Characterization of bovine neutrophil beta2-adrenergic receptor function.

This study compares bovine leukocyte beta-adrenergic receptor densities to that of the rat, demonstrates for the first time a functional beta(2)-adrenergic receptor signaling pathway in steer neutrophils, and investigates the effect of an inflammatory stimulus on that signaling pathway. The beta(1)-/beta(2)-adrenergic antagonist ([3H])CGP-12177 demonstrated that rat lymphocyte specific binding-site density was highest, followed by steer and dairy cow lymphocytes, and lastly steer and dairy cow neutrophils. The beta(2)-adrenergic agonist terbutaline stimulated steer neutrophil adenosine 3,5-cyclic monophosphate (cAMP) production, an effect increased by inclusion of > or = 1 x 10(-8) M phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C. Both terbutaline and the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) independently decreased steer neutrophil superoxide anion production in a concentration-dependent manner, with 1 x 10(-4) M IBMX enhancing both the potency and efficacy of the terbutaline effect (up to 74% reduction in superoxide anion production). Superoxide anion production was also reduced by the synthetic cAMP analog 8-bromo-cAMP, which increased the potency of the IBMX effect on superoxide anion production. Taken together, these data demonstrate the presence of a beta(2)-adrenergic receptor signaling pathway in bovine neutrophils much like that described in other animal species, as well as the potential for an inflammatory stimulus to alter its function.

Iodine-131 metaiodobenzylguanidine for the locating of suspected pheochromocytoma: experience in 400 cases.

The efficacy of the newly developed pheochromocytoma-seeking radiopharmaceutical, [131I]MIBG, was examined in the first 400 patients (441 studies) investigated for suspected pheochromocytoma at our institution. The results of [131I]MIBG scintigraphy were classified as true positive, false positive, true negative, and false negative. Using this classification the sensitivity was found to be 78.4% in primary, sporadic pheochromocytoma, 92.4% in malignant pheochromocytoma, and 94.3% in familial pheochromocytoma giving an overall sensitivity of 87.4%. The specificity was 98.9% in primary, sporadic pheochromocytoma, 100% in malignant pheochromocytoma, and 100% in familial pheochromocytoma. The overall specificity was 98.9%. Iodine-131 MIBG scintigraphy was thus found to be a safe, noninvasive, and efficacious technique for the location of pheochromocytomas, especially for those arising from nonadrenal sites, recurring postoperatively, and exhibiting malignant metastatic disease. We find that, where available, [131I]MIBG scintigraphy is the study of choice to initiate the location of suspected pheochromocytoma.

An analysis of "ablation of thyroid remnants" with I-131 in 511 patients from 1947-1984: experience at University of Michigan.

Between January 1947 and June 1983, 511 patients were given treatment doses of I-131 after surgery for thyroid cancer in the presence of I-131 uptake in thyroid remnants. Thirty-four patients were removed from the study leaving 462 patients with a 99% follow-up at 1 or more yr, with a mean follow-up of 15 yr. Of 267 patients with radioiodine uptake confined to the thyroid bed, 233 (87%) had ablation from the first dose of I-131 ranging from 100 to greater than 200 mCi. The higher the percent uptake, the more difficult it was to achieve ablation. In the percentages of successful ablation, there were no significant differences between I-131 doses of: 100-149 mCi, 150-174 mCi, 179-199 mCi, and 200 mCi or more. The 100-149 mCi ablative dose may furnish "adjuvant" therapy for occult metastases.

Iodine-131 metaiodobenzylguanidine scintigraphy for the location of neuroblastoma: preliminary experience in ten cases.

Ten patients with histologically proven neuroblastoma were studied by [131I]MIBG scintigraphy. Tumor uptake of the radiopharmaceutical showed a spectrum varying from no uptake in one case, to slight uptake in two, moderate uptake in two and intense uptake in five cases. Iodine-131 MIBG scintigraphy was more effective in demonstrating the extent of neuroblastoma spread than were conventional bone scan and CT in one patient, equal to these modalities in four cases, almost equal in two cases and significantly inferior in three cases. These preliminary results suggest that [131I]MIBG scintigraphy is useful in detecting the presence and delineating the distribution of neuroblastoma and may, in certain cases, have therapeutic potential.

