Presented at the 36th Annual Meeting, American College of Angiology, San Francisco, California, October, 1989. Although single proton emission computerized tomography (SPECT) was introduced more than twenty-five years ago only in the past decade has it become clinically useful in evaluating parameters of brain physiology. This was made possible because of advances in several converging areas-the development of a family of amines that accumulate in the brain proportionally to the blood flow; the optimization of gamma cameras; the improvement in collimators, detectors, and system designs; and an increasing interest in the area of brain function and circulation. The development of groups of tracers was a particular asset, for different tracers permit differential measurement of brain perfusion and metabolism. SPECT has made it possible to examine blood flow and metabolism in the living brain and to relate the findings to symptoms presented by the patient. The technique has the potential of distinguishing reversible ischemia from irreversible infarction.2-4 Cerebrovascular diseases are the third leading cause of death. The management of cerebrovascular diseases remains more variable than that of any other major diagnostic group. This may be a reflection of

Norepinephrine (NE) failed to increase thyroid hormone release in mice when endogenous TSH secretion had been greatly reduced by a variety of means. This was demonstrated by radioiodine release in mice pretreated with 131I and with thyroxine (T4) or 3,5,3′ triiodothyronine (T3. by radioimmunoassay (RIA) in mice pretreated with 131I and T3, and in mice which had been hypophysectomized, or where TSH secretion had been decreased by prolonged administration of exogenous TSH. T4 could not be measured by RIA in mice pretreated with T4.

Thyroid-catecholamine and thyroid-acetylcholine interrelation has been known for a number of years. Catecholamines and thyroid hormones affect the peripheral response to each other (1). Catecholamines and acetylcholine also affect the thyroid directly, stimulating some functions and inhibiting others, in conjunction or not with TSH. This review covers only catecholamine and acetylcholine effects on the thyroid gland.

Previous studies had suggested that norepinephrine (NE) and its precursors dopamine (DA) and L-DOPA acted similarly on iodine metabolism of isolated thyroid cells. Present studies indicate that this similarity extends to the inhibition by catecholamines of TSH-stimulated T4 release by mouse thyroids incubated in vitro. DA (5 X 10(-4) M), like NE, shown previously, inhibits TSH-stimulated T4 release. This inhibition was reversed by the alpha-blockers phentolamine, prazosin, and yohimbine, but not by the beta-blocker L-propranolol. DU-18288 and diethyldithiocarbamate, inhibitors of DA beta-hydroxylase, did not reduce DA inhibition, suggesting that prior conversion to NE was not a condition for DA activity. Apomorphine, a dopaminergic agonist but not a NE precursor, acted like DA, and its inhibition was also reversed by alpha-blockers. Furthermore, sulpiride, a dopaminergic blocker, reversed DA and apomorphine inhibition of TSH stimulation. These results suggest that DA inhibits TSH-stimulated T4 release through both adrenergic and dopaminergic receptors. On the other hand, L-DOPA, exerting an inhibition like that of DA, was also reversed by alpha-blockers, but its activity was greatly diminished by carbidopa, an inhibitor of aromatic L-amino acid decarboxylase, the enzyme converting L-DOPA to DA. This indicated that L-DOPA had to be converted to DA for activity. Both DA and L-DOPA inhibited stimulation of T4 release induced by (Bu)2cAMP, suggesting that their effect was exerted at a locus distal to cAMP generation. Indirect confirmation of a cAMP-independent pathway was obtained when DA inhibited TSH-stimulated cAMP formation, but, contrary to T4 release, this inhibition was not reversed by dopaminergic or adrenergic blockers. Presumably, therefore, DA inhibition of TSH-stimulated cAMP production was not related to T4 release. We conclude that 1) DA inhibits TSH-stimulated T4 release in mouse thyroids via alpha-adrenergic and dopaminergic receptors; 2) L-DOPA has to be converted to DA to produce inhibition; and 3) cAMP is unlikely to be an intermediary in DA inhibition.

