Pulmonary vasoconstriction due to impaired nitric oxide production after cardiopulmonary bypass

Morita, Kiyozo; Ihnken, Kai; Buckberg, Gerald D.; Sherman, Michael P.; Ignarro, Louis J.

doi:10.1016/0003-4975(96)00146-4

Cited by 86 publications

(48 citation statements)

References 17 publications

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“…19,20 Investigations on changes in basal NO production induced by the CPB generated conflicting evidence with divergent results. 21,22 As the reduction in basal NO release did not correlate with the extent of CPB induced pulmonary hypertension, other reasons have been discussed, such as the release of ET-1. 23 An increase in ET-1 plasma levels during CPB has been related to a PVR increase and correlated with the PVR/SVR ratio in patients with pulmonary hypertension.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Circulating Endothelin-1 and Big Endothelin by Nitric Oxide Inhalation Following Left Ventricular Assist Device Implantation

et al. 2003

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Background-Inhaled nitric oxide (iNO) is an established therapy in the treatment of pulmonary hypertension and right ventricular dysfunction following left ventricular assist device implantation. Since it is known that endothelin-1 contributes to pulmonary hypertension, and nitric oxide modulates endothelin-1 synthesis in vitro, we investigated the effects of iNO on circulating endothelin-1 and big endothelin following left ventricular assist device implantation. Methods and Results-On weaning from cardiopulmonary bypass, 15 consecutive patients with secondary pulmonary hypertension after implantation of a left ventricular assist device were treated with iNO. Endothelin-1 and big endothelin plasma levels were measured preoperatively, on cardiopulmonary bypass prior to iNO, 12, 24, and 48 hour postoperatively, and 72 hour after cessation of iNO. Endothelin-1 levels were increased preoperatively (1.05Ϯ0.20 fmol/L), and were highest on cardiopulmonary bypass (1.65Ϯ0.27 fmol/L). During iNO therapy endothelin-1 and big endothelin decreased significantly (endothelin-1: 12 hour 1.24Ϯ0.18, 24 hour 0.93Ϯ0.20, and 48 hour 0.81Ϯ0.14 fmol/L); they were lowest 72 hour post-iNO (endothelin-1: 0.56Ϯ0.09 fmol/L). Plasma endothelin-1 concentrations and iNO dose were inversely correlated (rϭϪ0.657, PϽ0.015). A significant correlation was also found between endothelin-1 versus PA pressures and PVR/SVR ratio, but not with CI and SVR. Conclusions-Since it is known that endothelin-1 mediates pulmonary hypertension, we suggest a 2-fold effect of iNO therapy: firstly, a selective vasodilation of the pulmonary vasculature; and secondly, iNO mediated modulation of endothelin-1.

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Section: Discussionmentioning

confidence: 99%

Modulation of Circulating Endothelin-1 and Big Endothelin by Nitric Oxide Inhalation Following Left Ventricular Assist Device Implantation

et al. 2003

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“…Non-nitrovaso-42 Pharmacology 1999;58: [34][35][36][37][38][39][40][41][42][43] Wall/Patterson/Kavanagh/Pearl dilators such as adenosine and other agents that do not interact with cGMP should affect pulmonary and systemic circulations independently of endogenous NO production. In contrast, nitrovasodilators such as SNP and NTG will have increased effects when endogenous NO production is decreased in systemic or pulmonary circulations.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, nitrovasodilators such as SNP and NTG will have increased effects when endogenous NO production is decreased in systemic or pulmonary circulations. Pulmonary endogenous NO production appears to be decreased in primary and chronic secondary pulmonary hypertension [4] and after cardiopulmonary bypass [34], wheras systemic endogenous NO production may be decreased as a result of endothelial dysfunction in patients with essential hypertension [26], diabetes [35], hypercholesterolemia [36] and atherosclerosis [37]. Studies will be required to determine if the relative pulmonary and systemic effects of nitrovasodilators versus non-nitrovasodilators are altered in these disease states.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Endogenous Nitric Oxide Synthesis Potentiates the Effects of Sodium Nitroprusside but Not of Adenosine in Experimental Pulmonary Hypertension