Pharmacology of bovine pulmonary vein anaphylaxis in vitro.

1. The bovine pulmonary vein contracts in response to acetylcholine, histamine, 5-hydroxytryptamine and bradykinin. The tissue is particularly sensitive to 5-hydroxytryptamine (>0.1 ng/ml). Specific Schultz-Dale reactions were elicited in the pulmonary vein in response to horse plasma.2. The Schultz-Dale reaction is inhibited both by antihistaminics and by the anti-5-hydroxytryptamine agent methysergide, but not by atropine.3. Sodium meclofenamate inhibited anaphylactic contraction but showed a strong tendency to antagonize many agonists indiscriminately.4. Disodium cromoglycate (DSCG: 100 mug/ml) which inhibits some immunological reactions of mast cells, and diethylcarbamazine citrate (DECC: 50 mug/ml) which inhibits slow-reacting substance of anaphylaxis (SRS-A) elaboration, each inhibited anaphylaxis incompletely (50% or less). However, a combination of DSCG and DECC virtually abolished the Schultz-Dale reaction in this preparation. It is tentatively suggested that the component of the anaphylactic contraction which is resistant to cromoglycate but sensitive to diethylcarbamazine could be due to SRS-A.5. The bovine pulmonary Schultz-Dale reaction appears to be a complex interaction of histamine, 5-hydroxytryptamine, SRS-A and possible other agents including kinins.

Histamine H2-receptors in the sheep bronchus and cat trachea: the action of burimamide.

Histamine-induced relaxation of the sheep bronchus was antagonized by burimamide but not by mepyramine, indicating the presence of H(2)-receptors. Mepyramine or burimamide alone produced partial antagonism of histamine-induced relaxation of the cat trachea. Both inhibitors added simultaneously effectively abolished the histamine response, suggesting that both H(1)- and H(2)-receptors are active in relaxing the cat trachea.

Release of dopamine from bovine lung by specific antigen and by compound 48-80.

1. Dopamine was shown to be released from the isolated lung of calves sensitized with horse serum by compound 48/80 and by specific antigen.2. Dopamine contracts the bovine pulmonary artery and pulmonary vein. Phentolamine, the alpha-adrenoceptor blocking agent, inhibits this activity of dopamine and also strongly reduces the Schultz-Dale response of the pulmonary vessels.3. The results are consistent with the suggestion that dopamine (together with histamine and 5-hydroxytryptamine) may participate in the pulmonary vasoconstriction associated with anaphylaxis in cattle.

Atypical tryptamine receptors in sheep pulmonary vein.

Both the pulmonary artery and vein of the sheep contracted dose-dependently to histamine, carbamoylcholine, prostaglandin F2a, noradrenaline and bradykinin and relaxed in the presence of isoprenaline or prostaglandin E1. 2 The effect of 5-hydroxytryptamine (5-HT) on the artery was consistently to produce dose-dependent contractions without tachyphylaxis. The effect on the vein was biphasic. 5HT 5 X 10(-10) to 5 X 10(-8) M relaxed the partially constricted vein. 5-HT 10(-7) to 10(-6) m caused brief venoconstriction followed by relaxation. 5-HT greater than 10(-6) M caused dose-related contraction of the vein. 3 Methysergide effectively blocked the contractile response of the artery to 5-HT, but only weakly inhibited the contractions of the vein (dose-ratio less than 20). 4 Each of ten antagonists tested failed to inhibit the 5-HT-induced relaxation of the vein. Sheep pulmonary vein possesses tryptamine receptors which mediate relaxation and which are not of the classicl M- or D-type. These receptors appear not to be involved directly or indirectly with responses to acetylcholine, catecholamines, histamine or prostaglandins.

Coronary anaphylaxis in vitro.

