Objective: To determine the effect of estrogen treatment on the contractile, relaxation, and chronotropic responses of hearts of female rabbits to cessation of perfusion.
Methods: Adult female rabbits were treated either with estradiol or with the vehicle (control). The hearts were then isolated and perfused at constant pressure by the Langendorff technique. A saline-filled balloon connected to a pressure transducer was inserted in the left ventricle in order to assess the mechanical function of the isolated heart. Cardiac stunning was induced by halting the perfusion of the coronary vasculature for four successive periods of 1, 3, 5, and 5 minutes, followed by reperfusion between nonperfusion periods. Changes in cardiac function induced by the cessation of perfusion were assessed by monitoring the changes in heart rate and in left ventricular pressure ([dP/dt]max as an index of ventricular contractility and [dP/dt]min as an index of ventricular relaxation). Changes in coronary flow were determined at baseline and following reperfusion.
Results: Halting coronary perfusion decreased (dP/dt)max and (dP/dt)min and slowed left ventricular contractions both in control and in estrogen-treated hearts. The depressant effects of flow cessation on left ventricular (dP/dt)max and (dP/dt)min were smaller in estrogen-treated hearts than in control hearts. Treatment with estrogen had no effect on the changes on the heart rate in responses to cessation of flow and to reperfusion. Treatment with estrogen increased coronary flow by 40%. Coronary reperfusion increased coronary flow transiently, but the effects did not differ signifiicantly between control and estrogen-treated hearts.
Conclusion: Short-term treatment of adult female rabbits with doses of estrogen that are physiologic for the rabbit exerts a protective effect on cardiac contractility from repetitive periods without perfusion.
1. Gorodeski GI, Utian WH. Epidemiology and risk factors of cardiovascular disease in postmenpoausal women. In: Lobo RA, ed. Treatment of the postmenopausal woman: basic and clinical aspects. New York: Raven Press, 1994;199-221.
2.
2. Gorodeski GI. Mechanisms of action for estrogen in cardioprotection. In: Wren BG, ed. Progress in the management of menopause. Carnforth, Lancashire, UK: Parthenon Publishing Group, 1997:402-418.
3.
3. Webb CM, Rosano GMC, Collins P. Oestrogen improves exercise-induced myocardial ischaemia in women. Lancet1998;351:1556-1557.
4.
4. Williams JK, Adams MR, Klopfenstein HS. Estrogen modulates responses of atherosclerotic coronary arteries. Circulation1990;81:1680-1687.
5.
5. Williams JK, Adams MR, Herrington DM, Clarkson TB. Shortterm administration of estrogen and vascular responses of atherosclerotic coronary arteries. J Am Coll Cardiol1992;20:452-457.
6.
6. Gorodeski GI, Yang T, Levy MN, Goldfarb J, Utian WH. Effects of estrogen in vivo on coronary vascular resistance in perfused rabbit hearts. Am J Physiol1995;269:R1333-R1338.
7.
7. Gorodeski GI, Yang T, Levy MN, Goldfarb J, Utian WH. Modulation of coronary vascular resistance in female rabbits by estrogen and progesterone. J Soc Gynecol Invest1998;5:197-202.
8.
8. Schaible TF, Malhotra A, Ciambrone G. The effect of gonadectomy on left ventricular function and cardiac contractile proteins in male and female rats. Circ Res1984;54:38-49.
9.
9. Scheuer J, Malhotra A, Schaible TF. Effects of gonadectomy and hormonal replacement on rat hearts. Circ Res1987;61:12-19.
10.
10. Delyani JA, Murohara T, Nossuli TO, Lefer AM. Protection from myocardial reperfusion injury by acute administraiton of 17β-estradiol. J Mol Cell Cardiol1996;28:1001-1008.
11.
11. Hale SL, Birnbaum Y, Kloner RA. βEstradiol, but not α-estradiol, reduces myocardial necrosis in rabbits after ischemia and reperfusion. Am Heart J1996;132:258-262.
12.
12. McHugh NA, Cook SM, Schairer JL, Bidgoli MM, Merrill GF. Ischemia and reperfusion-induced ventricular arrhythmias in dogs: Effects of estrogen. Am J Physiol1995;268:H2569-H2573.
13.
13. Kim YD, Lees DE. Estrogen and ischemic heart disease. Chonnam J Med Sci1996;9:62-70.
14.
14. Kim YD, Chem B, Beauregard J, et al. 17-Beta-estradiol prevents dysfunction of canine coronary endothelium and myocardium and reperfusion arrhythmias after brief ischemia/reperfusion. Circulation1996;94:29001-29008.
15.
15. Martin LG, Brenner GM, Jarolim KL, Banschbach MW, Coons DL, Wolfe AK. Effects of sex steroids on myocardial anoxic resistance. Proc Soc Exp Biol Med1993;202:288-294.
16.
16. Jennings RB, Steenbergen C Jr, Reimer KA. Myocardial ischemia and reperfusion. Monogr Pathol1995;37:47-80.
17.
17. Rubboli A, Sobotka PA, Euler DE. Effect of acute edema on left ventricular function and coronary vascular resistance in the isolated rat heart. Am J Physiol1994;267:H1054-H1054.
18.
18. Hilliard J, Eaton JW. Estradiol-17β, progesterone and 20α-hydroxypregn-4-en-3-one in rabbit ovarian venous plasma. II. From mating through implantation. Endocrinology1971;89:522-527.
19.
