Early pulmonary endothelial enzyme dysfunction after phorbol ester in conscious rabbits

We investigated changes in angiotensin converting-enzyme (ACE) activity before and at 5, 15, 60, and 240 min after 20 micrograms phorbol myristate acetate/kg body wt iv in conscious rabbits. ACE activity was estimated in vivo from the single-pass transpulmonary metabolism of the synthetic substrate [3H]benzoyl-Phe-Ala-Pro [( 3H]BPAP) under first-order reaction conditions. Within 5 min after PMA administration, all animals developed profound granulocytopenia (15% of control) and moderate thrombocytopenia (57% of control), both lasting for the duration of the experiment. Concomitantly, there was a significant decrease in the transpulmonary metabolism of [3H]BPAP and the calculated apparent first-order reaction constant Amax/Km of ACE for [3H]BPAP. No histological evidence of lung injury was observed at these times. Since a concomitant fall in the permeability surface area product for urea was also observed, we considered that the apparent decline in ACE activity might have resulted from a reduction in perfused endothelial surface area. To resolve this, we studied the effect of PMA on the Km (a measure of enzyme affinity for its substrate) and Amax (a derivative of Vmax that is dependent upon total enzyme present and thus capillary surface area) of ACE and 5'-nucleotidase for [3H]BPAP and [14C]AMP, respectively. A significant increase in Km for both enzymes was observed at 1 h after PMA, whereas Amax was unaffected, suggesting that low-dose PMA may indeed produce endothelial cell enzyme dysfunction independent of its effect on capillary surface area. These results provide evidence of pulmonary capillary functional injury before or in the absence of structural endothelial damage.     

Epithelial and endothelial flux after bypass in dogs: effect of positive end-expiratory pressure

Cardiopulmonary bypass (CPB) causes lung injury that occasionally progresses to the adult respiratory distress syndrome (ARDS). We measured the effect of 10 cmH2O of positive end-expiratory pressure (PEEP) on small solute and protein flux in dogs 1 wk before and 2 h after the completion of CPB. As an index of alveolar epithelial permeability, the clearance from lung to blood of inhaled technetium-99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA) was measured. To assess microvascular endothelial integrity, the rate of accumulation in the lung interstitium of intravascular 113mIn-transferrin was measured. The clearance half time (t 1/2) for 99mTc-DTPA in the study dogs declined from 18.8 +/- 1.9 min (mean +/- SE) at base line to 9.4 +/- 2.0 min during PEEP (P less than 0.05). Two hours after CPB, the t 1/2 was 8.1 +/- 1.6 min at base line and unchanged during PEEP. The 113mIn-transferrin rate of accumulation was unchanged by PEEP before CPB. After CPB, the index was 3.25 +/- 0.95 slope/min X 10(-3) (P less than 0.05). Of the five dogs with a significant slope, four showed a decrease in microvascular flux during PEEP, although for the group the mean change in slope was not significant (P = 0.10). We conclude that the application of PEEP does not increase 99mTc-DTPA clearance in lungs already injured by CPB, and may actually decrease the apparent microvascular protein flux in some cases.     

Simvastatin upregulates coronary vascular endothelial nitric oxide production in conscious dogs

