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G J Dusting

Publications and source records attributed to G J Dusting.

At least 55 records · Page 3Linked to original sources
PubMed1991

N-nitro L-arginine causes coronary vasoconstriction and inhibits endothelium-dependent vasodilatation in anaesthetized greyhounds.

1. The effect of N-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide biosynthesis, on large coronary artery diameter and coronary blood flow was examined in anaesthetized greyhounds. The effects of L-NNA on the coronary vascular responses to acetylcholine (ACh), glyceryl trinitrate (GTN) and 5-hydroxytryptamine (5-HT) were also assessed. 2. L-NNA (5 mg kg-1), infused into the left circumflex coronary artery, increased systemic mean arterial pressure and decreased the external diameter of the artery. Infusion of L-NNA decreased coronary blood flow in 5 of the 7 dogs tested and increased mean coronary resistance but neither of these effects was statistically significant. There was no change in heart rate. 3. Intra-arterial injection of both ACh (0.01-0.05 micrograms kg-1) and GTN (0.1-0.5 micrograms kg-1) increased large coronary artery diameter and coronary blood flow. Coronary vascular responses to the endothelium-dependent vasodilator ACh were significantly reduced by L-NNA, whereas the responses to the endothelium-independent vasodilator GTN were not significantly affected. 4. 5-HT (0.1 microgram kg-1, injected into the left circumflex coronary artery) decreased coronary artery diameter but increased coronary blood flow. After the administration of L-NNA the 5-HT-induced dilatation of the coronary resistance vessels was significantly attenuated whereas the constriction of the circumflex coronary artery was increased in 3 out of 3 dogs in which diameter could be measured, although the latter effect was not statistically significant. 5. These data indicate that L-NNA causes coronary and systemic vasoconstriction and selectively inhibits endothelium-dependent vasodilatation in the coronary circulation of the anaesthetized greyhound. Therefore endothelium-derived NO has an important role in the regulation of coronary vascular tone in the large arteries and the resistance vessels.

Acetylcholine↗
PubMed1990

Hyperpolarization and relaxation of arterial smooth muscle caused by nitric oxide derived from the endothelium.

Stimulation of the endothelial lining of arteries with acetylcholine results in the release of a diffusible substance that relaxes and hyperpolarizes the underlying smooth muscle. Nitric oxide (NO) has been a candidate for this substance, termed endothelium-derived relaxing factor. But there are several observations that argue against the involvement of NO in acetylcholine-induced hyperpolarization. First, exogenous NO has no effect on the membrane potential of canine mesenteric arteries. Second, although haemoglobin (believed to bind and inactivate NO (refs 11-15)) and methylene blue (which prevents the stimulation of guanylate cyclase) inhibit relaxation, neither has an effect on hyperpolarization. Finally, nitroprusside, thought to generate NO in vascular smooth muscle, relaxes rat aorta without increasing rubidium efflux. Nevertheless, nitrovasodilators, nitroprusside and nitroglycerin cause hyperpolarization in some arteries. NO might therefore be responsible for at least part of the hyperpolarization induced by acetylcholine. We now report that hyperpolarization and relaxation evoked by acetylcholine are reduced by NG-monomethyl-L-arginine, an inhibitor of NO biosynthesis from L-arginine. Thus NO derived from the endothelium can cause hyperpolarization of vascular smooth muscle, which might also contribute to relaxation by closing voltage-dependent calcium channels. Our findings raise the possibility that hyperpolarization might be a component of NO signal transduction in neurons or inflammatory cells.

Acetylcholine↗
PubMed1990

Prostacyclin and vascular function: implications for hypertension and atherosclerosis.

Prostacyclin and endothelium-derived relaxing factor (or nitric oxide) are unstable mediators produced by the vascular endothelium, that are important for local regulation of platelet behavior and blood flow. This review focuses on the basic biochemistry and pharmacology of prostacyclin, its interactions with nitric oxide and nitrovasodilator drugs, and the implications of disturbances in this system for vascular disease, particularly hypertension and atherosclerosis. Prostacyclin and its stable analogs are also finding limited therapeutic applications in preservation of platelet function, pulmonary hypertension, and investigation into the cytoprotective and antiatherosclerotic properties is continuing.

Animals↗
PubMed1990

Overview of eicosanoid metabolism and relationship to platelet-activating factor.

