Abstract-Abdominal aortic aneurysm (AAA) is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation, although the mechanisms for progression of aneurysm are poorly understood. In the present study, we carried out histological study of AAA tissues of patients, and interventional animal and cell culture experiments to investigate a role of mast cells in the pathogenesis of AAA. The number of mast cells was found to increase in the outer media or adventitia of human AAA, showing a positive correlation between the cell number and the AAA diameter. Aneurysmal dilatation of the aorta was seen in the control (ϩ/ϩ) rats following periaortic application of calcium chloride (CaCl 2 ) treatment but not in the mast cell-deficient mutant Ws/Ws rats. The AAA formation was accompanied by accumulation of mast cells, T lymphocytes and by activated matrix metalloproteinase 9, reduced elastin levels and augmented angiogenesis in the aortic tissue, but these changes were much less in the Ws/Ws rats than in the controls. Similarly, mast cells were accumulated and activated at the adventitia of aneurysmal aorta in the apolipoprotein E-deficient mice. The pharmacological intervention with the tranilast, an inhibitor of mast cell degranulation, attenuated AAA development in these rodent models. In the cell culture experiment, a mast cell directly augmented matrix metalloproteinase 9 activity produced by the monocyte/macrophage. Collectively, these data suggest that adventitial mast cells play a critical role in the progression of AAA. Key Words: adventitia Ⅲ inflammation Ⅲ mast cell Ⅲ matrix metalloproteinase Ⅲ aneurysm A bdominal aortic aneurysm (AAA), a relatively common disorder among elderly people, is pathologically characterized by atherosclerosis of the intima and disruption or attenuation of the elastic media with various degrees of adventitial inflammatory infiltration. 1,2 Because approximately 4% of adults older than 65 years harbor AAA, it is among the leading 15 causes of death in elderly persons in the United States. 3 Although substantial efforts have been made to clarify the mechanism of development of AAA, there is currently no effective method to inhibit enlargement of AAA. Repair surgery is necessary to prevent rupture in patients with progressively enlarging AAA, whereas the operative risk is often relatively high because of the other complications resulting from aging.Recent reports suggest that chronic inflammation of the aortic wall and progressive degradation of extracellular matrix proteins are involved in the development, progression, or rupture of AAA. 2,4 -8 As a component of the immune system, mast cells play a critical role in defending hosts against pathogens by releasing a number of immunoregulatory mediators. 9 These cells have also been shown to initiate the inflammatory response by releasing proinflammatory cytokines, growth factors, angiogenic mediators, and proteases, 10 as well as by recruiting other inflammatory cells, such as neutrophils, macrop...

Abstract-Adrenomedulhn(AM), a potent vasodllator peptlde, exists m the cardiac ventricle, however, the role of AM m the ventricular tissue remams unknownIn the present study, we mvestlgated the production and secretlon of AM m cultured neonatal rat cardlomyocytes, and we exammed the effect of AM on de novo protein synthesis m these cells by measurmg ['4C] any efforts have been made to clarify the mechanisms of growth regulation of the cardiac myocardmm because of comphcatlons of the heart caused by cardiac hypertrophy At the cellular level, cardiac myocytes are known to compensate for increased workload by an Increase m their size but not m their number because these cell? are unable to dlvlde later m life ' Multiple factors such as hemodynamlc overload and humoral factors were shown to be mvolved m the process of the cardiac hypertrophy,2-4 but the detailed mechanism remams to be elucidated AM, a potent vasodllator peptlde first detected m human pheochromocytoma, has slight homology with CGRP' In addltlon to the direct vasodllator actlvlty, AM has been shown to possess a broad spectrum of blologlcal actions such as dluresls, mhlbltlon of aldosterone secretion, and mhlbltlon of prohferatlon of vascular smooth muscle cells '-* A specific RIA revealed that AM circulates m the blood and 1s present m the adrenal medulla, kidney, lung and cardiac ventricle of humans and rats ')I" The plasma AM concentration m patients with essential hypertension or primary aldosteromsm was reported to be higher than that m normotenslve control subjects, suggesting a possible role of AM m acting against further elevation of blood pressure "J' In the cardiac ventricle, AM mRNA 1s expressed at a level comparable to that of the adrenal medulla,'3b'4 and both the AM content and mRNA expression are increased m Dahl salt-sensmve and renovascular hypertensive rats compared to respective controls I516 However, at present, It remains unknown whether the cardiac myocytes secrete AM, and what the role of AM 1s m the cardiac tissueIn the first part of this study, we exammed the production and secretion of AM from cultured neonatal cardiac myocytes In the second, we investigated the effect ofAM on the de novo protein synthesis m these cells by measurmg ['4C]phenylalanme mcorporatlon, and we evaluated the action of endogenous AM by using a peptlde analogue of CGRP and anti-AM monoclonai antibody Chemicals Methods Ang II, rat AM, human

