EXPERIMENTAL
Cadmium
AND MOLECULAR
PATHOLOGY
22,
326-334
(19%)
und Zinc Distribution in Cardiovascular of Normal and Cadmium-Treated GURDARSHAN Department
Bockus
S. THIND
AND
GRACE
of
M.
and Other Dogs l FISCHER
Medicine, Cochran VA Hospital, and Washington School of Medicine, St. Louis, Missouri 63125 Research lnstitute and Department of Physiology, University School of MedXne, Philadelphia, PennsylvanIa 19104 Received
August
Tissues
University
of
Pennsylvania
9, 1974
Cadmium, zinc and water concentrations in arterial segments from 11 different sites-heart, kidney cortex and medulla, liver, spleen, diaphragm, rib and sternum+f eight normal control and eight cadmium-treated dogs were compared. Cadmium treatment resulted in significant cadmium deposition in all of the tissues analyzed. Cardiovascular cadmium distribution in normal and treated dogs revealed higher cadmium levels in more peripheral and smaller arteries in comparison with the more central arteries and the myocardium. The distal mesenteric artery, mesenteric artery branches, main renal artery and coronary arteries tended to accumulate more cadmium in normal or cadmium-treated dogs or both. Zinc distribution in cardiovascular tissues revealed the highest zinc concentration in the mesentaic artery branches of normal dogs. Cadmium was, however, preferentially retained by the normal kidney and by the kidney and liver of cadmium-treated dogs. There were significant increases in zinc concentration of the kidney, liver and sternum in response to cadmium administration. Tissue cadmium/zinc ratio increased by a factor of 7.c282.6 after cadmium administration. There were no significant alterations in the water content of the cadmium-treated tissues. The pathophysiological implications of these data in cadmium-induced hypertension are discussed.
INTRODUCTION Arterial
hypertension has been induced by the parenteral administration of in the rat by Schroeder et al. (1967a) and in the rabbit by Thind et al. ( 1970). More recently, hypertension has been produced in the dog by the same technique (Thind et al., 1973b). It is well recognized that the cardiovascular and renal vascular reactivity is determined among other factors by the relative proportions of the smooth muscle and connective tissue, and by the blood vessel wall content of different electrolytes, water and trace metals. Cadmium, an environmental trace element, has been shown to significantly alter the vasopressor-induced reactivity and the stress-strain characteristics of the blood vessel wall (Thind, 1974, and Thind et al., 1970, 1970a). There was a measurcadmium
1 This investigation was supported-in-part by US Veterans Administration Medical Research Information System #8470-01 and USPHS grant No. HE-07762. This investigation was presented at the 57th Annual Meeting of Federation of American Societies for Experimental Biology, Atlantic City, NJ, April 15-20, 1973 and an abstract was published in Federation Proceedings 32:351, 1973.
Copyright @ 1975 by Academic Press, Inc. All rights of reproduction in any form reserved.
TISSUE
DISTRIBUTION
Cadmium
Fro 1. Each injection arterial P of or < 0.05) 18th and 21st weeks after the
Acetate
OF CADMIUM
Administered
AND ZINC
327
(mg)
vertical bar after cadmium injections was compared with the pre-cadmium blood pressure considered as 100%. There was significant elevation (* = of the average mean arterial blood pressure 1 week after the sixth, 12th, cadmium injection and s&r&ant systolic arterial hypertension ( ** ) 3-5 24th cadmium injection. For details refer to Results section.
able cadmium accumulation in the cardiovascular tissues of young, normal rabbits and a very significant cadmium deposition in the cardiovascular tissues of rabbits with cadmium-induced hypertension (Fischer and Thind, 1971). The pervasive metal was, however, predominantly sequestered in the kidney of normal rabbits, and in the kidney and liver of the cadmium-hypertensive rabbits. Pursuing vascular reactivity studies in the renal vasculature of intact dogs, we have shown that the vasopressor-induced renal vasoconstrictive responses in normal dogs (Thind et al., 1971) and cadmium-hypertensive dogs (Thind et al., 1973a) were markedly influenced by the administered cadmium. The present investigation was undertaken: (1) to determine the degree of cadmium and zinc deposition in the tissues of normal and cadmium-hypertensive dogs; and (2) to estimate the tissue cadmium/zinc ratios in these animals, since Schroeder et al. (1967a) had shown that the ratio of renal cadmium to zinc was a good correlate of the level of blood pressure of normal and cadmium-injected rats. METHODS Eight healthy adult mongrel female dogs, following an extensive laboratory and hemodynamic work-up in the pre-cadmium administration period, were given 2 mg cadmium acetate per kilogram of body weight intraperitoneally once a week for 18 weeks and then once every third week during the following 18 weeks. The cadmium-injected dogs were killed 4-6 weeks after the 24th
THIND
328
0.5 0, KC~,
AND FISCHER
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c
I
L
c
11
KMed
LIV.
A.&
D.&
T&z
Ab.Ao
0 &.A.
PA.
0
s
IQ
&.A.
MRA
PMA
r QM.A.MABr.
1
z
1
Sp.
HI.
Dia.
FIG. 2. Tissue Distribution of Cadmium (mean * SEM) in normal and cadmium-treated Dogs; open circle ( 0 ), normal control dogs; dark circle ( l ), cadmium-treated dogs; K. Cor., kidney cortex; K. Med., kidney medulla; Liv., liver; A.Ao., ascending aorta; D.Ao., descending aorta; T.Ao., thoracic aorta; Ab.Ao., abdominal aorta; Co.A., coronary arteries; P.A., pulmonary artery; Ca.A., carotid artery; M.R.A., main renal artery P.M.A., proximal mesenteric artery; D.M.A., distal mesenteric artery; M.A.Br., mesenteric artery branches; Sp., spleen; Ht., heart; Dia., diaphragm.
cadmium injection by a lethal intravenous dose of sodium pentobarbital. Direct arterial blood pressures were also determined in eight age- and weight-matched healthy mongrel female dogs used as controls for tissue analyses. The control dogs were handled and killed in a manner similar to that of the cadmiuminjected dogs. Specimens of tissues were dissected immediately from arterial segments from 11 different sites in the arterial tree, heart, kidney cortex and medulla, liver, spleen, diaphragm, rib and sternum. The dissection was completed rapidly to minimize possible atmospheric drying of the tissues. The tissue samples were weighed, dried and defatted, and cadmium determinations were made by atomic absorption techniques (Berman, 1967; Fischer and Llaurado, 1966; Fischer and Thind, 1971). The analytical procedure consisted of wet ashing, chelaton, and extraction into an organic solvent. Analysis was performed on a Perkin Elmer Model 303 atomic absorption spectrophotometer equipped with a three slot Boling burner head. Zinc determinations were performed in paired tissue samples from each dog. The tissues were weighed, dried, defatted and ashed at 500°C in silica crucibles (Fischer et al., 1968). The ashed specimens were dissolved in 0.36 N HCl, the the amount varying from 1 ml for the small specimens to 10 ml for large
TISSUE
DISTRIBUTION
OF
CADMIUM
AND
329
ZINC
specimens. These solutions provided the proper dilutions for the sensitivity of the instrument, The solutions were analyzed on the atomic absorption spectrophototometer with a standard single slot burner head. All standards and blanks were prepared in 0.36 iV HCl. While comparing two independent means by the student t test, probability value of or