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Groups of 16 female Long-Evans rats received 0, 1, 2.5, 5, 10, 25, and 50 mg cadmium/liter dringking water (parts per million (ppm)), from the time they were weaned until they were 30 mo old. Systolic pressure was measured indirectly in triplicate at 6-mo intervals. Both 2.5 and 5 ppm cadmium consistently induced significant elevations in mean systolic pressure, ranging from 13 to 33 mmHg. At 6 mo, 10 and 25 ppm cadmium also induced significant elevations, whereas at 12 mo and subsequently 1 ppm cadmium induced significant elevations. With 10 ppm cadmium or less weight gain was normal and there was no evidence of cadmium toxicity. With 25 and 50 ppm cadmium weight gain was diminished, suggesting toxicity. Five rats with each level of exposure were sacrificed every 6 mo from a second population of similarly handled rats in order to determine renal cadmium concetrations. Cadmium intakes that had induced hypertension were associated with mean renal cadmium concentrations ranging from 5 to 50 mug/g kidney.

Concentrations of trace elements in human tissues characteristically vary widely, and the distributions of most concentrations are skewed to the right. Examination of some of the factors which contribute to the marked variability and skewness of the concentrations revealed that: (1) distributions of concentrations are satisfactorily normal (Gaussian) after logarithmic transformation, (2) ash weight is the best frame of reference in which to report results, (3) the distributions of metal concentrations are not further normalized by adjustments which assume that tissue lipid or collagen contains a fixed fraction of the metal found in the parenchyma, and (4) the choice of sample site within the liver is of minimal significance.

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 but 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.

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.

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.

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.

Female Long-Evans hooded rats received Schroeder's rye-based diet and 0 or 1 microgram/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 Pj, 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.

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.

Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced disturbances within the cardiovascular system. The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system.

Groups of 15 to 18 female weanling Long-Evans rats fed a rye-based diet low in lead (0.25 ppm) were exposed to 0.1, 1.0, and 5.0 ppm lead in drinking water. No suggestion of clinical lead toxicity was recognized. Systolic pressures were measured at 3-month intervals after weaning. The groups of lead-exposed animals had consistently and significantly higher average pressures than control animals, the increase approximating 15 mm Hg. With the lowest lead exposure (0.1 ppm), the increase in average pressure was gradual, being half minimal at 3 months and requiring 1 year to become maximal. After 1 year, half of these rats had pressures from 0 to 10 mm Hg above the control average; 40, 20, and 10% had pressures that were 20, 30, and 40 mm Hg, respectively, above the control average. Thus, rats exposed to lead in amounts comparable to the environmental exposure of many Americans had an average elevation in systolic pressure comparable to that of human beings with essential hypertension.

Industrial exposure to large amounts of cadmium is known to be toxic to man; however, the low levels of cadmium in water, food, and air to which everyone is continually exposed have no obvious effects. During childhood and adolescence, ingestion and inhalation of cadmium are responsible for the average American accumulating about 30 mg of cadmium in his body, with the highest concentration being in the kidney. It has been suggested on the basis of two observations that elevated renal cadmium might be associated with essential hypertension: (1) Hypertensives have been reported to have higher renal cadmium concentrations than normotensives. (2) Long-term exposure to low levels of cadmium has reproducibly caused mild hypertension in animals. Finally, increased levels of cadmium have been found in lungs and other tissues of emphysematous subjects.

Defective copper metabolism was demonstrated in male mice bearing the blotchy (Moblo/y) allele at the mottled locus on the X-chromosome. Copper absorption from the gut was only 64% of that found in normal mice and hepatic copper levels were only 56% of the controls. Ceruloplasmin and heart cytochrome c oxidase activities were normal, yet lysyl oxidase activity from cultured fibroblasts was only 45% of control levels. Copper accumulated in fibroblasts cultured from these mutants to values that were five times normal. The accumulation of copper in the fibroblasts was associated with a protein of approximately 12,000 molecular weight.

The aim of this experiment was to test whether a chelating agent, D-myo-inositol-1,2,6-trisphosphate (PP56), could reverse cadmium-induced hypertension. Four groups of weanling female Long-Evans rats received ad libitum a rye-based, metal-poor diet and deionized water fortified with essential metals for 15 mo from the time of weaning. A control group received neither cadmium nor chelating agent. A second group had 0.1 ppm cadmium added to their water from weaning through mo 5. A third group had 60 ppm PP56 added to their water for mo 6-10. The fourth group had 0.1 ppm cadmium added to their water from weaning through mo 5 and 60 ppm PP56 from mo 6-10. All groups were followed without either cadmium or PP56 for mo 11-15. At approximately monthly intervals, systolic pressure was measured by the indirect tail cuff method in unanesthetized rats. Chronic cadmium feeding induced the expected hypertension, with an average increase in systolic pressure of about 15 mm Hg; the pressor effect persisted with little change for the 10 mo after cadmium was withdrawn. PP56 completely reversed the cadmium-induced hypertension, and the inhibition persisted for 5 mo after PP56 was withdrawn. PP56 by itself had no demonstrable depressor effect.