Statin drugs can upregulate endothelial nitric oxide (NO) synthase (eNOS) in isolated endothelial cells independent of lipid-lowering effects. We investigated the effect of short-term simvastatin administration on coronary vascular eNOS and NO production in conscious dogs and canine tissues. Mongrel dogs were instrumented under general anesthesia to measure coronary blood flow (CBF). Simvastatin (20 mg. kg(-1). day(-1)) was administered orally for 2 wk; afterward, resting CBF was found to be higher compared with control (P < 0.05) and veratrine- (activator of reflex cholinergic NO-dependent coronary vasodilation) and ACh-mediated coronary vasodilation were enhanced (P < 0.05). Response to endothelium-independent vasodilators, adenosine and nitroglycerin, was not potentiated. After simvastatin administration, plasma nitrate and nitrite (NO(x)) levels increased from 5.22 +/- 1.2 to 7. 79 +/- 1.3 microM (P < 0.05); baseline and agonist-stimulated NO production in isolated coronary microvessels were augmented (P < 0.05); resting in vivo myocardial oxygen consumption (MVO(2)) decreased from 6.8 +/- 0.6 to 5.9 +/- 0.4 ml/min (P < 0.05); NO-dependent regulation of MVO(2) in response to NO agonists was augmented in isolated myocardial segments (P < 0.05); and eNOS protein increased 29% and eNOS mRNA decreased 50% in aortas and coronary vascular endothelium. Short-term administration of simvastatin in dogs increases coronary endothelial NO production to enhance NO-dependent coronary vasodilation and NO-mediated regulation of MVO(2).     

Acute renal dysfunction after cardiac surgery with cardiopulmonary bypass is associated with plasmatic IL6 increase

Background: Acute renal dysfunction (ARD) is common after cardiac surgery with cardiopulmonary bypass (CPB). CPB results in a sudden systemic inflammatory response. Systemic and local pro-inflammatory cytokines synthesis has been linked with sub-clinical renal injury, especially tubular lesions. Therefore, we sought to assess the systemic synthesis pro-inflammatory cytokines and its association with perioperative ARD after cardiac surgery with CPB. Methods: Sixty-two patients undergoing cardiac surgery with CPB were prospectively included. Four groups of patients were defined according to blood creatinine increase: no ARD (less than 25% increase), faint ARD (25–50% increase), moderate ARD (50–100% increase), severe ARD (more than 100% increase). Results: Within the 48 post-operative hours was ARD observed as no dysfunction (41.9%), faint (32.2%), moderate (16.1%), severe (9.6%). One patient had to undergo a dialysis. Pre-operative characteristics were homogenous between the four groups excepted the left ventricle ejection fraction. ARD was associated with a low urinary output with high sodium excretion fraction. Significant increase of IL-6 level occurred when patients underwent a severe ARD despite no significant differences for the CRP and TNF-α concentrations. Conclusion: Severe acute renal dysfunction after cardiac surgery with CPB is associated with a significant increased IL-6 systemic production.     

Ventilatory responses to partial cardiopulmonary bypass at rest and exercise in dogs

We determined the role of blood flow-induced changes in CO2 load to the lungs on ventilatory control, at rest and in the steady-state of electrically induced exercise, in the anesthetized dog. A portion of the vena caval blood was diverted to the descending aorta following "arterialization" through an extracorporeal gas exchanger. Ventilation typically decreased, both at rest and during exercise (i.e., at 2 different levels of mixed venous CO2), in proportion to the CO2 loss; arterial PCO2 was consequently regulated. There were concomitant increases of the pulmonary and peripheral vascular resistance. Bilateral cervical vagosympathectomy markedly attenuated the ventilatory response at rest, thus disrupting arterial PCO2 homeostasis, but not so during exercise. The results therefore provide evidence for and support the suggestion of CO2 flow-related hyperpnea both at rest and during muscular exercise.     

Plasma vasopressin levels during and after cardiopulmonary bypass in man

The effect of cardiopulmonary bypass (CPB) using high dose fentanyl anaesthesia on the concentrations of plasma arginine vasopressin (pAVP), serum electrolytes and osmolality was studied in 12 patients by repeated sampling up to 4th postoperative day. These values were also followed in another 20 patients for the first postoperative day. Fentanyl abolished the pAVP response often seen in major operations but not that produced by CBP. The pAVP concentration 4.8 +/- 0.8 pg/ml immediately after sternotomy increased to 27.2 +/- 1.5 pg/ml (P less than 0.001) after 5-10 minutes on CPB. By the 4th postoperative day the pAVP levels had reached normal values. The main reason for the elevated pAVP concentrations seems to be the onset of CPB, which provokes a fall in mean arterial pressure leading to pAVP release.     

