Effects of bradykinin, histamine and serotonin on pulmonary vascular resistance and permeability.

The effects of bradykinin, histamine and serotonin on vascular resistance and microvascular permeability were investigated in isolated cell-free perfused rabbit lungs. The capillary filtration coefficient was determined from the slope of lung weight changes over periods of venous pressure elevation before application of bradykinin (n = 6), histamine (n = 6) and serotonin (n = 6), and 5, 20 and 50 min afterwards. To prevent rapid inactivation of bradykinin by the angiotensin-converting enzyme in the pulmonary circulation, the bradykinin effects were additionally studied in the presence of the angiotensin-converting enzyme inhibitor captopril (n = 6). Bolus application of each substance resulted in a short-lasting increase in the pulmonary vascular resistance (3.7-9.1 mmHg). Which was most pronounced in the bradykinin+captopril group. The capillary filtration coefficient was significantly increased after histamine application, and to an even greater extent after serotonin application, whereas bradykinin on its own, as well as bradykinin given in the presence of captopril, had no measurable influence on capillary filtration in the lung. As a result of the bradykinin challenge, there was an immediate massive generation of prostacyclin, which could not be further augmented by a application. Histamine injection entailed a delayed onset of prostacyclin generation after the second stimulation, whereas no prostacyclin increase was measured in the serotonin-treated lungs. Thromboxane A2 generation was exclusively observed after the first serotonin application. The data exemplify different pathophysiological characteristics of bradykinin, histamine and serotonin on lung barrier function. Histamine and serotonin induce oedema formation by enhancing microvascular permeability, whereas bradykinin does not.

Alteration of n-3 fatty acid composition in lung tissue after short-term infusion of fish oil emulsion attenuates inflammatory vascular reaction.

OBJECTIVES: To investigate whether modulation of the fatty acid profile can be achieved by the short-term infusion of a fish oil emulsion which may attenuate the pulmonary response to inflammatory stimulation. Changes of fatty acid pattern in-lung tissue and perfusate were analyzed and correlated with physiologic data after a 3-hr infusion of fish oil in comparison with a soybean oil preparation. DESIGN: Prospective, randomized, controlled trial. SETTING: Experimental laboratory in a university teaching hospital. SUBJECTS: Forty standard breed rabbits of either gender. INTERVENTIONS: Isolated lungs from anesthetized rabbits were ventilated and recirculation-perfused (200 mL/min) with 200 mL of cell-free buffer solution to which either 2 mL of saline (control, n = 6), 2 mL of a 10% soybean oil preparation (n = 6), or 2 mL of a 10% fish oil emulsion (n = 6) were added. Samples of perfusate and lung tissue were collected for analysis of fatty acid composition. Tissue and perfusate fatty acid composition were analyzed by capillary gas chromatography. To study metabolic alterations in states of inflammatory stimulation, lungs of each group were stimulated with small doses of the calcium ionophore, A23187 (10(-8) M), during the 180-min lipid perfusion period and again after washing out the lipids by exchanging the perfusion fluid. Pulmonary arterial pressure and lung weight gain were monitored, and eicosanoids were analyzed in the perfusate. MEASUREMENTS AND MAIN RESULTS: Free eicosapentaenoic acids increased several-fold in lung tissue and perfusate during a 3-hr infusion with fish oil. The intravenously administered n-3 fatty acids were rapidly hydrolyzed, as indicated by the appearance of substantial quantities of eicosapentaenoic acid in the perfusate free fatty acid fraction. This increase of perfusion levels of eicosapentaenoic acid was paralleled by an attenuated pressure increase and edema formation due to calcium ionophore challenge and an altered eicosanoid spectrum determined in the perfusate compared with soybean oil-treated lungs. CONCLUSION: Short-term n-3 lipid application (fish oil emulsion) exerts anti-inflammatory effects on lung vasculature, which may be due to the metabolism of eicosapentaenoic acid resulting in the generation of less potent inflammatory eicosanoids.

