All cells in living organisms have a limited life span, and when the time set by their biological clocks has run out, they will die , their highly orga­ nized macromolec ular structure will disintegrate, and the low-molec ul ar degrad ation products be­ come part of the disorder of the surroundings . In thermodynamic terms, this series of events consti­ tutes what has been c alled the entropic doom. We know little about those molec ul ar mechanisms that limit the life span of cells in the absence of dise ase. For the clinician, therefore, the important task is to prevent or tre at dise ases that jeopardize the proper functioning and viability of cells whose biologic al clocks have not yet run out . Measures instituted to prevent brain cell death have a special importance . This i s partly due t o the fact that w e equate human life with the functioning of the brain. However, this importance also resides in the v ulnerability of brain cells to conditions that allow cells of most other tissue to survive , and to continue or res ume their activitie s . The clinically most important conditions leading to brain cell death are those associated with cere­ brovascul ar dise ase, particularly stroke, and with head trauma. We will begin, though, by rec alling the traditional view of the occ urrence and loc alization of neuronal damage in four conditions that lead to more disseminated alterations, e specially since they have been considered to c ause nerve cell injury of a

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1981.18

Cell Damage in the Brain: A Speculative Synthesis

Publisher Summary This chapter discusses prostaglandins and thromboxanes. The prostaglandins are C 20 acids formed from polyunsaturated fatty acids by oxygenation and cyclization. The thromboxanes, which were originally found in platelets, have now been identified in a variety of tissues. Rapid progress is being made in understanding their biological roles. Earlier studies on vascular and airway smooth muscle demonstrated that endoperoxides had unique effects that could not be attributed to conversion into the stable prostaglandins. Because aspirin, an inhibitor of endoperoxide formation, inhibits the second wave of aggregation, it was suggested that the endoperoxides play a role in the release reaction. The potency of the endoperoxides in causing contractions of the isolated rabbit aorta was of particular interest. However, the occurrence of thromboxanes is not limited to platelets. The transformation of arachidonic acid into thromboxane B 2 has also been observed in lung tissue, spleen, kidney, leukocytes, umbilical artery, and brain.

Prostaglandins and thromboxanes.

Extensive microscopic examination of epicardial arteries and myocardium was performed in 25 cases of sudden death due to acute coronary thrombosis. Eighty-one percent of the thrombi had a layered structure with thrombus material of differing age, indicating that they were formed successively by repeated mural deposits that caused progressive luminal narrowing over an extended period of time. This episodic growth of the thrombus was accompanied by intermittent fragmentation of thrombus in 73% of the cases, with peripheral embolization causing microembolic occlusion of small intramyocardial arteries associated with microinfarcts. The period of unstable angina before the final heart attack was, in all but one of 15 patients, characterized by such an ongoing thrombotic process in a major coronary artery where recurrent mural thrombus formation seemed to have alternated with intermittent thrombus fragmentation. The culmination of this "dynamic" thrombotic process in total vascular occlusion caused the final infarction and/or sudden death.

Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion.

From January 1970 to December 1977, transient reversible episodes of S-T segment elevation were documented in 138 patients (80 with angina only at rest, 58 with angina both on exertion and at rest). Electrocardiographic monitoring in 33 patients with hemodynamic monitoring revealed that (1) during 6,009 transient episodes of myocardial ischemia, pain was always a late phenomenon and, in some patients, often did not occur; (2) during such transient episodes, ST-T wave behavior was often variable in the same patient with alternation of elevation, depression or only T wave changes with or without pain; (3) independent of the direction of the S-T segment and T wave changes, the episodes were never preceded by an increase of the hemodynamic determinants of myocardial demand but were associated with obvious impairment of left ventricular function. Thallium scintigraphy in 32 patients revealed a regional massive and localized reduction of myocardial perfusion during S-T segment elevation and pseudonormalization of T waves. During S-T segment depression the reduction of thallium uptake was diffuse with fuzzy limits. Coronary angiography revealed no significant stenosis in 8 patients and single, double and triple vessel disease in 38, 34 and 26 patients, respectively. Angiography in all 37 patients studied during angina revealed a severe coronary vasospasm involving vessels with extremely variable extent of atherosclerosis. Severe arrhythmias were recorded in 27 patients, and a myocardial infarction occurred in 28. A total of five patients died within 1 month of hospital admission. Thus, variable intensity and extension of coronary vasospasm and the presence of collateral vessels may result in different degrees of ischemia and various electrocardiographic patterns with or without anginal pain. Vasospastic angina can occur in the presence of extremely variable degrees of coronary atherosclerosis and in any phase of ischemie heart disease. It may evolve into acute myocardial infarction and sudden death: Variant angina appears to be only its most striking electrocardiographic manifestation. When vasospastic angina is appropriately searched for, its incidence rate appears to be high.

“Variant” angina: One aspect of a continuous spectrum of vasospastic myocardial ischemia: Pathogenetic Mechanisms, Estimated Incidence and Clinical and Coronary Arteriographic Findings in 138 Patients

To investigate the pathogenesis of myocardial infarction we undertook a systematic study of patients with angina at rest, a syndrome known to evolve frequently into infarction. Among 187 consecutive patients, 37 had infarction, all in the area that showed electrocardiographic changes during angina. In all 76 patients who underwent hemodynamic monitoring, 201thallium myocardial scintigraphy or angiography during angina, a vasospastic origin of the attacks was documented. In six patients with infarction shortly after these studies and in two in whom the infarction developed during hemodynamic monitoring or during angiography the onset of infarction was indistinguishable from the onset of anginal attacks. One patient in whom spasm was observed at the onset of infarction died six hours later; at post-mortem examination, a fresh laminar thrombus was found at the site of the spasm. After infarction, complete thrombotic occlusion of the branch shown to undergo vasospasm was documented in two patients by...

