Alguns aspectos da função endotelial em cirurgia cardíaca

Évora, Paulo Roberto B; Pearson, Paul J; Schaff, Hartzell V

doi:10.1590/S0102-76381993000300004

Resumos

Este estudo mostra alguns aspectos da função endotelial relacionados, diretamente, com a cirurgia cardíaca: 1) Após isquemia miocárdica global seguida de reperfusão, o endotélio coronariano perde a habilidade de expressar vasodilatação endotélio-dependente mediada por receptores, ao passo que o relaxamento endotélio-dependente mediado pelo cálcio ionóforo A23187 e a fosfolipasec C, que não dependem de estimulação de receptores, encontra-se inalterada. O relaxamento produzido pelo fluoreto de sódio, o qual atua através de G-proteína(s), encontra-se comprometido. Estes experimentos indicam que o comprometimento da produção de EDRF/NO mediada por receptores após a lesão de reperfusão possa ser devido a uma disfunção de G-proteínas que liga os receptores da célula endotelial à via da síntese de EDRF/ NO; 2) Quarenta e cinco minutos de parada cardioplégica de corações de cães, pela solução St.Thomas não comprometem a produção de EDRF/NO em artérias epicárdicas coronárias. Estudos farmacológicos in vitro semelhantes, testando-se os efeitos da solução UW, suportaram o conceito de que ela não lesa o endotélio coronariano sendo segura para a preservação cardíaca durante transplantes cardíacos; 3) Em segmentos de artérias coronárias, renais, femorais, e em segmentos de artéria pulmonar, a protamina induziu vasodilatação endotélio-dependente, mediada pela estimulação da liberação de EDRF/NO. Nas circulações coronariana e sistêmica, ao contrário do que se verificou nos experimentos envolvendo a circulação pulmonar, este efeito foi independente da presença de heparina; 4) Em 83% dos ensaios biológicos, o efluente da AMI esquerda induziu um relaxamento maior do anel coronariano bioensaiado do que o efluente da AMI direita,por liberação basal de EDRF/NO. Este inibe a adesividade e a agregação plaquetárias e a aterogêne, contribuindo para os resultados superiores obtidos quando se utiliza esta artéria para a revascularização do miocárdio. Quando expostos à hipoxia, as atividades vasodilatadoras da AMI e da veia safena foram maiores. Esta acentuação da vasodilatação causada pela hipoxia foi inibida pelo tratamento com a indometacina, e, rapidamente, revertida, quando se restabeleceu a normóxia.

endotélio vascular; óxido nítrico

This study shows some aspects of endothelial function closely related with cardiac surgery: 1) Following global myocardial ischemia and reperfusion, the coronary endothelium has an impaired ability to express endothelium-dependent vasodilation to the receptor-dependent agonists while endothelium-dependent relaxation to the receptor-independent A23187 and phospholipase C is unaltered. The relaxation to sodium fluoride, which acts on a pertussis toxin-sensitive G-protein is impaired. These experiments indicate that impaired receptor-mediated production of EDRF/NO following reperfusion injury could be due to G-protein dysfunction in the pathway which links endothelial cell receptors to the pathway of EDRF/NO synthesis; 2) Forty-five minutes of cardioplegic arrest of the canine heart does not alter the production EDRF/NO in the epicardial coronary artery. Similar experiments support the concept that UW solution is safe for cardiac preservation during heart transplantation; 3) In coronary, renal, femoral and pulmonary arterial segments, protamine induced endothelium-dependent vasodilation mediated by the stimulated release of EDRF/NO. In the pulmonary circulation, differently of the coronary, renal and femoral arteries, protamine-induced endothelium-dependent vasodilation could be inhibited by comparable amounts of heparin, and this effect was overcome by adding additional protamine; 4)ln 83% of the superfusion experiments, effluent from the left IMA induced greater relaxation of the bioassay ring than did the right IMA due to the basal release of EDRF/NO. Because EDRF/NO induces vasodilation and also inhibits platelet adhesion, platelet aggregation, and atherogenesis, luminal release of EDRF/NO by the IMA could contribute to superior results when the artery is used in bypass grafting. Upon exposure of the grafts to hypoxia, the vasodilator activity of effluent from both IMA and saphenous vein grafts was augmented.This hypoxic augmentation could be inhibited by indomethacin treatment and the relaxation was quickly reversed with return to normoxia.