Effects of N-acetylcysteine on bacterial clearance.

The aim of this study was to investigate whether the oxygen radical scavenger N-acetylcysteine (N-AC) impairs bacterial clearance, thus predisposing the host to increased risk of disease. Blood clearance of Escherichia coli and organ colonization were investigated in anaesthetized rabbits after pretreatment with N-AC (250 mg kg-1 body weight, n = 16) and in sham-operated animals (n = 12). To enable quantification of the clearance process, defined numbers of exogenous E. coli [1.3 x 108 colony-forming units (CFUs)] were injected intravenously. Parameters monitored were kinetics of bacterial elimination from the blood, and polymorphonuclear leucocyte (PMN) oxidative burst activity. Samples of liver, kidney, spleen and lung were collected for bacterial counts. Compared with controls, pretreatment with N-AC resulted in delayed bacterial elimination from blood and higher organ colonization with increased numbers of E. coli in liver, lung and kidney (P < 0.05). N-AC treatment was associated with a suppressed PMN oxidative burst activity. Impaired bacterial clearance and enhanced organ colonization in N-AC-treated animals correlated with reduced oxidative burst activity, suggesting impaired granulocyte-dependent bacterial killing due to N-AC application.

Influence of B2 receptor antagonists on bradykinin-induced vasodilation and edema formation in isolated rabbit hindlimbs.

In search of new possibilities to prevent acute inflammatory vascular reaction, we examined the effect of two selective B2 receptor antagonists, CP 0127 ([Bissuccimidohexane (L-Cys6)-1] and HOE 140 (D-Arg[Hyp3, Thi5, D-Tic7, Oic8]BK), on changes in perfusion pressure and on edema formation caused by bradykinin (BK) in the isolated perfused rabbit hindlimbs. CP 0127 and HOE 140 were added to the perfusion fluid 2 min prior to the first BK-administration (5 x 10(-9) mol/l). A second BK-stimulation was performed after 30 minutes. The antagonists were tested in groups of 6 experiments each at concentrations of 10(-6) mol/l, 5 x 10(-9) mol/l and 10(-10) mol/l. CP 0127 was also tested in a concentration of 10(-8) mol/l. The application of BK resulted in an acute decrease of the mean arterial pressure and in a continual edema formation, reflected by an increase of organ weight (controls, n = 6). Pretreatment with CP 0127 as well as with HOE 140 attenuated dose-dependently the BK-induced vasodilation (p < 0.005) and edema formation. The current results indicate that CP 0127 and HOE 140 are able to reduce BK-induced effects on vascular tone and edema formation.

Distinct down-regulation of cardiac beta 1- and beta 2-adrenoceptors in different human heart diseases.

Cardiac beta-adrenoceptor density and beta 1- and beta 2-subtype distribution were examined in human left ventricular myocardium from transplant donors serving as controls and from patients with mitral valve stenosis, aortic valve stenosis, idiopathic dilated cardiomyopathy, and ischaemic cardiomyopathy respectively. The total beta-adrenoceptor density was similar in transplant donors and patients with moderate heart failure (NYHA II-III) due to mitral valve stenosis, but was markedly reduced in all forms of severe heart failure (NYHA III-IV) studied. A reduction of both beta 1- and beta 2-adrenoceptors was found in patients with severe heart failure due to mitral valve stenosis or ischaemic cardiomyopathy. In contrast, a selective down-regulation of beta 1-adrenoceptors with unchanged beta 2-adrenoceptors and hence a relative increase in the latter was observed in idiopathic dilated cardiomyopathy and aortic valve stenosis. It is concluded that the extent of total beta-adrenoceptor down-regulation is related to the degree of heart failure. Selective loss of beta 1-adrenoceptors is not specific for idiopathic dilated cardiomyopathy but also occurs in aortic valve stenosis. Changes in beta 1- and beta 2-subtype distribution are rather related to the aetiology than to the clinical degree of heart failure.