This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pfister, S. L. Articles by Campbell, W. B. Search for Related Content PubMed PubMed Citation Articles by Pfister, S. L. Articles by Campbell, W. B. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

(Hypertension. 1997;29:303.)
© 1997 American Heart Association, Inc.

Arthur C. Corcoran Memorial Lecture

Vascular Smooth Muscle Thromboxane A₂ Receptors Mediate Arachidonic Acid-Induced Sudden Death in Rabbits

Sandra L. Pfister; Donna A. Kotulock; William B. Campbell

From the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee.

Correspondence to Sandra L. Pfister, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail spfister{at}post.its.mcw.edu

We recently identified a subgroup of rabbits (called nonresponders) that were deficient in vascular thromboxane A₂ receptors. Thromboxane A₂-mediated platelet aggregation was not different between responders and nonresponders. In the present study, we utilized these nonresponders as a model to study the relative contribution of the platelet and vascular thromboxane A₂ receptors to the observed hemodynamic responses associated with arachidonic acid-induced sudden death. Mean arterial pressure was slightly but not significantly lower in the nonresponders compared with the responders. However, nonresponders were protected from arachidonic acid-induced sudden death. While 100% of the responders died at the 2.0 mg dose of arachidonic acid, only 27% of nonresponders died at this same dose. Administration of the thromboxane A₂ mimetic U46619 (5 µg/kg IV) decreased blood pressure by 41±6 mm Hg in responders but had no effect in the nonresponders. The affinity and density of thromboxane A₂ receptors in cultured aortic vascular smooth muscle cells obtained from both responders and nonresponders were assessed using radioligand binding. The K_d values were not different (4.4±1.0 versus 2.4±0.6 nmol/L, responder versus nonresponder). However, there was a significant decrease in the density of receptors from vascular smooth muscle cells of nonresponders (B_max=397±59 versus 157±59 fmol/10⁶ cells, responder versus nonresponder, P<.01). U46619 produced a concentration-dependent increase in [³H]-thymidine incorporation into responder vascular smooth muscle cells but had no effect in the nonresponder cells. Using an anti-thromboxane A₂ receptor antibody, we compared the amount of receptor expressed in aortic tissue obtained from responders and nonresponders. Consistent with the results observed with [³H]-thymidine uptake and radioligand binding assays, the expression of thromboxane A₂ receptor protein was decreased in nonresponder compared with responder vascular tissue. Platelet thromboxane A₂ receptor expression was not different. These studies demonstrate that the vascular smooth muscle cells of nonresponder rabbits are deficient in the thromboxane A₂ receptor. Furthermore, the reduction in arachidonic acid-induced sudden death in nonresponders indicates that the vascular smooth muscle thromboxane A₂ receptor mediates this effect.

Key Words: thromboxane A₂ • vascular smooth muscle cells • arachidonic acid • mean arterial pressure • radioligand binding • U46619 • mitogenesis

Abbreviations: HR = heart rate • I-BOP = [1S-(1,2ß(5Z),3(1E,3R*),4)]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo [2.2.1]heptan-2-y1]-5-heptenoic acid • MAP = mean arterial pressure • PAGE = polyacrylamide gel electrophoresis • PG = prostaglandin • PRP = platelet-rich plasma • TTBS = Tris-buffered saline (20 mmol/L TRIZMA hydrochloride; 500 mmol/L NaCl, pH 7.5) with Tween-20 • TX = thromboxane

This article has been cited by other articles:

				A. H. Stephenson, R. S. Sprague, J. L. Losapio, and A. J. Lonigro Differential effects of 5,6-EET on segmental pulmonary vasoactivity in the rabbit Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2153 - H2161. [Abstract] [Full Text] [PDF]

				R. D. Minshall, D. Pavcnik, P. V. Halushka, and K. Hermsmeyer Progesterone regulation of vascular thromboxane A2 receptors in rhesus monkeys Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1498 - H1507. [Abstract] [Full Text] [PDF]