Animal models of complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanoparticles

Intravenous injection of some liposomal drugs, diagnostic agents, micelles and other lipid-based nanoparticles can cause acute hypersensitivity reactions (HSRs) in a high percentage (up to 45%) of patients, with hemodynamic, respiratory and cutaneous manifestations. The phenomenon can be explained with activation of the complement (C) system on the surface of lipid particles, leading to anaphylatoxin (C5a and C3a) liberation and subsequent release reactions of mast cells, basophils and possibly other inflammatory cells in blood. These reactions can be reproduced and studied in pigs, dogs and rats, animal models which differ from each other in sensitivity and spectrum of symptoms. In the most sensitive pig model, a few miligrams of liposome (phospholipid) can cause anaphylactoid shock, characterized by pulmonary hypertension, systemic hypotension, decreased cardiac output and major cardiac arrhythmias. Pigs also display cutaneous symptoms, such as flushing and rash. The sensitivity of dogs to hemodynamic changes is close to that of pigs, but unlike pigs, dogs also react to micellar lipids (such as Cremophor EL) and their response includes pronounced blood cell and vegetative neural changes (e.g., leukopenia followed by leukocytosis, thrombocytopenia, fluid excretions). Rats are relatively insensitive inasmuch as hypotension, their most prominent response to liposomes, is induced only by one or two orders of magnitude higher phospholipid doses (based on body weight) compared to the reactogenic dose in pigs and dogs. It is suggested that the porcine and dog models are applicable for measuring and predicting the (pseudo)allergic activity of particulate "nanodrugs".     

Complement activation-related cardiac anaphylaxis in pigs: role of C5a anaphylatoxin and adenosine in liposome-induced abnormalities in ECG and heart function

Cardiac anaphylaxis is a severe, life-threatening manifestation of acute hypersensitivity reactions to allergens and drugs. Earlier studies highlighted an amplifying effect of locally applied C5a on the process; however, the role of systemic complement (C) activation with C5a liberation in blood has not been explored to date. In the present study, we used the porcine liposome-induced cardiopulmonary distress model for 1) characterizing and quantifying peripheral C activation-related cardiac dysfunction; 2) exploring the role of C5a in cardiac abnormalities and therapeutic potential of C blockage by soluble C receptor type 1 (sCR1) and an anti-C5a antibody (GS1); and 3) elucidating the role of adenosine and adenosine receptors in paradoxical bradycardia, one of the symptoms observed in this model. Pigs were injected intravenously with different liposomes [Doxil and multilamellar vesicles (MLV)], zymosan, recombinant human (rhu) C5a, and adenosine, and the ensuing hemodynamic and cardiac changes (hypotension, tachy- or bradycardia, arrhythmias, ST-T changes, ventricular fibrillation, and arrest) were quantified by ranking on an arbitrary scale [cardiac abnormality score (CAS)]. There was significant correlation between CAS and C5a production by liposomes in vitro, and the liposome-induced cardiac abnormalities were partially or fully reproduced with zymosan, rhuC5a, adenosine, and the selective adenosine A1 receptor agonist cyclopentyl-adenosine. The use of C nonactivator liposomes or pretreatment of pigs with sCR1 or GS1 attenuated the abnormalities. The selective A1 blocker cyclopentyl-xanthine inhibited bradycardia without influencing hypotension, whereas the A(2) blocker 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-24135) had no such effect. These data suggest that 1) systemic C activation can underlie cardiac anaphylaxis, 2) C5a plays a causal role in the reaction, 3) adenosine action via A1 receptors may explain paradoxical bradycardia, and 4) inhibition of C5a formation or action or of A1-receptor function may alleviate the acute cardiotoxicity of liposomal drugs and other intravenous agents that activate C.     

