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Biomedical subjects

A L Willis

Publications and source records attributed to A L Willis.

At least 19 recordsLinked to original sources
PubMed1989

Inhibition of platelet-derived mitogen release by nitric oxide (EDRF).

Platelets exposed to thrombogenic surfaces adhere, aggregate and release mitogenic substances from their alpha-granules. Endothelium-derived relaxing factor (EDRF) which has been identified as nitric oxide (NO) has been reported to inhibit platelet aggregation. We now report that NO inhibits mitogen release from stimulated human platelets. Mitogenic activity was assayed on mouse fibroblast 3T3 cells using incorporation of 3H-thymidine. Serum from collagen-aggregated platelets significantly increased 3H-thymidine incorporation by 3T3 cells above that of serum from control platelets. Both this increase and platelet aggregation were blocked by NO and prostacyclin in a dose related manner. The inhibitory activity of NO decayed with time when incubated in platelet-free plasma at 37 degrees C, but was still detectable after 2 minutes.

Blood Platelets↗
PubMed1989

Eskimo plasma constituents, dihomo-gamma-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid inhibit the release of atherogenic mitogens.

Studies in man and laboratory animals suggest that omega 3 polyunsaturated fatty acid constituents of fish oils have antiatherosclerotic properties. We have studied the effects of several such polyunsaturated fatty acids for ability to modify the in vitro release of mitogens from human platelets. Such mitogens may produce the fibro-proliferative component of atherosclerotic plaques. Both 5,8,11,14,17-eicosapentaenoic acid (20:5 omega 3) and 4,7,10,13,16,19-docosahexaenoic acid (22:6 omega 3), major constituents of fish oils, inhibited adenosine diphosphate-induced aggregation of platelets and the accompanying release of mitogens. These effects are dose dependent. Linolenic acid (18:3 omega 3), the biosynthetic precursor of eicosapentaenoic acid, also inhibited platelet aggregation and mitogen release. Eicosapentaenoic acid also inhibited mitogen release from human monocyte-derived macrophages, which, in vivo, are an additional source of mitogens during atherogenesis. Potent inhibition of human platelet aggregation and mitogen release was also seen with dihomo-gamma-linolenic acid (8,11,14-eicosatrienoic acid 20:3 omega 6), whose levels are reportedly elevated in Eskimos subsisting on marine diets. We conclude that diets that elevate plasma and/or tissue levels of eicosapentaenoic acid, docosahexaenoic acid and dihomo-gamma-linolenic acid precursor gamma-linolenic acid (18:3 omega 6) may exert antiatherosclerotic effects by inhibiting the release of mitogens from platelets and other cells.

8,11,14-Eicosatrienoic Acid↗
PubMed1989

Selective anti-platelet aggregation synergism between a prostacyclin-mimetic, RS93427 and the nitrodilators sodium nitroprusside and glyceryl trinitrate.

1. Citrated platelet-rich plasma from human donors was used to examine turbidometrically the platelet aggregation response to collagen (2.5 micrograms ml-1) and ADP (1.6 microgram ml-1). 2. With collagen as an aggregating agent, the limited (35% maximal inhibition) inhibitory effects of glyceryl trinitrate (GTN, 0.78-50 micrograms ml-1) were markedly potentiated by threshold (3.3-10 ng ml-1) concentrations of RS93427, an orally active prostacyclin-mimetic. Almost complete inhibition of aggregation could then be produced. 3. A threshold concentration of RS93427 (3.3 ng ml-1) similarly potentiated the ability of sodium nitroprusside (NaNp, 0.78-10 micrograms ml-1) to inhibit collagen-induced platelet aggregation. There was an 8 fold reduction in the IC25 concentration of NaNp. 4. Threshold concentrations of the nitrodilators were also able to potentiate the anti-aggregatory effects of RS93427 (0.03-30 ng ml-1) on collagen-induced platelet aggregation. With threshold concentrations of either GTN (6.3-25 micrograms ml-1) or NaNp (0.3-1.3 microgram ml-1), the mean IC50 concentration of RS93427 was reduced 4 or 6 fold, respectively, while the IC25 concentration was reduced 6 or 10 fold, respectively. 5. No similar synergistic interactions were seen between RS93427 and the nitrodilators when ADP was used as an aggregating agent. 6. In spontaneously hypertensive rats, the dose-response for the hypotensive response to bolus doses of RS93427 was not altered by concomitant steady state infusion of a threshold dose (1 micrograms kg-1 min-1) of GTN. 7. Possible therapeutic implications of these findings are discussed.