Patients in chronic hemodialysis were injected i.v. 1mCi each Thallium Chloride 201 (TlCl) and Technetium 99m pertechnetate (Tc99m) and imagings of the thyroid and parathyroid glands were taken after 30, 60 and 90'. Parathyroid scans were obtained by computerized subtraction of the Tc99m from the TlCl image. The percentage uptake of TlCl and Tc99m was measured at 1 and 3 hrs in normal, hemodialyzed and thyroxine treated subjects as well as in untreated and thyroxine treated mice. Thyroid tests and serum electrolytes were routinely determined. Enlarged parathyroid glands were visualized in 5 out of 6 patients on hemodialysis. TlCl uptake was greatly decreased and thyroid imagings poor in patients in renal failure. This was parallel in all cases with a high serum K/sup +/. Tc99m uptake and scans were unaffected by renal status. Administration of L-thyroxine greatly reduced the thyroidal uptake and accompanying scans after both Tc99m and TlCl in human subjects as well as in experimental animals. The authors conclude the following: a) TlCl - Tc99m subtraction scans enabled visualization of hyperplastic parathyroid glands in patients in chronic hemodialysis; b) Thyroid uptake of TlCl was inversely related to the serum K/sup +/ level; and c) Both Tc99m and TlClmore » thyroidal uptake were inhibited by administration of L-thyroxine, hence TSH dependent.« less

Acetylcholine (ACh; 5 X 10(-4) M), like norepinephrine (NE; 6 X 10(-6) M), as shown previously, stimulated iodide organification by mouse thyroids in vitro, while at the same time it inhibited TSH- or (Bu)2cAMP-induced T4 release. However, thyroid cAMP was not changed by ACh, suggesting that ACh, like NE, exerted its effects at a step beyond cAMP production. Also, while ACh increased cGMP concentrations, (Bu)2cGMP and 8-bromo-cGMP were not effective on thyroid function in this system. Neurotransmitters, then, presumably do not exert their action through cyclic nucleotide stimulation ACh-induced stimulation of organification and inhibition of release was reversed by 10(-5) M atropine (ATR) but not by 10(-5) M d-tubocurarine, indicating that muscarinic receptors were involved. ATR also reversed inhibition of T4 release induced by NE, suggesting that the presynaptic cholinergic pathway may be responsible for stimulation of postsynaptic cholinergic and adrenergic neurotransmitters in the thyroid gland.

Excised mouse thyroids incubated in Ca++-free medium were stimulated to release increased amounts of stable thyroxine. This stimulation of thyroxine release by incubated thyroid tissue was not additive with TSH or (Bu)2cAMP. It was reversed by norepinephrine through an alpha adrenergic receptor, similar to TSH or (Bu)2cAMP stimulation. Depletion of Ca++ did not result, however, in an increase in the concentration of cAMP in incubated thyroid glands, suggesting that its locus of action was subsequent to TSH stimulation or cAMP production.

Patients injected with 201Thallium (201Tl) for myocardial scanning present good thyroid visualization. Determinations in mice injected with 201Tl indicated a high thyroid/serum concentration ratio (T/S). The 201Tl biological half-life (t 1/2) in serum (30 - 135 s) was much shorter than in thyroid (53 - 55 h) for human subjects and experimental animals. The 1 h 201Tl T/S ratio was comparable to that of 131I and 99mTc, indicating presence of a gradient for 201Tl also. Increase of endogenous TSH induced by propylthiouracil led to a significant rise in in T/S for 99mTc, 131I and 201Tl, whereas TSH inhibition by feeding l-thyroxine led to decrease in T/S for 99mTc and 201Tl. In vitro thyroid/medium concentration ratio (T/M) of 99mTc and 201Tl was decreased after 20' incubation with ouabain, an inhibitor of the Na+, K+, activated ATP-ase. However, perchlorate in vitro or in vivo failed to diminish the 201Tl T/M ratios or to affect the t 1/2 of 201Tl in human subjects, whereas T/M of 201Tl was depressed by KCl addition to the medium.