Mechanisms of hypotension produced by platelet-activating factor

Platelet-activating factor (PAF) is a phospholipid mediator that induces cardiovascular collapse and release of the secondary mediator thromboxane A2 (TxA2). To clarify mechanisms involved in this collapse and, specifically, the relative contribution of left ventricular and right ventricular dysfunction, we studied 12 open-chest pigs. PAF infusion (0.04-0.28 nmol.kg-1.min-1) induced a 5- to 120-fold increase in pulmonary vascular resistance, a 75-98% fall in cardiac output, and systemic arterial hypotension. Right ventricular failure was indicated by chamber enlargement, decreased shortening, and increased right atrial pressures. In contrast, left ventricular dysfunction was accompanied by decreases in chamber dimensions and filling pressures that were unresponsive to volume expansion. U 46619 (a stable TxA2 analogue) and mechanical pulmonary artery constriction induced changes similar to PAF. In 11 additional closed-chest pigs, TxA2 blockade with indomethacin attenuated the PAF-induced rise in pulmonary vascular resistance, right ventricular dysfunction, and systemic hypotension. A specific TxA2 synthase inhibitor, OKY-046, also diminished hemodynamic effects of PAF in six other pigs. Tachyphylaxis was not observed in five pigs repeatedly given PAF. We conclude that acute right ventricular failure as the result of severe increase in pulmonary vascular resistance is the primary mechanism early in the course of PAF-induced shock in the pig. PAF-induced release of TxA2 may contribute significantly to these events.     

Cerebrovascular Involvement in Liposome—Induced Cardiopulmonary Distress in Pigs

Intravenous administration of liposomes, including Doxil, can cause severe life-threatening hemodynamic changes in pigs. The reaction is due to complement activation, and it is characterized by massive pulmonary hypertension, systemic hypotension, and severe cardiac abnormalities including falling cardiac output, tachy-or bradycardia with arrhythmia. There were no data suggesting the involvement of cerebrovascular changes in this reaction; however, clinical observations allowed this hypothesis. Here we measured the accompanying changes during liposome infusion by monitoring pulsatile electrical impedance (rheoencephalogram- REG) on the skull (n = 24 pigs, 57 trials, 19 types of liposomes). A transient but significant decrease of REG pulse amplitudes followed the injection of liposomes (78.43% in the total sample, and 91.66% in the Doxil subgroup; P = 0.003, n = 12), indicating the involvement of cerebrovascular reaction during liposome infusion.     

Cerebrovascular involvement in liposome-induced cardiopulmonary distress in pigs

Intravenous administration of liposomes, including Doxil, can cause severe life-threatening hemodynamic changes in pigs. The reaction is due to complement activation, and it is characterized by massive pulmonary hypertension, systemic hypotension, and severe cardiac abnormalities including falling cardiac output, tachy-or bradycardia with arrhythmia. There were no data suggesting the involvement of cerebrovascular changes in this reaction; however, clinical observations allowed this hypothesis. Here we measured the accompanying changes during liposome infusion by monitoring pulsatile electrical impedance (rheoencephalogram- REG) on the skull (n=24 pigs, 57 trials, 19 types of liposomes). A transient but significant decrease of REG pulse amplitudes followed the injection of liposomes (78.43% in the total sample, and 91.66% in the Doxil subgroup; P=0.003, n=12), indicating the involvement of cerebrovascular reaction during liposome infusion.     

Effects of induced hypothermia on organ blood flow in a hibernator and a nonhibernator

Regional blood flow and hemodynamic variables during induced hypothermia were compared in six guinea pigs and four hedgehogs. Tracer microspheres were used for blood flow measurements, since this technique is more accurate than the earlier method (86Rb+ distribution) used for cardiac output distribution measurements in hibernators. Heart rate and blood pressure decreased with reduced temperature in a comparable fashion in the two species, while cardiac output was less affected in the hedgehogs than in the guinea pigs. Total peripheral resistance increased in both species. At 34 degrees C the hedgehogs had a higher myocardial blood flow per gram tissue than the guinea pigs and it was not reduced in the hedgehogs when the body temperature was lowered to 22 degrees C, whereas in the guinea pigs it was markedly reduced. The brown adipose tissue of the hedgehogs showed a fourfold increase in blood perfusion at 22 degrees C when compared with 34 degrees C. In the hedgehogs the fractional distribution of cardiac output to the myocardium increased with decreasing body temperature, while the renal fraction decreased. In the guinea pigs, on the other hand, the fractional distribution of cardiac output to the myocardium remained unchanged but increased to the kidneys.     

Cardiopulmonary effects of hemorrhagic shock in splenic autotransplanted pigs: a new surgical model

The spleen is an important organ for hemodynamic compensation during hemorrhagic shock. The aim of the study was to compare the hemodynamic and metabolic responses of sham-operated pigs with intact spleen, splenectomized pigs, and splenic autotransplanted pigs during hemorrhagic shock. Hemorrhagic shock was induced by 30% total blood volume bleed in sham-operated, splenectomized and splenic autotransplanted pigs (n = 20). Cardiopulmonary and metabolic variables were measured before, immediately after, and at 20, 60 and 100 minutes after hemorrhage. Upon hemorrhagic shock induction, body temperature, mean arterial pressure, mean pulmonary arterial pressure, cardiac output, cardiac index and oxygen delivery decreased, while lactate and shock index increased. Hemoglobin and hematocrit were significantly lower in the splenectomized and splenic autotransplant groups as compared with the control group at 60 and 100 minutes after hemorrhage (p < 0.05). Unlike intact spleen, splenic autotransplant could not improve hemodynamic parameters in hemorrhagic shock in pigs. In comparison to mice, rats or dogs, this species could be an interesting investigation model to test new surgical procedures during splenic related hemorrhagic shock, with potential applications in human medicine.     

