Adrenergic Receptor Sites Research Articles

In-vitro Observations on Isolated Adipose Tissue Cells from Hyperobese Subjects

Isolated adipose tissue cells were prepared from subcutaneous samples obtained from nine morbidly obese subjects weighing from 187 to 306% of ideal body weight. The responsiveness of these adipocytes to a number of test substances was determined by measuring cellular cyclic AMP concentration at one-half hour and glycerol release at four hours. Theophylline (10(-3) M) and epinephrine (10(-5) M) stimulated lipolysis; theophylline stimulated an increase in cyclic AMP, while epinephrine failed to prompt a significant change in the nucleotide. Neither the alpha blocker, phentolamine (10(-5) M), nor the beta blocker, propranolol (3 X 10(-5) M), affected lipolysis or cyclic AMP; when these agents were incubated in combination with epinephrine, changes occurred indicative of the presence of both alpha and beta adrenergic receptor sites. Insulin significantly reduced both basal and stimulated lipolysis but failed to affect cyclic AMP. With minor exceptions, adipocytes from hyperobese subjects behaved similarly to cells from unselected donors; at the concentration used, there was no evidence of resistance to insulin.

The effects of an alpha blocking agent on the respiratory distress syndrome with disseminated intravascular coagulation in the newborn infants and experimental animals

Firstly, the preventive effects of the alpha adrenergic receptor site blocking agent, phenoxybenzamine (POB) on rabbits which had been placed in an asphyxic condition, were observed. In the case of the asphyxiated rabbit which was treated with POB, shortening of recalcification time, and decrease in fibrinogen and platelets which were shown remarkably in the asphyxiated rabbit without POB, were clearly prevented. Secondly, the clinical trials of POB for the newborn infants suffering from RDS with DIC were carried out. One mg per kg of POB, was infused every 24 hours with alkali therapy and mechanical respiration. After the administration of POB, the clinical conditions improved as did the findings of coagulation studies. Little is known about the effect of alpha blocking agents on DIC in newborn infant with RDS.

Neural and Humoral Control of Apocrine Glands

Evidence is presented that apocrine sweat glands are controlled by adrenergic and by circulating catecholamines of adrenomedullary origin. Sympathetic denervation of glands and neural stimulation experiments have demonstrated that a functional nerve supply exists although in some species no nerves can be demonstrated histologically. Adrenomedullary hormones do not supplement the sweating caused by heat exposure, but exercise and asphyxiation may increase adrenalin secretion caused by heat exposure, but exercise and asphyxiation may increase adrenalin secretion sufficiently to cause sweat gland stimulation. Experiments with adrenergic blocking drugs confirm the above findings and demonstrate species differences in the adrenergic receptor site, e.g., α-receptor antagonists inhibit the sweat glands of bovids and β-receptor antagonists those of equids. This kind of sweat gland control is taken as evidence for convergent evolution from a common, but unidentified, primitive form or sweat gland.

Acute parathyroid hormone response to epinephrine in vivo.

The acute effects of epinephrine, norepinephrine, and isoproterenol on the plasma immunoreactive parathyroid hormone (iPTH) response were studied in 13 550-600 kg cows. Catecholamines were infused for 7.0 min. During epinephrine infusions at 0.08 mumol/min iPTH increased from 0.48+/-0.12 (mean+/-SE, ng/ml) to 1.09+/-0.18 ng/ml (P < 0.02). Small increases in plasma free fatty acids and glucose could be detected with 0.08 mumol/min epinephrine; the iPTH response to epinephrine was as sensitive as the free fatty acid and glucose responses and possibly of physiological importance. Plasma calcium (total and ionized) and magnesium did not change. The responses were more pronounced at 0.8 mumol/min epinephrine with a mean iPTH increase from 0.49+/-0.16 ng/ml to 1.74+/-0.35 ng/ml (P < 0.01). Small decreases in plasma calcium occurred at 0.8 mumol/min epinephrine, but the plasma magnesium remained unchanged. However, when the plasma calcium was lowered with ethylene glycol bis(beta-aminoethyl ether)-N, N'-tetraacetic acid (EGTA), a much more pronounced lowering of the plasma calcium was required to produce comparable increases of the plasma iPTH concentrations than when epinephrine was infused. It appears that epinephrine has a direct effect on the release of iPTH from the parathyroid glands. Simultaneous infusions of calcium and epinephrine suppressed the stimulation by epinephrine. This points towards a common mechanism of the regulation of parathyroid hormone secretion caused by decreases in the extracellular calcium concentration and/or alterations in the distribution of calcium within parathyroid cells following the administration of epinephrine. The iPTH response to epinephrine was suppressed in the presence of propranolol. Isoproterenol was less active in raising iPTH than epinephrine, and norepinephrine was the least active. The stimulation by isoproterenol and the suppression by propranolol suggest beta adrenergic receptor sites within the parathyroid glands.