The pathways of arachidonic acid metabolism are becoming increasingly complex. Although it is unlikely that every pharmacological action of these eicosanoids reflects a physiological function, some of these compounds undoubtedly act as mediators of pathophysiological processes. Analogues of PGs have been exploited to a limited extent, and the emphasis for future therapeutic approaches will be on development of specific inhibitors and antagonists of eicosanoids that will alter the profile of products formed. These will be in the areas of inflammation (including asthma), cytoprotection of gastric mucosa, ischaemic protection and reperfusion injury, prevention of vascular disease, and human and animal reproduction. Because of the broad range of biological functions in which eicosanoids are involved, it is difficult to predict upon which of these areas new drugs will have the greatest impact.

Animals↗
PubMed1990

Platelet-activating factor may act as a second messenger in the release of icosanoids and superoxide anions from leukocytes and endothelial cells.

Platelet-activating factor (PAF) is generated by endothelial cells, polymorphonuclear leukocytes, and macrophages after activation by appropriate receptor agonists, but much of the PAF remains intracellular. We have investigated whether PAF formation is important for the subsequent generation of icosanoids and superoxide anions by these cells. The generation of prostacyclin and leukotriene B4 were measured by radioimmunoassay, superoxide anion was measured by reduction of cytochrome c, and PAF was measured by bioassay. In each cell type, PAF formation preceded or accompanied icosanoid generation. Bradykinin-induced prostacyclin generation in endothelial cells was markedly reduced by the PAF receptor antagonists WEB 2086 or CV 6209. In guinea pig adherent macrophages in vitro, basal prostacyclin generation and that induced by endotoxin and fMet-Leu-Phe were inhibited by either WEB 2086 (1-100 microM) or CV 6209 (0.1-10 microM). In isolated rabbit polymorphonuclear leukocytes, fMet-Leu-Phe stimulated the generation of both leukotriene B4 and superoxide anion. WEB 2086 and CV 6209 caused concentration-dependent inhibition of both these markers of leukocyte activation. These observations lead us to suggest that PAF may be a second messenger in leukocytes and endothelial cells.

Animals↗
PubMed1990

Supersensitivity to vasoconstrictor action of serotonin precedes the development of atheroma-like lesions in the rabbit.

We have studied the relationship between the early morphological changes and arterial responsiveness to vasoactive agents in a new animal model that is proposed to mimic the events of early human atherosclerosis. Atheroma-like lesions were produced by positioning a hollow Silastic collar (referred to as a cuff) around the common carotid arteries of rabbits. Following a period of either 48 h or 1, 2, or 4 weeks after surgery, vessels from both cuffed and sham-operated animals were removed, and vascular reactivity to cumulative concentrations of agonists were studied in isolated rings in organ baths. The contralateral arteries were perfused and fixed, studied by light microscopy, and the degree of intimal thickening was quantified by computer-assisted morphometric analysis and expressed as changes in the ratios of the cross-sectional areas of the intima and media in each artery. At 48 h, rings prepared from cuffed arteries were sixfold more sensitive to the contractile effects of serotonin (5-HT) than the corresponding controls. Histologically, such vessels showed some perivascular inflammation but no other morphological abnormality. At 7 days, cuffed vessels were again sixfold more sensitive to 5-HT than controls, and showed a thickened intima with marked smooth muscle proliferation and some infiltration by monocytes. Intimal/medial cross-sectional area ratios remained elevated at 2 and 4 weeks, but the supersensitivity to 5-HT diminished by 2 weeks to threefold and was absent at 4 weeks. The augmented reactivity to 5-HT at 48 h was specific, in that it did not occur for the alpha-adrenoceptor agonist, phenylephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Inhibition of endothelial nitric oxide biosynthesis by N-nitro-L-arginine.

1. The actions of N-nitro-L-arginine (NOLA) on the release of nitric oxide (NO) from arterial endothelial cells was studied in rat isolated thoracic aortic rings and by bioassay of NO derived from cultured bovine aortic endothelial cells. 2. NOLA (3-10 mumol/L) caused concentration-dependent inhibition of acetylcholine-induced relaxation of phenylephrine-contracted rat aortic rings, which is dependent on the release of NO from the endothelium. The inhibitory actions of NOLA could be prevented by pre- and co-incubation with L-arginine (1 mmol/L). 3. Endothelium-independent relaxation induced by sodium nitroprusside was not affected by NOLA. 4. The release of NO from bovine aortic endothelial cells, induced by bradykinin (10 nmol/L), was detected by bioassay on pre-contracted rabbit aortic strips. NOLA (1-3 mumol/L, given through the cell column) reduced or abolished the release of NO, but did not affect relaxations of the bioassay tissues induced by glyceryl trinitrate or authentic NO. 5. These data indicate that NOLA potently inhibits the biosynthesis of NO from L-arginine, and thus prevents its release from arterial endothelial cells. It may be a useful pharmacological tool for probing the significance of NO biosynthesis in cardiovascular function.