Sequential release of eicosanoids during endotoxin-induced shock in anesthetized pigs

The release of eicosanoids during endotoxin shock was investigated in anesthetized pigs receiving 5 micrograms/kg Escherichia coli lipopolysaccharide (LPS) over 60 min into the superior mesenteric artery. TXB2, 6-keto PGF1 alpha and LTB4 concentrations in blood obtained from the superior mesenteric vein (SMV), right ventricle (RV) and aorta, during LPS infusion and an additional period of 2 h, were assessed along with hemodynamic variables, blood gases and pH and laboratory parameters. Half of the animals died within 30 min after termination of LPS infusion (non-survivors, n = 8), while the other half survived the experimental period of 3 h, though in a shock state (survivors, n = 9). The non-surviving pigs demonstrated progressively reduced cardiac output, hypotension and hypoperfusion in all organs. The surviving pigs demonstrated also a reduced cardiac output, which however was compensated by an elevated systemic vascular resistance resulting in a maintenance of arterial blood pressure. After exhausting this compensation the flow to non-vital organs increased and consequently arterial blood pressure was reduced resulting in hypoperfusion. In survivors a marked, though, transient increase was measured in concentrations of TXB2 and 6-keto PGF1 alpha level. A significant increase was measured in plasma concentration of LTB4 in SMV without any elevation in RV and aorta. LTB4 production started when prostanoid release had decreased. In contrast to survivors, no changes could be observed in eicosanoid release for non-survivors. A correlation was observed between systemic vascular resistance and TXB2 to 6-keto PGF1 alpha ratio.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Role of Complement Activation in Hypersensitivity to Pegylated Liposomal Doxorubicin (Doxil®)

Abstract

Liposomal formulations of some drugs, most importantly pegylated liposomal doxorubicin (Doxil®), have been reported to cause immediate hypersensitivity reactions that cannot be explained with the conventional paradigm of IgE-mediated (type I) allergy. Here we present a rationale and experimental evidence for the concept that these reactions represent a novel type of drug-induced hypersensitivity that can be called complement (C) activation-related pseudoallergy (CARPA). The theoretical foundation includes the facts that 1) some liposomes have been known to activate C, 2) most of the clinical symptoms of liposome-induced reactions coincide with those caused by C activation by other activators, and 3) the C mechanism explains those manifestations which are atypical for type 1 reactions. The experimental evidence includes the observations that 1) Doxil caused massive C activation in a high ratio (4/10) of normal human sera, 2) high dose IgG attenuated Doxil-induced C activation in serum and prevented further C activation by amplification, and 3) intravenous injection of therapeutically relevant doses of Doxil in pigs caused significant pulmonary hypertension with consequent systemic hypotension and decline of cardiac output, which changes mimicked the cardiovascular manifestations of the human reaction and were shown to be triggered by C activation. As for the question how Doxil, a long-circulating “stealth” liposome formulation, avoids phagocytic uptake by macrophages despite its potential opsonization by C3b, we demonstrated efficient inactivation of Doxil-bound and free C3b to iC3b in human serum. Thus, it is unlikely that PEG would interfere with CD11b/CD18-mediated phagocytosis by inhibiting the formation of its main ligand, iC3b.     

Dangers in the Use of Some Potent Drugs

The chief dangers reported with some common drugs are reviewed. Hazards of antibiotic therapy include: the increasing incidence of sensitization to penicillin with occasional anaphylactic reactions; aplastic anemia with chloramphenicol, and the poor tolerance of infants for chloramphenicol; staphylococcal enterocolitis; unnecessary “prophylactic” use of antibiotics. Thiazide diuretics may precipitate potassium depletion, skin reactions, pancreatitis, blood dyscrasias, gout, diabetes mellitus and hepatic coma. Reserpine can increase gastric acidity, induce mental depression, and when used with digitalis lead to ventricular premature beats. Hydralazine may aggravate angina pectoris, cause tachycardia, and bring about a syndrome resembling disseminated lupus erythematosus. Guanethidine may result in loose stools, impotence, and postural hypotension. Hazards of phenothiazines include jaundice, parkinsonian states and tremors, convulsions, hypotension, and blood dyscrasias. The butanediols have numerous side effects including gastrointestinal, cutaneous and hypotensive reactions. Prolonged corticosteroid therapy introduces a new danger in surgical treatment. The progesterone-like drugs may induce masculinization of the female fetus.     

