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Biomedical subjects

P Ramwell

Publications and source records attributed to P Ramwell.

At least 19 recordsLinked to original sources
PubMed1996

L-arginine prevents heart transplant arteriosclerosis by modulating the vascular cell proliferative response to insulin-like growth factor-I and interleukin-6.

BACKGROUND: L-arginine, a nitric oxide precursor, inhibits myointimal hyperplasia induced by balloon injury in native vessels. No studies are published on L-arginine effects on transplant arteriosclerosis. Insulin-like growth factor-I and interleukin-6 are mitogenic for smooth muscle cells and are involved in the cell-mediated and humoral immune response. METHODS: New Zealand White rabbits received cardiac allografts from Dutch Belted rabbits. All animals were fed a 0.5% cholesterol diet and received drinking water with (eight pairs) or without (eight pairs) L-arginine (2.5%) from day 7 to until they were killed at day 42. The recipients received cyclosporine A 10 mg/kg/day from transplantation until the time they were killed. RESULTS: Dietary L-arginine reduces myointimal hyperplasia in allograft coronary arteries from 44% +/- 4% in the non-L-arginine group to 16% +/- 2% (p < 0.002). The L-arginine significantly inhibits graft vascular cell proliferation induced by (1) insulin-like growth factor-I, from 328% +/- 66% to 154% +/- 28% (p < 0.05), (2) interleukin-6, from 376% +/- 97% to 138% +/- 30% (p < 0.05) and (3) the combination of insulin-like growth factor-I and interleukin-6 from 710% +/- 201% to 226% +/- 72% (p < 0.05). In recipient native aorta explants L-arginine also abolishes vascular cell proliferation stimulated by insulin-like growth factor-I and interleukin-6. The rejection grading is similar in the L-arginine (2.9 +/- 0.1) and control groups (2.7 +/- 0.1). Class II major histocompatibility antigen expression, T-lymphocyte, and macrophage infiltration in the cardiac allograft are unaffected by L-arginine. However, the diet significantly increased plasma nitric oxide from 15.4 +/- 2.3 to 45.1 +/- 11 mumol (p < 0.05). CONCLUSIONS: Dietary L-arginine attenuates transplant arteriosclerosis in vivo without affecting rejection. The protective effect seen in these experiments may relate to the generation of sufficient nitric oxide to prevent smooth muscle cell response to mitogens like insulin-like growth factor-I and interleukin-6.

Animals↗
PubMed1988

Antagonism of PAF-induced death in mice.

The ability of three platelet activating factor (PAF) antagonists, BN52021, L652,731 and 48740RP, and the leukotriene antagonist FPL55712 to block iv PAF-induced death was tested in mice. PAF-induced sudden death has been previously characterized as a model of systemic anaphylaxis and circulatory shock related its hypotensive actions. Of the drugs, BN5201 and L652,731 provided dose-dependent protection against PAF toxicity, whereas the others had no effect. 48740RP was, however active against PAF-induced rabbit platelet aggregation. BN52021 was inactive in three other mouse sudden death models in which arachidonic acid, U46619 or collagen combined with epinephrine is injected iv to provoke a thrombotic/ischemic sudden death. In contrast, the TXA2 antagonist SQ29548 inhibited the acute toxicity of two of these latter challenges (arachidonic acid and thromboxane agonist U46619), but was inactive against PAF lethality. These results suggest that PAF toxicity in mice is a specific model for PAF agonism, and is not mediated by TXA2 or peptido-leukotrienes. Further, PAF-induced mortality should be a simple and useful technique for testing potential PAF antagonists for in vivo activity by various routes of administration.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1987

The vasodilatation induced by hydroperoxy metabolites of arachidonic acid in the rat mesenteric and pulmonary circulation.

The effects of 15-hydroperoxy metabolites of arachidonic acid on vascular tone were evaluated in the perfused mesenteric preparation, the isolated perfused lung and segments of pulmonary arteries of the rat. In the mesenteric preparation, precontracted with phenylephrine, both 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid (15-HPETE, ED50 1.6 nmol) and 8,15-dihydroperoxy-5,9,11,13-eicosatetraenoic acid (8,15-diHPETE, ED50 0.3 nmol) induced dose-dependent vasodilatation, whereas 5,15-diHPETE (0.2-100 nmol) had no effect. Prostacyclin (ED50 0.01 nmol) was, however, more potent than the hydroperoxides. In the rat isolated lung, precontracted with the stable thromboxane agonist U-46619, dose-dependent decrease in the perfusion pressure occurred with 15-HPETE(ED50 40 nmol), 5,15-diHPETE (ED50 30 nmol) and 8, 15-diHPETE (ED50 7 nmol) while 13-hydroperoxide of linoleic acid had no effect. Prostacyclin was 10 times more potent than 8, 15-diHPETE. The vasodilator effects were not affected by indomethacin. In both endothelium intact and denuded rat pulmonary arteries the hydroperoxides 15-HPETE, 8,15-diHPETE, and 5,15-diPETE induced dose-dependent relaxation. The hydroperoxide, 8,15-diHPETE was at least 3 times more potent than 15-HPETE or 5,15--diHPETE. The hydroperoxides had no effect on the basal tone of vessel segments and the relaxation induced by 15-HPETE was not attenuated by methylene blue (5 microM). These data indicate that 8,15-diHPETE may be a significant endothelium-independent vasodilator product of arachidonate lipoxygenation.