Animals↗
PubMed1989

Reflex epicardial coronary vasoconstriction elicited by nicotine in anaesthetized dogs.

The effects of arterial chemoreceptor activation by nicotine on coronary artery diameter was studied in anaesthetized, artificially ventilated dogs. Left circumflex coronary artery diameter, coronary blood flow, calculated mean coronary resistance, systemic arterial blood pressure and heart rate were measured. In control dogs (n = 10) the injection of nicotine (100 micrograms) into the carotid artery evoked an increase of arterial pressure (+22 +/- 9 mm Hg) and a decrease in heart rate (-36 +/- 13 beats/min), and tended to increase coronary blood flow (+7 +/- 4 ml/min). Intracarotid nicotine had no effect on large coronary artery diameter (+0.02 +/- 0.03 mm) or total coronary resistance (+0.04 +/- 0.09 mm Hg min/ml) under these conditions. When heart rate was controlled by (1) beta-adrenoceptor blockade (propranolol, 1 mg/kg i.v.) plus pacing of the right ventricle (n = 4) or (2) beta-adrenoceptor blockade plus bilateral vagotomy (n = 7), the chemoreflex-induced constriction of the large coronary artery (-0.07 +/- 0.02 mm and -0.12 +/- 0.03 mm, respectively; p less than 0.05). In contrast, there was no chemoreflex-induced change in total coronary resistance after beta-adrenoceptor blockade plus pacing (+0.01 +/- 0.09 mm Hg min/ml, but after beta-adrenoceptor blockade plus vagotomy coronary resistance was increased (+0.75 +/- 0.31 mm Hg min/ml; p less than 0.05). The constriction of both large and small coronary arteries was abolished by phentolamine (0.5 mg/kg i.v.). These results suggest that carotid body chemoreceptor stimulation by nicotine can produce reflex alpha-adrenoceptor-mediated constriction of both large and small coronary arteries, and that the constriction of the small vessels is balanced by vagally-mediated dilatation.

Adrenergic beta-Antagonists↗
PubMed1989

Rat aortic endothelium antagonizes nitroprusside-induced relaxation by release of the peptide endothelin.

1. The effects of porcine endothelin were examined in rat thoracic aortic rings. 2. Endothelin was a potent contractile agonist (EC50 4.0 +/- 0.6 nmol/L). 3. Endothelin (1 nmol/L) did not affect contractile responses to cumulative concentrations of the thromboxane analogue, U46619. 4. In the presence of U46619, but not phenylephrine, endothelin (1 nmol/L) and endothelium abrogated the vasodilator response to cumulative concentrations of sodium nitroprusside. 5. The inhibitory effect of endothelin on vasodilator responses to nitroprusside in the presence of U46619 was abolished by nifedipine (0.1 mumol/L) but unaffected by indomethacin (3 mumol/L) or haemoglobin (10 mumol/L). 6. These data suggest that endothelin generated by native endothelium exerts a physiological antagonism of sodium nitroprusside in the presence of thromboxane.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Evidence for an intracellular action of platelet-activating factor in bovine cultured aortic endothelial cells.

Bovine culture endothelial cells (BAECs) generate platelet-activating factor (Paf) following activation by bradykinin (Bk 0.1 nM), the ionophore, A23187 (3 microM), and ATP (10 microM), but Paf is not released from the cells. These stimuli also elicit generation of prostacyclin (PGI2). The specific and competitive Paf receptor antagonists, WEB 2086 (0.1-1.0 microM) and CV 6209 (0.01-0.1 microM), inhibited Bk-, A23187- and, to a lesser extent, ATP-induced PGI2 generation but had no effect on basal PGI2 generation. These data suggest a role for intracellular Paf in signal transduction.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Cyclic nucleotide interactions involved in endothelium-dependent dilatation in rat aortic rings.