Coronary vasospasm as a possible cause of myocardial infarction. A conclusion derived from the study of "preinfarction" angina.

When human platelets are aggregated by thrombin, material is released that rapidly contracts strips of spirally cut porcine coronary artery. Prevention of the contraction by indomethacin suggested mediation by a prostaglandin. The contraction produced by aggregating platelets was unlike those produced by prostaglandins E2, F2alpha, G2, or H2, but resembled that evoked by thromboxane A2, which is formed by platelets during aggregation.

https://science.sciencemag.org/content/sci/193/4258/1135.full.pdf

Coronary arterial smooth muscle contraction by a substance released from platelets: evidence that it is thromboxane A2.

Ethyl arachidonate was administered orally to 4 healthy male volunteers in a dose of 6 gm daily for a 2 to 3 wk period after 10-day control period. The increased intake of this precursor of the dienoic prostaglandins resulted in significant increases in the relative and absolute amount of arachidonate in plasma triglycerides, phospholipids, and cholesteryl esters. Similar changes in lipid composition were noted in platelets. The excretion of 7alpha-hydroxy-5,11-diketotetranoprostane-1,16-dioic acid, the major urinary metabolite of E prostaglandins in man, was increased by an average of 47% in 3 of the 4 volunteers. Platelet reactivity was assessed by determining the threshold concentration of adenosine diphosphate (ADP) necessary to induce secondary, irreversible aggregation of platelet-rich plasma. This threshold concentration dropped significantly in all volunteers (10% to 60% of control values). It is concluded that the biosynthesis and function of prostaglandins can be augmented in man by oral administration of an esterified precursor fatty acid.

Increased arachidonate in lipids after administration to man: effects on prostaglandin biosynthesis.

The dose and plasma levels of indomethacin correlated with inhibition of prostaglandin synthesis as measured both by urinary excretion of the major metabolite of prostaglandin E2 (PGE-M) and by the release of prostaglandin E2 from thrombin-stimulated platelets. Considerable intersubject variability was observed in the suppression of PGE-M excretion. In some patients 37.5 mg indomethacin daily, usually considered subtherapeutic, caused suppression. Maximal suppression (greater than 90%) occurred in some after a daily dose of 75 mg, whereas 150 mg was required to achieve this level of inhibition in others. Suppression of the excretion of PGE-M by 60% occurred when the end of the dosage interval plasma levels of indomethacin were in the range 0.05 to 0.3 microgram/ml, which implies that a somewhat higher average steady-state concentration during the dosage interval was required to achieve this effect. A similar degree of inhibition of the release of PGE2 on thrombin-stimulated platelets was associated with the same range of plasma levels. Upon discontinuation of the drug, the levels of indomethacin in plasma decreased exponentially; inhibition of the release of PGE2 from platelets by indomethacin declined linearly with time and in parallel with the logarithm of the diminishing plasma levels.

Relation between plasma concentration of indomethacin and its effect on prostaglandin synthesis and platelet aggregation in man

Biosynthesis of prostaglandin D2 1. Formation of prostaglandin D2 by human platelets

The role of calcium in triggering prostaglandin and thromboxane synthesis was studied in several systems with ionophores of different ion specificities. Divalent cationophore A23187 stimulates prostaglandin and thromboxane production by washed human platelets in a concentration-dependent manner (0.3-9 μM). A23187 also induces an antimycin A-insensitive burst in oxygen utilization which is partially blocked by 5 mM aspirin or 10 μM indomethacin. Under our conditions, A23187 (up to 10 μM) does not appear to damage platelet membranes since it does not cause appreciable loss of lactate dehydrogenase or β-glucuronidase. Mono- and divalent cationophore X537A also stimulates platelet thromboxane B2 production and oxygen utilization, but monovalent cationophores nigericin, monensin A, A204, and valinomycin have no effect. The synthesis of prostaglandins E2, D2, and F2α by rat renal medulla mince is stimulated by 1 and 5 μM A23187 without changes in tissue ATP content, lactate output, or K+ efflux. X537A, monensin A, and nigericin (all 5 μM) stimulate both prostaglandin output and K+ efflux from renal medulla, while 5 μM valinomycin or A204 has no effect on either. None of the ionophores stimulates renomedullary prostaglandin production if calcium is omitted from the incubation medium. A23187 also stimulates prostaglandin production by human lymphoma cells, rat stomach and trachea preparations, and guinea pig polymorphonuclear leukocytes. These observations suggest a major role for Ca2+ in stimulating prostaglandin and thromboxane biosynthesis, and also indicate that prostaglandin and/or thromboxane release may partially mediate some of the previously described effects of ionophores on cells and tissues.

https://www.pnas.org/content/pnas/74/10/4251.full.pdf

Oswald Oelz

Papers

Coronary arterial smooth muscle contraction by a substance released from platelets: evidence that it is thromboxane A2.

Increased arachidonate in lipids after administration to man: effects on prostaglandin biosynthesis.

Relation between plasma concentration of indomethacin and its effect on prostaglandin synthesis and platelet aggregation in man

Biosynthesis of prostaglandin D2 1. Formation of prostaglandin D2 by human platelets

Ionophores stimulate prostaglandin and thromboxane biosynthesis.