vascular endothelium; nitric oxide; EDRF

ARTIGOS ORIGINAIS

Alguns aspectos da função endotelial em cirurgia cardíaca

Some aspects of the enothelial function in cardiac surgery

Paulo Roberto B. Évora^I; Paul J. Pearson^II; Hartzell V. Schaff^III

^IDa Faculdade de Medicina de Riberão Preto da Universidade de São Paulo

^IIDa Mayo Clinic and Mayo Foundation. Section of Cardiovascular Surgery, Cardiac Surgical Research

^{Endereço para separatas} Endereço para separatas: Paulo Roberto B. Évora Rua Rui Barbosa, 455, Apto. 140 14015-120, Ribeirão Preto, SP, Brasil

RESUMO

Este estudo mostra alguns aspectos da função endotelial relacionados, diretamente, com a cirurgia cardíaca: 1) Após isquemia miocárdica global seguida de reperfusão, o endotélio coronariano perde a habilidade de expressar vasodilatação endotélio-dependente mediada por receptores, ao passo que o relaxamento endotélio-dependente mediado pelo cálcio ionóforo A23187 e a fosfolipasec C, que não dependem de estimulação de receptores, encontra-se inalterada. O relaxamento produzido pelo fluoreto de sódio, o qual atua através de G-proteína(s), encontra-se comprometido. Estes experimentos indicam que o comprometimento da produção de EDRF/NO mediada por receptores após a lesão de reperfusão possa ser devido a uma disfunção de G-proteínas que liga os receptores da célula endotelial à via da síntese de EDRF/ NO; 2) Quarenta e cinco minutos de parada cardioplégica de corações de cães, pela solução St.Thomas não comprometem a produção de EDRF/NO em artérias epicárdicas coronárias. Estudos farmacológicos in vitro semelhantes, testando-se os efeitos da solução UW, suportaram o conceito de que ela não lesa o endotélio coronariano sendo segura para a preservação cardíaca durante transplantes cardíacos; 3) Em segmentos de artérias coronárias, renais, femorais, e em segmentos de artéria pulmonar, a protamina induziu vasodilatação endotélio-dependente, mediada pela estimulação da liberação de EDRF/NO. Nas circulações coronariana e sistêmica, ao contrário do que se verificou nos experimentos envolvendo a circulação pulmonar, este efeito foi independente da presença de heparina; 4) Em 83% dos ensaios biológicos, o efluente da AMI esquerda induziu um relaxamento maior do anel coronariano bioensaiado do que o efluente da AMI direita,por liberação basal de EDRF/NO. Este inibe a adesividade e a agregação plaquetárias e a aterogêne, contribuindo para os resultados superiores obtidos quando se utiliza esta artéria para a revascularização do miocárdio. Quando expostos à hipoxia, as atividades vasodilatadoras da AMI e da veia safena foram maiores. Esta acentuação da vasodilatação causada pela hipoxia foi inibida pelo tratamento com a indometacina, e, rapidamente, revertida, quando se restabeleceu a normóxia.

Descritores: endotélio vascular, cirurgia cardíaca; óxido nítrico, fator relaxante endotelial.

