Atherosclerosis, the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan. The lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. A large number of growth factors, cytokines and vasoregulatory molecules participate in this process. Our ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.

The pathogenesis of atherosclerosis: a perspective for the 1990s

https://www.cell.com/cell/pdf/S0092-8674(00)80949-6.pdf

Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior

IN the 19th century there were two major hypotheses to explain the pathogenesis of atherosclerosis: the "incrustation" hypothesis and the "lipid" hypothesis. The incrustation hypothesis of von Rokitansky,1 proposed in 1852 and modified by Duguid,2 suggested that intimal thickening resulted from fibrin deposition, with subsequent organization by fibroblasts and secondary lipid accumulation. The lipid hypothesis, proposed by Virchow3 in 1856, suggested that lipid in the arterial wall represented a transduction of blood lipid, which subsequently formed complexes with acid mucopolysaccharides; lipid accumulated in arterial walls because mechanisms of lipid deposition predominated over those of removal. The two hypotheses are now . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199201233260406?articleTools=true

The pathogenesis of coronary artery disease and the acute coronary syndromes (1).

/pdf/inositol-trisphosphate-and-diacylglycerol-as-second-4drzjsg27y.pdf

Inositol trisphosphate and diacylglycerol as second messengers.

Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

Physiology of Microglia

Relationship between serum glufosinate level and development of serious poisoning caused by the ingestion of Basta®, a herbicide containing glufosinate

BACKGROUND The present study was designed to determine whether augmentation of cardiac performance by milrinone is affected by acidosis in in vivo canine and in vitro guinea pig preparations, and to elucidate a mechanism in relation to the cyclic adenosine monophosphate (cAMP) formation. METHODS Halothane-anesthetized, ventilated dogs were randomly assigned to a control group (arterial pH [pHa] approximately 7.4, base excess [BE] > -2 mM; n = 7), mild acidosis group (pHa approximately 7.2, BE < -9 mM; n = 7); or severe acidosis group (pHa < 7, BE < -20 mM; n = 6). Arterial blood pressure, left ventricular pressure (including maximum rate of increase, LV dP/dtmax), and pulmonary blood flow (PBF) were measured. Acidosis was induced by transient hypoxia and maintained with hydrogen chloride infusion. Hemodynamic responses to milrinone infusions at 2 and 5 microg x kg(-1) x min(-1) were then studied. In addition, left atria and right ventricular strips were dissected from guinea pig hearts and suspended in HEPES-Tyrode solution, with pH values adjusted to 7.4, 7, or 6.6. The concentration-response relation of isometric contractions for milrinone (10(-7) to 10(-4) M) and 8-bromo-cAMP (10(-4) to 10(-3) M) were determined. RESULTS In the control group of dogs, significant increases in LV dP/dtmax (2,674 +/- 822 to 3,999 +/- 1,016 mmHg/s [means +/- SD]) and PBF (2.04 +/- 0.98 to 2.44 +/- 0.96 l/min [means +/- SD]) were seen with a milrinone infusion of 5 microg x kg(-1) x min(-1). In the mild acidosis group, 5 microg x kg(-1) x min(-1) milrinone also increased LV dP/dtmax and PBF. However, neither LV dP/dtmax nor PBF changed in the severe acidosis group. In in vitro experiments, milrinone exerted a positive inotropic effect in a concentration-dependent manner on the right ventricular preparations at pH 7.4, but not at pH 7 and 6.6, whereas no significant difference was observed in inotropic responses to 8-bromo-cAMP at pH values of 6.6, 7, and 7.4 on the right ventricular strips. In the right ventricular in vitro preparation, 10(-4) M milrinone was accompanied by a significant increase in intracellular cAMP content at apH of 7.4 but not 7. CONCLUSIONS These results indicate that the inotropic effect of milrinone is attenuated by acidosis due, at least in part, to decreased cAMP formation in acidotic muscle.