Mechanisms of Responses of Systemic Circulation: Role of the Endothelial Factor of Vascular Tone Control

Experimental data on the effect of NO synthase inhibition on hemodynamic changes (blood pressure, cardiac output, and peripheral resistance) induced by an increased (polyglucin infusion) or decreased (orthostasis) cardiac output are presented. Under conditions of NO synthase inhibition, the pressor effects of polyglucin and orthostatic hypotension increased by 70 and 72%, respectively. The response of peripheral resistance had a similar trend. Significance of NO secretion by vascular endothelium for the development of systemic hemodynamic responses is proposed.     

Prevention of Hemodynamic Instability in Extra-Cranial Carotid Angioplasty and Stenting Using Temporary Transvenous Cardiac Pacemaker

Hemodynamic instability is a common condition during extra-cranial carotid angioplasty and stenting (CAS). We evaluated the safety and efficacy of prophylactic placement of temporary cardiac pacemaker during extra-cranial CAS for the prevention of hemodynamic instability. For this, forty-seven carotid artery stents were deployed in 41 high-risk patients. Temporary transvenous cardiac pacemakers were inserted before CAS procedure. The pacers were set to capture a heart rate <60 bpm. Clinical symptoms, blood pressure, heart rate, and pacing activation were monitored and data were collected. We found that pacing occurred in 25 carotid lesions during balloon predilatation; pacemakers were activated transiently in 25 patients. The longest pacing continued for 1 day. Among cases with pacemaker activation, 1 patient developed post-procedural symptomatic hypotension that lasted for 4 days. No related complications were observed. It was, therefore, concluded that pacing was technically effective in producing electrical ventricular responses and was hemodynamically effective in 25 carotid lesions which underwent balloon predilatation. The prophylactic use of a temporary transvenous cardiac pacemaker during CAS was rapid and effective in controlling peri-operative hemodynamic instability and preventing stroke and other complications. The prophylactic use of temporary pacemaker is particularly recommended for patients at high risk for developing hemodynamic instability.     

Effect of volume expansion on hemodynamic variables in nephrectomized dogs

We have previously demonstrated that blood pressure elevation by acute blood volume expansion is volume-dependent during the infusion period and resistance-dependent in the post-infusion period in normal anesthetized dogs, and that such an increase in blood pressure is associated with a potentiation of the pressor response to norepinephrine. To evaluate the possible renal contribution to these hemodynamic changes, blood volume expansion was performed for 1 h with dextran dissolved in lactated Ringer's solution (20 ml/kg) in 15 nephrectomized dogs. The mean blood pressure, cardiac output and total peripheral resistance at the end of infusion were 126%, 225% and 60%, respectively; 3 h after volume expansion they were 126%, 151%, and 92% respectively. However, in 4 dogs, there was an increase in mean blood pressure (138%) 3 h after volume expansion. This was thought to result from an increase in the total peripheral resistance (133%) associated with the recovery of cardiac output (106%). The pressor response to norepinephrine (0.5 microgram/kg) was potentiated after volume expansion. These results indicate that the handling of volume by the kidney contributed to the maintenance of an elevated level of cardiac output. However, nephrectomy did not seem to interfere with the hemodynamic switching of the causative factor for blood pressure elevation from increased cardiac output to increased total peripheral resistance. Neither was the potentiation of pressor response to norepinephrine affected.     

Effect of age on cardiovascular responses to static muscular contraction in beagles.

