Morihito Okada

Role of Endothelin-1 in Beagles With Dehydromonocrotaline-Induced Pulmonary Hypertension

BACKGROUND Although plasma levels of endothelin-1 (ET-1) increase in patients with pulmonary hypertension (PH), its role in PH is unknown. We investigated the contribution of endogenous ET-1 to cardiopulmonary changes in beagles with dehydromonocrotaline (DMCT)-induced PH. METHODS AND RESULTS Eight 3-month-old beagles were given a single injection of 3 mg/kg DMCT via the right atrium. During the 8 weeks after injection, the mean pulmonary arterial pressure (PAP) and plasma ET-1 level increased significantly from 11.6 +/- 2.3 to 35.9 +/- 7.1 mm Hg and from 1.24 +/- 0.25 to 3.25 +/- 0.94 pg/mL, respectively. In controls, ET-1 infusion elevated the systemic arterial pressure (SAP) but did not alter PAP. In PH beagles, ET-1 infusion increased SAP, which was attenuated by FR139317 (an endothelin type [ET] A receptor antagonist), and produced a dose-dependent decrease in PAP, which was attenuated by RES-701-1 (an ETB receptor antagonist). In PH beagles, FR139317 infusion decreased PAP, and RES-701-1 infusion increased PAP. Sarafotoxin S6c (an ETB agonist) infusion decreased PAP in PH beagles. CONCLUSIONS These results suggest that endogenous ET-1 is elevated in PH disease and may mitigate PH by acting on ETB receptors.

Endothelin receptor antagonists in a beagle model of pulmonary hypertension: Contribution to possible potential therapy?

OBJECTIVES This study investigated the pharmacologic effect of endothelin receptor antagonists on cardiopulmonary hemodynamic variables in a beagle model of pulmonary hypertension. BACKGROUND We recently developed a beagle model of pulmonary hypertension that allows accurate determination of cardiopulmonary hemodynamic variables and is associated with elevated plasma endothelin-1 concentrations similar to those in pulmonary hypertension in humans. METHODS Twelve beagles (pulmonary hypertension, n = 6; control group, n = 6) were studied during baseline conditions and during right atrial infusion of FR139317 (an ETA receptor antagonist), RES-701-1 (an ETB receptor antagonist), nitroglycerin and prostaglandin E1. Pulmonary hypertension was induced in experimental beagles 8 weeks after injection with 3 mg/kg body weight of dehydromonocrotaline. RESULTS FR139317 lowered pulmonary artery and systemic arterial pressures in both pulmonary hypertensive and control beagles, with a significantly greater effect on pulmonary artery pressure in pulmonary hypertensive dogs. RES-701-1 tended to increase pulmonary artery pressure only in pulmonary hypertensive beagles. Nitroglycerin depressed pulmonary artery and systemic arterial tone equally well in control and pulmonary hypertensive animals. Prostaglandin E1 produced a greater decrease in systemic arterial pressure in pulmonary hypertensive than in normal beagles despite having the same effect on pulmonary artery pressure in both. CONCLUSIONS ETA receptor antagonists decrease pulmonary artery pressure in a beagle model and may therefore be clinically useful for treatment of pulmonary hypertension.

Successful 24-hour reabbit heart preservation by hypothermic continuous coronary microperfusion with oxygenated university of wisconsin solution

BACKGROUND This study assessed whether a combination of hypothermic continuous coronary microperfusion and oxygenated University of Wisconsin Solution (UWS) improves postischemic functional recovery and minimizes myocardial tissue edema. METHODS Isolated rabbit hearts were divided into four groups (n = 6 each): group I (immediate reperfusion), group II (simple cold storage in UWS), group III (hypothermic continuous coronary microperfusion with UWS), and group IV (hypothermic continuous coronary microperfusion with oxygenated UWS). Hearts in groups II, III, and IV were preserved for 24 hours. Preischemic and postischemic cardiac function was measured using a Langendorff apparatus. RESULTS Hearts in group I showed complete functional recovery, whereas cardiac output in group II was inadequate. In groups III and IV, the percentage recovery rate (post/pre) of cardiac output was 57.0% +/- 3.1% and 82.2% +/- 9.1%, respectively (p < 0.05). In groups III and IV, perfusion pressures at the end of 24-hour preservation increased from the initial 5 mm Hg to 12.3 +/- 2.7 and 8.3 +/- 1.4 mm Hg (p < 0.05), respectively. In groups I, III, and IV, the percentage tissue water content was 82.8 +/- 1.0, 86.7 +/- 1.7, and 83.8 +/- 1.6, respectively (p < 0.05 for group III versus groups I and IV). There was a significant correlation between the percentage tissue water content and coronary perfusion pressure at the end of the 24-hour preservation (r = 0.60, p = 0.040) and a significant inverse correlation between percentage tissue water content and percentage recovery rate of cardiac output (r = -0.69, p = 0.014). In ultrastructural examination, myocardial tissue edema was limited and mitochondria were well preserved in group IV. CONCLUSION We conclude that the combination of a hypothermic continuous coronary microperfusion technique and oxygenation of UWS was the procedure of choice for reducing tissue edema and improving both the coronary microcirculation and functional recovery during 24-hour heart preservation.

Usefulness of cardiopulmonary bypass in reconstruction of inferior vena cava occupied by renal cell carcinoma tumor thrombus

Aggressive surgical treatment in renal cell carcinoma is still controversial. The aim of this paper is to assess inferior vena caval (IVC) reconstruction for suprahepatic vena caval renal cell carcinoma (RCC) tumor thrombus. Twelve patients with suprahepatic vena caval thrombus from renal cell carcinoma who underwent surgical repair with cardiopulmonary bypass were evaluated. The vena caval defect was reconstructed by direct suture, patch repair, or graft replacement. Of 12 patients undergoing partial cardiopulmonary bypass, tumor thrombus extended to the junction of the hepatic vein in three patients and to the right atrium in one. Tumor thrombus was removed manually or with balloon catheter. Tumor thrombus in the right atrium was removed during electrical ventricular fibrillation. Repair of the IVC was performed by direct suture of the IVC wall in two patients, patch repair with expanded polytetrafluoroethylene (EPTFE) graft in seven, and graft replacement with an EPTFE graft in three. There were no operative deaths and the only postoperative complication was one patient death from pulmonary emboli. The four patients with nonlocalized disease died within 2 years, but four patients lived for more than 3 years postoperatively. Survival was 37.5% at 3 years and 18.8% at 5 years by the Kaplan-Meiers method. Conclusions: (1) Partial cardiopulmonary bypass is useful for the control of bleeding when tumor thrombus in the IVC extends to the junction of the hepatic vein. (2) Nephrectomy with tumor thrombectomy of the IVC is valuable, and long-term survival is possible in patients without distant metastases or regional lymph node metastases.

Successful resection of a recurrent leiomyosarcoma of the pulmonary trunk

We successfully performed a total resection of the pulmonary artery trunk and replaced it with an equine pericardial xenograft roll in a patient with a recurrent leiomyosarcoma. We believe, based on anatomic and embryologic principles, total rather than partial resection of the pulmonary artery trunk should be the treatment of choice for primary leiomyosarcomas of the pulmonary artery.