Adenosine Diphosphate↗
PubMed1989

Therapeutic impact of eicosanoids in atherosclerotic disease.

Polyunsaturated fatty acid (PUFA) components of the diet, especially of the omega-3 variety, protect against atherosclerosis and its related thrombotic complications. Mechanisms involved probably involve the eicosanoids. Classic PGE1 has now found a role in the treatment of peripheral vascular disease. Prostacyclin (PGI2) discovered over ten years ago has also been introduced into clinical medicine; orally active analogs are being introduced with clinical potential in a variety of atherosclerotic and thrombotic disorders. "Endothelium-derived relaxing factor (EDRF)" has been identified with nitric oxide, an active metabolite of the classic nitrodilator compounds, which (like NO itself) is synergistic with prostacyclins in inhibition of platelet activation, but without similar synergistic effects on vasodilation. This finding is of considerable importance both from physiological and therapeutic standpoints. The therapeutic efficacy of acetylsalicylic acid (ASA, aspirin) in the secondary prevention of myocardial infarction is now established. For primary prevention, it is probably inferior to diet (e.g. fish oil) and lifestyle changes due to increased incidence of cerebrovascular bleeding. The unfulfilled therapeutic promise of thromboxane synthesis inhibitors may be overcome by introduction of dual TX receptor/synthesis inhibitors. Recent advances suggest that PGE1, prostacyclin analogs and high dose fish oil could act beneficially against background nitrodilator therapy in preventing thrombosis and mitogen-stimulated restenosis following thrombolytic or surgical treatment of coronary artery occlusion.

Animals↗
PubMed1989

Mechanisms responsible for inhibition of vein-graft arteriosclerosis by fish oil.

Favorable changes in lipoproteins, inhibition of platelet aggregation, reduction of serum thromboxane (TX), altered plasma-membrane fluidity, and reduced production of growth factors (mitogens) have all been implicated as possibly being involved in the inhibition of arteriosclerosis by fish oil (FO), which is rich in omega 3 fatty acids; however, causal relations are mostly lacking. Several putative mechanisms responsible for the salutary effects of FO were investigated in a canine model of accelerated vein-graft arteriosclerosis. Venoarterial autografts (N = 192) were implanted in 48 hypercholesterolemic dogs divided into six groups: group A, control; B, FO (as MaxEPA, 200 mg/kg/day eicosapentaenoic acid); C, aspirin (ASA, 50 mg/kg/day); D, TX synthetase inhibitor (TXSI [CGS-12970], 10 mg/kg/day); E, FO + ASA; and F, FO + TXSI. At sacrifice 3 months later, there was no significant difference in plasma lipoproteins, hepatic low density lipoprotein-receptor concentration, red blood cell fragility, bleeding time, or platelet count compared with controls; the decrease in platelet aggregation (30 +/- 5% [mean +/- SEM]) was similar in all treatment groups. Arterialized vein-graft intimal thickening was significantly inhibited by FO (with or without ASA), while ASA alone was ineffective. Conversely, serum TX was significantly lower only in the ASA and FO + ASA groups. Serum mitogenic activity was higher at 3 months in the control group versus all treatment groups. Compared with baseline values, serum mitogenic activity rose significantly over time in the control and the TXSI groups, and an increase or rising trend was present in all other treatment groups except for the FO-treated animals. Thus, the salutary biologic effect of FO in this hypercholesterolemic model of arterialized vein grafts may have been more related to in vivo inhibition of platelet-mitogen growth factor release than to changes in lipoproteins, low density lipoprotein receptors, platelet function, or eicosanoid metabolism. These observations underscore the need for further studies to clarify the interactions between FO (omega 3 fatty acids) and paracrine cellular mitogenic factors in the context of atherosclerosis prevention.

Animals↗
PubMed1987

Platelet aggregation inhibitory activity and vasodepressor activity of a series of bicyclo[3.2.0]hept-6-ylidene iminoxy alkanoic acids with modified lower side chains.

