Hemodynamic effects of endotoxin and platelet activating factor in cirrhotic rats.

Acute infections may influence the hemodynamic alterations of liver disease. Therefore, the hemodynamic effects of endotoxin (LPS E. coli 0111:B4) in conscious, normal, and cirrhotic rats were compared. Endotoxin decreased cardiac index in cirrhotic but not in normal rats. Although the effect of endotoxin on portal tributary blood flow was minor in all animals, a reduction in portal pressure was found in cirrhotic rats. Because the most marked hemodynamic effects were observed in cirrhotic rats, the second part of our study investigated whether platelet activating factor played a role in endotoxin-induced hemodynamic alterations in the cirrhotic model. Platelet activating factor reduced cardiac index and kidney blood flow but did not influence portal tributary blood flow. Two antagonists to platelet activating factor reduced the adverse renal blood flow lowering effects of endotoxin in cirrhotic rats. Thus, it is suggested that the hemodynamic changes observed in cirrhosis may be aggravated during acute infections. Under this condition, antagonists to platelet activating factor may be of benefit in the prevention of hemodynamic complications induced by endotoxin.     

Platelet activating factor vasoconstriction of dog kidney. Inhibition by alprazolam

Systemic administration of platelet activating factor (PAF; acetyl glyceryl ether phosphorylcholine) reduces renal blood flow, but the mechanism responsible for that effect has not been defined. To address that problem, we determined the effects on renal blood flow of PAF administered directly into the renal artery in pentobarbital (30 mg/kg)-anesthetized dogs. Bolus injections of PAF (0.2-0.8 microgram) caused transient renal vasoconstriction, reducing renal blood flow by 20 to 60% without altering systemic blood pressure; lyso-PAF (1 microgram) had no effect. The effects of PAF on renal blood flow were not altered by alpha-adrenergic blockade (phentolamine, 3 mg/kg) or by angiotensin II receptor blockade ([Sar1,Ala8]angiotensin II, 6 micrograms/kg/min), but they were increased in magnitude and duration by meclofenamate (5 mg/kg), a cyclooxygenase inhibitor. Methysergide (3 mg/kg), a serotonin antagonist, slightly reduced PAF effects, but a specific blocker of vascular serotonin receptors did not. Renal venous plasma platelet density was not altered by infusion of PAF into the renal artery at a dose (1-2 micrograms/min) that caused a sustained 20% renal blood flow decrease. Alprazolam, a benzodiazepine that competitively inhibited PAF-induced aggregation in canine platelet-rich plasma, also inhibited the renal vasoconstrictor action of PAF (0.8 mg/min, into the renal artery) but did not alter renal vasoconstrictor effects of norepinephrine or angiotensin II.     

The influence of platelet activating factor on the effects of platelet agonists and antiplatelet agents in vitro

We assessed the effect of the intercellular mediator of inflammation, platelet activating factor (PAF), on platelet function. The interaction between PAF and the platelet agonists ADP, thrombin and convulxin was analyzed in vitro in whole blood with the use of flow cytometry and was further characterized with the use of receptor antagonists to PAF (ABT-491), P2Y1 (MRS-2179), and P2Y12 (cangrelor) as well as a monoclonal anti-PSGL-1 antibody (anti-CD162). Low concentrations of PAF (0.1 nM) synergistically augmented platelet activation induced by other agonists (P < 0.01). Augmentation by PAF was receptor mediated and did not require platelet–leukocyte interaction. With >99% inhibition of P2Y receptor-mediated platelet activation, greater than additive activation was still observed with the combination of ADP plus PAF. Accordingly, PAF synergistically augments platelet activation in response to ADP and thrombin, and the extent of inhibition exerted by P2Y receptor antagonists is decreased in the presence of PAF.     

