Sage Journals: Discover world-class research

Abstract

Objective: To determine the contribution of decreased calcium responsiveness of fetal coronary arteries to decreased contractile responses to potassium and the thromboxane A₂ analogue U46619 in these arteries after exposure to chronic hypoxemia.

Methods: Concentration-response curves to Ca²⁺ in β-escin-permeabilized left circumflex (LCx), left anterior descending (LAD), and right coronary artery (RCA) rings from high-altitude (HA) and control (CON) fetuses were measured. In a second set of β-escin-permeabilized coronary artery rings, the effect of U46619 on Ca²⁺ sensitivity was tested.

Results: Maximum Ca²⁺-activated force (T_max) was decreased in HA LCx (CON 0.091 ± 0.010 versus HA 0.057 ± 0.006 g/cm²; P < .05) and HA LAD (CON 0.065 ± 0.012 versus HA 0.031 ± 0.007 g/cm²; P < .05). No significant difference was observed in the RCA. There was no change in the pD₂ (-log EC₅₀) values between CON and HA coronary rings. The Ca²⁺ sensitizing effect of U46619 on submaximal Ca²⁺-activated force was lower only in the HA LCx (CON 0.044 ± 0.010 versus HA 0.023 ± 0.006 g/cm² at 10^-5 mol/L; P < .05).

Conclusion: These results indicate that maximum tension development in response to Ca²⁺ was decreased in the HA LCx and LAD but not the RCA; however, Ca²⁺ sensitivity of the contractile apparatus was unaltered in all of them. Decreased Ca²⁺ responsiveness may partially explain the decreased contractile capability of fetal LCx and LAD during long-term, high-altitude intrauterine hypoxemia.

Keywords

Intrauterine hypoxemia Ca2+ sensitivity thromboxane A2 β-escin

Get full access to this article

View all access options for this article.

References

1. Rembold CM . Regulation of contraction and relaxation in arterial smooth muscle. Hypertension 1992;20:129-137.

2. Somlyo AP , Somlyo AV . Signal transduction and regulation in smooth muscle. Nature 1994;372:231-236.

3. Akopov S , ZhangL , Pearce WJ . Physiological variations in ovine cerebrovascular calcium sensitivity. Am J Physiol 1997;272:H2271-H2281.

4. Kobayashi S , Kitazawa T , Somlyo AV , Somlyo AP . Cytosolic heparin inhibits muscarinic and β-adrenergic Ca2+ release in smooth muscle. J Biol Chem 1989;264:17997-18004.

5. Savineau JP , Marthan R . Diosmin-induced increase in sensitivity to Ca2+ of the smooth muscle contractile apparatus in the rat isolated femoral vein. Br J Pharmacol 1994;111:978-980.

6. Satoh S , Kreutz R , Wilm C , Ganten D , Pfitzer G . Augmented agonist- induced Ca2+-sensitization of coronary artery contraction in genetically hypertensive rats. J Clin Invest 1994;94:1397-1403.

7. Ohlstein EH , Kopia GA , Zeid RL , et al. Effects of the thromboxane receptor antagonist SK&F 88046 in the canine, monkey, and human vasculature. Prostaglandins 1988;36:69-84.

8. Dalen T , Vestereng M , Wadsworth R , Kane K . Effect of hypoxia on contraction and 45Ca2+ uptake induced by the thromboxane mimetic U46619 in sheep coronary artery. Eur J Pharmacol 1994;270:313-319.

9. Yamagishi T , Yanasigawa T , Satoh K , Taira N . Relaxant mechanisms of cyclic AMP-increasing agents in porcine coronary artery. Eur J Pharmacol 1994;251:253-262.

10.

10. Kamitomo M , Alonso JG , Okai T , Longo LD , Gilbert RD . Effects of long-term, high-altitude hypoxemia on fetal ovine cardiac output and blood flow redistribution. Am J Obstet Gynecol 1993;169:701-707.

11.

11. Harrison SM , Bers DM . Temperature dependence of myofilament Ca2+ sensitivity of rat, guinea pig, and frog ventricular muscle. Am J Physiol 1990;258:C274-C281.

12.

12. Kurata R , Takayanagi I , Hisayama T . Eicosanoid-induced Ca2+ release and sustained contraction in Ca2+ free media are mediated by different signal transduction pathways in rat aorta. Br J Pharmacol 1993;110:875-881.

13.

13. Grynkiewicz G , Peonie M , Tsien RY . A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 1985;260:3440-3450.

14.

14. Akao M , Hirasaki A , Jones KA , Wong GY , Bremerich DH , Warner DO . Halothane reduces myofilament Ca2+ sensitivity during muscarinic receptor stimulation of airway smooth muscle. Am J Physiol 1996;271:L719-L725.

