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In our laboratory, chronically feeding cadmium to groups of rats has been reproducibly associated with average increases of 15 to 20 mm Hg in systolic pressure. A total of 497 female Long-Evans rats were continuously provided with drinking water fortified with five essential elements and containing from 0.01 to 50 ppm cadmium, as the acetate, from weaning for as long as 30 months. These rats, plus 311 matched control animals which received fortified water without added cadmium, were fed a special low-cadmium diet. All 808 rats were weighed at least monthly as a screen for cadmium toxicity, and their systolic pressures were measured every 3 or 6 months. The two lowest concentrations of cadmium tested (0.01 and 0.03 ppm) were not pressor; the three highest concentrations (10, 25, and 50 ppm) ultimately proved to be toxic. All indirect systolic pressures (each measured in triplicate) of all rats which received 0.1 to 5 ppm cadmium (i.e., nontoxic pressor doses) averaged 15.0 mm Hg more than simultaneously measured pressures of control rats. This average increase over the control pressure is extremely significant statistically, even though it seems relatively small in absolute terms. Occasionally, however, some rats had much larger than average increases in pressure; thus, 10 of 60 rats receiving from 0.1 to 0.5 ppm cadmium for 18 months had systolic pressures that were more than 50 mm Hg above the average pressure of the control rats. Cadmium-induced hypertension is not limited to females or to a particular strain. Although we have usually used one strain of female Long-Evans rat from a single source, males of the same strain and female Sprague-Dawley rats have also developed comparable hypertension. All subgroup II elements can apparently induce similar increases in systolic pressure averaging 15 to 20 mm Hg, but cadmium is pressor in much smaller amounts than mercury or zinc. Thus, to induce a demonstrable increase in pressure requires more than ten times as much divalent mercuric ion as cadmium and more than 1000 times as much zinc as cadmium. Exposure to another metal along with cadmium can markedly alter the ability of cadmium to induce hypertension. Selenium protects against the hypertension induced by twice as much cadmium. Large excesses of both zinc and copper have also inhibited the induction of hypertension by cadmium. In contrast, lead, which like cadmium, can also induce hypertension, augments rather than inhibits cadmium-induced hypertension; thus, lead and cadmium together can induce an average increase in systolic pressure in excess of 40 mm Hg, at least twice as large as is usually induced by either metal alone.

Chronic feeding of non-toxic doses of cadmium induces an average increase of 15 to 20 mm Hg in indirectly measured systolic pressure of lightly anaesthetized rats. The mechanism of this increase is not known, but cadmium has several potentially pressor effects, including increased sodium retention. This report describes both sodium balance and blood pressure in a pair of experiments where cadmium was fed and in a pair where it was injected. All four cadmium challenges induced sodium retention and also induced hypertension. Thus, rats with either low or moderate chronic exposure to fed cadmium (well below the exposures required to induce toxicity) retained more intraperitoneally injected radiosodium than controls and at the same time developed higher systolic pressures than controls. Immediately following intraperitoneally injected cadmium, rats lost a radiosodium load more slowly than controls or alternately accumulated dietary radiosodium more rapidly than controls; in both situations the blood pressure was higher than in controls. These data indicate that some of the pressor effect associated with cadmium exposure could result from its concomitant antinatriuretic effect.

SummaryExposing female Long-Evans rats to 0.1, 0.25, or 0.5 ppm of cadmium in drinking water for 6 to 18 months from the time of weaning induced a statistically significant average increase in systolic pressure of 10 to 24 mm Hg, and there was no evidence of cadmium toxicity. Comparable exposure to 0.01 or 0.03 ppm of cadmium was much less effective in raising pressure and probably had no pressor effect. After 18 months of exposure, the average renal cadmium level for the “0.1 ppm cadmium group” approximated 1 μg/g in contrast to more than 40 μg/g for the standard “5 ppm group” and less than 0.1 μg/g for the control group.

Female Long-Evans hooded rats received 0 or 5 parts per million Cd, Pb, or Cd + Pb in the drinking water from weaning to 20 mo. Growth, measured as body weight, and organ weights were comparable among heavy metal and control animals. Indirect blood pressure responses measured trimonthly are discussed. Analysis of His bundle electrograms (HBE) and electrocardiograms recorded in sodium pentobarbital-anesthetized animals at 20 mo demonstrated that Cd selectively depressed conduction system excitability proximal to the common His bundle (atrioventricular node region), whereas Pb and Pb + Cd impaired conductivity distal to the common His bundle (His-Purkinje system). Perchloric acid extracts of liquid N2-freeze-clamped isolated perfused hearts, derived from a subpopulation of control and Cd-fed rats in which HBE analyses were not performed, were analyzed by phosphorus-31 nuclear magnetic resonance (31P-NMR) spectroscopic techniques to quantitate [31P]phosphate metabolite profiles. Cardiac active tension and atrioventricular node excitability were depressed in the Cd group. High-energy phosphate and glycerol 3-phosphorylcholine concentrations were depressed. Results demonstrate potentially significant pathophysiological changes within cardiovascular tissues that develop in the absence of overt heavy metal toxicity manifestations.