Lysine-vasopressin: Hemodynamic effects in the anesthetized dog

Vasopressin (ADH) is known to reduce secretin-stimulated pancreatic exocrine secretion. The present study attempts to relate this inhibitory effect to the vasoconstrictive potency of ADH. Regional blood flow was measured electromagnetically in anesthetized dogs. ADH reduced blood flow inmmost of the vascular areas. The greatest reduction in blood flow was seen in the gastrointestinal area especially in the left gastric artery, cranial and caudal pancreaticoduodenal arteries, as well as the cranial and caudal mesenteric arteries. Renal blood flow was not altered by those concentrations of ADH that reduced gastrointestinal blood flow. ADH reduced pancreaticoduodenal blood flow in concentrations comparable to those concentrations that reduced pancreatic secretory flow. The reduction of gastrointestinal blood flow was due to increased impedance and not to diminished cardiac inotropy.Mr. J.A.J. Schuurkes work was supported by the Foundation for Medical Research FUNGO.     

Hemodynamic effects of intravenous sodium nitroprusside in the conscious dog

The hemodynamic effects of 7 min i.v. sodium nitroprusside (NP) were studied in conscious dogs previously instrumented for measurement of arterial pressure, cardiac output, regional blood flow distribution, left ventricular (LV) pressure, and internal dimensions. Nitroprusside, 25 microgram/kg/min, reduced mean arterial pressure by 23 +/- 3%. Cardiac output increased initially by 39 +/- 7% and returned toward control by the end of the infusion. Regional blood flows increased initially; the relative rise was greatest in the coronary (+ 225 +/- 39%), intermediate in the mesenteric (+ 98 +/- 23%) and iliac (+ 38 +/- 6%), and least in the renal (+ 10 +/- 3%) bed. By the end of the infusion period the vasodilation was unchanged in the iliac bed, less intense in the coronary and mesenteric, while in the iliac bed, blood flow was reduced and resistance was actually increased by 33 +/- 11% above control. A generalized vasonconstriction ensued after cessation of infusion. In contrast, when the drug was administered intra-arterially to the iliac bed, arterial pressure did not fall and only iliac vasodilation was observed. Peak cardiac effects were characterized by increases in heart rate and LV dP/dt, along with marked reduction in LV end-systolic diameter (- 13 +/- 2%), and in end-diastolic diameter (-17 +/- 2%) and pressure. LV end-diastolic diameter fell even heart rate was maintained at a constant rate by pacing. Thus, in the conscious dog, NP reduced LV dimensions substantially, while inducing changes in peripheral beds. The differences in these effects depend on interactions between the direct effects of NP and the opposing effects of reflex adjustments which appear sufficiently powerful to result in net constriction of the iliac bed late during the infusion.     

Age-related effects of platelet activating factor (PAF) in the isolated perfused rat heart.

Platelet Activating Factor (PAF) is a phospholipid that has been implicated as an important mediator of anaphylactic cardiac dysfunction and involved in the toxic effects of the ischaemia-reperfusion process. In the elderly, these phenomena are thought to be exaggerated by the age-related changes in response to several chemical factors and myocardial ischaemia. We evaluated the effects of PAF (acetyl-o-alkyl-l-phosphatidylcholine) on left ventricular systolic (LVSP) and diastolic (LVDP) pressure, coronary flow rate (CFR) and heart rate (HR) in adult (6 months, AH) and senescent (24 months, SH) rat hearts. The perfusion of PAF (10(-8), 10(-7) and 10(-6) M) induced a concentration-related reduction of LVSP, CFR and HR and a linear increase in LVDP. Contractile modifications were more pronounced in senescent hearts: LVSP decreased (P < 0.01) and LVDP increased with respect to younger animals (P < 0.01 vs. AH). This negative inotropic effect was also present in electrically paced hearts. PAF produced conduction arrhythmias ranging from second-degree atrio-ventricular conduction block to cardiac standstill both in adult and senescent hearts; at a higher dose (10(-6) M), cardiac standstill appeared after 96.5 +/- 15.3 s in adult hearts and after 45.5 +/- 17.6 s in senescent hearts (P < 0.01). Lyso-PAF did not modify while specific PAF antagonist compounds CV-3988 inhibited all electromechanical responses both in adult and senescent hearts. These data suggest that age influences the effect of PAF on contractile parameters, coronary flow and conduction arrhythmias by acting on receptors, whose function is unaffected by age.     

