor responses to U46619 in a dose-dependent manner.
- GR32191 exhibited selectivity, with no significant effect on responses to prostaglandin D2, PGF2 alpha, serotonin, BAY K8644, or norepinephrine.
- The blockade was competitive and reversible, with recovery of responses observed 90-180 minutes post-administration.
Conclusions:
- Discrete thromboxane A2 receptors, distinct from PGF2 alpha and PGD2 receptors, are present in the feline pulmonary vascular bed.
- GR32191 selectively and reversibly antagonizes thromboxane A2 receptor-mediated responses.
- GR32191 shows promise as a therapeutic agent for pulmonary hypertensive and thromboembolic conditions.