Animals↗
PubMed1986

Induction of vascular relaxation by hydroperoxides.

Hydrogen peroxide, tert-butyl hydroperoxide, cumene hydroperoxide, and 3-chloroperoxybenzoic acid (CPB) and 15-HPETE relaxed, in a concentration dependent manner rat aortic rings contracted with PGF2 alpha (1 X 10(-5)). Relaxation is not inhibited by either indomethacin (2 X 10(-5) M), a cyclo-oxygenase inhibitor or eicosatetraynoic acid (1 X 10(-5) M), a dual cyclo-oxygenase and lipoxygenase inhibitor. Rings with intact endothelium relaxed to a greater degree on exposure to CPB and 15-HPETE. Methylene blue, a soluble guanylate cyclase inhibitor (1 X 10(-5) M) blocked the relaxation elicited by the five peroxides, whereas both superoxide dismutase (scavenger of superoxide anion) and mannitol (scavenger of hydroxyl radical) have no effect. We conclude that relaxation of vascular smooth muscle is a general property of peroxides and that the endothelium may in some instances facilitate this effect.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1986

Sex differences in mouse platelet aggregation.

The role of platelets in the sex difference observed in mouse thrombosis models was evaluated by examining platelet diminution in vivo after thrombotic challenge, and aggregation of mouse platelets in PRP. A fall in platelet count was observed in both sexes after i.v. injection of either arachidonic acid or the thromboxane agonist, U46619. Platelet diminution induced by high dose arachidonate (50 mg/kg) was significantly greater in males compared to female mice. Responses to U46619 were similar in both sexes. In PRP, male platelets exhibited a greater response than female platelets to both ADP (15 uM) and arachidonate (0.3 mM), but not to U46619 (4.6 and 6.9 uM). These results suggest that the gender difference in arachidonate-induced sudden death, in which males are more susceptible than females, is related to a sex difference in mouse platelet function.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

Comparison of verapamil and nifedipine in thrombosis models.

Calcium blockers and calmodulin antagonists have been reported to inhibit the aggregation of blood platelets in vitro. In the present study, the effects of two calcium blockers, verapamil and nifedipine, were compared in several rodent thrombosis models. In rat and mouse platelet-rich plasma, preincubation with either verapamil or nifedipine had a dose-dependent inhibitory effect on collagen-induced aggregation (P less than 0.01). The concentration required for 50% inhibition of rat platelet aggregation was 0.91 X 10(-4) M for verapamil and 1.77 X 10(-4) M for nifedipine. In in vivo thrombosis models in mice, acute pretreatment with nifedipine had a significant, dose-dependent protective effect (P less than 0.05). At a dose of 500 micrograms/kg, nifedipine inhibited thrombotic sudden death provoked by arachidonic acid, a thromboxane agonist (U46619), or a combination of collagen and epinephrine. In vivo platelet depletion induced by U46619 was also inhibited by this calcium blocker. Thus, nifedipine is protective against a variety of thrombotic stimuli, and its antiplatelet aggregatory effect apparently extends to the in vivo situation. In contrast, no in vivo antithrombotic activity was observed for verapamil. Two additional calcium blockers, perhexilene and diltiazem, and three calmodulin antagonists, W-7, chlorpromazine, and trifluoperazine, were also tested in the U46619-induced thrombotic sudden death model. Of these, only diltiazem (5 and 10 mg/kg) had an acute protective effect.

Animals↗
PubMed1984

A routine source of human peritoneal macrophages.

The routine availability of nucleated human cells for experimental use in limited in the absence of venipuncture. In this paper we have demonstrated that macrophages may be harvested routinely from the waste dialysis bags of patients undergoing continuous ambulatory peritoneal dialysis. These cells were identified as macrophages by morphology, adherence, phagocytosis, chemotaxis, non-specific esterase staining and peroxidase staining. Macrophages from patients with end-stage renal disease produced arachidonate cyclo-oxygenase products in a pattern similar to that of ascites macrophages obtained from patients with normal kidney function. Arachidonate metabolism was shown to be manipulatable. Thus, indomethacin blocked synthesis of cyclooxygenase products, and OKY-1581, a specific thromboxane synthase inhibitor, increased the release of prostaglandin E2 and prostacyclin, measured as its stable breakdown product 6-keto-prostaglandin F1, whereas the thromboxane B2 synthesis was effectively inhibited.

Adolescent↗
PubMed1984

Responses to leukotriene C4 in the perfused rat lung.