槲皮素抑制血小板活化因子受体结合作用的研究

目的 :观察槲皮素对氚标记的血小板活化因子与血小板膜上受体结合的影响 ,试图证明该药为一新型血小板激活因子 (PAF)受体拮抗剂。方法 :以放射配基结合试验观察 [3H]PAF与兔血小板受体特异性结合的作用 ;以分光光度法测定PAF诱发血小板黏附的强度。结果 :槲皮素可浓度依赖地抑制2 5 ,5 0 ,10 0nmol·L- 1 [3H]PAF与兔血小板受体的特异性结合 ;该药可明显抑制PAF诱发的血小板黏附 ,具明显的量效关系 ,其IC50 为 39 8μmol·L- 1 。结论 :槲皮素具抗PAF作用 ,为一新的PAF受体拮抗剂。     

Hemodynamic and myocardial effects of long-lasting venodilation in the conscious dog

Summary The effect of molsidomine-induced venodilation on cardiac preload was studied in conscious resting dogs, instrumented to analyze left ventricular function and inyocardial perfusion. Direct effects on veins were studied during chloralose anesthesia by measuring regional venous capacitance changes with an induction angiometer. Kinetics of molsidomine-induced effects were compared to those induced by nitroglycerin and isosorbide dinitrate. This comparison was restricted to low i.v. dosages, causing only transient threshold effects on peripheral resistance and heart rate.During molsidomine-induced venous pooling, neither any direct effect on the coronary circulation nor any direct cardiac depressant activity of the drug was detected. 100 g/kg molsidomine caused a reduction of left ventricular preload by 5 mm Hg, lasting at least 4 hours. This effect was significantly more pronounced than that induced by 1 g/kg nitroglycerin or by 25 g/kg isosorbide dinitrate, lasting 2 min or 20 min, respectively. However, in raising regional venous capacitance, these nitrate dosages were equi-effective to 100 g/kg molsidomine, the effect of which was persistent and with a greater delay in onset. These results indicate that the lasting persistance of venodilation is a decisive factor for the amount of volume pooled in the capacitance system and, consequently, for the extent of preload reduction obtained. It is concluded, that lasting vasodilation, restricted to the veins, is beneficial for ventricular performance in ischemic heart disease.

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Hämodynamische und myokardiale Wirkungen von langanhaltender Venendilatation im wachen Hund

Zusammenfassung Die Wirkung von Molsidomin-induzierter Venendilatation auf die Vordehnung des Herzens wurde an wachen, ruhenden Hunden untersucht, bei denen die Funktion der linken Herzkammer und die Myokarddurchblutung analysiert werden konnten. Direkte Wirkungen auf die Venen wurden in Chloralose-Narkose durch Messung lokaler Kapazitätsänderungen mit einem Induktionsangiometer untersucht. Die Kinetik der Molsidomin-Wirkung wurde mit der von Nitroglyzerin und Isosorbid-Dinitrat verglichen. Dabei war dieser Vergleich auf niedrige, intravenös verabreichte Dosierungen begrenzt, die jeweils nur eine vorübergehende, minimale Wirkung auf den peripheren Widerstand und die Herzfrequenz hatten.Während der Molsidomin-induzierten Venendilatation war weder eine direkte Wirkung des Medikaments auf die Koronardurchblutung noch eine abschwächende Wirkung auf die Herzkraft erkennbar. 100 g/kg Molsidomin verursachten eine Erniedrigung des linksventrikulären Füllungsdruckes um 5 mm Hg während eines Zeitraumes von 4 Stunden. Dieser Effekt war deutlich stärker als die entsprechende Wirkung von 1 g/kg Nitroglyzerin oder von 25 g/kg Isosorbid-Dinitrat, die 2 bzw. 20 Minuten lang anhielt. Diese beiden Nitrat-Dosierungen waren jedoch ebenso wirksam wie 100 g/kg Molsidomin bei der Erhöhung der lokalen Venenkapazität, wobei Molsidomin nach verzögertem Beginn lang anhaltend wirkte. Diese Ergebnisse deuten darauf hin, daß die Dauer der Venendilatation wichtig ist für das Ausmaß der Volumenansammlung im Kapazitätssystem und damit für das erzielbare Ausmaß der Herzentlastung durch Erniedrigung des Füllungsdruckes. Es wird gefolgert, daß anhaltende, auf die Venen beschränkte Vasodilatation günstig ist für die Arbeitsweise des Herzens bei ischämischer Herzerkrankung.

