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Daltroban blocks thromboxane responses in the pulmonary vascular bed of the cat
J S Hood1, B D Nossaman, I N Ibrahim
1Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112.
Insights
Daltroban selectively blocks thromboxane (Tx) A2 receptors in cat pulmonary vasculature. This agent reversibly inhibits TxA2 mimic responses without affecting other vasoactive substances, supporting distinct TxA2 receptors.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Pulmonary Circulation
Background:
- Thromboxane (Tx) A2 is a potent vasoconstrictor.
- The role of TxA2 receptors in pulmonary vascular responses requires further elucidation.
- Daltroban is a selective TxA2 receptor antagonist.
Purpose of the Study:
- To investigate the effects of daltroban on pulmonary vascular responses in cats.
- To determine the selectivity of daltroban against TxA2 receptor-mediated vasoconstriction.
- To explore the presence of distinct TxA2 receptors in the feline pulmonary vasculature.
Main Methods:
- Intact-chest cat model with constant-flow pulmonary circulation.
- Administration of daltroban (5 mg/kg iv).
- Assessment of vascular pressure responses to TxA2 mimics (U-46619, U-44069), prostaglandins (PGF2α, PGD2, 9α,11β-PGF2), arachidonic acid, norepinephrine, serotonin, angiotensin II, BAY K 8644, endothelin peptides, and platelet-activating factor.
Main Results:
- Daltroban significantly decreased responses to U-46619 and U-44069 without affecting responses to PGF2α, PGD2, or 9α,11β-PGF2.
- Dose-response curves for TxA2 mimics were shifted rightward in a parallel manner.
- Daltroban did not alter responses to norepinephrine, serotonin, angiotensin II, BAY K 8644, endothelin peptides, or platelet-activating factor.
- Responses to U-46619 recovered to 50% of control within 90 minutes, indicating reversibility.
- Responses to arachidonic acid were significantly decreased post-daltroban administration.
Conclusions:
- Daltroban selectively and competitively antagonizes TxA2-receptor-mediated responses in the feline pulmonary vasculature.
- The findings support the existence of discrete TxA2 receptors, separate from those activated by PGF2α, PGD2, or 9α,11β-PGF2.
- Pulmonary vasoconstriction induced by platelet-activating factor and endothelin peptides is not mediated via TxA2 receptor activation in cats.
Abstract:
The influence of daltroban (BM13.505; SK&F 96148), a thromboxane (Tx) A2-receptor-blocking agent, on responses to the TxA2 mimics U-46619 and U-44069 was investigated in the pulmonary vascular bed of the intact-chest cat under constant-flow conditions. Daltroban (5 mg/kg iv) had no significant effect on mean baseline vascular pressures but significantly decreased responses to the TxA2 mimics without altering responses to prostaglandin (PG) F2 alpha or PGD2 or the PGD2 metabolite 9 alpha, 11 beta-PGF2. Dose-response curves for U-46619 and U-44069 were shifted to the right in a parallel manner, and daltroban had no significant effect on responses to norepinephrine, serotonin, angiotensin II, BAY K 8644, endothelin-(ET) 1, ET-2, or platelet-activating factor (PAF). After administration of daltroban, responses to U-46619 returned to 50% of control in 90 min and responses to the PG and TxA2 precursor arachidonic acid were decreased significantly. These results suggest that daltroban selectively antagonizes TxA2-receptor-mediated responses in a competitive and reversible manner. These data provide support for the hypothesis that discrete TxA2 receptors unrelated to receptors stimulated by PGF2 alpha, PGD2, or 9 alpha, 11 beta-PGF2 are present in the pulmonary vascular bed of the cat. The present data suggest that pulmonary vasoconstrictor responses to PAF and ET peptides are not dependent on activation of TxA2 receptors in the cat.