The role of endogenous calcitonin gene-related peptide (CGRP) in the nonadrenergic noncholinergic depressor response to spinal cord stimulation was studied in the pithed rat in vivo. Pithed rats were given hexamethonium (2 mg/kg per minute i.v.) to block autonomic outflow, and mean blood pressure was artificially maintained at approximately 100 mm Hg with methoxamine (10-15 micrograms/kg per minute i.v.). Electrical stimulation of the spinal cord at the level of the lower thoracic vertebra (T9-12) caused a fall in blood pressure in a frequency-dependent (0.5-10 Hz), voltage-dependent (2.5-50 V), and pulse duration-dependent (0.25-8 msec) manner. The heart rate did not change during the depressor response. The depressor response was long lasting, and the maximum response was elicited by stimulation at 4-6 Hz. The neurotoxin tetrodotoxin (100 micrograms/kg i.v.) abolished the depressor response to spinal cord stimulation, whereas treatment with propranolol (0.5 mg/kg per minute i.v.), atropine (0.05 mg/kg per minute i.v.), or a combination of pyrilamine (0.5 mg/kg per minute i.v.) and cimetidine (0.5 mg/kg per minute i.v.) did not affect the response. In pithed rats treated with capsaicin (total dose of 500 mg/kg s.c.), spinal cord stimulation caused a slight depressor response. Exogenous CGRP, but not acetylcholine, isoproterenol, histamine, or substance P, caused a sustained fall in blood pressure that mimicked the spinal cord stimulation-induced depressor response. Continuous infusion of CGRP[8-37] (60 nmol/kg per minute i.v.), a CGRP receptor antagonist, markedly inhibited the depressor responses not only to spinal cord stimulation but also to exogenous CGRP.(ABSTRACT TRUNCATED AT 250 WORDS)

We measured plasma concentrations of adrenomedullin (AM), a novel bioactive peptide with potent vasodilator activity, in 21 patients with chronic congestive heart failure due to various heart diseases and compared them to levels in age- and sex-matched healthy subjects to examine the pathophysiological role of plasma AM in heart failure. In addition, the relationship between plasma AM and other hormones known to control the cardiovascular system was examined in these patients. The plasma AM level in the patients with heart failure was significantly (P < 0.01) higher than that in the control subjects (mean +/- SEM, 2.94 +/- 0.15 fmol/mL; n = 16), with a significantly (P < 0.05) higher concentration in patients in class III or IV (11.82 +/- 1.81 fmol/mL; n = 5) of the New York Heart Association functional classification than in those in class I or II (8.74 +/- 0.44 fmol/mL; n = 16). There were no significant correlations between plasma AM and catecholamine levels, whereas the plasma AM level was significantly correlated with the concentrations of plasma atrial natriuretic peptide (r = 0.58; P < 0.01), brain natriuretic peptide (r = 0.47; P < 0.05), and PRA (r = 0.77; P < 0.01) in the patients. Thus, the plasma AM concentration increased in proportion to the severity of heart failure along with the hormones known to modulate the development of congestive heart failure. The present findings suggest a possible role for AM as a circulating hormone participating in the defense mechanism against further deterioration of congestive heart failure in patients with heart disease.

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