The role of cyclic nucleotides in the dilation of rat aortic rings induced by isoprenaline was studied by measuring changes in isometric tension and in cyclic nucleotide levels in rings preconstricted with phenylephrine or U46619. Isoprenaline produced significantly greater relaxation in endothelium-containing than in endothelium-denuded rings. Relaxation of endothelium-containing rings to isoprenaline was markedly inhibited by pretreating the rings with methylene blue (30 microM) or haemoglobin (10 microM). Basal cyclic-AMP levels were not affected by the presence of endothelium in the rings, but basal cyclic-GMP levels were 5-6-fold higher in endothelium-containing rings. Isoprenaline (1 microM) elevated levels of cyclic-AMP to an extent which was not affected by the presence of endothelium. In contrast, isoprenaline had no effect on cyclic-GMP levels in rings with or without endothelium. Pretreatment of de-endothelialized rings with sodium nitroprusside or 8-bromo-cyclic-GMP, in concentrations that by themselves caused minor alterations in vascular tone, markedly amplified the relaxant responses to isoprenaline and mimicked the relaxant responses of endothelium-containing rings to isoprenaline. These data indicate that isoprenaline does not stimulate release of endothelium-derived relaxing factor, but suggest a major synergistic interaction between cyclic-GMP-mediated and cyclic-AMP-mediated relaxation in rat aorta.

Animals↗
PubMed1988

Synergistic inhibition of platelet aggregation by endothelium-derived relaxing factor and prostacyclin.

The anti-aggregatory effect of endothelium-derived relaxing factor (EDRF) on aggregation of washed, aspirin-treated platelets was compared with that of nitric oxide. Nitric oxide produced a dose-dependent inhibitory effect on PAF-induced aggregation: the antiaggregatory activity was unstable and was completely preventable by pretreating the platelets with haemoglobin (10 mumol/l). Bovine aortic endothelial cells (EC) were grown to confluence on microcarrier beads, pretreated with aspirin (1 mmol/l), and their addition to the platelet cuvette also caused a dose-dependent inhibition of aggregation induced by PAF, thrombin and A23187. The inhibitory effect of the EC on platelet aggregation was partly prevented in the presence of haemoglobin (10 mumol/l). Both nitric oxide and EC showed synergy with prostacyclin, in that the latter potentiated the anti-aggregatory action of both these factors against PAF-induced platelet aggregation. Thus cultured endothelial cells release a non-prostanoid anti-aggregatory factor, which, like nitric oxide, shows a synergistic interaction with prostacyclin and is blocked by haemoglobin. This anti-aggregatory factor has the characteristics of EDRF.

Animals↗
PubMed1988

Inhibition of vascular smooth muscle relaxation by LY83583.

The ability of LY83583 to antagonize vascular smooth muscle relaxation elicited by a number of vasodilators was examined in rings of rat aorta. LY83583 (0.3-10 microM) inhibited relaxant responses to acetylcholine, calimycin (A23187), adenosine triphosphate (ATP) and sodium nitroprusside, whereas responses to atriopeptin III an activator of particulate guanylate cyclase, and papaverine were unaffected. For acetylcholine and calimycin the major effect of LY83583 (0.3-10 microM) was to reduce the maximal response without appreciably altering the EC50 values whereas for ATP the EC50 values were markedly increased by low concentrations of LY83583 (0.3-1 microM) with depression of maximal responses occurring at higher concentrations (10 microM) of the antagonist. In contrast LY83583 produced nonparallel rightward shifts of the curve for sodium nitroprusside without altering the maximal response. In addition, LY83583 (10 microM) reduced basal levels of cyclic GMP and prevented acetylcholine and sodium nitroprusside-induced elevations of cyclic GMP, in parallel with reductions in the relaxant responses. In the presence of LY83583 (10 microM) higher concentrations of sodium nitroprusside restored both the relaxant response and the elevation of cyclic GMP. The results of this study show that LY83583 antagonises only those vasodilators which are thought to act via stimulation of soluble guanylate cyclase. The nonsurmountable inhibition of relaxation to acetylcholine, calimycin and ATP probably reflects a limited maximal capacity of the endothelium to release EDRF in response to these agents.

Acetylcholine↗
PubMed1988

Endothelium-derived relaxing factor released from cultured cells: differentiation from nitric oxide.