1 The reactivity of isolated coronary arteries and cardiac veins of the calf to selected chemical mediators of anaphylaxis and to sensitizing antigen (horse plasma) was studied. 2 Both the coronary arteries and cardiac veins contracted to bradykinin, 5-hydroxytryptamine (5-HT), prostaglandin E2 (PGE2), PGF2 alpha, histamine and carbachol. 3 Isoprenaline and PGE1 relaxed vessels which had been partially contracted by PGF2 alpha, PGE2, histamine, 5-HT, bradykinin, carbachol or antigen. 4 Horse plasma (antigen) contracted coronary vessels obtained from sensitized calves, but not from control calves. Subsequent antigen 'challenge' produced 'densensitization' (tachphylaxis). After 1 or 2 h of rest, the anaphylactic response partially recovered although there was no change in tissue reactivity to the exogenous agonists. 5 Specific doses of atropine, mepyramine (H1-blocker) and methysergide (5-HT antagonist) did not modify the anaphylactic reaction in coronary arteries, suggesting a negligible role for these biogenic amines. 6 Compound PRD-92-EA (a new anti-allergic agent) exhibited non-specific receptor blocking activity towards histamine, 5-HT and carbachol and inhibited the coronary anaphylactic reaction.

Anaphylactic contraction of pulmonary blood vessels of chicken.

1 Isolated pulmonary arterial and vein strips from sensitized or non-sensitized chickens exhibited dose-dependent contractions to adrenaline greater than, noradrenaline greater than, 5-hydroxytryptamine greater than, histamine greater than, dopamine. Individual variability in the responsiveness of the vessels to agonists was marked. In general veins were 2 to 25 times more sensitive to agonists than arterial strips. 2 Isoprenaline (a relatively specific beta-adrenoceptor agonist) induced relaxation of the submaximally contracted pulmonary vein and arteries at low doses and contractions at high concentrations. 3 Contractile responses to acetylcholine or carbachol were not regularly recorded; only 50% of the vessels reacted to cholinoceptor agonists over a wide threshold dose range. 4 Chicken pulmonary vessels were found relatively insensitive to bradykinin. 5 Effects of prostaglandins were variable. Prostaglandin F2alpha induced dose-related contractions of the vein and arterial strips; prostglandins E1 and E2 at low doses partially contracted pulmonary artery irrespective of the spasmogen used and further increase in doses induced either no effect or contractions. Prostaglandin E1 induced marked and rapid contractions of the vein. Prostaglandin E2 induced relaxations of the prostaglandin F2alpha-contracted vein only, but produced no effect or slight contractions of the veins partially contracted to other spasmogens. 6 Pulmonary arterial and vein strips obtained from chickens sensitized to horse plasma exhibited Schultz-Dale contractions of variable magnitude and duration to specific antigenic challenge only. In many vessels, antigen-induced contractions were associated with marked increase in spontaneous activity. 7 The importance of the Schultz-Dale reaction in avian pulmonary vessels is discussed in relation to the right heart dilatation associated with anaphylaxis in the chicken.

The pharmacology of anaphylaxis in the chicken intestine.

1 The Schultz-Dale phenomenon has been demonstrated in several circular smooth muscle strips of oesophagus, crop, duodenum, jejunum and ileum taken from young and adult domestic fowl sensitized actively to crystalline bovine albumin or horse plasma. 2 The ileal strips contract to acetylcholine, histamine, 5-hydroxytryptamine (5-HT), prostaglandins E1, E2, F2alpha, bradykinin and bovine slow reacting substance of anaphylaxis (SRS-A). Marked seasonal and individual variations in the responsiveness of gut tissues to these exogenous agonists were noted. 3 Antagonism of contractions to histamine by mepyramine suggests the existence of H1-histamine receptors in chicken ileum. Blockade of 5-HT-induced contractions by methysergide shows the preponderance of 'D'-musculotropic tryptamine receptors. 4 Failure of selective receptor antagonists of acetylcholine, histamine and 5-HT to modify the Schultz-Dale reaction suggests the nonparticipation of aminergic mechanisms in this reaction. 5 Partial to complete blockade of the Schultz-Dale reaction by a prostaglandin receptor antagonist (polyphloretin phosphate, PPP); prostaglandin synthetase inhibitors (sodium meclofenamate and phenylbutazone); inhibitors of synthesis and release of histamine and SRS-A (PR-D-92-EA, M & B 22948, diethylcarbamazine citrate, and PPP) and an inhibitor of proteinases (aprotinin) strongly suggests the involvement of vasoactive lipids and polypeptides in the anaphylactic response of chicken ileum to specific antigen.