ABSTRACT

This study shows some aspects of endothelial function closely related with cardiac surgery: 1) Following global myocardial ischemia and reperfusion, the coronary endothelium has an impaired ability to express endothelium-dependent vasodilation to the receptor-dependent agonists while endothelium-dependent relaxation to the receptor-independent A23187 and phospholipase C is unaltered. The relaxation to sodium fluoride, which acts on a pertussis toxin-sensitive G-protein is impaired. These experiments indicate that impaired receptor-mediated production of EDRF/NO following reperfusion injury could be due to G-protein dysfunction in the pathway which links endothelial cell receptors to the pathway of EDRF/NO synthesis; 2) Forty-five minutes of cardioplegic arrest of the canine heart does not alter the production EDRF/NO in the epicardial coronary artery. Similar experiments support the concept that UW solution is safe for cardiac preservation during heart transplantation; 3) In coronary, renal, femoral and pulmonary arterial segments, protamine induced endothelium-dependent vasodilation mediated by the stimulated release of EDRF/NO. In the pulmonary circulation, differently of the coronary, renal and femoral arteries, protamine-induced endothelium-dependent vasodilation could be inhibited by comparable amounts of heparin, and this effect was overcome by adding additional protamine; 4)ln 83% of the superfusion experiments, effluent from the left IMA induced greater relaxation of the bioassay ring than did the right IMA due to the basal release of EDRF/NO. Because EDRF/NO induces vasodilation and also inhibits platelet adhesion, platelet aggregation, and atherogenesis, luminal release of EDRF/NO by the IMA could contribute to superior results when the artery is used in bypass grafting. Upon exposure of the grafts to hypoxia, the vasodilator activity of effluent from both IMA and saphenous vein grafts was augmented.This hypoxic augmentation could be inhibited by indomethacin treatment and the relaxation was quickly reversed with return to normoxia.

Descriptors: vascular endothelium, cardiac surgery; nitric oxide, endothelium-derived relaxing factor; EDRF.

Texto completo disponível apenas em PDF.

Full text available only in PDF format.

Apoio: CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico do Brasil.

Trabalho realizado na Mayo Clinic and Mayo Foundation. Section of Cardiovascular Surgery, Cardiac Surgical Research. Rochester, Minnesota, U.S.A.

Apresentado ao 20º Congresso Nacional de Cirurgia Cardíaca. Maceió - Al, 2 e 3 de Abril de 1993.

Senior Fellow in Research. Mayo Clinic and Mayo Foundation.