1. Endothelium-derived relaxing factor (EDRF) is an extremely labile mediator thought to be identical to nitric oxide (NO). 2. A cascade superfusion technique was used to bioassay EDRF released from bovine aortic endothelial cells grown to confluence on microcarrier beads. 3. Bradykinin (1-100 nmol/l), infused through a 1 cm column of endothelial cells on microcarriers, released an EDRF-like substance that caused relaxations of de-endothelialized strips of rabbit aorta (precontracted with phenylephrine). These relaxations diminished on successive tissues in the cascade, when compared with those produced by glyceryl trinitrate as a stable standard. 4. Haemoglobin (1 mumol/l), infused directly over the bioassay tissues, abolished bradykinin-induced relaxations and these were restored within 5 min after removal of haemoglobin. The infusion did not affect the relaxations produced by glyceryl trinitrate in this system. 5. Methylene blue (20 mumol/l) inhibited bradykinin-induced relaxations when infused over the rabbit aortae, and reduced those relaxations produced by glyceryl trinitrate. The effects of bradykinin, but not glyceryl trinitrate, were partially restored after removing methylene blue. 6. These data are consistent with the known effects of these compounds on the activity of NO, and on EDRF in isolated blood vessels. 7. The activity of EDRF (released by bradykinin) was compared directly with NO on strips of guinea-pig trachea (de-epithelialized) interposed in cascade between two rabbit aortae; all strips were precontracted with histamine and phenylephrine. 8. A submaximal dose of NO that matched the relaxation produced by EDRF on the uppermost aorta, caused relaxation of the trachea, but EDRF had no effect on this tissue. In addition, the NO-induced relaxation of the lower aorta was greater than that produced by EDRF. 9. These data indicate that EDRF does not have identical biological activity to NO. EDRF could contain an NO moiety attached to a carrier molecule that is bound and stabilized in tracheal tissue.

Animals↗
PubMed1988

Inhibition of vasodilatation by methylene blue in large and small arteries of the dog hindlimb in vivo.

1. Injection of acetylcholine (ACh, 0.0005-2 micrograms/kg) or glyceryl trinitrate (GTN, 0.01-20 micrograms/kg) into the femoral artery increased femoral artery diameter, femoral blood flow and heart rate, and reduced femoral vascular resistance and systemic arterial blood pressure in anaesthetized dogs. The intravenous (i.v.) injection of ACh (2 micrograms/kg) produced a small decrease in systemic arterial pressure and an increase in heart rate, but did not dilate the hindlimb vessels. 2. Methylene blue, a guanylate cyclase inhibitor, continuously infused into the femoral artery (10 mg/min), attenuated the increase in femoral artery diameter and femoral blood flow, and the decrease in femoral vascular resistance produced by intra-arterial injections of both ACh and GTN. 3. In addition, methylene blue potentiated the decrease in systemic arterial pressure produced by ACh (injected directly into the femoral artery or i.v.), but did not affect the depressor response to GTN. This selective potentiation of ACh-induced hypotension was not affected by autonomic ganglion blockade with hexamethonium (25 mg/kg, i.v.). 4. These results suggest that both ACh- and GTN-induced vasodilatation in vivo occurs through a mechanism involving guanylate cyclase activation in large arteries and resistance vessels in the dog hindlimb. Methylene blue inhibited the local vasodilator actions of ACh in the femoral vasculature despite potentiating the systemic depressor response to that agent.

Acetylcholine↗
PubMed1988

Characterization of receptors for platelet-activating factor on platelets, polymorphonuclear leukocytes and macrophages.

1. We have compared the potency of the putative platelet-activating factor (Paf) receptor antagonists (WEB 2086, L-652,731 and BN 52021) against Paf-induced aggregation of rabbit and guinea-pig platelets, aggregation of rabbit polymorphonuclear leukocytes (PMNLs) and prostacyclin generation by guinea-pig resident peritoneal macrophages. 2. On rabbit washed platelets and PMNLs WEB 2086, L-652,731 and BN 52021 each antagonized competitively Paf-induced aggregation. The rank order of potency was WEB 2086 congruent to L-652,731 greater than BN 52021 and was the same for the two cell types. 3. The pA2 values for each of the three antagonists were similar on rabbit washed platelets and PMNLs. Moreover, the pA2 for WEB 2086 on rabbit platelets (7.58) did not differ significantly from that on guinea-pig platelets (7.69). 4. On guinea-pig resident peritoneal macrophages WEB 2086 was 10 fold less potent for receptors mediating increased generation of 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) than for those mediating platelet aggregation. 5. The potencies of L-652,731 and BN 52021 were also markedly less (2 log units) for the macrophage receptors than for platelet or PMNL receptors and BN 52021 was more potent than L-652,731 in the macrophages. 6. WEB 2086 and L-652,731 significantly reduced basal 6-oxo-PGF1 alpha produced by macrophages, but none of the antagonists affected 6-oxo-PGF1 alpha production during stimulation by A23187. 7. These data raise the possibility that there may be a Paf receptor-subtype mediating prostacyclin generation in macrophages that is different from that on the platelet and PMNL. Hence, the potency of Paf antagonists against platelet aggregation would not be a good predictor of antagonist potency in disorders involving macrophages.

Animals↗