Document EdeZXJo6Oyody9YzL4K8gYR0L

Li ' m>rau H I -- .Csi'tiiB.e affects of-' lead' I TOXBIB/84/005181 D - Fed Prcmj VOL 42L.JS3,,.J.3:? l?83j P2989-93 (REF l 35) Uaraiac enecis oi imu BETTY J, WILLIAMS,12 MILTON ft. HEJTMANGIK, JR.,3 AND MARY ABREU Department ofPharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77550 Oliriical reports indicate that cardioloxicity is a potentially .lethal, although rarely recognized, complication of lead (Pb) intoxication. Relatively little ex perimental work, however, has exam ined the direct effects of Pb oh the heart. This report will focus on the ef fects of experimental Pb exposure on the heart. ACUTE Pb EXPOSURE To explain sudden deaths of patients receiving Pb-contaminated i.v. solu tions, Patel (26) exposed isolated frog hearts ip lead nitrate, which caused a decrease in contractility. Negative inotropism in isolated rat. hearts has been drown in response to perfusion with Pb (19). Pb caused an increase in the PR interval of the electrocardiogram (EGG) that was progressive with time and ter minated in heart block in four of six hearts. The effect was concluded to occur at the level of the His-Purkinje astern., In a later study perfusion of isolated rat hearts with a Pb-containing solution was shown to attenuate the in n-ease in contractility caused by isopro terenol or calcium (Ca) (20). Pb also lattsed a decrease in the incorporation if;,2P into myosin light chain 2 (MLCa), and reduced Ga-stimulated incorpora tion into tropomyosin, aettrt, tropo myosin-binding subunit of troponin, troponin inhibitory subunit, and MLC. iiie isoproterenol-stimulated increase in 52P incorporation into troponin in hibitory subunit and MLCg was also seduced by Pb. These investigators suggest dial Pb may interfere with inutsmembrane Ca transport either dirmiy by interfering with Ca bind ing or indirectly by inhibiting: phos phorylation of sarcoiemmal proteins necessary for Ca translocation. in this laboratory the effects on the heart of Pb administered i.v. to intact i,its were compared with those seen trlie.it Pb was added to the perfusion ABSTRACT Symptoms consistent with cardiac disease have been noted as pan of the syndrome of lead (Pb) intoxication. All types of cardiotoxicity noted in patients have been reproduced in experimental animals exposed acutely to high concentrations of Pb, or chronically exposed to lower levels. Types of cardiac effects observed include negative inotropism and electrocardiogram abnormalities, particularly conduction delects. Neonatal rats exposed to Pb via the milk of dams provided a drinking solution of lead acetate exhibit approximately four times the sensitivity to the arrhythnmgenic effect of norepinephrine as adults fcompnretl with controls. Cardio toxicity occurs after exposure as short as the first 10 postnatal days, but is tint expressed until the nits are adult. Increased sensitivity to the arrhythmogenic effect of norepinephrine was seen in Pb-exposed animals in vivo and jt isolated hearts from Pb-exposed animals in vitro. Norepinephrine art-hythmogenesis in vivo was attenuated by atropine or vagotomy, which indicates vagal nerve involvement. Pos sible mechanisms including interference with central 7-aininobtuyric acid systems, alteration of adrenergic nerve development, and Pb-Ca interaction are discussed.-- Williams, B.J.; Hejtmancik, M- R-,|r.} Abreu, M. Cardiac effects of lead. Federation Prac. -12: 2989-2993; 1983. fluid ofisplaled hearts. Administration of sufficient Pb in vivo to achieve blood levels of 10" r~1 O'"1 M caused only small decreases in heart rate and increases in the PR interval. In contrast, 10'l! M Pb in tin.* perfusion fluid caused significant decreases in rate and contractility of isolated hearts. In addition, two to three times as .much lead was accu mulated in isolated hearts after a 20min perfusion with Pb-containing so lution than was accumulated by hearts in vivo in the 80-90 min after Pb in jection. These data suggest the exis tence of sottte protective mechanism in the intact animal. tion to the obvious differences in ex perimental design, such as exposure time and level, differences in age of the experimental population can greatly influence the results. In the following studies Pb was administered chroni cally to mature animals. . Chronic administration of Pb to rab bits caused EGG abnormalities that cor related with myocardial histopatholqgical changes found on necropsy (23). Ultrastructural changes in the myocar dium were observed in rats allowed free access to water containing Pb (I mg/liter) (25). More extensive ultrasirneutral damage was seen in the CHRONIC Pb EXPOSURE IN MATURE ANIMALS Human Pb intoxication is probably best modeled by chronic experimental exposure because the majority of clin ical cases result from long-term expo sure. Studies of chronic Pb exposure have used a wide variety of exposure models, which makes direct compari sons among studies difficult. In addi 1 from the Symposium Toxic Effects ofMetals on the Kidney and Cardiovascular System presented by the American Society lor Pharmacology ami Ex perimental Therapeutics at the iHillt Annual Meeting ol'the federation of American Societies for Kxpcrimcnlai Biology, New Orleans, Louisi ana, April 21. i 982. '* Supported by National Institute of Environ mental i leakh Sciences grant Pill IS US 017(57. 3 Present address: Gulf South Research insti tute, New Iberia, i.A 705li0. 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