Anti-hypertensive effect of hydrogen peroxide acting centrally.

Intracerebroventricular (icv) injection of hydrogen peroxide (H2O2) or the increase of endogenous H2O2 centrally produced by catalase inhibition with 3-amino-1,2,4-triazole (ATZ) injected icv reduces the pressor responses to central angiotensin II (ANG II) in normotensive rats. In the present study, we investigated the changes in the arterial pressure and in the pressor responses to ANG II icv in spontaneously hypertensive rats (SHRs) and 2-kidney, 1-clip (2K1C) hypertensive rats treated with H2O2 injected icv or ATZ injected icv or intravenously (iv). Adult male SHRs or Holtzman rats (n = 5-10/group) with stainless steel cannulas implanted in the lateral ventricle were used. In freely moving rats, H2O2 (5 µmol/1 µl) or ATZ (5 nmol/1 µl) icv reduced the pressor responses to ANG II (50 ng/1 µl) icv in SHRs (11 ± 3 and 17 ± 4 mmHg, respectively, vs. 35 ± 6 mmHg) and 2K1C hypertensive rats (3 ± 1 and 16 ± 3 mmHg, respectively, vs. 26 ± 2 mmHg). ATZ (3.6 mmol/kg of body weight) iv alone or combined with H2O2 icv also reduced icv ANG II-induced pressor response in SHRs and 2K1C hypertensive rats. Baseline arterial pressure was also reduced (-10 to -15 mmHg) in 2K1C hypertensive rats treated with H2O2 icv and ATZ iv alone or combined and in SHRs treated with H2O2 icv alone or combined with ATZ iv. The results suggest that exogenous or endogenous H2O2 acting centrally produces anti-hypertensive effects impairing central pressor mechanisms activated by ANG II in SHRs or 2K1C hypertensive rats.

Endogenous hydrogen peroxide affects antidiuresis to cholinergic activation in the medial septal area.

Cholinergic activation of the medial septal area (MSA) with carbachol produces thirst, natriuresis and antidiuresis. Hydrogen peroxide (H2O2) injected into the medial septal area (MSA) impairs behavioral and renal responses induced by carbachol at the same site, suggesting the exogenous H2O2 may modulate the responses to cholinergic activation in the MSA. In the present study, we investigated if the accumulation of endogenous H2O2 in the MSA after the injection of the catalase inhibitor 3-amino-1,2,4-triazole (ATZ) also affects cholinergic responses. In addition, the effects of the combination of ATZ with a non-effective dose of H2O2 in the MSA were also tested. Male Holtzman rats (280-320 g) with stainless steel cannulas implanted in the MSA were used. The treatment with ATZ (10 nmol) into the MSA partially reverted the antidiuretic effect of carbachol (10.5 ± 0.7, vs. saline + carbachol: 7.3 ± 0.6 ml/120 min), without changing carbachol-induced water intake (9.5 ± 1.9, vs. saline + carbachol: 10.7 ± 1.6 ml/60 min). The combination of a low dose of ATZ (2.5 nmol) with an ineffective dose of H2O2 (0.5 µmol) into the MSA reduced carbachol-induced thirst (7.5 ± 2.0, vs. saline + carbachol: 14.9 ± 1.2 ml/15 min) and reverted the antidiuresis (8.1 ± 1.1, vs. saline + carbachol: 5.3 ± 0.9 ml/120 min). Sodium and potassium excretion were not modified regardless the treatment. Although exogenous H2O2 injected in the MSA may affect most of the responses to cholinergic activation of the MSA, the antidiuresis is the response clearly modulated by endogenous H2O2.

(99m)Tc-amitrole as a novel selective imaging probe for solid tumor: In silico and preclinical pharmacological study.

Lactoperoxidase (LPO) inhibitors are very selective for solid tumor due to their high binding affinity to the LPO enzyme. A computational study was used to select top-ranked LPO inhibitor (alone and in complex with (99m)Tc) with high in silico affinity. The novel prepared (99m)Tc-amitrole complex demonstrated both in silico and in vivo high affinity toward solid tumors.(99m)Tc-amitrole was radio-synthesized with a high radiochemical yield (89.7±3.25). It showed in vitro stability for up to 6h. Its preclinical evaluation in solid tumor-bearing mice showed high retention and biological accumulation in solid tumor cells with a high Target/Non-Target (T/NT) ratio equal to 4.9 at 60min post-injection. The data described previously could recommend (99m)Tc-amitrole as potential targeting scintigraphic probe for solid tumor imaging.

