Decrease in vascular TxA2 receptors in a subgroup of rabbits unresponsive to a TxA2 mimetic

Abstract

In rabbit pulmonary artery, endothelium-dependent contractions to arachidonic acid and methacholine are mediated by thromboxane (Tx) A2. The TxA2 mimetics U-46619 and (1S-[1 alpha,2 beta(5Z),3 alpha(1E,3R*),4 alpha])-7-[3- [3-hydroxy-4-(4'-iodophenoxy)-1-butenyl]-7-oxabicyclo(2.2.1)hep tan-2-yl]- 5-heptenoic acid (I-BOP), norepinephrine, and endothelin produced endothelium-independent contractions. Arachidonic acid, methacholine, U-46619, and I-BOP failed to produce contractions in a subgroup of rabbits (25%). Nonresponder arteries contracted similarly to norepinephrine and endothelin as responder arteries. The affinity (Kd) and density (Bmax) of TxA2 receptors in crude pulmonary artery membranes were assessed via equilibrium binding studies using 125I-BOP. There was no difference in Kd between the two groups (0.49 +/- 0.17 vs. 0.32 +/- 0.14 nM, responder vs. nonresponder). There was a significant decrease in Bmax (123 +/- 21 vs. 28 +/- 11 fmol/mg protein, responder vs. nonresponder; P < 0.01) of receptors in the nonresponders. Nonresponder aortas also did not contract to U-46619 and exhibited a decrease in TxA2 receptors, indicating that the difference is not specific for the pulmonary artery. Nonresponder platelets aggregated to U-46619, suggesting that the platelet receptor is not altered. TxA2-receptor expression may be regulated in vivo. Nonresponder rabbits may provide a useful model for studying these receptors in vascular disease.

Role of superoxide and thromboxane receptors in acute angiotensin II-induced vasoconstriction of rabbit vessels

“…Thromboxane mimetics like U46619 do not contract blood vessels from vTPϪ rabbits. However, as previously reported, contractions to other vasoconstrictors, like KCl, norepinephrine and endothelin are identical in vTPϩ and vTPϪ rabbits (5). For all described studies, the presence or absence of functional vascular TP receptors was confirmed by testing for U46619-induced contractions.…”

“…Finally, to support that a portion of angiotensin II-induced contractions required an interaction with the vascular TP receptor, we used the vascular TPreceptor-deficient rabbits. These rabbits have been well characterized in previous studies (5,25) and have been shown to contract similarly to agonists like KCl, endothelin, and norepinephrine. This is the first study to evaluate angiotensin II responses, and results showed that contractions were decreased in vTPϪ compared with the vTPϩ rabbits.…”

“…Arteries were cleaned of adhering fat and connective tissue and used for either vascular reactivity or eicosanoid metabolism studies. We previously identified a subgroup of NZW rabbits that have a significant decrease in vascular smooth muscle cell TP receptors and are referred to as vTPϪ (5). Rabbits with vascular TP receptors are called vTPϩ.…”

Thromboxane A2-induced arrhythmias in the anesthetized rabbit

“…The variability of the rabbit TxA 2 receptor stimulation does have empirical support. Buzzard et al (3) reported that 25% of isolated pulmonary blood vessels did not respond positively to TxA 2 mimetics. Animals that did not exhibit positive responses to TxA 2 receptor stimulation were designated as nonresponders and were shown to have a significant decrease in the number of vascular TxA 2 receptors but not platelet receptors.…”

Characterization of endothelial thromboxane receptors in rabbit aorta

“…In previous studies, we observed that blood vessels obtained from approximately 25% of New Zealand White (NZW) rabbits did not contract to TXA 2 agonists (16, 17). Using a combination of physiological, biochemical and pharmacological studies, this subgroup of rabbits was found to be deficient in the vascular smooth muscle cell TP receptor, but not the platelet TP receptor.…”