Role of Na + and anions in the triple response of isolated frog skin to norepinephrine

1. 1. Isolated short-circuited frog skin in NaCl or NaHCO 3 solutions responded to norepinephrine (3–10 −5 M), added to the epithelial side, with an increase in short-circuit current (s.c.c.) and open-skin potential ( V) with little if any change in total skin conductance ( G = s.c.c./ V). Skins in Na 2SO 4 solutions gave a greatly diminished response to norepinephrine added to the epithelial side, with indication of depression of s.c.c. and V later during the experiment. Thus, the response is dependent on Cl − or HCO 3 −. 2. 2. Omission of Na + from the solution at the epithelial side (arginine chloride (outside), NaCl (inside)) resulted in a very weak norepinephrine (outside) response, suggesting that norepinephrine (outside) stimulates active inward Na + transport. Skins in arginine sulfate (outside), NaCl (inside); choline bicarbonate (outside), sodium bicarbonate (inside); arginine sulfate (outside), sodium bicarbonate (inside) also failed to give the marked response noted in 1. 3. 3. When applied to the corium side, norepinephrine led to an increase in s.c.c. and G but a decrease in V by action on the glandular epithelium in the presence on the inside of NaCl or NaHCO 3, regardless of the presence or absence of Na + on the epithelial side. Flux measurements proved that active outward Cl − transport occurred. Active outward HCO 3 − transport, suggested by the s.c.c. results, was unmeasurably small because of a 100 times greater C flux in the form of CO 2 which was equal in both directions and unaffected by norepinephrine on the corium side. Active outward Cl − transport was greatly depressed when Na + on the corium side was replaced by arginine +. There was good recovery of V and s.c.c. when NaCl solutions were present on both sides. 4. 4. Ouabain (5·10 −4 M), or propranolol (5·10 −5 M) greatly decreased active glandular Cl − transport following application of norepinephrine to the corium side. Diamox (5·10 −3 M) had a small depressing effect of norepinephrine (inside) on Cl − transport, and it depressed completely a relatively weak norepinephrine (inside) response, presumably because of a decrease in HCO 3 − transport. 5. 5. The results are interpreted as showing functional dependency of α-inhibitory and β-stimulatory adrenergic receptor sites in frog skin epidermis on the nature of the anion present (SO 4 2 vs Cl − and HCO 3 −), and of β-stimulatory receptor sites in the glandular epithelium on the presence of Na +.

Alteration of electrical and motor activity of human and dog rectum by diphenylhydantoin.

The present in vitro study on isolated colon strips in humans and dogs indicates that diphenylhydantoin acts both on neuromuscular junctions and directly on smooth muscle. Diphenylhydantoin (DPH) opposes the action of acetylcholine (ACH) and 5-hydroxytryptamine (5-HT) on neuromuscular junctions and exerts its relaxing effect on postganglionic or nonadrenergic adrenergic receptor sites, since its effects are not influenced byα− orβ− adrenergic blocking agents or by ganglionic blockade with hexamethonium. Diphenylhydantoin acts directly on smooth muscle, inhibiting spontaneous contraction, possibly by altering myogenic electrical activity. It also inhihits contraction of smooth muscle induced by neuromuscular agonists and by electrical stimulation. These results indicate that DPH has a peripheral as well as a central effect and provide a theoretic basis for its use in patients with “spastic colon” syndrome.

Vessel Wall and Thrombogenesis - Endotoxin

SummaryThe generalized Shwartzman reaction is a definitive disease process which is the result of two minor episodes of acute inflammation of the circulating blood. The identifying feature of the reaction is thrombosis of the micro circulation, specifically of glomerular capillary thrombosis which persists long enough to cause bilateral renal cortical necrosis. The reaction is the result of an interplay between leukocytes, platelets, complement, the contact system, the extrinsic prothrombin activator system, adrenal glucocorticoids, adrenal catecholamines, alpha - adrenergic receptor sites and the fibrinolytic enzyme system. The reaction occurs only when these systems are affected within narrow quantitative limits. It is a model of the effects of bacterial endotoxin on the blood-vascular system and has important implications for acute inflammatory episodes of the circulating blood induced by other inflammatory agents such as antigen-antibody complex and particulate matter.