Norepinephrine (NE), which has previously been shown to inhibit TSH-induced T4 release by mouse thyroids in vitro, was found to stimulate iodide organification. The concentration of NE (6 X 10(-7) M) necessary to stimulate organification of iodide was 10 times less than the concentration (6 X 10(-6) M) required for inhibition of TSH-induced T4 release. Both actions of NE were exerted through an alpha-adrenergic receptor, since they were inhibited by phentolamine but not by l-propranolol. One milliunit of TSH maximally stimulated T4 release only, but larger amounts (100 mU) also stimulated organification. TSH stimulation of T4 release and organification was not affected by adrenergic antagonists and therefore was not mediated by adrenergic receptors. N6, O2-Dibutyryl cAMP and isobutylmethylxanthine, like TSH, stimulated T4 release. Their actions were inhibited by NE. However, both compounds, unlike TSH, failed to enhance organification in mouse thyroids. The effects of TSH and NE on the cAMP content of incubated mouse thyroids were also studied. TSH induced a prolonged increase in thyroidal cAMP during the 90-min incubation; this increase was unaffected by alpha- or beta-adrenergic antagonists. In contrast, NE (6 X 10(-5) M) produced a transient but significant increase in cAMP only within the first 5 min. Unlike the action of NE on organification, this short term stimulatory effect on cAMP production was mediated by a beta-adrenergic receptor, since it was blocked by l-propranolol but not by phentolamine. The following conclusions were reached: 1) stimulation of iodide organification and thyroid hormone release involves different sensitivity thresholds for TSH and NE; 2) TSH stimulation of iodide organification, hormone release, and cAMP formation is not exerted through adrenergic receptors; 3) NE stimulates organification and inhibits TSH-stimulated T4 release through alpha-adrenergic receptors, but stimulates cAMP production through beta-receptors; and 4) cAMP may not be the mediator of all TSH actions on the thyroid.

The administration of GTG to mice leads to death of all structures in a circumscribed area of the VMH as a result of loss of blood circulation. The loss of circulation is due to damage by GTG of neural processes adjacent to some of the capillaries in this area; damage to these processes leads to abnormal capillary permeability. Pericapillary damage occurs under conditions where capillary damage and consequent necrosis are prevented. Abnormal capillary permeability appears to follow release of a vasoactive substance from the damaged neural processes. Damage to the pericapillary neural processes by GTG is insulin-dependent and is counteracted by glucocorticoids.

Adenosine, like catecholamines, inhibits the thyroidal T4 release in vitro, when stimulated by TSH,N,O'-dibutyryl cyclic AMP [(Bu) 2cAMP], and phosphodiesterase inhibitors. Unlike catecholamines, the adenosine-induced inhibition is independent of adrenergic receptors. It is postulated that TSH stimulates thyroidal T4 release through a cAMP activated, adenosine-sensitive, protein kinase.

LATS containing sera and a number of Graves’ disease sera stimulated T4 release from mouse thyroids in vitro as, determined by RIA, thus confirming the presence of a thyroid hormone releasing factor in sera of thyrotoxic patients. The pattern of stimulation was similar to that previously shown for TSH in terms of T4 release time sequence, cAMP increase and catecholamine inhibition via or-adrenergic receptors. In the same in vitro system, neutralization with a human thyroid homogenate showed presence of LATS-Protector (LPA) in LATS negative thyrotoxic sera. The present study describes a simpler procedure for estimating LATS or similar activity, as compared to the McKenzie assay, and suggests identical receptor sites for TSH and other thyroid stimulators.

Thyrotropin (TSH), 1 MU/ml and N6, O2'-dibutyryl adenosine 3',5-cyclic monophosphoric acid (dbcAMP) greatly enhanced the release of thyroxine (T4) and triiodothyronine (T3) from mouse thyroids incubated in vitro. L-Epinephrine (E) and L-norepinephrine (NE) strongly inhibited the TSH and dbcAMP-stimulated release of thyroid hormones; L-isoproterenol (IPNE) exerted a relatively weak inhibition. The inhibition by catecholamines was prevented by the alpha-adrenergic blocker, phentolamine; L-propranolol, a beta-adrenergic blocker, had no effect on the inhibition. The TSH-induced release of thyroid hormones was not affected by adrenergic blockers. Epinephrine did not affect the increase in thyroidal cAMP content induced by TSH. These results indicate that catecholamines act by way of an alpha-adrenergic receptor to suppress TSH-stimulated release of thyroid hormones at a point beyond cAMP formation.