Induced muscular contraction in anesthetized animals results in significant hemodynamic and regional blood flow (RBF) changes. Although reflex cardiovascular responses initiated in contracting muscle have been firmly established, little is known about the effects of age on these responses. Because other reflex responses that involve sympathetic activation appear to be attenuated with age, it was hypothesized that reflex efferent cardiovascular responses that normally occur during muscular contraction would be impaired in senescent dogs. Therefore, hemodynamic and RBF responses to induced static hindlimb contraction (HLC) were evaluated in 8- to 14- and 2- to 3-yr-old beagles during alpha-chloralose anesthesia. Most baseline hemodynamic parameters were similar in both groups, but heart rate was significantly (P < 0.05) higher in old dogs. During HLC, heart rate and blood pressure increased in the young and old dogs. However, increases in stroke volume and cardiac output were greater in old dogs, combined with a reduction in systemic vascular resistance not observed in young dogs. No age-related difference in baseline RBF (microspheres) was observed in six of eight abdominal regional circulations and in each of four skeletal muscle groups. During HLC, RBF reductions occurred in six of eight abdominal organs in young and old dogs. However, the reduction in RBF and concomitant increase in vascular resistance in all eight abdominal regions combined was almost twice as great in young vs. old dogs. In noncontracting skeletal muscle, RBF decreased and vascular resistance increased four times more in young vs. old dogs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Repeated daily injections and osmotic pump infusion of isoproterenol cause similar increases in cardiac mass but have different effects on blood pressure

We found in mice that repeated single daily subcutaneous (s.c.) isoproterenol (ISO) injections, like constant infusions using osmotic minipumps, caused increased biventricular mass or weight relative to body weight (VW/BW). We found that 5 (1/d) s.c. injections of 2, 10, or 20 microg/g body weight caused equivalent VW/BW increases as compared with 5-d infusions at 20 microg/(g.d)). While it is often presumed that ISO elicits hypertrophy by a direct effect on the myocytes, growth may also be secondary to systemic hemodynamic effects. The 2 modes of ISO administration had different effects on mean arterial blood pressure (MABP) and heart rate. Using telemetry we observed that single injections of ISO (0, 0.5, 2, and 10 microg/g) were associated with hypotension and tachycardia with a duration but not a magnitude that was dose dependent. MABP dropped rapidly to 60 mm Hg for more than 2 h at the highest dose. Constant s.c. infusion of ISO at 20 microg/(g.d) initially lowered MABP to about 70 mm Hg for 24 h. At 48 h MABP was normal, but rose 10 mm Hg higher than baseline by day 5. Thus, different routes of administration of ISO that cause comparable increases in VW/BW had different effects on MABP. Thus when evaluating mouse models of ISO-induced cardiac hypertrophy, both repeated daily injections or infusions can cause similar increases in VW/BW, but the daily doses that are required are not the same. Furthermore, these different routes of administration have different hemodynamic sequelae and could potentially evoke different cardiac phenotypes.     

Regional hemodynamics during postexercise hypotension. I. Splanchnic and renal circulations.

Moderate exercise elicits a relative postexercise hypotension that is caused by an increase in systemic vascular conductance. Previous studies have shown that skeletal muscle vascular conductance is increased postexercise. It is unclear whether these hemodynamic changes are limited to skeletal muscle vascular beds. The aim of this study was to determine whether the splanchnic and/or renal vascular beds also contribute to the rise in systemic vascular conductance during postexercise hypotension. A companion study aims to determine whether the cutaneous vascular bed is involved in postexercise hypotension (Wilkins BW, Minson CT, and Halliwill JR. J Appl Physiol 97: 2071-2076, 2004). Heart rate, arterial pressure, cardiac output, leg blood flow, splanchnic blood flow, and renal blood flow were measured in 13 men and 3 women before and through 120 min after a 60-min bout of exercise at 60% of peak oxygen uptake. Vascular conductances of leg, splanchnic, and renal vascular beds were calculated. One hour postexercise, mean arterial pressure was reduced (79.1 +/- 1.7 vs. 83.4 +/- 1.8 mmHg; P < 0.05), systemic vascular conductance was increased by approximately 10%, leg vascular conductance was increased by approximately 65%, whereas splanchnic (16.0 +/- 1.8 vs. 18.5 +/- 2.4 ml.min(-1).mmHg(-1); P = 0.13) and renal (20.4 +/- 3.3 vs. 17.6 +/- 2.6 ml.min(-1).mmHg(-1); P = 0.14) vascular conductances were unchanged compared with preexercise. This suggests there is neither vasoconstriction nor vasodilation in the splanchnic and renal vasculature during postexercise hypotension. Thus the splanchnic and renal vascular beds neither directly contribute to nor attenuate postexercise hypotension.     