Effects of the administration of a catalase inhibitor into the fourth cerebral ventricle on cardiovascular responses in spontaneously hypertensive rats exposed to sidestream cigarette smoke.

OBJECTIVE: Previous studies have demonstrated a relationship between brain oxidative stress and cardiovascular regulation. We evaluated the effects of central catalase inhibition on cardiovascular responses in spontaneously hypertensive rats exposed to sidestream cigarette smoke. METHODS: Male Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SH) (16 weeks old) were implanted with a stainless steel guide cannula leading into the fourth cerebral ventricle (4th V). The femoral artery and vein were cannulated for arterial pressure and heart rate measurement and drug infusion, respectively. The rats were exposed to sidestream cigarette smoke for 180 minutes/day, 5 days/week for 3 weeks (CO: 100-300 ppm). The baroreflex was tested using a pressor dose of phenylephrine (8 µg/kg, bolus) and a depressor dose of sodium nitroprusside (50 µg/kg, bolus). Cardiovascular responses were evaluated before and 5, 15, 30 and 60 minutes after injection of a catalase inhibitor (3-amino-1,2,4-triazole, 0.001 g/100 µL) into the 4th V. RESULTS: Vehicle administration into the 4th V did not affect the cardiovascular response, whereas administration of the central catalase inhibitor increased the basal HR and attenuated the bradycardic peak (p<0.05) to a greater extent in WKY rats exposed to sidestream cigarette smoke than in WKY rats exposed to fresh air. However, in spontaneously hypertensive rats, the effect of the catalase inhibitor treatment was stronger in the fresh air condition (p<0.05). CONCLUSION: Administration of a catalase inhibitor into the 4th V combined with exposure to sidestream cigarette smoke has a stronger effect in WKY rats than in SH rats.

Effects of the administration of a catalase inhibitor into the fourth cerebral ventricle on cardiovascular responses in spontaneously hypertensive rats exposed to sidestream cigarette smoke

OBJECTIVE: Previous studies have demonstrated a relationship between brain oxidative stress and cardiovascular regulation. We evaluated the effects of central catalase inhibition on cardiovascular responses in spontaneously hypertensive rats exposed to sidestream cigarette smoke. METHODS: Male Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SH) (16 weeks old) were implanted with a stainless steel guide cannula leading into the fourth cerebral ventricle (4th V). The femoral artery and vein were cannulated for arterial pressure and heart rate measurement and drug infusion, respectively. The rats were exposed to sidestream cigarette smoke for 180 minutes/day, 5 days/week for 3 weeks (CO: 100-300 ppm). The baroreflex was tested using a pressor dose of phenylephrine (8 μg/kg, bolus) and a depressor dose of sodium nitroprusside (50 μg/kg, bolus). Cardiovascular responses were evaluated before and 5, 15, 30 and 60 minutes after injection of a catalase inhibitor (3-amino-1,2,4-triazole, 0.001 g/100 μL) into the 4th V. RESULTS: Vehicle administration into the 4th V did not affect the cardiovascular response, whereas administration of the central catalase inhibitor increased the basal HR and attenuated the bradycardic peak (p<0.05) to a greater extent in WKY rats exposed to sidestream cigarette smoke than in WKY rats exposed to fresh air. However, in spontaneously hypertensive rats, the effect of the catalase inhibitor treatment was stronger in the fresh air condition (p<0.05). CONCLUSION: Administration of a catalase inhibitor into the 4th V combined with exposure to sidestream cigarette smoke has a stronger effect in WKY rats than in SH rats. .

Catalase inhibition into the fourth cerebral ventricle affects bradycardic parasympathetic response to increase in arterial pressure without changing the baroreflex.

Exogenous catalase influences neural control of cardiovascular system; however, we do not know yet if its inhibition into the fourth cerebral ventricle (4(th) V) influences baroreflex regulation. We evaluated the effects of central catalase inhibition on baroreflex in conscious Wistar rats. We used males Wistar rats (320-370 g), which were implanted with a stainless steel guide cannula into 4(th) V. The femoral artery and vein were cannulated for mean arterial pressure (MAP) and heart rate (HR) measurement and drug infusion, respectively. After basal MAP and HR recordings, the baroreflex was tested with a pressor dose of phenylephrine (PHE, 8 µg/kg, bolus) and a depressor dose of sodium nitroprusside (SNP, 50 µg/kg, bolus). Baroreflex was evaluated before 5, 15, 30 and 60 minutes after 3-amino-1, 2, 4-triazole (ATZ, 0.001 g/100 µL) injection into the 4(th) V. Vehicle treatment did not change baroreflex responses. ATZ attenuated bradycardic peak and reduced HR range at 30 minutes. ATZ into the 4(th) V reduced bradycardic and tachycardic reflex responses to increase and decrease MAP, respectively (p<0.05) 30 minutes after its microinjection without significantly changing the basal MAP and HR. In conclusion, central catalase inhibition influenced the highest parasympathetic response to MAP increase in conscious Wistar rats without change baroreflex gain.