et al. 1998

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This study examined the systemic and pulmonary vasodilator effects of sodium nitroprusside (SNP) and adenosine during experimental pulmonary hypertension with and without inhibition of endogenous NO synthesis. Male New Zealand White rabbits were anesthetized and mechanically ventilated. The NO synthesis inhibitor N^G-nitro-L-arginine methyl ester (L-NAME) was administered to 15 of the 28 rabbits. Pulmonary hypertension was then produced in all rabbits by U46619, a thromboxane A₂ mimetic. SNP was infused in 14 rabbits (7 L-NAME, 7 control) at doses of 0.5–20 µg/kg/min; adenosine was infused in the other 14 rabbits (8 L- NAME, 6 control) at doses of 12.5–300 µg/kg/min. The U46619 dose required to produce pulmonary hypertension was significantly lower in the L-NAME group. SNP dose-dependently decreased pulmonary (Ppa) and systemic (Psa) artery pressures and systemic vascular resistance (SVR). Both Ppa and Psa were decreased more with SNP in the L-NAME than in the no L-NAME group. The SNP ED₅₀ for the decrease in PVR was almost threefold lower in the L-NAME group. Adenosine dose-dependently decreased Ppa, Psa, PVR and SVR. The adenosine ED₅₀ for the decreases in PVR and SVR were similar in the L-NAME group and the control group. We conclude that inhibition of endogenous NO synthesis shifts the dose-response curves for both the pulmonary and systemic vasodilator effects to the left for the nitrovasodilator SNP but not for the non-nitrovasodilator adenosine.

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“…Normal endothelial cell responses to thrombin are altered by CPB [20, 65,107,119,136]. In high-risk patients these abnormalities are more pronounced, especially for generation of protein C via thrombomodulin, and the net effect is increased blood loss [21].…”

Section: Protection Of the Endotheliummentioning

confidence: 99%

Thrombin and cardiopulmonary bypass – A paradigm for evaluation of the regulation of hemostasis

Ferraris

2011

Int J Angiol

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Extracorporeal circulation for the purpose of cardiopulmonary bypass (CPB) is used extensively for repair of cardiac defects. Complex mechanisms, many of which involve the generation of thrombin, are initiated by the institution of CPB. Thrombin is generated during CPB in spite of high doses of heparin. The tissue factor/ factor VII pathway is also activated and is probably responsible for generation of most of the thrombin seen during CPB. Plasma proteins (humoral phase) along with platelets, endothelium and white cells (cellular phase) are also activated by contact of blood with synthetic surfaces. Small amounts of thrombin activate endothelial cells which then generate tissue plasminogen activator (t-PA). Plasmin is generated by the action of t-PA and fibrinolysis ensues. The blood becomes a mix of vasoactive substances that alter vascular smooth muscle tone and endothelial cell contraction. The sum of these reactions is called the Ôwhole body inflammatory responseÕ and is responsible for postoperative morbidity including bleeding and organ system dysfunction.Attempts to control the morbidity of CPB have focused on reversible inhibitors of some of the reactions described above. Potentially helpful new strategies may include: 1) enhanced production of thrombin-activatable fibrinolysis inhibitor (TAFI) to limit fibrinolysis, 2) synthesis of thrombin receptor blockers to limit platelet and endothelial activation, 3) protection of endothelial cell receptors during CPB, 4) control of CPB-induced platelet-PMN and endothelial-PMN adhesion in order to limit postoperative organ system dysfunction, and 5) limitation of tissue factor pathway activation in order to minimize thrombin production during CPB. This review highlights recent developments in the understanding of the molecular mechanisms of the action of thrombin induced by CPB.

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Pulmonary vasoconstriction due to impaired nitric oxide production after cardiopulmonary bypass

Cited by 86 publications

References 17 publications

Modulation of Circulating Endothelin-1 and Big Endothelin by Nitric Oxide Inhalation Following Left Ventricular Assist Device Implantation

Modulation of Circulating Endothelin-1 and Big Endothelin by Nitric Oxide Inhalation Following Left Ventricular Assist Device Implantation

Inhibition of Endogenous Nitric Oxide Synthesis Potentiates the Effects of Sodium Nitroprusside but Not of Adenosine in Experimental Pulmonary Hypertension

Thrombin and cardiopulmonary bypass – A paradigm for evaluation of the regulation of hemostasis

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