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With 4 figures and 2 tables

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Supported by Deutsche Forschungsgemeinschaft and USPHS Grant HL 17591. Parts of the results have been presented at the 1st Molsidomine-Symposion München, 1978 (References 1, 15)     

Effects of recombinant platelet activating factor acetylhydrolase in obstructive jaundice

BACKGROUND/AIMS: The aim of this study was to investigate effects of recombinant PAH (platelet activating factor acetylhydrolase), on tissue damage and on antioxidant response. METHODOLOGY: A total of 30 Wistar-Albino type rats were used in this PAH treatment, and the subjects were divided into 3 groups namely sham, ligation and PAH treatment groups, each containing 10 rats. In PAH treatment and ligation groups, laparotomy was made; common bile duct was ligated and incised. Following ligation, blood and liver tissue were taken. In the sham group, the common bile duct was turned but no other procedure was applied. The subjects in the ligation group were given intraperitoneal placebo on the 2nd to 6th days; and those in the PAH treatment group were applied PAH at a 5-mg/kg dose. Blood and liver tissue were taken on postoperative day 7. The parameters examined in the blood sample included, liver function tests, superoxide dismutase, glutathione peroxidase, tumor necrosis factor-alpha and interleukin-6. In liver tissue, histopathologic examination was made. RESULTS: Levels of AST, ALT, GGT, ALP, tumor necrosis factor-alpha and interleukin-6 were significantly higher than the levels in the sham group. These parameters, measured on the 7th day in the PAH treatment group were found to be significantly lower than the ligation group. Portal inflammation in the PAH given group was significantly lower than the ligation group. CONCLUSIONS: Administration of PAH in experimental jaundice has produced improvement in liver functions, significant reductions in serum GGT and ALP, tumor necrosis factor-alpha and interleukin-6, and in liver damage whereas it has brought about an increase in the levels of antioxidant enzymes.     

Role of adrenal steroids in the recovery from platelet activating factor challenge

Previous studies have shown that platelet activating factor (PAF) is a potentially important mediator of the acute hypotensive response to endotoxin. Direct administration of PAF to rodents induces profound hypotension and hemoconcentration; normal blood pressure recovery requires an intact sympatho-adrenal medullary system. Because adrenal steroids are also important in the physiological response to shock, the present studies were conducted to determine whether treatment of rodents with cortisone or surgical adrenalectomy would alter cardiovascular parameters during recovery from PAF challenge. When rats were pretreated daily for four days with cortisone (25 mg/kg, sc), the hypotensive response to PAF injection (2 micrograms/kg, iv) was significantly blunted (P less than 0.05). In adrenalectomized rats, recovery of blood pressure was significantly delayed (P less than 0.01). Heart rate was not significantly changed in the anesthetized rat preparation used. Pretreatment of mice with cortisone (25 mg/kg/day, sc, 4 days) completely blocked the increased vascular permeability, as measured by a rise in hematocrit induced by PAF (2 micrograms/kg, iv) (P less than 0.001). Adrenalectomized mice had a rise in hematocrit similar to that in sham-operated animals. Lung wet:dry weight ratio after PAF challenge was unaffected by cortisone or adrenalectomy. These results suggest that adrenal cortical glucocorticoids, in addition to adrenal medullary catecholamines, participate in the recovery from the cardiovascular alterations following PAF administration. Further, the efficacy of steroid pretreatment in shock models might involve, in part, the inhibition or reversal of PAF-induced cardiovascular alterations.     