Urinary soluble IL-6 receptor levels after cardiopulmonary bypass

To investigate the possible role of soluble interleukin 6 receptor (sIL-6r) in the inflammatory response to cardiopulmonary bypass (CPB) with extracorporeal circulation (ECC), we examined the levels of sIL-6r in the urine of 50 patients undergoing coronary artery bypass surgery. The presence of sIL-6r in urine was confirmed in these patients, with levels rising from 6 pg/ml preoperatively to 19.5 pg/ml at 6 h and 41 pg/ml at 24 h after the start of cardiopulmonary bypass. Cardiopulmonary bypass leads to a rise in sIL-6r in urine that has not returned to normal after 24 h, suggesting a role for sIL-6r and IL-6 in the inflammatory response to such surgery. Determination of cytokine receptor presence in urine offers a non-invasive approach to the monitoring of the immune and inflammatory response to the stress of surgical and traumatic injury.     

Cardiac diastolic dysfunction in conscious dogs with heart failure induced by chronic coronary microembolization

Left ventricular (LV) diastolic dysfunction is a fundamental impairment in congestive heart failure (CHF). This study examined LV diastolic function in the canine model of CHF induced by chronic coronary embolization (CCE). Dogs were implanted with coronary catheters (both left anterior descending and circumflex arteries) for CCE and instrumented for measurement of LV pressure and dimension. Heart failure was elicited by daily intracoronary injections of microspheres (1.2 million, 90- to 120-microm diameter) for 24 +/- 4 days, resulting in significant depression of cardiac systolic function. After CCE, LV maximum negative change of pressure with time (dP/dt(min)) decreased by 25 +/- 2% (P < 0.05) and LV isovolumic relaxation constant and duration increased by 19 +/- 5% and 25 +/- 6%, respectively (both P < 0.05), indicating an impairment of LV active relaxation, which was cardiac preload independent. LV passive viscoelastic properties were evaluated from the LV end-diastolic pressure (EDP)-volume (EDV) relationship (EDP = be(alpha*EDV)) during brief inferior vena caval occlusion and acute volume loading, while the chamber stiffness coefficient (alpha) increased by 62 +/- 10% (P < 0.05) and the stiffness constant (k) increased by 66 +/- 13% after CCE. The regional myocardial diastolic stiffness in LV anterior and posterior walls was increased by 70 +/- 25% and 63 +/- 24% (both P < 0.05), respectively, after CCE, associated with marked fibrosis, increase in collagen I and III, and enhancement of plasminogen activator inhibitor-1 (PAI-1) protein expression. Thus along with depressed LV systolic function there is significant impairment of LV diastolic relaxation and increase in chamber stiffness, with development of myocardial fibrosis and activation of PAI-1, in the canine model of CHF induced by CCE.     

Time course of sympathovagal imbalance and left ventricular dysfunction in conscious dogs with heart failure

To elucidate thetime course of sympathovagal balance and its relationship to leftventricular function in heart failure, we serially evaluated leftventricular contractility and relaxation and autonomic tone in 11 conscious dogs with tachycardia-induced heart failure. We determined adynamic map of sympathetic and parasympathetic modulation by powerspectral analysis of heart rate variability. The left ventricular peak+dP/dt substantially fell from 3,364 ± 338 to 1,959 ± 318 mmHg/s (P < 0.05) on the third day and declined gradually to 1,783 ± 312 mmHg/s at 2 wk of rapid ventricular pacing. In contrast, the timeconstant of left ventricular pressure decay and end-diastolic pressureincreased gradually from 25 ± 4 to 47 ± 5 ms(P < 0.05) and from 10 ± 2 to21 ± 3 mmHg (P < 0.05), respectively, at 2 wk of pacing. The high-frequency component(0.15-1.0 Hz), a marker of parasympathetic modulation, decreasedfrom 1,928 ± 1,914 to 62 ± 68 × 10³ms²(P < 0.05) on the third day andfurther to 9 ± 12 × 10³ms²(P < 0.05) at 2 wk. Similar to thetime course of left ventricular diastolic dysfunction, plasmanorepinephrine levels and the ratio of low (0.05- to 0.15-Hz)- tohigh-frequency component increased progressively from 135 ± 50 to 532 ± 186 pg/ml (P < 0.05) and from 0.06 ± 0.06 to 1.12 ± 1.01 (P < 0.05), respectively, at 2 wk ofpacing. These cardiac and autonomic dysfunctions recovered graduallytoward the normal values at 2 wk after cessation of pacing. Thus aparallel decline in left ventricular contractility with parasympatheticinfluence and a parallel progression in left ventricular diastolicdysfunction with sympathoexcitation suggest a close relationshipbetween cardiac dysfunction and autonomic dysregulation duringdevelopment of heart failure.