15.

15. Savineau JP , Marthan R . Activation properties of chemically skinned fibers from human isolated bronchial smooth muscle. J Physiol 1994;474:433-438.

16.

16. Tomita F , Hattori Y , Kanno M , Kohya T , Sasaki M , Kitabatake A . Different regulation of myofilament Ca2+ sensitivity in β-escin-skinned cardiac and vascular smooth muscles. Eur J Pharmacol 1997;326:157-162.

17.

17. Bruce L , Nixon GF . Increased sensitization of the myofilaments in rat neonatal portal vein: A potential mechanism. Exp Physiol 1997;82:985-993.

18.

18. Soloviev AI , Basilyuk OV . Evidence of decrease in myofilament responsiveness to Ca2+ during hypoxia in spontaneously active vascular smooth muscle in rats. Exp Physiol 1993;78:395-402.

19.

19. Karaki H . Ca2+ localization and sensitivity in vascular smooth muscle. Trends Pharmacol Sci 1989;10:320-325.

20.

20. Zhang L . Adaptation of pharmacomechanical coupling of vascular smooth muscle to chronic hypoxia. Comp Biochem Physiol 1998;119A:661-667.

21.

21. Hathaway DR , March KL , Lash JA , Adam LP , Wilensky RL . Vascular smooth muscle: A review of the molecular basis of contractility. Circulation 1991;83:382-390.

22.

22. Payne ME , Elzinga M , Adelstein R . Smooth muscle myosin light chain kinase: Amino acid sequence at the site phosphorylated by adenosine cyclic-3′,5′-phosphate dependent protein kinase whether or not calmodulin is bound. J Biol Chem 1984;259:8429-8436.

23.

23. Hathaway DR , Konicki MV , Coolican SA . Phosphorylation of MLCK from VSM by cAMP and cGMP-dependent protein kinases. J Mol Cell Cardiol 1985;17:841-850.

24.

24. Kitazawa T , Gaylinn BD , Denney GH , Somlyo AP . G-protein-mediated Ca2+ sensitization of smooth muscle contraction through myosin light chain phosphorylation. J Biol Chem 1991;266:1708-1715.

25.

25. Hori M , Karaki H . Regulatory mechanisms of calcium sensitization of contractile elements in smooth muscle. Life Sci 1998;62:1629-1633.

26.

26. Knezevic I , Borg C , Le Breton GC . Identification of Gq as one of the G-proteins which copurify with human platelet thromboxane A2/prostaglandin H2 receptors. J Biol Chem 1993;268:26011-26017.

27.

27. Kinsella BT , O'Mahony DJ , Fitzgerald GA . The human thromboxane A2 receptor isoform (TP alpha) functionally couples to the G proteins Gq and G11 in vivo, and is activated by the isoprostane 8-epi prostaglandin F2 alpha. J Pharmacol Exp Ther 1997;281:957-964.

28.

28. Dorn GW II , Becker MW . Thromboxane A2 stimulated signal transduction in vascular smooth muscle. J Pharmacol Exp Ther 1992;265:447-456.

29.

29. Toyofuku K , Nishimura J , Kobayashi S , Nakano H , Kanaide H . Effects of U46619 on intracellular Ca++ concentration and tension in human umbilical artery. Am J Obstet Gynecol 1995;172:1414-1421.

30.

30. Tosun M , Paul RJ , Rapoport RM . Role of extracellular Ca++ influx via L-type and non-L-type Ca++ channels in thromboxane A2 receptor-mediated contraction in rat aorta. J Pharmacol Exp Ther 1998;284:921-928.

31.

31. Nishimura J , Khalil RA , van Breemen C . Agonist-induced vascular tone. Hypertension 1989;6:834-844.

32.

32. Bradley AB , Morgan KG . Alterations in cytoplasmic calcium sensitivity during porcine coronary artery contractions as detected by aequorin. J Physiol 1987;385:437-448.

33.

33. Himpens B , Kitazawa T , Somlyo AP . Agonist-dependent modulation of Ca2+ sensitivity in rabbit pulmonary artery smooth muscle. Pfluegers Arch 1990;417:21-28.

34.

34. Crichton CA , Templeton AGB , McGrath JC , Smith GL . Thromboxane A2 analogue, U-46619, potentiates calcium-activated force in human umbilical artery. Am J Physiol 1993;264:H1878-H1883.

Ca2+ Sensitivity of Fetal Coronary Arteries Exposed to Long-Term,High-Altitude Hypoxia

Abstract

Keywords

Get full access to this article

References