Metabolic and functional (heart only) effects of long-term (15 months), low level (5 parts/10 6 in drinking water) cadmium and/or lead ingestion on myocardial, hepatic and renal tissues were assessed. Myocardial peak active tension was lower and tissue heavy metal levels were elevated significantly in cadmium and/or lead-exposed rats. The ATP ( P P P P P

Female Long-Evans hooded rats received Schroeder's rye-based diet and 0 or 1 μg/ml cadmium, or cadmium plus lead in mineral fortified drinking water from weaning to 18 months. The heavy metal-fed rats were normal with respect to control, including growth rates and final body weights. Rats receiving added cadmium and cadmium plus lead in the diet were characterized by a persistent hypertension which was evident after 2 months. Cardiac conduction system excitability was depressed preferentially in cadmium- (atrioventricular nodal region) and cadmium plus lead- (His-Purkinje system) fed rats. Although heart rates were comparable to control, myocardial contractile activity (peak active tension and dT dt ) was significantly decreased in intact perfused heart preparations from both heavy metal-treated groups. In conjunction with the observed physiologic changes, various tissue-specific metabolic alterations were detected in heart, kidney, and liver. Generally, prolonged heavy-metal ingestion at these levels resulted in impaired energy metabolism (e.g., decreased ATP, PCr; increased Pi, ADP concentrations) and altered essential mineral composition (e.g., calcium, magnesium, zinc, and to a lesser extent, sodium and potassium; copper levels were unaffected) that varied in severity according to the tissue. The addition of lead to the cadmium diet had little additive effect on the cardiovascular system; however, renal and hepatic tissues did exhibit apparent additive effects further suggesting that cadmium and lead actions and interactions may be tissue dependent. These experimental findings and the biologic inferences derived are consonant with the hypothesis that chronic, life-long cadmium exposure approximating environmental levels may have significant adverse effects on mammalian systems, that include effects on cardiovascular tissues.

In a low cadmium environment, adding 10 parts per million (ppm) of cadmium to the drinking water of rats for 3 to 18 months induced increases in systolic pressure averaging 12 to 18 mm Hg. The pressor effect of the cadmium was inhibited by adding 3.6 ppm of selenium or 200 ppm of zinc to the drinking water or by dissolving the cadmium in hard water rather than deionized water. A second experiment with 2.5 ppm of cadmium and smaller amounts of selenium and zinc was confirmatory. Exposure to 10 ppm of cadmium increased renal, hepatic, and cardiac cadmium many fold from barely detectable control levels; however, the increases were much less when the cadmium was dissolved in hard water. Cadmium exposure also increased tissue zinc by 30 to 60%. The addition of selenium to cadmium further increased cardiac cadmium, but the addition of zinc to cadmium had no further effect on tissue cadmium. Tissue selenium concentrations were suggestively bot not significantly higher following selenium exposure. Cadmium alone, or combined with selenium or zinc, increased renal copper; while the combination of cadmium and selenium increased hepatic copper.

One percent salt, 1 ppm cadmium, or 1 ppm cadmium plus 1 ppm lead in drinking water caused similar mild hypertension in rats. The hypertensive effect of salt, given for 4 months beginning at weaning, disappeared when the salt was withdrawn but subsequently returned without further exposure. Rats continuously given 1 ppm cadmium during and after salt exposure were continuously hypertensive, but salt did not increase their hypertension. Rats continuously exposed to cadmium or cadmium plus lead without extra salt remained hypertensive for 20 months. Rats exposed to cadmium or cadmium plus lead for months 4 through 8 remained hypertensive after metal exposure was discontinued; addition of 0.35 ppm selenium corrected the hypertension in cadmium-fed rats but had little effect in the cadmium plus lead exposed rats.

Cadmium is known to dissociate myocardial excitation-contraction coupling and to depress the excitability of the cardiac conduction system in vitro (1-7). Short-term feeding experiments concluding that cadmium increases conduction time through the atrioventricular node-His-Purkinje system have partially extended these in vitro observations to in vivo systems (8, 9). Although the cadmium content of the heart increases with age and exposure (10-14), the effects of cadmium have not been systematically analyzed for possible significance as a contributing factor to degenerative heart disease. This preliminary study was undertaken to investigate electrocardiographical, biochemical, and morphological changes in mammalian hearts associated with long-term, low-level cadmium feeding.Methods. Eighteen weanling female rats of the Long-Evans strain were obtained and housed as described (15). They received a special rye-based, low-cadmium diet and deionized water fortified with Mn, Co, Cu, Zn, and Mo, as described by S...

A low intake of dietary cadmium induces specific dose-dependent functional and biochemical changes in the cardiovascular tissues of rats. Maximum changes occur when the cadmium intake is 10 to 20 micrograms per kilogram of body weight per day. The changes reflect the accumulation of "critical" concentrations of cadmium in the cardiovascular tissues. The biologic activity of cadmium is demonstrated for intakes that approach those of the average American adult exposed to the usual environmental concentrations of the element but not to industrial concentrations. The sensitivity of the cardiovascular system to low doses of cadmium could not be anticipated by extrapolation from data on exposure to high concentrations of cadmium. The data support the hypothesis that ingested or inhaled environmental cadmium may contribute to essential hypertension in humans.