The isolated rat lung was used to study both the effect of leukotriene C4 on pulmonary perfusion pressure and the synthesis and release of cyclooxygenase products in the pulmonary circulation. A cell-free perfusate was passed only once through the pulmonary circulation or was recirculated. During single transit, leukotriene C4 produced dose-dependent increases in pulmonary perfusion pressure that were abolished by FPL-55712, a leukotriene receptor antagonist, but were not altered significantly by indomethacin. The duration of the pulmonary pressor response to leukotriene C4 was markedly prolonged during recirculation compared to single transit. Leukotriene C4 also induced dose-dependent increases in effluent levels of 6-keto-prostaglandin F1 alpha and thromboxane B2 that were attenuated by indomethacin or FPL-55712 pretreatment. We conclude that leukotriene C4 directly constricts the pulmonary vasculature independent of cyclooxygenase products, is not rapidly degraded by the pulmonary circulation and stimulates the release of cyclooxygenase products in the pulmonary circulation that can be attenuated by pretreatment with indomethacin or FPL-55712.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Glucocorticoid protection against PAF-acether toxicity in mice.

Intravenous platelet activating factor (PAF-acether, 10 to 25 micrograms/kg body weight) produced dose-dependent mortality in both male and female mice. Pretreatment with indomethacin (50 mg/kg), verapamil (40 mg/kg) or nifedipine (4 mg/kg) failed to inhibit the lethal effect of 20 micrograms/kg PAF-acether. This suggests that neither arachidonate cyclo-oxygenase products nor availability of extracellular Ca2+ mediate the toxic action. In contrast, pretreatment with 100 mg/kg cortisone acetate (s.c.) daily for four days exerted a highly protective effect, i.e. 100% and 93% survival in males and females, compared to 13% and 7% respectively, in untreated animals. PAF-acether-induced death may be a useful model for the in vivo evaluation of pharmacological agents in anaphylactic shock.

Animals↗
PubMed1983

Thromboxane agonism and antagonism in a mouse sudden death model.

The effects of the stable thromboxane agonist, U46619, and sodium arachidonate were tested by i.v. injection into male and female mice. U46619 produced dose-dependent mortality in both sexes equally, in contrast to the gender-differentiated effects of arachidonic acid. The thromboxane receptor antagonist, SQ 26,536, protected in a dose-dependent manner against both arachidonate and U46619. The thromboxane antagonist was more effective against arachidonate toxicity in male than in female mice, but was equiactive against U46619 in both sexes. Neither the thromboxane synthetase inhibitor, OKY-1581, nor the cyclooxygenase inhibitor, indomethacin, protected against U46619-induced sudden death. However, cortisone acetate increased survival of mice challenged with U46619. The results support the hypothesis that thromboxane A2 mediates arachidonate-induced sudden death. The effects of arachidonate can be mimicked by the thromboxane agonist and are attenuated by the thromboxane antagonist. The gender difference in arachidonate toxicity is apparently not due to differences in sensitivity to thromboxane A2, as the thromboxane agonist was equally toxic in males and females. The greater protective effect of the thromboxane antagonist against arachidonate toxicity in males suggests that thromboxane A2 is a more important mediator of arachidonate-induced sudden death in males compared to female mice.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1982

Sexual differentiation of arachidonate toxicity in mice.

Mature male and female mice 50 days of age were challenged with i.v. sodium arachidonate at doses of 12.5, 25, 50 and 100 mg/kg. A dose-dependent response in terms of mortality was observed. Males were significantly more susceptible to arachidonate-induced mortality than females at the 25 and 50 mg/kg doses (P less than .05). The 100 mg/kg dose produced 100% mortality in both sexes. When mice aged 23, 29, 35 and 50 days were challenged with 50 mg/kg of arachidonate, no gender difference was observed until mice were 35 days of age, at which time the male mortality was 80%, compared to 57% for female mice (P less than .05). Mice gonadectomized at 23 days and intact mice 23 days of age were treated with s.c. estradiol, testosterone or vehicle for 7 days before arachidonate challenge. Among these groups, the gonadectomized females and intact males were significantly protected by estradiol when compared to the appropriate controls (P less than .05). In contrast, testosterone pretreatment had no significant effect on mortality. These results demonstrate that the development of the gender difference in arachidonate-induced mortality in mice is dependent upon the presence of gonadal hormones in the immature stages.

Adrenal Glands↗
PubMed1981

Acute protection against arachidonate toxicity by hydrocortisone and dexamethasone in mice.

1. Pharmacologic doses of hydrocortisone sodium succinate (100 mg/kg) has a rapid protective action against arachidonate-induced mortality in mice when administered intravenously 5 to 60 min before intravenous infusion of arachidonate. 2. Intravenous dexamethasone sodium phosphate (4 mg/kg) has a similar protective effect. 3. The time course of the development of the protective effect of intravenous glucocorticoids suggests that DNA transcription and protein synthesis are not involved in the mechanism of this action. 4. Longer pretreatment with glucocorticoids are required to reduce mortality when subcutaneous or intraperitoneal routes of administration of the steroids used.

Animals↗