Biological properties of the antagonist SRI 63–441 in the PAF and endotoxin models of hypotension in the rat and dog

Handley, Dean A.; Valen, Ronald G. Van; Tomesch, John C.; Melden, Mary Kay; Jaffe, James M.; Ballard, Frances; Saunders, Robert

doi:10.1016/0162-3109(87)90049-x

Cited by 31 publications

(14 citation statements)

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“…Finally, the inhibitory effects of the PAF receptor antagonists, WEB-2170(Casals-Stenzel, 1987 and SRI-63441 (Handley et al, 1987), were assessed against the PAFinduced vasoactive responses on both sides of the mesenteric vasculature. Our results suggest that PAF induces an endothelium-dependent arterial dilatation and an endothelium-independent venoconstriction of the mesenteric vasculature.…”

Section: Introductionmentioning

confidence: 99%

Role of R‐type calcium channels in the response of the perfused arterial and venous mesenteric vasculature of the rat to platelet‐activating factor

Claing

Bkaily

Berthiaume

et al. 1994

British J Pharmacology

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1 The vasoactive properties of platelet-activating factor (PAF) were studied in the arterial and venous vasculature of the rat double-perfused mesenteric bed. Although PAF (0.01-0.3 pmol) induced a dose-dependent vasodilatation of the arterial mesenteric vasculature, it triggered only vasoconstrictions on the venous side, with an intact endothelium as bradykinin induced a significant venodilatation.2 NG-nitro-L-arginine methyl ester (L-NAME, 100 gM), a nitric oxide synthase inhibitor, markedly reduced the vasodilatation induced by PAF in the arterial mesenteric vasculature and potentiated the contractile responses of the venous side to the same agent. 3 The PAF antagonist, WEB-2170, markedly reduced the response to PAF on both sides of the mesenteric vasculature. However, the ICm of WEB-2170 against PAF was reached at a much higher concentration (1 x 108 M) on the arterial side than on the venous side (5.3 x 10-" M). Furthermore, a second antagonist of PAF receptors, SRI-63441, although being less potent on the venous vasculature than WEB-2170, was equipotent in antagonizing the venoconstriction and the arterial dilatation induced by PAF (IC50 of SRI-63441, arterial side: 2.9 x 1O-9M; venous side: 3.1 x 10-M).4 The dual L-and R-calcium channel blocker, isradipine , but not the L-type calcium channel blocker, nifedipine, markedly reduced the PAF-induced vasoactive properties on both sides of the mesenteric vasculature. 5Our results illustrate the differential vasoactive properties of PAF in the mesenteric vasculature of the rat. These vasoactive responses occur following activation of specific receptors for PAF or, alternatively, through activation of R-type calcium channels.

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Section: Introductionmentioning

confidence: 99%

Role of R‐type calcium channels in the response of the perfused arterial and venous mesenteric vasculature of the rat to platelet‐activating factor

Claing

Bkaily

Berthiaume

et al. 1994

British J Pharmacology

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“…SRI 63-441 (a generous gift from Dr. Dean Handley, Sandoz Research Institute, Hanover, NY) and WEB 2086 (a generous gift from Dr. H. 0. Heuer, Boehringer Ingelheim, Mainz, Germany) are two structurally unrelated PAF receptor antagonists that effectively inhibit PAFinduced shock and intestinal injury (15,16). Both antagonists were tested in control animals and had no effect on blood pressure, intestinal blood flow, or intestinal injury.…”

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confidence: 99%

Endotoxin and Hypoxia-Induced Intestinal Necrosis in Rats: The Role of Platelet Activating Factor

1992

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ABSTRACT. We have previously shown that intravascular platelet activating factor (PAF) causes ischemic bowel necrosis in rats morphologically similar to neonatal necrotizing enterocolitis (NEC). Because endotoxin (LPS) and hypoxia are risk factors for NEC, we studied their effect on PAF metabolism and the development of intestinal injury. Young male Sprague-Dawley rats were anesthetized with pentobarbital and divided into six experimental groups: 1 ) control, 2) LPS alone (2 mglkg), 3) hypoxia alone (5% 04, 4) LPS + hypoxia, 5) WEB 2086 (PAF antagonist) + LPS + hypoxia, and 6) SRI 63-441 (PAF antagonist) + LPS + hypoxia. Evaluations included blood pressure recording, superior mesenteric artery blood flow, arterial blood gas, white blood cell count, hematocrit, plasma PAF, plasma acetylhydrolase, plasma tumor necrosis factor, intestinal perfusion, and intestinal injury at 3 h.We found that LPS + hypoxia synergistically contributed to hypotension (mean blood pressure 27 f 5.6% baseline versus 101 f 3.9% control), metabolic acidosis (pH 7.05, base deficit 24 mEq/L), hemoconcentration, decreased superior mesenteric artery blood flow (2.2 f 0.3 mL/min versus 5.8 f 0.2 mL/min control), and intestinal injury.The morbidities resulting from LPS + hypoxia were partially or completely prevented by PAF antagonists. In addition, animals treated with LPS + hypoxia had neutropenia, elevated plasma acetylhydrolase, and elevated plasma TNF. These results suggest that endogenous PAF may contribute to LPS + hypoxia-induced intestinal hypoperfusion and necrosis. (Pediatr Res 31: 428-434,1992) Abbreviations PAF, platelet activating factor LPS, lipopolysaccharide, endotoxin WBC, white blood cell count TNF, tumor necrosis factor NEC, necrotizing enterocolitis SMA, superior mesenteric artery NEC is a common gastrointestinal disease of premature infants that has a high incidence of morbidity and mortality (1). Alto the development of the disease (2, 3). We have previously shown that intravascular administration of PAF (PAF-acether), an endogenous phospholipid inflammatory mediator, produces intestinal injury in an animal model (4). In addition, it is known that endotoxin (LPS)-induced shock and intestinal injury can be prevented by PAF receptor antagonists (5, 6). Because we have recently reported increased plasma PAF concentrations in newborns afflicted with NEC (7), it is possible that, in addition to causing experimental intestinal injury, PAF is an important endogenous mediator of the human disease.Additional factors related to PAF metabolism may play a role in the development of intestinal injury. PAF is rapidly degraded to the inactive metabolite lysoPAF by acetylhydrolase (8), a 43-kD acid-labile enzyme critical to PAF regulation. We have shown that serum acetylhydrolase is decreased in NEC patients compared with controls (7) and that newborn infants have lower acetylhydrolase activity than older children and adults (9). Because the majority of NEC cases occur in the neonatal period, suppressed PAF degradation may contribut...