     

Neopterin kinetics after cardiac surgery with or without cardiopulmonary bypass

Cardiac surgery (CS) with cardiopulmonary bypass (CPB) induces systemic inflammatory response by activating plasma proteins and blood cells. Activated monocytes/macrophages produce inflammatory marker neopterin (NP). The aim was to explore the NP kinetics in first 24 hours after CS according to the CPB use. Significant difference between groups was found for NP levels 12 and 24 hrs after CS, being higher in on-pump group. Strong association was found between NP levels 12 hrs after CS and the length of ICU stay for on-pump group (r=0.744, p<0.001). Strong association was found between preoperative NP levels and the length of ICU stay for those on-pump patients with elevated preoperative NP (r=0.855, p=0.001; linear regression equation y=0.50x-5.14, p<0.001). Preoperative NP levels higher than 10 nmol/L in on-pump group could predict prolonged ICU stay and outpoint patients at higher risk for developing postoperative complications and, therefore, help to determine the necessary therapeutic interventions.     

Selective endothelial overexpression of arginase II induces endothelial dysfunction and hypertension and enhances atherosclerosis in mice

Background

Cardiovascular disorders associated with endothelial dysfunction, such as atherosclerosis, have decreased nitric oxide (NO) bioavailability. Arginase in the vasculature can compete with eNOS for L-arginine and has been implicated in atherosclerosis. The aim of this study was to evaluate the effect of endothelial-specific elevation of arginase II expression on endothelial function and the development of atherosclerosis.

Methodology/Principal Findings

Transgenic mice on a C57BL/6 background with endothelial-specific overexpression of human arginase II (hArgII) gene under the control of the Tie2 promoter were produced. The hArgII mice had elevated tissue arginase activity except in liver and in resident peritoneal macrophages, confirming endothelial specificity of the transgene. Using small-vessel myography, aorta from these mice exhibited endothelial dysfunction when compared to their non-transgenic littermate controls. The blood pressure of the hArgII mice was 17% higher than their littermate controls and, when crossed with apoE −/− mice, hArgII mice had increased aortic atherosclerotic lesions.

Conclusion

We conclude that overexpression of arginase II in the endothelium is detrimental to the cardiovascular system.     

氨甲环酸对体外循环术后炎症因子的影响

目的观察氨甲环酸(TA)对体外循环(CPB)围术期炎症因子的影响。方法将40例行体外循环心脏手术的患者随机分为实验组(A组)20例和对照组(B组)20例。A组在麻醉诱导后、体外循环结束时、手术结束时3个时段每次给予TA 10mg/kg;B组给予等量生理盐水。观察两组术前(T1),CPB停机时(T2),术后6h(T3)、12h(T4)和24h(T5)血IL-6、IL-8和CRP的计数水平。结果实验组血清中的IL-6和IL-8水平在CPB停机时、术后6h和12h均显著升高,术后24h均呈下降趋势,并显著低于对照组(P<0.05);CRP水平在术后12h显著升高,术后24h对照组较实验组显著升高(P<0.05)。结论氨甲环酸能减少CPB术后炎症因子的释放,减轻全身炎性反应。