Inhibition of central angiotensin II-induced pressor responses by hydrogen peroxide.

Hydrogen peroxide (H(2)O(2)), important reactive oxygen species produced endogenously, may have different physiological actions. The superoxide anion (O(2)(·-)) is suggested to be part of the signaling mechanisms activated by angiotensin II (ANG II) and central virus-mediated overexpression of the enzyme superoxide dismutase (that dismutates O(2)(·-) to H(2)O(2)) reduces pressor and dipsogenic responses to central ANG II. Whether this result might reflect elevation of H(2)O(2) rather than depletion of O(2)(·-) has not been addressed. Here we investigated the effects of H(2)O(2) injected intracerebroventricularly (i.c.v.) or ATZ (3-amino-1,2,4-triazole, a catalase inhibitor) injected intravenously (i.v.) or i.c.v. on the pressor responses induced by i.c.v. injections of ANG II. Normotensive male Holtzman rats (280-320 g, n=5-13/group) with stainless steel cannulas implanted in the lateral ventricle were used. Prior injection of H(2)O(2) (5 µmol/1 µl) or ATZ (5 nmol/1 µl) i.c.v. almost abolished the pressor responses induced by ANG II (50 ng/1 µl) also injected i.c.v. (7 ± 3 and 5 ± 3 mm Hg, respectively, vs. control: 19 ± 4 mm Hg). Injection of ATZ (3.6 mmol/kg b.wt.) i.v. also reduced central ANG II-induced pressor responses. Injections of H(2)O(2) i.c.v. and ATZ i.c.v. or i.v. alone produced no effect on baseline arterial pressure. Central ANG II, H(2)O(2) or ATZ did not affect heart rate. The results show that central injections of H(2)O(2) and central or peripheral injections of ATZ reduced the pressor responses induced by i.c.v. ANG II, suggesting that exogenous or endogenous H(2)O(2) may inhibit central pressor mechanisms activated by ANG II.

Antioxidative effects of melatonin in Drosophila melanogaster: antagonization of damage induced by the inhibition of catalase.

In Drosophila melanogaster strain Canton S, the catalase inhibitor 3-amino-1,2,4-triazole was used to enhance oxidative stress from endogenous sources. This treatment was chosen as an alternative to direct administration of oxidants, which would cause damage and interact with melatonin already in the extracellular space before they reach the intracellular compartments. Male flies were kept in constant darkness and fed 1% sucrose as the only diet, with or without additions of melatonin (2 mM), inhibitor (100 mM), or combinations of both. After 20 or 24 hr, most of the animals exposed to 3-amino-1,2,4-triazole only had died, whereas a large number of flies had survived the inhibitor treatment in the presence of melatonin. Protein carbonyl, an indicator of oxidative protein modification, and lipid peroxidation, as determined by the formation of malondialdehyde and 4-hydroxyalkenal, were measured in flies treated for 20 hr. Melatonin alone did not substantially change these parameters, but prevented the increase in protein carbonyl caused by the catalase inhibitor. The effect of 3-amino-1,2,4-triazole on lipid peroxidation was relatively minor, but a clear-cut inhibition was found after simultaneous administration of melatonin. The preferential suppression of oxidative damage of proteins, as compared to lipids, indicates a particular protective role for melatonin in the aqueous phase of cellular compartments.

H2O2 is an important mediator of UVB-induced EGF-receptor phosphorylation in cultured keratinocytes.

