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Biomedical subjects

D Hosford

Publications and source records attributed to D Hosford.

31 records · Page 2Linked to original sources
PubMed1989

Ginkgolide B protects isolated hearts against arrhythmias induced by ischemia but not reperfusion.

The effect of ginkgolide B (BN 52021), a specific platelet-activating factor (PAF) antagonist, applied in doses of 1.5, 3.0, 6.0 X 10(-5) and 1.2 X 10(-4) mol/l, in comparison to that of metoprolol (10(-5) mol/l) and diltiazem (10(-7) mol/l), two widely used antiarrhythmic agents, on ischemia- and reperfusion-induced arrhythmias and heart functions, such as heart rate (HR), coronary flow (CF), aortic flow (AF), left ventricular developed pressure (LVDP), its first derivative (LVdp/dtmax), and left ventricular end-diastolic pressure (LVEDP) in isolated working rat hearts was examined. BN 52021 caused a dose-related protection against dysrhythmias, such as ventricular fibrillation, ventricular tachycardia, and premature ventricular beats induced by ischemia (30 min ligation of the left anterior descending coronary artery). The antiarrhythmic effect of BN 52021 given in a dose of 6.0 X 10(-5) mol/l was comparable to that of diltiazem and superior to the activity of metoprolol. None of the drugs influenced reperfusion-induced rhythm disturbances. BN 52021 did not alter heart functions, while metoprolol reduced (LVEDP only, and diltiazem increased CF, decreased AF, LVDP, and LVdp/dtmax during regional ischemia, indicating a negative inotropic effect. The antiarrhythmic effect of BN 52021 appears to be related to an antagonism of an increase in slow calcium influx induced by PAF in myocardial cells. Similarly to the mechanism of action of established antiarrhythmic drugs, BN 52021 can presumably prevent the re-entry mechanism involved in the development of ischemia-induced rhythm disturbances.

Animals↗
PubMed1989

Is there a case for PAF antagonists in the treatment of ischemic states?

It is becoming clear that PAF plays an important role in a variety of life-threatening pathologies including shock, asthma, graft rejection and ischemia-induced damage. Pierre Braquet and colleagues analyse recent reports on PAF and ischemia and propose a hypothesis based on the catastrophe theory to explain why PAF antagonists are effective in countering ischemic injury and many other disorders. PAF antagonists, perhaps in combination with other agents, may consequently prove to have extensive therapeutic potential.

Humans↗
PubMed1989

Platelet-activating factor and cytokine interactions in shock.

Many types of shock are characterized by profound hemodynamic alterations and depression of immune processes. Among the various mediators implicated in shock conditions, there is much evidence to suggest that, together with various cytokines, the inflammatory and chemotactic autacoid, platelet-activating factor (PAF), plays an important role. Studies on several animal models have shown that infusion of PAF mimicks the shock state, that markedly increased levels of PAF are produced in shock and that PAF antagonists afford significant protection against diverse forms of shock. The precise mechanism by which PAF antagonists protect against shock remains unclear; however, it is becoming apparent that in traumatic states a complex interaction occurs between PAF and cytokines, which leads to the acute phase reaction and circulatory collapse. We propose that PAF antagonists may be effective in counteracting shock because of their antiprotease activity and their ability to inhibit deleterious PAF/cytokine auto-generated feedback processes.

Animals↗
PubMed1989

Effect of endothelin-1 on blood pressure and bronchopulmonary system of the guinea pig.

The bronchopulmonary and pressor effects of endothelin-1 (ET-1), a newly described vasoconstrictor peptide produced by endothelial cells, were investigated in the guinea pig. Intravenous injection of ET-1 (1 nmol/kg) induced an increase in pulmonary inflation pressure (PIP) as well as an important and sustained increase in arterial blood pressure (BP). Pretreatment of these animals with propranolol (1 mg/kg i.v.), provoked a significant enhancement of the ET-1-induced increase in PIP, accompanied by a dramatic and significant decrease of BP. When administered by aerosol for 1 min, ET-1 (1, 5, or 10 micrograms/ml) induced a dose-dependent increase in PIP that was maximal by 4-5 min, but no significant change of BP. Pretreatment of guinea pigs with propranolol (1 mg/kg), mepyramine (1 mg/kg i.v.), nifedipine (50 mg/kg i.p.), or verapamil (0.3 mg/kg i.v.) did not inhibit the bronchopulmonary response evoked by aerosol administration of 10 micrograms/ml of ET-1. In contrast, pretreatment of the animals with indomethacin (10 mg/kg i.v.) or BN 52021 (10 mg/kg i.v.) significantly reduced the bronchopulmonary response of ET-1 given by aerosol. Injection of ET-1 (0.1, 0.3, and 1 micrograms) into isolated guinea pig lungs caused significant increases in PIP that were accompanied by the release of TxB2 but not histamine. These results demonstrate that ET-1 induces bronchopulmonary alterations in the guinea pig that appear to be dissociated from the systemic vascular effects of the peptide.

Animals↗
PubMed1989

Role of cytokines and platelet-activating factor in microvascular immune injury.

Inflammation is usually a tightly controlled process which confines tissue damage, prevents infection, and assists in cellular regeneration. However, if the inflammatory response becomes unregulated, this normally beneficial local event may escalate into a wider malignant activity, characterized by endothelial injury, excessive cell infiltration, and vascular leakage. Due to the ability of platelet-activating factor and tumor necrosis factor to elicit the release of each other, 'prime' cell responses, and influence the activity of other cytokines, we propose that these two mediators play a pivotal role in the formation of deleterious feedback cycles leading to the above endothelial damage which may underlie pathologies such as shock, sepsis, ischemia, and asthma. Platelet-activating factor antagonists such as BN 52021 inhibit the priming and other effects induced by platelet-activating factor and thus may be of therapeutic value in such conditions.

Animals↗
PubMedDate not supplied

PAF/cytokine auto-generated feedback networks in microvascular immune injury: consequences in shock, ischemia and graft rejection.

The catastrophe theory evolved by Thom and Zeeman proposes a mathematical definition for the abrupt or 'catastrophic' changes that can suddenly occur in normally well-ordered and smooth-running systems. We have integrated this theory with our own PAF/cytokine feedback network hypothesis to explain the control and dysfunction of the inflammatory response. This process involves the activation of cells and factors such as proteases, and is coordinated by mediators such as PAF, cytokines and growth factors, minute amounts of which can prime cells to respond in an enhanced manner to subsequent agonistic stimuli. PAF and certain cytokines also possess the unique property of being able to induce the release of each other and their own generation in vivo. This 'singularity' may enable a self-generating feedback network to become established. The priming ability of these mediators indicates the extreme sensitivity of the inflammatory process and importance of a homeostatic equilibrium between the vectors involved in the priming and feedback processes and internal suppressive mechanisms. In pathological conditions, one can consider the phenomenon of PAF and cytokine autogeneration as a 'fold' in the feedback network and an expression of the singularity characteristic of the catastrophe hypothesis. This may lead to systemic toxicity and microcirculatory collapse, a characteristic feature of shock, sepsis, asthma, ischemia and graft rejection. A combination of drugs antagonizing the various feedback components may inhibit this catastrophic process and thus provide more successful therapy of these conditions.

Animals↗