Cytokines, platelet activating factor and eosinophils in asthma.

Understanding of the pathogenesis of asthma has increased considerably during the past few years. These advances were possible through scientific progress in three areas which contribute to this complex and multifaceted disease: (a) the much clearer understanding of eosinophil function; (b) the defining of lipid mediators in tissue inflammation and bronchial obstruction; and (c) the growing knowledge about the biological action of a new class of protein hormones, collectively called cytokines. In line with this, evidence has accumulated of how these components may interact with each other in providing the basis of inflammatory processes in asthma. Hence it seems appropriate to review the potential implications of this new information for the pathogenesis and therapy of this disease.     

Tumour necrosis factor and endotoxin synergistically activate intestinal phospholipase A2 in mice. Role of endogenous platelet activating factor and effect of exogenous platelet activating factor.

Previous studies have shown that: (a) platelet activating factor induces shock and intestinal injury, (b) exogenous platelet activating factor stimulates synthesis of endogenous platelet activating factor, and (c) tumour necrosis factor alpha and endotoxin synergise to induce shock and bowel injury in animals. These last two effects are largely mediated by platelet activating factor forming phospholipase A2 A2, a key enzyme for platelet activating factor synthesis, was examined in mouse intestine. It was found that tumour necrosis factor alpha and endotoxin synergise to stimulate platelet activating factor forming phospholipase A2 activity in the intestine, as well as platelet activating factor production, and these effects were blocked by pretreatment with platelet activating factor antagonists, SRI-63-441 and WEB 2086. In addition, exogenous platelet activating factor stimulates intestinal phospholipase A2 activity. These results show that tumour necrosis factor alpha and lipopolysaccharide synergistically activate the phospholipase A2 that participates in platelet activating factor formation, and this activation is largely mediated by endogenous platelet activating factor. Furthermore, platelet activating factor itself increases phospholipase A2 activity, suggesting that platelet activating factor induces its own synthesis, probably by phospholipase A2 activation.     

Absence of platelet activating factor (PAF) mediated platelet aggregation: A new platelet defect

The failure of normal human platelets to aggregate in response to platelet activating factor (PAF) has not been previously observed. We report here the first case of a patient whose platelets did not aggregate to PAF on multiple occasions.     

Hemodynamic and inotropic effects of endothelin-1 in vivo

Summary Endothelin-1 (ET-1) is known to have strong vasoactive properties. Contradictory results have been reported with regard to its inotropic effects.This study examined the dose-dependent (500, 1000, 2500, 5000 and 10 000 ng ET-1/kg vs. NaCl controls) hemodynamic and inotropic effects of ET-1 in 53 open-chest rats during and after a 7-min infusion. Besides measurements in the intact circulation the myocardial function was examined by isovolumic registrations independent of peripheral vascular effects.A transient ET-1 induced (500, 1000, 2500, 5000 ng ET-1/kg) decrease of the left ventricular systolic pressure (LVSP) and the mean aortic pressure (AoP_mean) was followed by a dose-related rise of these pressures (LVSP: –1%, –1%, +8%, +16% vs. preinfusion values; AoP_mean:–11%, +9%, +39%, +52%). Heart rate (HR) was not influenced by ET-1. Due to the dose-dependent decrease of the stroke volume (SV) the cardiac output (CO) was reduced (CO:–8%, –23%, –40%, –50%). After an initial vasodilatation ET-1 elevates the total peripheral resistance (TPR:–1%, +49%, +139%, +215%) dose-dependently. 10000 ng ET-1/kg was a lethal dose resulting in cardiac failure within minutes (low output). Since the maximum of the isovolumic LVSP (peak LVSP) and the corresponding dP/dt_max (peak dP/dt_max) were unchanged under ET-1, the isovolumic measurements do not indicate a positive inotropic effect of ET-1 in vivo in contranst to published results of in vitro experiments.It may be possible that a direct positive inotropic effect of ET-1 observed in in vitro studies is counterbalanced in vivo by an indirect negative inotropic effect due to the coronar-constrictive effect of ET-1.Parts of the results were presented at the 13th European Section Meeting of the International Society for Heart Research, Heidelberg, FRG, 1992     