Exposure of human keratinocytes to physiologic doses of ultraviolet B (UVB) radiation induces phosphorylation of the epidermal growth factor receptor (EGFR). We demonstrate that H2O2 generated by UVB mediates EGFR phosphorylation. Using dihydrorhodamine 123 as a specific fluorescent dye probe, we show that UVB irradiation (50-800 J per m2) of keratinocytes leads within minutes to concentration-dependent intracellular production of H2O2. A corresponding concentration-dependent increase in the release of extracellular H2O2 was measured by using Amplex, a derivative of dihydrophenoxazine. The levels of intracellular H2O2 that are induced by UVB irradiation and that stimulate EGFR phosphorylation correlate strongly with the response induced by exogenously added H2O2. UVB or H2O2 demonstrated concentration- and time-dependent stimulation of EGFR phosphorylation that was initially observed within 1-5 min and exhibited a proportionate delay for UVB-induced production of H2O2. EGFR phosphorylation induced by UVB or H2O2 declined significantly toward baseline levels by 4 h and could be restimulated after H2O2 but not after UVB exposure. Phosphorylation of EGFR was inhibited by the structurally unrelated antioxidants butylated hydroxyanisole, N-acetyl-L-cysteine, and pyrrolidine dithiocarbamate, or by the H2O2-degrading enzyme catalase. These data indicate that generation of H2O2 by UVB radiation of human keratinocytes participates in the rapid, ligand-independent phosphorylation of EGFR and implicate H2O2 as a biologic mediator in EGFR activation and regulation of the downstream signaling cascade. UVB-induced H2O2 has the potential to initiate or modulate early EGFR-mediated signaling events that could play an important role in the cellular response to oxidative stress.

Role of catalase in retinal antioxidant defence system: its comparative study among rabbits, guinea pigs, and rats.

The role of catalase in the retinal antioxidant defence system was examined in rabbits, guinea pigs, and rats with and without prolonged administration of a diet containing 0.4% 3-aminotriazole (3-AT), a catalase inhibitor. When weanling rabbits, guinea pigs, and rats we administered 3-AT for 8, 7, and 10 weeks, respectively, retinal catalase activity was reduced by approximately 50% in all these animals. In the retina of rabbits with 3-AT administration, a decrease in superoxide dismutase (SOD) activity and an increase in lipid peroxide (LPO) concentration occurred. while glutathione peroxidase (GSH-px) activity did not change. In the retina of guinea pigs with 3-AT administration, an increase in LPO concentration occurred, while SOD and GSH-px activities did not change. In the retina of rats with 3-AT administration, a decrease in GSH-px activity and an increase in LPO concentration occurred, while SOD activity did not change. An increase in serum LPO concentration was found in rats with 3-AT administration, while the concentration did not change in rabbits and guinea pigs. These results indicate that catalase plays an important role in the retinal antioxidant defence system, but that the way catalase contributes to the maintenance of the retinal antioxidant defence system is different among these animals. The present results suggest that under the prolonged inhibition of catalase, the retina of rats, but not of rabbits and guinea pigs, may suffer from the influence of systemic oxidative stress.

Dose- and time-dependent effect of an acute 3-amino-1,2,4-triazole injection on rat brain catalase activity.

The results presented in this study demonstrate a progressive inhibition of rat brain catalase activity by AT in vivo. Furthermore, the inhibition of brain catalase by AT demonstrates the presence of hydrogen peroxide in brain, since AT inhibits catalase in the presence of this compound. The rate of inhibition of catalase seems to be dependent upon the rate by which H2O2 is generated. A time course study showed slower onset of the inhibition of brain as compared to liver catalase, possibly reflecting tissue hydrogen peroxide levels or, alternatively, a rate-limiting penetration of AT into brain and into the catalase compartment. The presence of AT in brain was confirmed over the time period of the observed inhibition of brain catalase. Catalase inhibitors are of particular interest in the study of the physiological role of catalase. This study further supports the use of AT in investigations designed to further understand the role of brain catalase.

Ultrastructural and histochemical observations in human and experimental alcoholic cardiomyopathy.

The morphologic features of alcoholic cardiomyopathy in human sudden death compared with those of experimental alcoholic cardiomyopathy (6 weeks of alcohol administration and simultaneous inhibition of catalase activity) proved to be nearly identical. Regular and similar alterations in alcoholic cardiomyopathy in both human victims of sudden death and experimental rats are described as a complex of alterations characteristic of alcoholic cardiomyopathy. This complex of changes was used as the basis for morphologic diagnosis of endomyocardial biopsy in two groups of patients: I) chronic alcoholics (second to third stages), and II) patients with clinically diagnosed congestive cardiomyopathy. Typical signs of alcoholic cardiomyopathy were found in 9 of the 11 patients in the first group and in 6 of 18 in the second group. The fact that the features of alcoholic cardiomyopathy were not found in all cases of chronic alcoholism supports the hypothesis that the administration of alcohol itself is not sufficient for the development of this disease. The level of enzyme activity in the metabolism of alcohol appears to be of great importance. This hypothesis is confirmed by experiments with rats in which this disease developed only when there was simultaneous alcohol administration and inhibition of catalase activity. Histochemical study showed that the alterations of enzyme (both energetic and alcohol metabolism) in rats were similar to those found in the biopsy specimens from patients with alcoholic cardiomyopathy. Certain questions regarding the pathogenesis of alcoholic cardiomyopathy are discussed.

