significantly reduced the compensatory renal hyper- trophy and splenomegaly induced by DOC, although cardiac hypertrophy and hepatomegaly induced by.
Parathyroidectomy Ameliorates Vascular Lesions Induced by Deoxycorticosterone in the Rat
PETER A. NICKERSON, PhD, and RICHARD M. CONRAN, PhD
From the Department of Pathology, State University of New York Buffalo, Buffalo, New York
at
The systolic blood pressures of rats that underwent parathyroidectomies and uninephrectomies reached hypertensive levels after implantation of deoxycorticosterone (DOC) pellets and were comparable to those in rats with intact parathyroids bearing 20-mg or 50-mg pellets of DOC. Parathyroidectomy, however, ameliorated the incidence and severity of cardiac and renal lesions induced by DOC. The beneficial effect of parathyroidectomy on vascular lesions may well be at-
SELYE ET AL1 reported that deoxycorticosterone (DOC) produces severe hypertensive cardiovascular disease in the rat; lesions are found in heart, kidney, brain, and blood vessels. Salgado2 showed that surgical thyroidectomy prevented DOC-induced hypertension. Undoubtedly, the parathyroid glands were also removed because of their anatomic location on or attached to the surface of the thyroid gland. There has been some doubt as to whether it is the removal of the thyroid, parathyroid, or both glands that interferes with evolution of the hypertension. Berthelot et al3-5 reported that parathyroidectomy prevents hypertension induced by deoxycorticosterone acetate (DOCA). We have shown recently that parathyroidectomy did not prevent adrenal regeneration hypertension (ARH),6 a model of cardiovascular disease produced in the rat by uninephroadrenalectomy with enucleation of the contralateral adrenal gland.7 The pathogenesis of this model of experimental hypertension is related to dysfunction of the adrenal cortex, which results in increased secretion of DOC.8:9 Therefore, it is difficult to reconcile our study with that of Berthelot et al.3-5 It was the purpose of the present study to determine whether DOC-induced hypertension is prevented by surgical removal of the parathyroid glands.
tributable at least in part to a reduced level of calcium in the serum or to the absence of parathyroid hormone, which is involved directly in the regulation of calcium transport and influx into the cell. Parathyroidectomy significantly reduced the compensatory renal hyper-
trophy and splenomegaly induced by DOC, although cardiac hypertrophy and hepatomegaly induced by DOC were not affected by parathyroidectomy. (Am J Pathol 1981, 105:185-190) tained from Holtzman Breeding Co. (Madison, Wis); animals were caged individually and allowed to acclimatize to the laboratory for 1 week before the experiment was begun. Half of the animals underwent surgical parathyroidectomy, and the excised tissue was examined microscopically to confirm the presence of parathyroid glands. All animals received 1 Wo CaCl2 as drinking solution for 3 days after operation to avoid tetany. At 1 week after parathyroidectomy, all animals were uninephrectomized on the right side under ether anesthesia; a 20-mg pellet of DOC (Sigma Chemical Co., St. Louis, Mo) was inserted beneath the skin in half of the unoperated rats and half of the parathyroidectomized animals. All animals received 1%o sodium chloride as drinking solution and lab chow ad libitum. In a second experiment, 60 female rats were treated identically to those in the first experiment, described above. In addition, a 50-mg pellet of DOC was inserted beneath the skin in half the animals, and another 50-mg pellet was inserted 3 weeks after start
Supported by Research Grant HL-06975 from the National Heart, Lung and Blood Institute. Accepted for publication July 15, 1981. Address reprint requests to Peter A. Nickerson, PhD, Department of Pathology, Faculty of Health Sciences, State University of New York at Buffalo, Buffalo, NY 14214.