Effect of monoamine oxidase inhibitors on metabolism and in vivo release of H 3-norepinephrine from the hypothalamus

Following the implantation of a push-pull cannula into the anterior hypothalamus of the rat and a polyethylene cannula into the lateral ventricle, the brain norepinephrine stores were labeled by intraventricular injection of H 3-norepinephrine. The spontaneous release of radioactivity into the perfusate from the hypothalamus of freely moving unanesthetized control animals was 4.19 ± 0.99 m μCi/hr, and the ratio R of deaminated-O-methylated metabolites to amines (norepinephrine and normetanephrine) in the perfusate was 1.79. Both the irreversible MAO-inhibitor pargyline and the reversible inhibitor BW 63-307 (2-chloro-4-acetylamino benzonitrile) decreased R from 1.79 to 0.02 and 0.42 respectively while not significantly altering the release of total radioactivity into the perfusate. Thus, in animals pretreated with either pargyline or BW 63-307, practically all the radioactivity released into the perfusate consisted of norepinephrine and normetanephrine. The argument that the increased availability of norepinephrine in the perfusate could merely reflect increased sympathetic activity rather than inhibition of MAO, is weakened because BW 63-307 did not elicit gross behavioral activation or sympathetic stimulation. The results, thus, support the view that an increase in the tissue levels of endogenous or exogenous norepinephrine accompanying the inhibition of MAO results in a “spillover” of norepinephrine onto adrenergic onto adrenergic receptor sites.

Effect of tranquilizers and antidepressants on glycogen phosphorylase of rat brain

Tranquilizers and antidepressants were investigated for their effect on the glycogen phosphorylase (α-1,4-glucan: orthophosphate glucosyltransferase; EC 2.4.1.1) activity of rat brain after sacrificing the animal with liquid nitrogen. The tranquilizers consisted of reserpine and four phenothiazines. Isoreserpine and promethazine, both not considered tranquilizers, were included as controls. All tranquilizers except prochlorperazine depressed the phosphorylase activity. The controls did not affect the phosphorylase level. A tentative explanation for the lack of effect of prochlorperazine is given. The antidepressants consisted of: two monoamine oxidase inhibitors, pargyline and iproniazid; a tricyclic antidepressant, desmethylimipramine; and a psychic stimulant, amphetamine. The antidepressants acted counter to tranquilizers, i.e. they enhanced the absolute or relative level of phosphorylase activity. However, the enhancing effect was best observed when rats were treated with reserpine before or after the drug. A unified explanation for the effect of most of both tranquilizers and antidepressants on the phosphorylase activity is given, based on a reasonable mode of action and a postulate stating that the phosphorylase activity is correlated with the availability of norepinephrine at the adrenergic receptor sites. These facts suggest that the phosphorylase activity of brain may be a barometer for CNS adrenergic activity. The results suggest that the glycogen phosphorylase of brain may be involved in actions of many drugs used as tranquilizers and antidepressants.

The Adrenergic Modulation of the Serum Insulin Response to Intravenous Arginine in Man

Abstract. The effect of adrenergic stimulation and blockade on metabolic responses to arginine have been studied. Phentolamine enhanced, and adrenalin diminished, the rise in serum immunoreactive insulin that followed intravenous arginine; these effects were not secondary to changes in blood levels of arginine, glucose or free fatty acids following the amino acid infusion. Phentolamine did not affect the clearance of infused insulin from the blood stream. It was concluded that adrenergic receptor sites are involved in the modulation of the secretion of insulin in response to an infusion of arginine.

Possible involvement of glycogen phosphorylase of brain in the affective states.

Tranquilizers and antidepressants were investigated for their effect on the glycogen phosphorylase of rat brain. In general, the tranquilizers depressed and the antidepressants enhanced the phosphorylase activity. A unified explanation for the effect of most of both tranquilizers and antidepressants on the phosphorylase activity is given, based on a reasonable mode of action and a postulate stating that the phosphorylase activity is correlated with the availability of noreprinephrine at the adrenergic receptor sites. These facts suggest that the phosphorylase activity of brain may be a barometer for CNS adrenergic activity. From the nature of drugs involved one could say that depression (an affective state) is associated with decreased phosphorylase activity and excitement or relief from depression with enhancement of the activity, either from the normal or the reduced state.

Chemical Mediators of Immediate Hypersensitivity

Two chemical substances, histamine and s R S-A, mediate the immunologic interactions that may eventuate in immediate hypersensitivity or anaphylactic reactions. Defining the pathways, initiated at the adrenergic receptor sites, through which these mediators are elaborated has made it possible to evaluate the antianaphylactic usefulness of such blocking agents as diethylcarbamazine and sodium cromoglycate.

