Thirty dogs were made hyperthyroid by feeding them 1 g/kg USP thyroid powder or injecting 1.2 mg/kg of 1-thyroxine/day. Seven of the 30 dogs used had surgically induced mild valvular lesions of the right heart to determine whether preexistent organic disease was a requisite to the induction of failure in hyperthyroidism. At 2 to 27 months the animals were subjected to cardiac catheterization for measurement of cardiac work and metabolism in vivo. The animals were then killed and the levels of the high energy phosphate compounds creatine phosphate (CP) and the adenine nucleotides (ATP+ADP) in the heart were measured as an index of the net efficiency of the processes of oxidative phosphorylation. By hemodynamic or histopathologic criteria, 13 dogs showed signs of failure, only 3 of which had preexistent valvular lesions. The failure was not accompanied by a decreased efficiency of oxidative phosphorylation. Net levels of CP and ATP + ADP in the myocardium were normal. Preliminary studies with sarcosomes isolated from 5 animals also revealed normal P/O ratios in 3 dogs with and in 2 without signs of cardiac failure. Liver mitochondria isolated from these same 5 animals all demonstrated decreased P/O ratios. Decreased myocardial extractions of both glucose and pyruvate occurred with failure, suggesting some degree of myocardial hypoxia with increased intracellular glycolysis. Areas of relative hypoxia may exist in a hypertrophied myocardium of the hyperthyroid animal.

No abstract

The effects of acute versus chronic hyperthyroidism on rat heart mitochondria were explored. Acute, severe hyperthyroidism with an 18% loss of body weight was induced by injecting subcutaneously 10 /i,g/100g/day of triiodothyronine for 6 to 14 days, and chronic, anabolic, moderate hyperthyroidism was induced by placing triiodothyronine in the drinking water at a dose of 25 or 50 yug/100 ml for 15 to 60 days. Mitochondrial function was assessed polarographically using a-ketoglutarate as the oxidizing substrate, and mitochondrial structure was assessed indirectly from changes in rates of swelling in decimolar alkaline salt solutions in vitro. The P-O ratios of heart mitochondria isolated with Nagarse incubation from both types of hyperthyroid rats decreased slightly (15%) but significantly (P = 0.05). Simple dilution of the hyperthyroid mitochondrial suspensions effected a 75% increase in the P-O ratio of the acutely treated rats but only a 19% increase in that of the chronically treated rats. Significantly increased susceptibility to swelling in vitro was exhibited only by the mitochondria of the chronically triiodothyronine-treated rats. On the other hand, only those of the acutely treated rats showed significant increases in the activity of Mg 2 + -stimulated mitochondrial ATPase. These data suggest that the mechanisms whereby excess thyroid hormone in vivo affects the function and structure of isolated rat heart mitochondria vary with the mode of induction and the duration of the hyperthyroid state.ADDITIONAL KEY WORDS thyrotoxicosis triiodothyronine Nagarse incubation oxidative phosphorylation phosphorylative capacity swelling in vitro mitochondrial ATPase and azide mitochondrial free fatty acid • The etiology of cardiac failure observed in the hyperthyroid patient (1, 2) and demonstrated in the chronic hyperthyroid dog (3) is as yet undefined. Studies to date suggest that a biochemical lesion in the area of oxidative phosphorylation is not involved in the heart as in other tissues. Neither sarcosomal function (3-5) nor myocardial levels of the end products of oxidative phosphorylation, phosphorylcreatine and adenosine triphosphate (ATP) (3, 4, 6) were decreased in acute or chronic hyperthyroid animals. Nevertheless, the reduced myocardial resistance to anoxia (7) and the increased oxygen consumption (3,8) in the hyperthyroid heart would appear to reflect involvement of energy production in the mitochondria. The question arises, therefore, as to whether the indices and the species used to assess mitochondrial integrity were sufficiently sensitive to demonstrate thyroidinduced changes in this remarkably resistant organ.This study was designed to explore the effects of a prolonged, chronic anabolic hyperthyroid state on the functional and structural integrity of heart mitochondria of the more susceptible species, the rat, and to compare these effects with those produced by

No abstract