Distribution of the antibody to influenza C virus in dogs and pigs in Yamagata Prefecture, Japan

The distribution of the antibody to influenza C virus in the dogs and pigs in Yamagata prefecture, Japan was investigated by using three different serological methods: hemagglutination-inhibition (HI), radioimmunoprecipitation (RIP), and immunoblotting. The antibody against influenza C virus glycoprotein (gp88) was detected in 5 out of 112 sera collected from mongrel dogs, three by RIP test and two by any of the three methods, suggesting that the virus can cause natural infection in dogs. Significant levels of HI activity were found in 58 out of 269 sera collected from domestic pigs, but none of them showed positive reaction in the more sensitive method, RIP, which suggests that the inhibitors against the hemagglutination by influenza C virus rather than the antibody to gp88 are responsible for the observed HI activity. It appears, therefore, that at least in the Yamagata area, pigs do not play significant roles in the spread of influenza C virus in humans.     

Comparison of Normal Saline,Hypertonic Saline Albumin and Terlipressin plus Hypertonic Saline Albumin in an Infant Animal Model of Hypovolemic Shock

Introduction

In series of cases and animal models suffering hemorrhagic shock, the use of vasopressors has shown potential benefits regarding hemodynamics and tissue perfusion. Terlipressin is an analogue of vasopressin with a longer half-life that can be administered by bolus injection. We have previously observed that hypertonic albumin improves resuscitation following controlled hemorrhage in piglets. The aim of the present study was to analyze whether the treatment with the combination of terlipressin and hypertonic albumin can produce better hemodynamic and tissular perfusion parameters than normal saline or hypertonic albumin alone at early stages of hemorrhagic shock in an infant animal model.

Methods

Experimental, randomized animal study including 39 2-to-3-month-old piglets. Thirty minutes after controlled 30 ml/kg bleed, pigs were randomized to receive either normal saline (NS) 30 ml/kg (n = 13), 5% albumin plus 3% hypertonic saline (AHS) 15 ml/kg (n = 13) or single bolus of terlipressin 15 μg/kg i.v. plus 5% albumin plus 3% hypertonic saline 15 ml/kg (TAHS) (n = 13) over 30 minutes. Global hemodynamic and tissular perfusion parameters were compared.

Results

After controlled bleed a significant decrease of blood pressure, cardiac index, central venous saturation, carotid and peripheral blood flow, brain saturation and an increase of heart rate, gastric PCO₂ and lactate was observed. After treatment no significant differences in most hemodynamic (cardiac index, mean arterial pressure) and perfusion parameters (lactate, gastric PCO₂, brain saturation, cutaneous blood flow) were observed between the three therapeutic groups. AHS and TAHS produced higher increase in stroke volume index and carotid blood flow than NS.

Conclusions

In this pediatric animal model of hypovolemic shock, albumin plus hypertonic saline with or without terlipressin achieved similar hemodynamics and perfusion parameters than twice the volume of NS. Addition of terlipressin did not produce better results than AHS.     

The role of the thrombocyte-activating factor in the development of circulatory disorders in the postischemic shock reaction

Experiments carried out on anesthetized dogs have shown that reperfusion of long-ischemized leg tissues is accompanied by a significant decrease of the cardiac output and myocardial contractility. Restriction of the venous return to the heart is important in the cardiac output decrease due to an increase of venous compliance and blood pooling on the peripheral circulation. The preliminary blockade of platelet-activating factor (PAF) receptors decreases degree of the cardio- and hemodynamic disturbances after reperfusion of ischemized tissues and prevents development of pulmonary hypertension. Similarity of the postreperfusion central and peripheral hemodynamic disturbances and animal responses to injection of the exogenous PAF as well as the presence of the protective effect of PAF-receptor antagonist BNo. 52021 permit concluding, that PAF takes part in the development of postischemic shock reaction and its receptor blockade can be used to prevent postreperfusion hemodynamic disorders.     

Characteristics and gender differences concerning pulmonary hemodynamics in Clawn miniature pigs.

The characteristics and gender differences of the pulmonary hemodynamic parameters of 16 Clawn miniature pigs were examined and the data were compared with reports concerning dogs and other pig species. The pulmonary systolic, diastolic and mean arterial blood pressures of the mini-pig were slightly higher than those of the dog, respectively, but both the right atrial pressure and pulmonary capillary wedge pressure were within the normal physiological ranges of the dog. Concerning gender differences in hemodynamic parameters of the mini-pig, the female values, except the right atrial pressure, were slightly higher than those of the male, but no significant differences were recognized. The present study results will help pulmonary researchers understand the differences between Clawn miniature pigs and dogs for accurate analysis of experimental results.