Role of platelet activating factor on severity of ischemic colitis

PURPOSE: Ischemic colitis develops after a sudden decrease in colonic blood supply and has a variety of clinical manifestations. The aim of this study was to assess the role of platelet activating factor in the pathogenesis of ischemic colitis with use of the platelet activating factor antagonist TCV-309. METHODS: Rats were randomly divided into four groups. Rats in Group RV underwent ring attachment around the rectum to induce partial obstruction and ligation of the marginal vessels of the left colon. As control, rats in Group R underwent the ring attachment and rats in Group V underwent the vascular ligation. Rat in Group C underwent sham operation. The effects of TCV-309 on lesion formation in the colon were evaluated. Thiobarbituric acid reactant level was determined in colonic mucosa, and the incidence and severity of ischemic lesions were also determined. RESULTS: Lesions of colitis were frequently observed in Group RV. TCV-309 did not prevent lesion formation, nor did it suppress the increase in thiobarbituric acid reactant level in Group RV. However, TCV-309 mitigated the severity of the lesion. CONCLUSIONS: Partial obstruction of the colon tends to induce ischemic colitis, and additional ischemia completes lesion formation. Platelet activating factor may play a role in the progression of ischemic lesions.Supported in part by Takeda Chemical Industries, Osaka, Japan. Presented in part at the Annual Meeting of the Japan Surgical Society, Chiba, Chiba, Japan, April 10 to 12, 1996.     

The central role of thromboxane and platelet activating factor receptors in ex vivo regulation of endotoxin-induced monocyte tissue factor activity in human whole blood

Expression of tissue factor (TF) by activated monocytes may initiate thrombotic episodes associated with diseases, such as thrombosis and atherosclerosis. In this study, steps in the regulatory pathways of lipopolysaccharide (LPS)-induced monocyte TF activity and released TNF-alpha in human whole blood were probed for using an array of inhibitors, comprising specific inhibitors of cytosolic phospholipase A(2) (PLA(2)) (AACOCF(3)), secretory PLA(2) (SB-203347), protein kinase (PK) (staurosporine), PKC (GF-109203; BIM), and serine protease (Pefabloc SC), antagonists of thromboxane prostanoid (TP) receptor (R) (SQ-29548), platelet activating factor (PAF) R (BN-52021), leukotriene B(4) R (SC-41930), serotonin R (cyproheptadine), fibronectin/fibrinogen R (RGDS), and finally, creatine phosphate/creatine phosphokinase (CP/CPK) which removes ADP. Whereas when added alone neither of these agents significantly inhibited LPS-induced TF or TNF-alpha, when presented as a reference cocktail comprising all the agents, TF activity and TNF-alpha were reduced by 77% and 49%, respectively. By subsequently testing a series of incomplete inhibitory cocktails equal to the reference except for deleted single agents or combinations of two or three active agents, the inhibitory effect of the reference cocktail could be shown to depend on the presence of the protease inhibitor and the thromboxane A(2) and PAF antagonists.