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2 AARNIO, P. T.; HARJULA, A. L.; VIINIKKA, L.; MERIKALLIO, E. M. ; MATTILA, S. P. - Prostacyclin production in free verses native IMA grafts. Ann Thorac. Surg, 45: 390-392, 1988.
3 BENYO, Z.; KISS, G.; SZABO, C.; CSAKI, C.; KOVACH, A. G. B. - Importance of basal nitric oxide synthesis in regulation of myocardial blood flow. Cardiovasc. Res, 25: 700-703, 1991.
4 BERRIDGE, M. J. & IRVINE, R. F. - Inositol triphosphate, a novel second messenger in cellular signal transduction. Nature, 312: 315-321, 1984.
5 BODELSSON, M.; ARNEKLO-NOBIN, B.; TORNE-BRANDT, K. - Cooling augments contractile response to 5-hydroxytryptamine via an endothelium-dependent mechanism. Blood Vessels, 26:347-359, 1989.
6 BUSSE, R.; POHL, U.; FOSTERMANN, U.; BASSENGE, E. - Endothelium-dependent modulation of arterial smooth muscle tone and PGI₂-release: pulsatile verses steady flow. In: POHL, U; FOSTERMANN, U; BUSSE, R; BASSENGE, E; SCHROR, E; (eds.) Prostaglandins and Other Eicosanoids in the Cardiovascular System, 2nd International Symposium 2. Basel, Karger, 1984. p. 553-558.
7 CARPENTER, S.; MURAWSKY, M.; CARPENTER, A. - Cytotoxicity of cardioplegic solutions: evaluation by tissue culture. Circulation, 64(Suppl. 2):90-95, 1981.
8 CHIAVARELLI, R.; MACCHIARELLI, G.; FAMILIARI, G.; CHIAVARELLI, M.; MACCHIARELLI, A.; DEL BASSO, P.; MARINO, B.; MOTTA, P. M. - Ultrastructural changes of coronary artery endothelium induced by cardioplegic solutions. Thorac. Cardiovasc. Surgeon, 37:151-157, 1989.
9 CUSHING, D. J.; SABOUNI, M. H.; BROWN, G. L.; MUSTAFA, S. J. - Fluoride produces endothelium-dependent relaxation and endothelium-independent contraction in coronary artery. J. Pharmacol. Exp. Therap, 254:28-32, 1990.
10 DOHLMAN, H. G.; CARON, M. G.; LEFKOWITZ, R. J. - A family of receptors coupled to guanine regulatory proteins. Biochemistry, 26:2657-2664, 1987.
11 FLAVAHAN, N. A. & VANHOUTTE, P. M. - Pertussis toxin inhibits endothelium-dependent relaxations evoked by fluoride. Eur. J. Pharmacol, 178:121-124, 1990.
12 FREISSMUTH, M.; CASEY, P. J.; GILMAN, A. G. - G proteins control diverse pathways of transmembrane signaling. FASEB J, 3:2125-2131, 1989.
13 GARG, U. C. & HASSID, A. - Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J. Clin. Invest, 83:1774-1777, 1989.
14 HAMASAKI, Y.; TAI, H.; SAID, S. I. - Hypoxia stimulates prostacyclin generation by dog lung in vitro. Prostagland, Leukotri. Med, 8:311-316, 1982.
15 HARJULA, A.; MATTILA, S.; MYLLARNIEMI, H.; MATTILA, I.; MATTILA, P.; SALMENPERA, M.; MERIKALLIO, E. Effects of synthetic blood and crystalloid cardioplegia solutions on coronary endothelium: an experimental scanning electron microscopic study. J. Surg. Res, 39:405-412, 1985.
16 HINES, R. L. & BARASH, P. G. - Protamine: Does it alter right ventricular function? Anesth Analg 65:1271-1274, 1986.
17 HORROW, J.C. Protamine: A review of its toxicity. Anesth. Analg, 64:348-361, 1985.
18 HUDLESTON, C. B,; STONEY, W. S.; ALFORD Jr., W. C. - Internal mammary artery grafts: technical factors influencing patency. Ann. Thorac. Surg, 42:543-549, 1986.
19 JAQUES, L. B. - A study of the toxicity of the protamine salmine. Br. J. Pharmacol, 4:135-144, 1949.
20 JOHNS, R. A.; PEACH, M. J.; FLANAGAN, T.; KRON, I. L. - Probing of the canine internal mammary artery damages endothelium and impairs vasodilation resulting from prostacyclin and endothelium-derived relaxing factor. J. Thorac. Cardiovasc. Surg, 97: 252-258, 1989.
21 KELM, M. & SCHRADER, J. - Control of coronary vascular tone by nitric oxide. Circ. Res, 66:1561-1575, 1990.
22 KIRKLIN, J.K.; CHENOWETH, D. E.; NAFTEL, D. C.; BLACKSTONE, E. H.; KIRKLIN, J. W.; BITRAN, D. D.; CURD, J. G.; REVER, J. G.; SAMUELSON, P. N. - Effects of protamine administration after cardiopulmonary bypass on complement, blood elements, and hemodynamic state. Ann. Thorac. Surg. 41:193-199, 1986.
23 KONTOS, H. A.; WEI, E. P. - Reversal of acetylcholine-induced cerebral vasodilation in acute hypertension. Microvasc. Res, 29:231-232, 1985.
24 LAM, J. Y. T..; CHESEBRO, J. H.; STEELE, P.; BADIMON, L.; FUSTER, V. - Is vasospasm related to platelet deposition? Relationship in a porcine preparation of arterial injury in vivo. Circulation, 75:243-248, 1987.
25 LAMBERT, T. L.; KENT, R. S.; WHORTON, R. - Bradykinin stimulation of inositol polyphosphate production in porcine aorta endothelial cells. J. Biol. Chem, 261:15288-15239,1986.