Prostacyclin analogues derived from modification of the lower side chain of the bicyclo[3.2.0]hept-6-ylidene iminoxyacetic acid (1) were studied in inhibition of in vitro and ex vivo platelet aggregation and in the spontaneously hypertensive rat. Iminoxyacetic acids (13a), (13b), (13c) and iminoxypropionic acid (14b) were 2.9, 3.0, 1.9 and 2.0 times respectively more potent than PGE1 in inhibiting ADP-induced aggregation of human platelets in vitro. Following intravenous administration at a dose of 90-110 micrograms/kg in the guinea pig, iminoxyacetic acids (13a), (13c) and iminoxypropionic acid (14b) showed a maximum inhibition of 82-92% with a half life in the range of 14-22 min. Following oral administration at a dose of 1 mg/kg in the guinea pig, iminoxyacetic acids (13a) and (13b) inhibited heterologous platelet aggregation for 4.5 h. Following intravenous administration in spontaneously hypertensive rats, acids (13a)-(13c) and (14b) lowered the mean blood pressure in a dose dependent manner. At a dose of 100 micrograms/kg, the effect lasted for 20-40 min.

Administration, Oral↗
PubMed1987

Orally active prostacyclin-mimetic RS-93427: therapeutic potential in vascular occlusive disease associated with atherosclerosis.

RS-93427 is a potent, orally active prostacyclin-mimetic that is very rapidly absorbed but with generally long-lived actions in most species. It has antithrombotic, thrombolytic, and antivasospastic potential. Alone among several tested PGI-mimetics, it inhibits release of platelet mitogens more potently than its ability to inhibit aggregation. It also inhibits mitogen release from macrophages and vascular endothelial cells. RS-93427 is also potent at inhibiting macrophage accumulation of cholesteryl esters. These data suggest a broad spectrum of potential therapeutic utility for RS-93427 via the oral route. It might be useful both in acute manifestations of vascular occlusive disease involving thrombosis and vasospasm, in addition to the more chronic conditions involving intimal hyperplasia (as in arteriovenous grafts) and possibly frank atherosclerosis. Much work remains to be done, including examination of RS-93427 in chronic studies with various dosage forms, particularly in the study of atherosclerosis.

Administration, Oral↗
PubMed1984

On the identification and biological properties of prostaglandin J2.

Prostaglandin D2 spontaneously decomposes at physiological pH and temperature to 9-deoxy-delta 9-PGD2 (designated PGJ2). We developed a TLC procedure for the isolation of PGJ2 which was identified by both proton-NMR and mass spectrometry. Freshly prepared PGJ2 was active in inhibiting aggregation induced by ADP in citrated human platelet rich plasma. As reported by Fukushima et al. (1). PGJ2 was less active (x 0.1-0.25) than PGD2 as an inhibitor. Concentrations of PGJ2 that markedly inhibited aggregation of human platelets were generally incapable of inhibiting aggregation of rat or guinea pig platelets. Using a heterologous system of human platelets mixed with guinea pig plasma samples (2), it was shown that the ability of PGJ2 to inhibit platelet aggregation was lost immediately following intravenous injection in anesthetized guinea pigs. This apparent rapid uptake and/or degradation of PGJ2 might also explain why PGJ2 had no effect on blood pressure of anesthetized guinea pigs. PGJ2 was potent in inhibiting proliferation of cultured vascular smooth muscle cells, mouse melanoma cells and mouse fibroblasts. Less potent anti-proliferative effects were seen with two other degradation products of PGD2, one of which was the delta 12 metabolite reported (3,4) to be formed from PGJ2 in a reaction catalyzed by serum albumin.

Adenosine Diphosphate↗
PubMed1984

Eicosanoid effects on cell proliferation in vitro: relevance to atherosclerosis.

Several eicosanoids were tested for ability to inhibit proliferation of cells in culture. In rabbit aortic smooth muscle cells and mouse B16BL6 melanoma cells, order of potency was: 12-HETE greater than PGJ2 greater than PGA1 greater than or equal to PGE1 greater than PGE2 greater than or equal to PGD2 greater than or equal to PGA2. PGB1 was active in smooth muscle cells (greater than PGD2) but not in B16 cells. 5-HETE and Leukotriene B4 were weakly active in smooth muscle cells, and PGB2, PGF2 alpha and TXB2 were inactive in both cells types. In Swiss albino mouse 3T3 fibroblasts, PGJ2 and PGE1 showed much lower relative potency than in the other two cell lines, although the profile was otherwise similar. These findings may be relevant to the anti-atherosclerotic (and perhaps anti-tumor activity) of some eicosanoids.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