Involvement of the autonomic nervous system in the genesis of cardiomyopathy in rats

J Mol Cell Cardiol 24 (Supplement II) (1992) THE PATXOGLQIEBIS OB CARDIOMYOPATHY IN THX SYXIAU HIIlIBTXR: -ITIES OF l%B MICROCIRCULATIOZI MID THX MYOCARDIAL CO-IVX TIeSUX MATRIX. Department of Pathology, Albert Einstein College of S.M.Factor. Medicine, Bronx, New York, U.S.A. The Syrian hamster develops a genetic dilated congestive cardiomyopathy (DCM) with death of 100% of affected animals in one year. The hamsters have multifocal areas of myocytolytic necrosis (MyoN) that The total area of affected left ventricle (LV) is 5scar and calcify. 8%. The sharply demarcated zones of MyoN suggested an abnormal microcirculation (MC). To study this, we perfused hamsters &l y+&~ and saw extensive microvascular spasm (MvSp) in arterioles. Since MyoN is due to reperfusion, we treated animals with verapamil as a vasodilator, and we prevented MvSp and the development of DCM. We also showed that cremaster MC had MvSp with topical norepinephrine in the acute disease phase further confirming our hypothesis. To explain the presence of DCM with limited MyoN, we studied the connective tissue matrix (CTM). We that more than doubled affected showed loss of CTM around foci of MyoN, LV area, which could lead to LV dilatation due to untethering of myocytes . This may be due to MvSp induced stunning in foci of microischemia. Despite the hereditary DCM, preventable MvSp and CTM loss may lead to LV failure and early death in this model of human disease.

O-8 ONTOGENETIC

DEVELOPMENT OF CARDIOTOXICITY FOR CATECHOLAMINES. B. O$&daI, Z. Rychter, I. OSfBdalovB. Institute of Physiology, Csechoslovak Academy of Sciences, Prague, Czechoslovakia. Information on the cardiotoxic effect of catecholamines (CA) in the immature heart is surprisingly scarce, even though these agents are used in clinical oractice both during pregnancy and in early post&al development. Beta:mimetic catecholamine isoproterenol (IPRO) induces malformations of the chick embrvonic cardiovascular system ; the type of change depends upon the time at which the CA was administered during embryogenesis. The sensitivity of the embryonic heart to the toxic effect of IPRO increases from the 2nd to 12th embryonic day and then gradually decreases. In the last week of embryonic life the heart seems to be resistant to the toxic effect of CA. Whereas beta blockers completely prevented the development of IPRO-induced changes, no protective effect was seen with a calcium antagonist verapamil. It seems that IPRO-induced changes in the chick embryonic heart are not necessarily related to the occurence of intracellular calcium overload. The long-term administration of beta-agonists to pregnant rats induced significant stimulation of fetal hearts. During postnatal ontogeny the cardiotoxicity of CA increased from birth to adulthood. All the existing data draw attention to the possible negative consequences of the clinical use of beta-mimetic8 during early phases of cardiac development.

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INVOLVEMENT OF THE AUTONOMIC NERVOUS SYSTEM IN THE GENESIS OF CARDIOMYOPATHY IN RATS Satoru Sugiyama, Kazuki Hattori, Yoshihiro Hanaki, Naohiko Akiyama, Tomoko Kato, Takayuki Ozawa. Institute of Applii Biochemistry, Gifu. Japan. Department of Internal Medicine and Biomedical Chemistry, Faculty of Medicine, University of Nagoya, Nagoya, Japan Itis weIlknownthatcatecholaminesareinvolvcdinthegenesis ofcardiomyopathy. Nonetheless, the role of the parasympathetic nervous system remains obscure. In the present study, changes in cardiac acetylcholine and norcpinephrine concentrations were investigated using rats with thyroidectomy, cyclophosphamide-administered rat, and rats treated with pyridostigmine, an acetylcholinesterase inhibitor. In each rat, heart mitochondrial electron-transport activities (NADHcytochrome c reductase, succinatccytochrome creductase andcytochrome coxidase)andace.tylcholine audnorepinephrine levels of left ventricles were measured. Significant increases in acetylcholine and norepinephrine concentrations were seen 6 weeks after thyroidcctomy. Activities of NADH-cytochrome c reductase and cytochrome c oxidase were reduced significantly. Similar changes in acetylcholine and norepinephrine concentrations and mitochondrial function were observedin rats administered with cyclophosphamide. In rats treated with pyridostigmine,significantincrcasesinacetylcholineconcenaationsandmitochondrialdysfunctionwere observed. However. epinephrine concentrations did not change significantly. From our results not only changes in sympatheticncrvousactivitybutalterab',onsintotalautonomicnervousactivitymightberelated tothegenesis ofcardiomyopathy. 5.43