26 LOOP, F. D.; LYTLE, B. W.; COSGROVE, D. M. - Influence of the internal mammary artery graft on 10-year survival and other cardiac events. N. Engl. J. Med, 314:50-51, 1986.
27 LOWENSTEIN, E.; ZAPOL, W. M. - Protamine reactions, explosive mediator release, and pulmonary vasoconstriction. Anesthesiology 73:373-375, 1990.
28 LUSCHER, T. F.; DIEDERICH, D.; SIEBENMANN, R. - Difference between endothelium-dependent relaxation in arterial and in venous coronary bypass grafts. N. Engl. J. Med, 319:462-467, 1988.
29 MANKAD, P. S.; CHESTER, A. H.; YACOUB, M. H. - Role of potassium concentration in cardioplegic solutions in mediating endothelial damage. Ann. Thorac. Surg, 51:89-93, 1991.
30 MARIN-NETO, J. A.; SYKES, M. K.; MARIN, J. L. B.; ORCHARD, C.; CHAKRABARTI, M. K.; - Effect of heparin and protamine on left ventricular performance in the dog. Cardiovasc. Res, 13:254-259, 1979.
31 MARTIN. W.; VILLANI, G. M.; JOTHIANANDAN, D.; FURCHGOTT, R. F. - Selective blockade of endothelium-dependent and glycerol trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. J. Pharmac. Exp. Ther, 232:708-716, 1985.
32 MOLINA, J. E.; GALLIANI, C. A.; EINZIG, S.; BIANCO, R.; RASMUSSEN, T.; CLACK, R. - Physical and mechanical effects of cardioplegic injection on flow distribution and myocardial damage in hearts with normal coronary arteries. J. Thorac. Cardiovasc. Surg, 97:870-877, 1989.
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35 PEARSON, P. J.; SCHAFF, H. V.; VANHOUTTE, P. M. - Long-term impairment of endothelium-dependent relaxations to aggregating platelets following reperfusion injury in canine coronary arteries. Circulation, 81:1921-1927, 1990.
36 PROCACCINI, B.; CLEMENTI, G.; BERSANETTI. L.; MAZZOLA, A.; GREGORINI, R.; DI MANICI, G. P.; ESPOSITO, G.; DI NARDO, D. W.; DI EUOSANIO, G. - Cardiorespiratory effects of protamine sulfate in man: Intra-aortic vs intra-right atrial rapid administration after cardiopulmonary bypass. J. Cardiovasc. Surg, 28:112-119, 1987.
37 RADOMSKI, M. W.; PALMER, R. M. J.; MONCADA, S. - The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br. J. Pharmacol, 92:639-646, 1987.
38 REES, D. D.; PALMER. R. M. J.; HODSON, H. F.; MONCADA, S. - A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br. J. Pharmacol, 96:418-424, 1989.
39 RUBANYI, G. M.; ROMERO, J. C.; VANHOUTTE, P. M. - Flow-induced release of endothelium-derived relaxing factor. Am. J. Physiol, 250 (Heart. Circ. Physiol. 19):H1145-H1149, 1986
40 SALDANHA, C. & HEARSE, D. J. - Coronary vascular responsiveness to 5-hydroxytryptamine before and after infusion of hyperkalemic crystalloid cardioplegic solution in the rat heart. J. Thorac. Cardiovasc. Surg, 98:783-787, 1989
41 SHIMOKAWA, H.; FLAVAHAN, N. A.; VANHOUTTE, P.M. - Loss of endothelial pertussis toxin-sensitive G protein function in atherosclerotic porcine coronary arteries. Circulation, 83:652-660,1991.
42 SHIMOKAWA, H.; FLAVAHAN, N. A.; VANHOUTTE, P. M. - Prostacyclin releases endo-thelium-derived relaxing factor and potentiates it's action in coronary arteries of the pig. Br. J. Pharmacol, 95:1197-1203, 1988.
43 SOLBERG, S.; LARSEN, T.; LINDAL, S.; PRYDZ, P.; JORGENSEN, L.; SORLIE, D. - The effects of two different crystalloid cardioplegic solutions on cultured human endothelial cells. J. Cardiovasc. Surg, 30:669-674, 1989.
44 STERNWEIS, P. C. & GILMAN, A. G. - Aluminum: a requirement for activation of the regulatory subunit of adenylate cyclase by fluoride. Proc. Natl. Acad. Sci. (USA), 79:4888-4891, 1982.
45 VALLANCE, P.; COLLIER, J.; MONCADA, S. - Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet, 2:997-1000, 1989.
46 WAKEFIELD, T. W.; HANTLER, C. B.; LINDBLAD, B.; WHITEHOUSE, W. M.; STANLEY, J. C. - Protamine pretreatment attenuation of hemodynamic and hematologic effects of heparin-protamine interaction. J. Vasc. Surg, 3:885-889, 1986.
47 WAKEFIELD, T. W.; TILL, G. O.; LINBLAD, B.; SAENZ, N.; STANLEY, J. C. - Complement depletion and persistent hemodynamic-hematologic responses in protamine-heparin reactions. J. Surg. Res, 45:320-326, 1988.
48 WHITMAN, G. J. R.; MARTEL, D.; WEISS, M.; POCHANAPRING, A.; SEE, W. M.; HOPEMAN, A.; HARKEN, A. H.; DAUBER, I. M. - Reversal of protamineinduced catastrophic pulmonary vasoconstriction by prostaglandin E₁ Ann. Thorac. Surg, 50:303-305, 1990.
49 YANG, Z.; VON, SEGESSER, L.; BAUER, E.; STULZ, P.; TURINA, M., LUSCHER, T. F. - Different activation of the endothelial L-arginine and cyclooxygenase pathway in the human internal mammary artery and saphenous vein. Circ. Res, 68:52-60, 1991.