Preliminary pharmacological characterization of the bovine isolated bronchial artery strip: a new preparation.

1 This paper describes a preliminary pharmacological study of the isolated helical strip of bovine bronchial artery under isotonic conditions in Krebs-Henseleit solution. 2 The tissue contracted to histamine and 5-hydroxytryptamine (5-HT), actions which were selectively antagonized by mepyramine and methysergide respectively. Histamine was not inhibited by metiamide and 5-HT was not affected by morphine. 3 Slow reacting substance of anaphylaxis (SRS-A), prostaglandin F2 alpha (PGF2 alpha) and PGE2 were spasmogenic, whereas PGE1 caused relaxation. No potential antagonists of these agents were tested. 4 Carbachol, at all concentrations, caused contractions of the bronchial artery which were completely, irreversibly blocked by atropine. 5 The spasmogenic action of phenylephrine was selectively blocked by dibenamine. Vessel strips which were partially contracted to histamine, relaxed to isoprenaline and salbutamol. The action of isoprenaline was inhibited similarly by either propranolol or practolol. The evidence therefore suggests the presence of functional alpha, beta 1 and beta 2-adrenoceptors.

Relaxant response of goat trachea to 5-hydroxy-tryptamine mediated by D-tryptamine receptors.

1 Goat isolated trachea contracted in response to carbachol, histamine and 2-pyridylethylamine (an H(1)-receptor agonist) and relaxed after application of isoprenaline. 5-hydroxytryptamine (5-HT) and phenylephrine.2 Mepyramine, a selective H(1)-receptor antagonist, blocked histamine- and 2-pyridylethylamine-induced contractions. In high doses it also exhibited some nonspecific antagonism to carbachol. After H(1)-receptor blockade, 4-methylhistamine and dimaprit (specific H(2)-agonists) relaxed the carbachol-contracted trachea.3 Propranolol, a beta-adrenoceptor blocker, antagonized relaxation in response to isoprenaline and phenylephrine. In high doses, it produced a reversal of the phenylephrine response.4 Indomethacin enhanced contractions in response to carbachol and histamine.5 Relaxation to 5-HT was not affected by propranolol, indomethacin, metiamide or cimetidine (H(2)-blockers). These findings appear to exclude the involvement of adrenergic, prostaglandinergic and H(2)-histaminergic mechanisms in the mediation of this response.6 Atropine potentiated 5-HT-induced relaxations. This suggests the participation of a ;masked' excitatory cholinergic mechanism.7 Methysergide, dibenamine and dibenzyline selectively antagonized or reversed 5-HT-induced relaxation. Dibenamine and dibenzyline enhanced relaxations to isoprenaline.8 This investigation showed (i) a relaxant response of goat trachea to 5-HT, mediated via D-muscular tryptamine receptors; (ii) a small population of excitatory M-neuronal tryptamine and alpha-adrenoceptors; and (iii) predominance of H(1)-histamine receptors in the goat trachea.

Production of kinins in bovine anaphylactic shock.

Calves were sensitized by subcutaneous injection of horse serum in Freund's adjuvant. Subsequent challenge with intravenous horse serum induced increased blood kinin activity. This kinin activation correlated with the protracted fall in systemic blood pressure seen in the same animals.

Acute systemic anaphylaxis in the horse.