Lipolysis by human adipose tissue: the role of cyclic 3',5'-adenosine monophosphate and adrenergic receptor sites.

Abstract The basal lipolytic activity of isolated human adipose tissue cells was greatly stimulated by dibutyryl cyclic adenosine monophosphate (DAMP) or theophylline. Insulin reduced but did not abolish the enhanced lipolysis due to DAMP and theophylline. Epinephrine, a mixed adrenergic receptor site agonist, and isoproterenol, a beta site agonist, were incubated with human cells and rat cells, alone and in combination with an alpha site blocker, phentolamine, and a beta site blocking agent, propranolol. Neither phentolamine alone nor propranolol alone influenced lipolysis by either human or rat cells. With human cells, epinephrine plus phentolamine further increased the lipolytic response prompted by epinephrine alone, while epinephrine plus propranolol caused depression of lipolysis below the basal level. With rat cells, phentolamine had no effect on epinephrine-stimulated lipolysis and propranolol abolished it. With both human and rat cells, isoproterenol, on an equimolar basis, was more potent than epinephrine; lipolysis stimulated by isoproterenol was unaffected by phentolamine and was abolished by propranolol. These results are interpreted to indicate that both alpha and beta sites are present in human adipose tissue and act in a divergent manner in mediating the effects of epinephrine, while only beta sites could be demonstrated in rat cells. With human cells, lipolysis stimulated by thyroid-stimulating hormone (TSH) and a related human pituitary fraction (DEAE II) was not influenced by either propranolol or phentolamine but was decreased when alpha sites were stimulated with epinephrine plus propranolol.

Growth hormone-adrenergic relationship

The effect of selective blocking of adrenergic receptor sites on plasma growth hormone responses to insulin-induced hypoglycaemia was studied in 4 adults. When β-receptor sites were blocked with propranolol, the degree of hypoglycaemia achieved with insulin was unaffected; plasma G.H. response was quantitively greater, was earlier in onset and sustained for a longer period of time. Blocking of the α-receptor sites with phentolamine was associated with a lesser degree of hypoglycaemia and the plasma G.H. response was essentially abolished. In a single experiment the sustained plasma G.H. elevation, induced by propanolol, was abolished within 30 minutes of phentolamine administration. These findings suggest that G.H. release from the pituitary is in part mediated by α-adrenergic activity and that blocking of the β-receptor sites in combination with insulin-induced hypoglycaemia may be a more reliable evocative procedure in the diagnosis of pituitary G.H. deficiency states.

Vanilmandelicaciduria in the different clinical phases of manic depressive psychosis.

The catecholamine hypothesis of affective disorders proposes that 'some-if not all-depressions are associated with an absolute or relative decrease in catecholamines, particularly norepinephrine, available at central adrenergic receptor sites. Elation, conversely, may be associated with an excess of such amines' (Schildkraut, 1965).

Adrenergic mechanisms in the systemic plasminogen active response to adrenaline in man.

Summary. The effect of propranolol, ICI 50172 and a combination of propranolol and phentolamine, on the plasminogen activator response to a 30 mm intravenous infusion of adrenaline hydrochloride (0.1 μg/kg/min) has been studied in five healthy subjects. Plasma factor VIII, serum free fatty acids, blood glucose and pulse rate changes were also monitored to confirm the efficacy of adrenergic blockade. Propranolol blocked the plasminogen activator response by a factor of 29% whereas ICI 50172 had no effect. The addition of phentolamine to propranolol failed to influence further the degree of blockade already present with propranolol alone. It is postulated that the plasminogen activator response to adrenaline is derived from two separate components, and that the relatively minor one may be secondary to vasoactive changes whereas the second and major component is quite independent of this phenomenon. It is also proposed that both components may share a common adrenergic receptor site.

