Objective:Thrombin is known to regulate vascular tone. We analyzed and compared mechanisms of thrombin action in primate renal and uterine arteries.
Results:Renal arteries responded to thrombin with relaxation, which was inhibited by NG-nitro-L-arginine or indomethacin and resersed to contractions by the combination. The relxations were also resersed to contractions by endohelial denudation. Conversely, thrombin caused uterine arterial contradictions that were unaffected by endothelial denudation. Relations in both renal arteries and contractions in uterine arteries were suppressed by hirudin (a specific thrombin inhibitor). Relaxant response to A23187 (Ca2+ ionophore), nitroprusside sodium (nitric oxide donor), and beraprost sodium (prostacyclin analogue) did not differ between renal and uterine arteries.
Conclusion:Thrombin-induced relaxation of renal artieries appears to be mediated by nitric oxide and vasodilaor prostaglandins liberated from the endothelium, whereas uterine arterial contraction is caused by an endothelium-independent mechanism.
1. Fleischer A, Schulman H, Farmakides G, et al. Uterine artery Doppler velocimetry in pregnant women with hypertension. Am J Obstet Gynecol1986;154:806-813.
2.
2. van Asselt K, Gudmundsson S, Lindqvist P, Marsal K. Uterine and umbilical artery velocimetry in preeclampsia. Acta Obstet Gynecol Scand1998;77:614-619.
3.
3. Cadroy Y, Grandjean H, Pichon J, et al. Evaluation of six markets of haemostatic system in normal pregnancy and pregnancy complicated by hypertension or pre-eclampsia. Br J Obstet Gynecol1993;100:416-420.
4.
4. Higgins JR, Walsh JJ, Darling MRN, Norris L, Bonnar J. Hemostasis in the uteroplacental and peripheral circulations in normotensie and pre-eclamptic pregnancies. Am J Obstet Gynecol1998;179:520-526.
5.
5. Coughlin SR. How the protease thrombin talks to cells. Proc Natl Acad Sci U S A1999;96:11023-11027.
7. Derkach DN, Ihara E, Hirano K, Nishimura J, Takahashi S, Kanaide H. Thrombin causes endothelium-dependent biphasic regulation vascular tone in the porcine renal interlobar artery. Br J Pharmacol2000;131:1635-1642.
8.
8. Ku DD, Zaleski JK. Receptor mechanism of thrombin-induced endothelium-dependent and endothelium-independent coronary vascular effects in dogs. J Cardiovasc Pharmacol1993;22:609-616.
9.
9. Jerius H, Beall A, Wooddrum D, Epstein A, Brophy C. Thrombin-induced vasospasm: Cellular signaling mechanisms. Surgery1998;123:46-50.
10.
10. Godin D, Rioux F, Marceau F, Drapeau G. Mode of action of thrombin in the rabbit aorta. Br J Pharmacol1995;115:903-908.
11.
11. Tesfamariam B. Thrombin receptor-mediated vascular relaxation differentiated by a receptor antagonist and desensitization. Am J Physiol1994;267:H1962-H1967.
12.
12. DeMey JG, Claeys M, Vanhoutte PM. Endothelium-dependent inhibitory effects o acetylcholine, adenosine triphosphate, thrombin and arachidonic acid in the canine femoral artery. J Pharmacol Exp Ther1982;222:166-173.
13.
13. Hamilton JR, Cocks TM. Heterogenous mechanismsof endothelium-dependent relaxation for thrombin and peptide activators of protease-activated receptor-1 in porcine isolated coronary artery. Br J Pharmacol2000;130:181-188.
14.
14. Hamilton JR, Nguyen PB, Cocks TM. Atypical protease-activated receptor mediates endothelium-dependent relaxation of human coronary arteries. Circ Res1998;82:1306-1311.
15.
15. Mizuno O, Hirano K, Nishimura J, Kubo C, Kanaiade H. Mechanismsof endothelium-dependent relaxation inducedby thrombin in the pig coronary artery. Eur J Pharmacol1998;351:67-77.
16.
16. Yang Z, Arnet U, Bauer E, et al. Thrombin-induced endothelium-dependent inhibition and direct activation of platelet-vessel wall interaction. Role of prostacyclin, nitric oxide, and thromboxane A2. Circulation1994;89:2266-2272.
17.
17. Chen G, Suzuki H. Some electrical properties of the endothelium-dependent hyperpolarization recorded from rat arterial smooth muscle cells. J Physiol1989;410:91-106.
18.
18. Toda N, Hatano Y, Hayashi S. Modificaion by stretches of the mechanical response of isolated cerebral and extracerebral arteries to vasoactive agents. Pflügers Arch1978;374:73-77.
19.
19. Kimura T, Toda N, Noda Y, Okamura T. Mechanisms of relaxation induced by angiotensin II in isolated canine and human uterine arteries. J Cardiovasc Pharmacol2001;37:585-595.
20.
20. Fenton JW, Villanueva GB, Ofosu FA, Maraganore JM. Thrombin inhibition by hirudin: How hirudin inhibits thrombin. Haemostasis1991;21:27-31.
21.
21. Toda N, Kimura T, Yoshida K, et al. Human uterine arterial relaxation induced by nitroxidergic nerve stimulation. Am J Physiol1994;266:H1446-H1450.
22.
22. Toda N. Beraprost sodium. Cardiovasc Drug Rev1988;6:222-238.
23.
23. Inoue M, Okamura T, Toda N. Influence of methylene blue and oxyhemoglobin on mammalian vascular responses to sodium nitroprusside and nitroglycerin. Arch Int Pharmacodynamics Ther1991;311:104-121.
24.
24. White RP, Shirasawa Y, Robertson JT. Comparison of responses elicited by alpha-thrombin in isolated canine basilar, coronary, measenteric, and renal arteries. Blood Vessels1984;21:12-22.
25.
25. Hatake K, Kakishita E, Wakabayashi I, Sakiyama N, Hishida S. Effect of aging on endothelium-dependent vascular relaxation of isolated human basilar artery to thrombin and bradykinin. Stroke1990;21:1039-1043.
26.
26. Singer HA, Peach MJ. Endothelium-dependent relaxation of rabbit aorta. II.Inhibition of relaxation stimulated by methacholine and A23187 with antagonists of arachidonic acid metabolism. J Pharmacol Exp Ther1983;226:796-801.
27.
27. Bird IM, Sullivan JA, Di T, et al. Pregnancy-dependent changes in cell signaling underlie changes in differential control of vasodilator production in uterine arery endothelial cells. Endocrinology2000;141:1107-1117.
28.
28. Di T, Sullivan JA, Magness RR, et al. Pregnancy-specific enhancement of agonist-stimulated ERK-1/2 signaling in uterine artery endothelial cells increase Ca2+ sensitivity of endothelial nitric oxide synthase as well as cytosolic phospholipase A2. Endocrinology2001;142:3014-3026.
29.
29. Levine AB, Lockwood CJ, Chitkara U, Berkowitz RL. Maternal renal artery Doppler velocimetry in normotemsive pregnancies and pregnancies complicated by hypertensive disorders. Obset Gynecol1992;79;264-267.