Materials and Methods In the first experiment, 48 female rats were ob-
0002-9440/81/1109-0185$00.80 X American Association of Pathologists
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NICKERSON AND CONRAN
of the experiment. The larger dose and reimplantation were employed to assure that DOC was available for absorption throughout the experiment. Blood pressures and body weights were measured weekly in lightly anesthetized animals as reported previously.'0 All animals were sacrificed by decapitation at 5 weeks in the first experiment and at 6 weeks in the second experiment. Serum was collected and frozen until calcium was measured colorimetrically by the method of Baginski et all' with a 60-second Calcium Kit (American Monitor, Indianapolis, Ind). Organs were removed at sacrifice and weighed after fixation in 10%o neutral formalin. Lesions in the heart and kidney were assessed by gross examination of unfixed organs in situ, and sections were prepared by conventional procedures for microscopic examination. The percentages of incidence of gross and microscopic lesions were calculated, and lesions were graded semiquantitatively on a scale of 1 to 4; a severity index was calculated relating the score obtained to the maximum possible severity.'0 Gross and microscopic findings were analyzed without knowledge of the particular group involved. Data were expressed as the mean + SEM and analyzed statistically by the Student t test.
Results One week after implantation of the pellets in the two experiments, neither blood pressure (Figures 1 and 2) nor body weight, respectively, differed from one another among the various groups. At sacrifice, the systolic blood pressures of rats that underwent parathyroidectomies did not differ significantly from those of control rats in either of the two experiments, although DOC induced significant increases in pressures in rats that underwent parathyroidectomies. The increases were comparable to those of parathyroid-intact rats administered pellets of DOC in both experiments (Figures 1 and 2). In the first experiment, the blood pressures of rats with parathyroidectomies at 3 weeks were significantly greater than the blood pressures of controls (P < 0.02) (Figure 1). In the second experiment, the blood pressures of animals with parathyroidectomies were significantly greater than those of controls at 4 weeks (P < 0.001) and at 5 weeks (P < 0.05) (Figure 2). Body weights of controls and rats with parathyroidectomies did not differ significantly from those of the group with parathyroidectomies and DOC. The body weights of the DOC group did not differ from those of controls at the completion of the first experiment, whereas weights were reduced significantly in the second experiment with higher doses of DOC (260 ± 9 g
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Figure 1-Effect of parathyroidectomy (PX) alone or in combination with DOC on systolic blood pressure in uninephrectomized rats. Parathyroidectomy was performed 1 week before implantation of a 20-mg pellet of DOC. Animals were sacrificed at 5 weeks after implantation. Mean + SEM.
for controls vs 228 ± 8 g in the DOC group). The incidence of hypertension in animals receiving a higher amount of DOC (66%) was comparable to that in animals with the 20-mg pellet in Experiment 1 (63%). On the other hand, rats with parathyroidectomies bearing 50-mg pellets of DOC showed a higher incidence of hypertension (71 %o) than those with the 20-mg pellets (50%). DOC caused a significant cardiomegaly, renal hypertrophy, and hepatomegaly in rats with intact parathyroids and rats that had parathyroidectomies (Table 1). In parathyroid-intact rats, DOC also induced splenomegaly in Experiments 1 and 2, but the difference was not significant in rats that had parathyroidectomies in Experiment 1. It is of special interest that parathyroidectomy significantly reduced the magnitude of the renal hypertrophy and splenomegaly (Table 1) (rats with DOC vs rats with parathyroidectomies and DOC, P < 0.001). A significant increase in brain weight was induced by DOC in Experiment 2. Completeness of parathyroidectomy was confirmed by a significant reduction in levels of calcium in the serum (Table 2). Microscopic examination of excised tissue showed parathyroid gland surrounded by a small rim of thyroid gland. Data from animals with incomplete parathyroidectomies were excluded from the calculations. Renal and Cardiac Lesions After the capsule had been stripped away, the sur-
PARATHYROIDECTOMY AND VASCULAR LESIONS
Vol. 105 No. 2
by exudate and a fibrotic Bowman's capsule. The lumen of the arterioles was often narrowed significantly, and the media showed hyalinization. Although gross lesions were not recognized in rats that had parathyroidectomies and carried pellets of DOC in the first experiment, lesions were seen in half of the kidneys in this group upon microscopic examination (Table 3). The severity of the lesions, however, was reduced by parathyroidectomy (Figure 4), and alterations in arterioles were eliminated almost
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