19. Feng J, Chahine R, Yamaguchi N, Lamontagne D, Nadeau R. Brief repetitive ischemia: Effect on norepinephrine release, arrhythmias, and functional recovery in isolated perfused rat heart. Can J Physiol Pharmacol1996;74:1351-1358.
20.
20. Cho M, Ziats NP, Abdul-Karim F, et al. Effects of estrogen on tight junctional resistance in cultured human umbilical vein endothelial cells. J Soc Gynecol Invest1998;5:260-270.
21.
21. Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA1995;90:7915-7922.
22.
22. Kendall MJ, Rajman I, Maxwell SRJ. Cardioprotective therapeutics drugs used in hypertension, hyperlipidaemia, thromboemolism, arrhythmias, the postmenopausal state and as antioxidants. Postgrad Med J1994;70:329-343.
23.
23. Sato I, Morita I, Kaji K, Ikeda M, Nagao M, Murota SI. Reduction of nitric oxide producing activity associated with in vitro aging in cultured human umbilical vein. Biochem Biophys Res Commun1993;195:1070-1076.
24.
24. Brunet J, Boily MJ, Cordeau S, Des Rosiers C. Effects of N-acetylcysteine in the rat heart reperfused after low-flow ischemia: Evidence for a direct scavenging of hydroxyl radicals and a nitric oxide-dependent increase in coronary flow. Free Radic Biol Med1995;19:627-638.
25.
25. Sugioka K, Shimosegawa Y, Nakano M. Estrogens as natural antioxidants of membrane phospholipid peroxidation. FEBS Lett1987;210:37-39.
26.
26. Sack MN, Rader DJ, Cannon RO. Estrogen and inhitition of oxidation of low density lipoproteins in postmenopausal women. Lancet1994;343:269-270.
27.
27. Rifici VA, Khachadurian AK. The inhibition of low-density lipoprotein oxidation by 17-beta estradiol. Metab Clin Exp1992;41:1110-1114.
28.
28. Siegfried MR, Erhardt J, Rider T, Ma X-L, Lefer AM. Cardioprotection and attenuation of endothelial dysfunction by organic nitric oxide donors in myocardial ischemia-reperfusion. J Pharmacol Exp Ther1992;260:668-675.
29.
29. Coughlan MG, Kenny D, Kampine JP, Bosnjak ZJ, Warltier DC. Differential sensitivity of proximal and distal coronary arteries to a nitric oxide donor following reperfusion injury or inhibition of nitric oxide synthesis. Cardiovasc Res1993;27:1444-1448.
30.
30. Patel VC, Yellon DM, Singh KJ, Neild GH, Woolfson RG. Inhibition of nitric oxide limits infarct size in the in situ rabbit heart. Biochem Biophys Res Commun1993;194:234-238.
31.
31. Pernow J, Uriuda Y, Wang QD, Li XS, Nordlander R, Rydeen L. The protective effect of L-arginine on myocardial injury and endothelial function following ischaemia and reperfusion in the pig. Eur Heart J1994;15:1712-1719.
32.
32. Amrani M, Chester AH, Jayakumar J, Schyns CJ, Yacoub MH. L-Arginine reverses low coronary reflow and enhances postischaemic recovery of cardiac mechanical function. Cardiovasc Res1995;30:200-204.
33.
33. Depre C, Vanoverschelde JL, Goudemant JF, Mottet I, Hue L. Protection against ischemic injury by nonvasoactive concentrations of nitric oxide synthase inhibitors in the perfused rabbit heart. Circulation1995;92:1911-1918.
34.
34. Engelman DT, Watanabe M, Maulik N, et al. L-Arginine reduces endothelial inflammation and myocardial stunning during ischemia/reperfusion. Ann Thorac Surg1995;60:1275-1281.
35.
35. Nasseem SA, Kontos MC, Rao PS, Jesse RL, Hess ML, Kukreja RC. Sustained inhibition of nitric oxide by NG-nitro-L-arginine improves myocardial function following ischemia/reperfusion in isolated perfused rat heart. J Mol Cell Cardiol1995;27:419-426.
36.
36. Hoshida S, Yamashita N, Igarashi J. et al. Nitric oxide synthase protects the heart against ischemia-reperfusion injury in rabbits. J Pharmacol Exp Ther1995;274:413-418.
37.
37. Sato H, Zhao ZQ, McGee DS, Williams MW, Hammon JW, Vinten-Johansen J. Supplemental L-arginine during cardioplegic arrest and reperfusion avoids regional postischemic injury. J Thorac Cardiovasc Surg1995;110:302-314.
38.
38. Schulz R, Wambolt R. Inhibition of nitric oxide synthesis protects the isolated working rabbit heart from ischaemia-reperfusion injury. Cardiovasc Res1995;30:432-439.
39.
39. Takeuchi K, McGowan FX, Danh HC, Glynn P, Simplaceanu E, del Nido PJ. Direct detrimental effects of L-arginine upon ischemia: Reperfusion injury to myocardium. J Mol Cell Cardiol1995;27:1405-1414.
40.
40. Weselcouch EO, Baird AJ, Sleph P, Grover GJ. Inhibition of nitric oxide synthesis does not affect ischemic preconditioning in isolated perfused rat hearts. Am J Physiol1995;268:H242-H249.
41.
41. Williams MW, Taft CS, Ramnauth S, Shao ZQ, Vinten-Johansen J. Endogenous nitric oxide (NO) protects against ischaemiareperfusion injury in the rabbit. Cardiovasc Res1995;30:79-86.
42.
42. Weiner CP, Lizasocain I, Baylis SA, Knowles RG, Charles IG, Moncada S. Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci USA1994;91:5212-5216.