1. Histamine in small doses caused systemic depressor responses in horses, whereas greater doses caused biphasic effects. All doses of 5-hydroxytrypt-amine (5-HT) were pressor and all doses of bradykinin depressor. All three active substances raised pulmonary artery pressure and lowered central venous pressure. 5-HT reduced ventilation volume. Histamine caused brief apnoea followed by hyperpnoea only.2. Acute anaphylaxis in the horse was accompanied by a severe systemic arterial depressor response, a pressor response in the pulmonary artery and vena cava, and alternating phases of apnoea and dyspnoea.3. During anaphylaxis, profound haemoconcentration, leucopoenia, thrombocytopoenia and hyperkalaemia were in evidence. Early during anaphylactic shock (2 to 4 min) there were profound increases in plasma histamine (five to six-fold) and plasma kinin activity (four to five-fold). Plasma 5-HT concentrations were reduced initially but recovered. Later in anaphylaxis (10 to 20 min) whole blood histamine concentration fell significantly. This coincided with the most profound period of leucopoenia.4. No significant differences were observed in histamine concentration in any of five tissues between six ponies subjected to anaphylaxis and six controls. Mast cell numbers were not reduced but mast cells were more metachromatic (pink) and there was spilling of mast cell granules.5. Gross pathological changes were noted mainly in the lungs which were extensively oedematous and congested. Inflamed, congested and oedematous areas in the large colon and caecum were seen, and the kidneys, spleen and liver were engorged. Alveolar emphysema, peribroncheolar oedema (containing mononuclear cells and neutrophils) were recorded. Alveoli contained erythrocytes.

Histamine H2-receptors modulate systemic anaphylaxis: a dual cardiovascular action of histamine in calves.

Depressor changes in carotid blood pressure caused by histamine or anaphylaxis in calves, were incompletely blocked by the H(1)-receptor antagonist mepyramine. Burimamide, the selective histamine H(2)-receptor antagonist, potentiated the depressor actions of histamine and anaphylaxis. Potentiated depressor responses were inhibited by mepyramine. Observations are consistent with histamine stimulating both H(1)- and H(2)-receptors to cause respectively vasodilatation and vasoconstriction.

Pharmacology of Schultz-Dale reaction in canine lung strip in vitro: possible model for allergic asthma.

1 Isolated lung parenchymal strips of the dog contracted in response to histamine > carbachol > prostaglandin F(2alpha) (PGF(2alpha)) > bradykinin (Bk) > 5-hydroxytryptamine (5-HT). The order of the relative activity of these agents on the tracheobronchial smooth muscles (TBSM) was carbachol > 5-HT > histamine; PGF(2alpha) and Bk were inactive. Thus there are marked differences in the responsiveness of the smooth muscle of central (trachea and bronchus) and peripheral (lung strip) airways to autonomic and autacoid agents.2 Lung strips and TBSM partially contracted by carbachol, histamine or horse plasma, were relaxed by isoprenaline, PGE(1) and PGE(2).3 Lung strips from dogs sensitized to horse-plasma contracted in response to antigen (Schultz-Dale anaphylactic reaction). Tachyphylaxis or desensitization to subsequent antigen challenge was invariably observed; it was followed after 1 to 2 h of rest by partial recovery of the anaphylactic response.4 Mepyramine selectively antagonized responses to histamine without altering responses to carbachol and antigen.5 Metiamide, an H(2)-receptor antagonist, did not influence responses to histamine, carbachol or horse plasma.6 Indomethacin was found to be ineffective as an inhibitor of the Schultz-Dale anaphylactic reaction.7 The results showed the presence of H(1)-histamine receptors mediating constriction in the peripheral airways of the dog. Histamine and PGF(2alpha) appear to have no important role in the anaphylactic reaction in this tissue. The involvement of slow reacting substance of anaphylaxis (SRS-A) and endoperoxides (thromboxanes) in allergic reactions of canine lung is strongly suggested.

Acute systemic anaphylaxis in the calf.