Endereço para separatas:

Paulo Roberto B. Évora

Rua Rui Barbosa, 455, Apto. 140

14015-120, Ribeirão Preto, SP, Brasil

Datas de Publicação

Publicação nesta coleção
17 Fev 2011
Data do Fascículo
Set 1993

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1 ANDO, T.; YAMASAKI, M.; SUZUKI, K. - Protamines. In: Kleinzeller A, Springer GF, Wittmann HG, (eds.) Molecular biology, biochemistry and biophysics. Berlin, Springer-Verlag, 1973.

[2] 2 AARNIO, P. T.; HARJULA, A. L.; VIINIKKA, L.; MERIKALLIO, E. M. ; MATTILA, S. P. - Prostacyclin production in free verses native IMA grafts. Ann Thorac. Surg, 45: 390-392, 1988.

[3] 3 BENYO, Z.; KISS, G.; SZABO, C.; CSAKI, C.; KOVACH, A. G. B. - Importance of basal nitric oxide synthesis in regulation of myocardial blood flow. Cardiovasc. Res, 25: 700-703, 1991.

[4] 4 BERRIDGE, M. J. & IRVINE, R. F. - Inositol triphosphate, a novel second messenger in cellular signal transduction. Nature, 312: 315-321, 1984.

[5] 5 BODELSSON, M.; ARNEKLO-NOBIN, B.; TORNE-BRANDT, K. - Cooling augments contractile response to 5-hydroxytryptamine via an endothelium-dependent mechanism. Blood Vessels, 26:347-359, 1989.

[6] 6 BUSSE, R.; POHL, U.; FOSTERMANN, U.; BASSENGE, E. - Endothelium-dependent modulation of arterial smooth muscle tone and PGI₂-release: pulsatile verses steady flow. In: POHL, U; FOSTERMANN, U; BUSSE, R; BASSENGE, E; SCHROR, E; (eds.) Prostaglandins and Other Eicosanoids in the Cardiovascular System, 2nd International Symposium 2. Basel, Karger, 1984. p. 553-558.

[7] 7 CARPENTER, S.; MURAWSKY, M.; CARPENTER, A. - Cytotoxicity of cardioplegic solutions: evaluation by tissue culture. Circulation, 64(Suppl. 2):90-95, 1981.

[8] 8 CHIAVARELLI, R.; MACCHIARELLI, G.; FAMILIARI, G.; CHIAVARELLI, M.; MACCHIARELLI, A.; DEL BASSO, P.; MARINO, B.; MOTTA, P. M. - Ultrastructural changes of coronary artery endothelium induced by cardioplegic solutions. Thorac. Cardiovasc. Surgeon, 37:151-157, 1989.

[9] 9 CUSHING, D. J.; SABOUNI, M. H.; BROWN, G. L.; MUSTAFA, S. J. - Fluoride produces endothelium-dependent relaxation and endothelium-independent contraction in coronary artery. J. Pharmacol. Exp. Therap, 254:28-32, 1990.

[10] 10 DOHLMAN, H. G.; CARON, M. G.; LEFKOWITZ, R. J. - A family of receptors coupled to guanine regulatory proteins. Biochemistry, 26:2657-2664, 1987.

[11] 11 FLAVAHAN, N. A. & VANHOUTTE, P. M. - Pertussis toxin inhibits endothelium-dependent relaxations evoked by fluoride. Eur. J. Pharmacol, 178:121-124, 1990.