Effect of 3-amino-1,2,4-triazole pretreatment on ethanol blood levels after intraperitoneal administration.

Aminotriazole (1 g/kg IP) pretreatment resulted in higher ethanol blood levels during the first hour after 90 mmole/kg IP ethanol administration and at 1 hour after when rats received 60 mmole/kg IP, than the respective controls receiving the same doses of ethanol. No difference in the blood levels at time higher than 1 hour were observed, in spite of the fact that the inhibitory effect of aminotriazole lasted more than 7 hours. These results are consistent with the idea that hepatic catalase may play a significant role in liver first pass effect when portal blood levels are expected to be rather high, but not when distribution balance is established.

Light and electron microscopical changes in the liver of mice following treatment with aminotriazole.

Light and electronmicroscopical alterations in the liver of mice were shown oral administration of aminotriazole. Intensity of damage depends on concentration. High dosage affects all inter- and intralobular portions. Presented light microscopical results show, next to an extreme hypertrophy of hepatocytes, well distinguishable nuclear deformations and increased pyknotic nucleoli. The cytoplasm contains numerous vacuoles and lipid droplets. Fine structural alterations after drug administration include defects on all cell organelles and membranes. Especially proliferations of smooth ER cisternae with simultaneous reductions of rough ER cisternae, increase of microbodies as well as numerous defects on mitochondria were obvious. Interpretations of the mode of action of aminotriazole is based on ultrastructural results and biochemical knowledge on this herbicide and compared with other toxicants.

Formation of diiodotyrosine from thyroxine. Ether-link cleavage, an alternate pathway of thyroxine metabolism.

Studies were performed to elucidate the nature of the pathway of hepatic thyroxine (T4) metabolism that is activated by inhibitors of liver catalase. For this purpose, the metabolism of T4 in homogenates of rat liver was monitored with T4 labeled with 125I either at the 5'-position of the outer-ring (125I-beta-T4) or uniformly in both the outer and inner rings (125I-U-T4). In homogenates incubated with 125I-beta-T4 in an atmosphere of O2, the catalase inhibitor aminotriazole greatly enhanced T4 degradation, promoting the formation of large proportions of 125I-labeled iodide (125I-I-) and chromatographically immobile origin material (125I-OM), but only a minute proportion of 125I-labeled 3,5,3'-triiodothyronine (125I-T3) (T3 neogenesis). In an atmosphere of N2, in contrast, homogenates produced much larger proportions of 125I-T3, and aminotriazole had no effect. In incubations with 125I-U-T4, under aerobic conditions, control homogenates degraded T4 slowly; formation of 125I-labeled 3,5-diiodotyrosine (125I-DIT) was seen only occasionally and in minute proportions. However, in homogenates incubated under O2, but not N2, aminotriazole consistently elicited the formation of large proportions of 125I-DIT, indicating that the ether link of T4 was being cleaved by an O2-dependent process. Formation of 125I-DIT in the presence of aminotriazole and O2 was markedly inhibited by the substrates of peroxidase, aminoantipyrine, and guaiacol. GSH greatly attenuated the increase in DIT formation induced by aminotriazole, whereas the sulfhydryl inhibitor N-ethylmaleimide (NEM) activated the DIT-generating pathway, even in the absence of aminotriazole. Activation of the in vitro formation of 125I-DIT from 125I-U-T4 was also produced by the in vivo administration of aminotriazole or bacterial endotoxin, an agent that reduces hepatic catalase activity. Studies with 125I-DIT as substrate revealed it to be rapidly deiodinated by liver homogenates under aerobic conditions. Recovery of 125I-DIT from 125I-U-T4 was increased by the addition of the inhibitor of iodotyrosine dehalogenase, 3,5-dinitrotyrosine. However, as judged from studies conducted in parallel with radioiodine-labeled DIT and 125I-U-T4 as substrates, none of the factors that altered the proportion of 125I-DIT found after incubations with 125I-U-T4 did so by altering the degradation of the 125I-DIT formed. The factors that influenced DIT formation from T4 in rat liver had opposite effects on T3 neogenesis. Thus, aminotriazole, endotoxin, NEM, and an aerobic atmosphere, all of which enhanced DIT formation, were inhibitory to T3 neogenesis. In contrast, anaerobiosis and GSH inhibited ether-link cleavage of T4, but facilitated T3 neogenesis. The foregoing results suggest that a pathway for the ether-link cleavage of T4 to yield DIT is present in rat liver. Activity of this pathway, which appears to be peroxidase mediated, is inversely related to activity of the pathway for the T3 neogenesis. It is further suggested that this reciprocity reflects a reciprocal relationship between hepatic GSH and H2O2, the former increasing T3 formation and inhibiting DIT formation, and the latter producing opposite effects.