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“…Published work on the role of PAF in endotoxemia, although scant, supports the involvement of this mediator in the early phase of the pulmonary vascular response, whether in causing systemic hypotension (19,20), or pulmonary hypertension and hypoxemia (18,34). Our data suggest that PAF is not a pivotal mediator of the pulmonary hypertension associated with GBS in neonatal pigs.…”

Section: Discussionmentioning

confidence: 44%

“…In newborn piglets, PAF-induced pulmonary hypertension is in large part mediated through TxA2 (35). Because these derangements resemble those produced by endotoxemia, the intravascular release and actions of PAF have been studied and found to be significant in a guinea pig model of Salmonella endotoxemia (17), and in Escherichia coli endotoxemia models in sheep (18, 34) and rats (19,20).GBS sepsis shares much of the pathophysiology of endotoxemia. As some of its effects are mediated by cyclooxygenase and lipoxygenase products (14,(21)(22)(23), in animal models pharmacologic blockade of either eicosanoid significantly attenuates the pathophysiologic abnormalities (5-9,24) and decreases mortality (25) in this condition.…”

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confidence: 99%

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Roles of Platelet-Activating Factor and Thromboxane in Group B Streptococcus-Induced Pulmonary Hypertension in Piglets

1989

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ABSTRACT. Platelet-activating factor causes pulmonary hypertension, shock, hypoxemia, neutropenia, and increased pulmonary vascular permeability; some of its effects are due to thromboxane Az release. Evidence for a possible role of these mediators in the genesis of group B Streptococcus (GBS)-induced pulmonary hypertension was sought using specific receptor antagonists for PAF and thromboxane Az (TxA2) in anesthetized, ventilated piglets (5 12 d of age; n = 22). Infusion of 1 x 10' GBS/kg/min for one hour resulted in a sustained and significant increase in pulmonary artery pressure (PpA) from 17 & 1 to 35 2 3 torr. Pretreatment with the TxA2 antagonist S Q 29548 (0.75 mg/kg intravenous), completely inhibited the effect of GBS on PpA. Pretreatment with either platelet-activating factor antagonists SRI 63072 (3 mg/kg intravenous) or SRI 63441 (1 mg/kg) did not affect the pulmonary hypertension due to GBS infusion. GBS-induced pulmonary hypertension could be reversed by S Q 29548; SRI 63072 did not affect PpA when administered to pigs with GBS-induced elevation in PpA. Inasmuch as prevention and reversal of GBS-induced pulmonary hypertension are accomplished with the TxAz antagonist but not with PAF antagonists, these data suggest that TxA2, rather than PAF, is responsible for the early pulmonary hypertension in this model of neonatal GBS sepsis. Therefore, TxA2 antagonists may be clinically useful in treating pulmonary hypertension related to GBS sepsis. (Pediatr Res 26: 420-424, 1989) Abbreviations GBS, group B Streptococcus SHETE, 5-hydroxyeicosatetraenoic acid PAF, platelet-activating factor PpA, pulmonary artery pressure TxA2, thromboxane AzIn the human neonate, GBS septicemia is associated with pulmonary hypertension, shock, hypoxemia, granulocytopenia, and a high mortality rate, despite antibiotic therapy (1). The pathophysiology of the clinical syndrome has been reproduced in animal models by infusion of live or heat-killed GBS or its endotoxins (2-4). Inflammatory mediators implicated in the early phase responses to endotoxemia (pulmonary hypertension Received March 14, 1988; accepted June 13, 1989. Correspondence Dr. Bruce R. Pitt, Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 1526 1.Supported in part by NIH Grant HL-32154 and HL-13315, as well as postdoctoral training support Grant HL-07410. This work was done during the tenure of B.R.P. as an Established Investigator of the American Heart Assocation. and hypoxemia) include cyclooxygenase products [TxA2 (5-9)], and leukotrienes (1 1). Lipoxygenase products [5-HETE, 12-HETE, leukotrienes C4 and D4 (lo)] may also play a role in the pathogenesis of the late phase pulmonary vascular injury and increased permeability. TxA2 and leukocytes appear to be important mediators of the pulmonary dysfunction induced by GBS toxin in lambs (33).PAF is an autocoid phospholipid mediator with a basic structure of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine. Its cellular sources include endothelial cells, platelets, neutrop...

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Biological properties of the antagonist SRI 63–441 in the PAF and endotoxin models of hypotension in the rat and dog

Cited by 31 publications

References 35 publications

Role of R‐type calcium channels in the response of the perfused arterial and venous mesenteric vasculature of the rat to platelet‐activating factor

Role of R‐type calcium channels in the response of the perfused arterial and venous mesenteric vasculature of the rat to platelet‐activating factor

Endotoxin and Hypoxia-Induced Intestinal Necrosis in Rats: The Role of Platelet Activating Factor

Roles of Platelet-Activating Factor and Thromboxane in Group B Streptococcus-Induced Pulmonary Hypertension in Piglets

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