[12] 12 FREISSMUTH, M.; CASEY, P. J.; GILMAN, A. G. - G proteins control diverse pathways of transmembrane signaling. FASEB J, 3:2125-2131, 1989.

[13] 13 GARG, U. C. & HASSID, A. - Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J. Clin. Invest, 83:1774-1777, 1989.

[14] 14 HAMASAKI, Y.; TAI, H.; SAID, S. I. - Hypoxia stimulates prostacyclin generation by dog lung in vitro. Prostagland, Leukotri. Med, 8:311-316, 1982.

[15] 15 HARJULA, A.; MATTILA, S.; MYLLARNIEMI, H.; MATTILA, I.; MATTILA, P.; SALMENPERA, M.; MERIKALLIO, E. Effects of synthetic blood and crystalloid cardioplegia solutions on coronary endothelium: an experimental scanning electron microscopic study. J. Surg. Res, 39:405-412, 1985.

[16] 16 HINES, R. L. & BARASH, P. G. - Protamine: Does it alter right ventricular function? Anesth Analg 65:1271-1274, 1986.

[17] 17 HORROW, J.C. Protamine: A review of its toxicity. Anesth. Analg, 64:348-361, 1985.

[18] 18 HUDLESTON, C. B,; STONEY, W. S.; ALFORD Jr., W. C. - Internal mammary artery grafts: technical factors influencing patency. Ann. Thorac. Surg, 42:543-549, 1986.

[19] 19 JAQUES, L. B. - A study of the toxicity of the protamine salmine. Br. J. Pharmacol, 4:135-144, 1949.

[20] 20 JOHNS, R. A.; PEACH, M. J.; FLANAGAN, T.; KRON, I. L. - Probing of the canine internal mammary artery damages endothelium and impairs vasodilation resulting from prostacyclin and endothelium-derived relaxing factor. J. Thorac. Cardiovasc. Surg, 97: 252-258, 1989.

[21] 21 KELM, M. & SCHRADER, J. - Control of coronary vascular tone by nitric oxide. Circ. Res, 66:1561-1575, 1990.

[22] 22 KIRKLIN, J.K.; CHENOWETH, D. E.; NAFTEL, D. C.; BLACKSTONE, E. H.; KIRKLIN, J. W.; BITRAN, D. D.; CURD, J. G.; REVER, J. G.; SAMUELSON, P. N. - Effects of protamine administration after cardiopulmonary bypass on complement, blood elements, and hemodynamic state. Ann. Thorac. Surg. 41:193-199, 1986.

[23] 23 KONTOS, H. A.; WEI, E. P. - Reversal of acetylcholine-induced cerebral vasodilation in acute hypertension. Microvasc. Res, 29:231-232, 1985.

[24] 24 LAM, J. Y. T..; CHESEBRO, J. H.; STEELE, P.; BADIMON, L.; FUSTER, V. - Is vasospasm related to platelet deposition? Relationship in a porcine preparation of arterial injury in vivo. Circulation, 75:243-248, 1987.

[25] 25 LAMBERT, T. L.; KENT, R. S.; WHORTON, R. - Bradykinin stimulation of inositol polyphosphate production in porcine aorta endothelial cells. J. Biol. Chem, 261:15288-15239,1986.

[26] 26 LOOP, F. D.; LYTLE, B. W.; COSGROVE, D. M. - Influence of the internal mammary artery graft on 10-year survival and other cardiac events. N. Engl. J. Med, 314:50-51, 1986.

[27] 27 LOWENSTEIN, E.; ZAPOL, W. M. - Protamine reactions, explosive mediator release, and pulmonary vasoconstriction. Anesthesiology 73:373-375, 1990.

[28] 28 LUSCHER, T. F.; DIEDERICH, D.; SIEBENMANN, R. - Difference between endothelium-dependent relaxation in arterial and in venous coronary bypass grafts. N. Engl. J. Med, 319:462-467, 1988.

[29] 29 MANKAD, P. S.; CHESTER, A. H.; YACOUB, M. H. - Role of potassium concentration in cardioplegic solutions in mediating endothelial damage. Ann. Thorac. Surg, 51:89-93, 1991.

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