Kidney structure in hypothyroidism.

Hypothyroidism is associated with changes in renal function and a decrease in kidney weight. The present study was carried out for examination of the effect of the antithyroid drug aminotriazole (ATZ) on kidney structure and especially for determination of whether hypothyroidism affects the whole nephron or only a specific segment of it. Female Sprague-Dawley rats received ATZ in their diet, 0.5 g/kg food for 4 weeks. Control rats received a normal diet. Additional groups of animals receiving ATZ in the diet were given daily injections of L-thyroxine (T4) for determination of whether ATZ-induced changes could be prevented by thyroid hormone. After collection of physiologic data the kidneys were fixed by in vivo perfusion with 3% glutaraldehyde in preparation for light-microscopic morphometry. Following ATZ treatment there was a significant decrease in serum triiodothyronine (T3) and in GFR. Kidney weights were decreased, mainly because of a reduction of cortical tissue. Morphometry showed no changes in the relative volumes of the various compartments of the kidney, indicating that the decrease in weight involved all segments of the nephron. Direct measurements of tubular diameters revealed a decrease in the peritubular diameters in both proximal tubules and the thick ascending limb and a decreased cell height in the thick ascending limb. All the ATZ-induced changes could be prevented by simultaneous treatment with T4, suggesting that the changes were caused by the antithyroid effect of ATZ and were not a nonspecific toxic effect.

Carcinogenic and antitumor effects of aminotriazole on acatalasemic and normal catalase mice.

Dietary 3-amino-1H-1,2,4-triazole (AT), although carcinogenic when administered alone, was an antitumor agent when combined with certain other carconogenic stimuli. The carcinogenic effect was prominent in the livers of C3H mice; thyroid tumors were less common because they required a longer period of development, and the life-span of the animal was shortened by the AT diet. The antitumor effects of AT included: delay in appearance of mammary tumors, striking reduction in gamma-radiation-induced lymphomas, and sharp reduction in neutron radiation-induced harderian gland and ovarian tumors. On an AT diet, the inbred C3H acatalasemic mouse substrain developed more liver tumors, starting earlier, than did the C3H normal catalase substrain. We suggest that our findings pointed to a possible relevance of catalase and H2O2 in carcinogenesis. The most probable mechanism for the increased incidence of liver tumors in AT-treated acatalasemic mice was the diminished rate of degradation of endogenous H2O2.

Reversal by theophylline of some changes characteristically accompanying hypothyroidism in rats.

Chronic dietary administration of theophylline (0.625, 1.25 or 2.50 g/kg food) for 7--9 weeks prevented the decrease in resting oxygen consumption, heart rate and systolic blood pressure characteristically observed in rats treated simultaneously with either of the antithyroid drugs, aminotriazole (ATZ; 0.25 g/kg food) or propylthiouracil (1.0 g/kg food). However, theophylline failed to restore both the food intake and growth rate of hypothyroid rats to that of euthyroid controls. Measurements of 131I uptake by the thyroid gland, thyroid acinar cell height and protein-bound iodine failed to reveal an effect of theophylline in either control or hypothyroid animals although theophylline increased thyroid to body weight ratio in both groups. Thus, the restoration of rate of oxygen consumption, heart rate and systolic blood pressure of hypothyroid rats to that of euthyroid controls was apparently not exerted through an increase in thyroid activity. The reduction in rate of oxygen consumption, heart rate and systolic blood pressure, generally associated with lack of thyroid hormone, appear more likely to be associated with reduced responsiveness to catecholamines in the hypothyroid rats. The results suggest that an increase in the half-life of cAMP by administration of theophylline to hypothyroid rats returned these functions to the level of euthyroid controls.