Studies on raised free fatty acids in hyperthyroidism

In thyrotoxicosis the plasma free fatty acid levels are high before, suppress normally during, and rebound excessively 4–5 hours after an oral glucose load. The abnormal responses bear no relation to the plasma glucose, insulin and cortisol levels, and apparently effective blockade of 11-β-hydroxylation as well as α and β adrenergic receptor sites, effect no changes. Plasma growth hormone is not elevated, though glucose induced suppression is poor. Free fatty acid values return to normal on restoration of euthyroidism but alter after readministration of triiodothyronine (T3) to treated thyrotoxic as well as normal subjects. Growth hormone suppressibility likewise returns with euthyroidism and alters after T3 treatment in thyrotoxics, but these latter changes do not achieve statistical significance and are not reproduced in T3 treated normal controls. Although these results may be interpreted as in vivo evidence of a possible direct stimulatory effect of tri-iodothyronine or thyroxine on lipolysis in hyperthyroidism, the possibility exists that impaired suppression of growth hormone plays a role. In thyrotoxicosis the plasma free fatty acid levels are high before, suppress normally during, and rebound excessively 4–5 hours after an oral glucose load. The abnormal responses bear no relation to the plasma glucose, insulin and cortisol levels, and apparently effective blockade of 11-β-hydroxylation as well as α and β adrenergic receptor sites, effect no changes. Plasma growth hormone is not elevated, though glucose induced suppression is poor. Free fatty acid values return to normal on restoration of euthyroidism but alter after readministration of triiodothyronine (T3) to treated thyrotoxic as well as normal subjects. Growth hormone suppressibility likewise returns with euthyroidism and alters after T3 treatment in thyrotoxics, but these latter changes do not achieve statistical significance and are not reproduced in T3 treated normal controls. Although these results may be interpreted as in vivo evidence of a possible direct stimulatory effect of tri-iodothyronine or thyroxine on lipolysis in hyperthyroidism, the possibility exists that impaired suppression of growth hormone plays a role.

Studies on raised free fatty acids in hyperthyroidism

In thyrotoxicosis the plasma free fatty acid levels are high before, suppress normally during, and rebound excessively 4–5 hours after an oral glucose load. The abnormal responses bear no relation to the plasma glucose, insulin and cortisol levels, and apparently effective blockade of 11- β -hydroxylation as well as α and β adrenergic receptor sites, effect no changes. Plasma growth hormone is not elevated, though glucose induced suppression is poor. Free fatty acid values return to normal on restoration of euthyroidism but alter after readministration of triiodothyronine (T3) to treated thyrotoxic as well as normal subjects. Growth hormone suppressibility likewise returns with euthyroidism and alters after T3 treatment in thyrotoxics, but these latter changes do not achieve statistical significance and are not reproduced in T3 treated normal controls. Although these results may be interpreted as in vivo evidence of a possible direct stimulatory effect of tri-iodothyronine or thyroxine on lipolysis in hyperthyroidism, the possibility exists that impaired suppression of growth hormone plays a role.

Contracture and catecholamines in mammalian myocardium.

Contractures induced by KCl are produced in cat ventricular muscle after depletion of catecholamine stores by previous treatment with reserpine or by selective blocking of adrenergic receptor sites with propranalol. Contractures are reproducible for 2 to 3 hours and are markedly depressed by the addition of epinephrine. The relaxation of contracture induced by epinephrine parallels the eftect of this compound of shortening the duration of the normal twitch. The failure of the normal mammalian myocardium to maintain tension in solutions of high KCI concentration appears to be related to the endogenous amounts of catecholamines in the tissue.

Hyperglycemia and inhibition of insulin secretion during administration of diazoxide and trichlormethiazide in man.

Reversible “diabetes” was produced in eight normal male subjects by administering between 400 mg. and 645 mg. of diazoxide and 8 mg. of trichlormethiazide per day for four to seven days. Insulin secretory responses to oral and intravenous glucose loads were determined on the last treatment day and the following morning, respectively. Four to six weeks later both tests were repeated to obtain control data. The speed of breakdown in glucose tolerance was proportional to daily diazoxide dosage, which in turn was limited by the severity of side effects. Carbohydrate turnover tended to worsen each day, even after correction of severe symptomatic hypokalemia in two subjects. The induced “diabetic” state was associated with sluggish insulin release as blood glucose rose, and with greatly decreased hormonal output per unit of glycemic stimulus—the same two secretory defects which characterize the clinical onset of hereditary diabetes mellitus. The dala suggest that the potent diabetogenicity of diazoxide given with trichlormethiazide may be almost entirely due io blockade of insulin release, either by direct action or by stimulating alpha adrenergic receptor sites in the beta cell. The synergistic effect of natriuretic analogues like trichlormethiazide probably reflects superimposed potassium deficiency, evidence of which consistently underlies the weaker hyperglycemic property of diuretic benzothiadiazines but is not caused by diazoxide itself. Thus, “diazoxide diabetes” appears to be functionally distinct from ordinary “thiazide diabetes” and, in fact, closely resembles spontaneous diabetes mellitus clinically. Since the condition can be predictably induced and is entirely reversible, it may provide a useful experimental model for further study of the inherited disease in man.