Influence of acidosis on cardiotonic effects of milrinone

Exercise causes an integrated physiological response (e.g., an increase in cardiac output and a significant redistribution of tissue blood flow), which greatly increases blood flow in active muscles but decreases it in the splanchnic circulation. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by vascular endothelial cells. We hypothesized that exercise causes a tissue-specific change in ET-1 production in various organs. We studied whether a bout of exercise alters the expression of preproET-1 mRNA in various tissues of rats. The rats were randomly divided into exercise rats and control rats. Exercise rats performed treadmill running for 30 minutes at a speed of 30 m/minute. Control rats remained at rest during the same period (30 minutes). Immediately after the exercise and rest, the abdominal artery, liver, muscles (tibialis anterior muscle, plantar muscle and soleus) and adipose tissue were quickly removed and the expression of preproET-1 mRNA in these tissues was determined by real-time quantitative polymerase chain reaction analysis. The expression of preproET-1 mRNA in these tissues was changed in a different manner by acute exercise (i.e., increased, decreased, or unchanged). The expression of preproET-1 mRNA in the aorta was significantly decreased by exercise, whereas that in the plantar muscle was significantly increased by exercise. There were no significant differences in the expression of preproET-1 mRNA in the liver, tibialis anterior muscle, soleus and adipose tissue between the exercise rats and the control rats. These results show that the expression of preproET-1 mRNA was changed tissue-specifically by acute exercise. We demonstrate that acute exercise causes tissue-specific changes in the production of ET-1 and that these alterations may participate in the integrated physiological response during exercise.

Exercise-induced tissue-specific change in gene expression of endothelin-1.

The effects of 8 imidazoline derivatives on pre- and postsynaptic alpha-adrenoceptors and [3H]norepinephrine release were investigated in the rat vas deferens and were compared with those of reference drugs, yohimbine, phentolamine, tolazoline, and prazosin. K-6341 and K-6343 activated postsynaptic alpha 1-adrenoceptor and were antagonized by prazosin. The order of potency series as alpha 1-antagonist, prazosin greater than phentolamine greater than yohimbine greater than K-4011 greater than K-3827 greater than K-4300, tolazoline was found in antagonism against phenylephrine. Many derivatives exhibited an antagonistic action against clonidine, and the potency series as alpha 2-antagonist was revealed as follows: phentolamine greater than yohimbine greater than K-3827 greater than K-4011 greater than K-6341 greater than K-6343 greater than K-4300, tolazoline greater than prazosin greater than K-4299. The antagonistic effect was more selective on presynaptic (alpha 2) than postsynaptic (alpha 1) adrenoceptor and the rank order of selectivity (KB-post/KB-pre) was K-3827 greater than yohimbine greater than K-4011 greater than tolazoline, K-4300 greater than phentolamine greater than prazosin. Imidazoline derivative increased [3H]norepinephrine release, the actions of K-3827, K-6341 and K-4300 being particularly potent. From these results, the structure-activity relationship was summarized. First, when 2',3'-methylenedioxyphenyl group is connected with the imidazoline ring via an amino or methylene residue, these compounds become alpha 1-agonist. Secondly, when the methylenedioxyphenyl group and the imidazoline ring are connected via an amino residue, these compounds show a weak agonistic and potent antagonistic characteristics at the presynaptic alpha 2-adrenoceptor. Thirdly, an addition of a methylenedioxy radical to the phenyl ring increased the affinity of the compounds to presynaptic alpha 2-receptor.

Pharmacological studies of imidazoline derivatives. I. A comparison of the effect on pre- and postsynaptic alpha-adrenoceptors in the rat vas deferens.

Endothelin-1 (ET-1) is produced by endothelial cells and cardiac myocytes. ET-1 has potent positive inotropic and chronotropic effects in the heart and causes myocardial cell hypertrophy. We investigated the alteration of gene expression of ET-1 in the heart of rats during acute exercise and 24 hour postexercise periods. Sprague-Dawley rats performed treadmill running for 30 minutes at a speed of 30 m/minute. We determined the expression of preproendothelin-1 mRNA in the rat hearts of resting (control) and 0, 0.5, 1, 3, 6, 12, and 24 hour post-exercise time points, respectively. The percent changes in expression of preproendothelin-1 mRNA in the heart from resting control rats were significantly increased at the time point of 1 hour post-exercise (199.0 +/- 33.6%, P < 0.05), and this enhancement returned to the level of resting control rats at the time points of 6, 12, and 24 hours post-exercise. These results suggest that a bout of exercise causes time-related enhancement of gene expression of ET-1 in the rat hearts during acute exercise and 24 hour post-exercise periods. Therefore, an exercise-induced change of ET-1 gene expression in the heart may participate in mechanisms of exercise-induced and/or training-induced adaptive responses of the heart.

Katsutoshi Goto

Papers

Relationship between serum glufosinate level and development of serious poisoning caused by the ingestion of Basta®, a herbicide containing glufosinate

Influence of acidosis on cardiotonic effects of milrinone

Exercise-induced tissue-specific change in gene expression of endothelin-1.

Pharmacological studies of imidazoline derivatives. I. A comparison of the effect on pre- and postsynaptic alpha-adrenoceptors in the rat vas deferens.

Time course alteration of endothelin-1 gene expression in the heart during exercise and recovery from post-exercise periods in rats.