1. Acute systemic anaphylaxis in calves was characterized by marked systemic hypotension; hypertension in the pulmonary arteries and abdominal vena cava, and transient apnoea. Calves responded with a second reaction to antigen, but a third anaphylactic response could not be evoked.2. Suppression of systemic anaphylaxis could not be effected with mepyramine, whereas methysergide or diethylcarbamazine each suppressed anaphylaxis by 50%. Disodium cromoglycate alone did not inhibit anaphylaxis: however, when disodium cromoglycate was combined with diethylcarbamazine almost total suppression (85%) was achieved. Sodium meclofenamate also was a powerful inhibitor of anaphylaxis (80%). It is tentatively suggested that slow reacting substance (SRS-A) may be an important mediator of bovine anaphylaxis.3. Bilateral vagotomy did not modify the circulatory responses to injected histamine, 5-hydroxytryptamine (5-HT) or antigen, whereas the effects of these agents on ventilation (apnoea) were abolished by vagotomy.4. Plasma histamine concentration was increased during anaphylaxis, whereas plasma 5-HT was not. Whole blood histamine concentration fell sharply and remained depressed during 20 min of anaphylactic shock. Reduced whole blood histamine levels probably reflect the severe leucopoenia in the calves.5. Histamine concentrations in six tissues taken from calves subjected to anaphylaxis were not different from those in control calves; mast cells were of similar numbers to controls, but showed some swelling, granular spilling and metachromasia.6. Histamine, 5-HT, bradykinin and antigen caused increased pulmonary artery perfusion pressure and ventilation resistance in isolated lungs from sensitized calves. However, there was no difference in histamine and 5-HT concentration in perfusates obtained during antigen infusion of sensitized and control lungs.7. Systemic anaphylaxis of calves may result from the interaction of histamine, 5-HT and SRS-A. The present data implicate (by indirect measurement) SRS-A as an important mediator of anaphylaxis in this species.

Anaphylactic contraction (Schultz-Dale reaction) of the bovine bronchial artery in vitro.

Bronchial arteries from sensitized calves contracted on antigenic challenge in the absence and presence of selected anti-allergic drugs and autonomic agents in vitro. Anaphylactic reactivity was inhibited by tripelennamine, isoprenaline and aminophylline, and potentiated by indomethacin and dopamine. Disodium cromoglycate, compound FPL 55712 and ketanserin failed to inhibit anaphylactic contraction.

Effects of histamine on bronchial artery blood flow and bronchomotor tone.

The effects of aerosolized 5% histamine (10 breaths) on bronchial artery blood flow (Qbr), airflow resistance (RL), and pulmonary and systemic hemodynamics were studied in mechanically ventilated sheep anesthetized with pentobarbital sodium. Histamine increased mean Qbr and RL to 252 +/- 45 and 337 +/- 53% of base line, respectively. This effect was significantly different from base line for 30 min after challenge. The histamine-induced increase in RL was blocked by pretreatment with the histamine H1 receptor antagonist, chlorpheniramine, whereas the histamine-induced elevation in Qbr was prevented by the H2 antagonist, metiamide. Both responses were blocked only when both antagonists were present. Changes in Qbr were not directly associated with alterations in systemic and pulmonary hemodynamics or arterial blood gas composition. In vitro histamine caused a dose-dependent contraction of ovine bronchial artery strips that was prevented by H1 antagonist. The H2 agonist, impromidine, caused relaxation of precontracted arterial strips and was more potent and efficacious than histamine, whereas H1 agonists failed to elicit a relaxant response. Thus these findings indicate that histamine aerosol induces a vasodilation in the bronchial vascular bed; histamine has a direct effect on Qbr that is independent of alterations in RL, systemic and pulmonary hemodynamics, or arterial blood gas composition; and, histamine-induced bronchoconstriction is mediated predominantly by H1-receptors, whereas increased Qbr is controlled predominantly by H2-receptors, probably located in resistance vessels. This local effect of histamine on Qbr may have important implications in the pathophysiology of bronchial asthma and pulmonary edema.