摘要:

The bronchodilator activities of AY-22093, prostaglandin E2(PGE2), and isoproterenol were compared usingin vivoandin vitrotechniques. In the conscious guinea pig, an aerosol of AY-22093, PGE2, and isoproterenol afforded significant protection against histamine-induced bronchospasm; AY-22093 and isoproterenol were equally effective in protecting against antigen-induced anaphylaxis. In the anesthetized guinea pig, using the Konzett and Rössler technique, PGE2(1 μg/kg, intravenously (i.v.)) inhibited the bronchoconstriction induced by histamine (10 μg/kg, i.v.) by 63% as compared with 37% inhibition after AY-22093 (1 μg/kg, i.v.). Larger intravenous doses of PGE2and AY-22093 (10 and 20 μg/kg) caused almost complete inhibition of the histamine-induced bronchoconstriction. The administration of PGE2(0.5–10 μg) or AY-22093 (5–100 μg) by aerosol inhibited the bronchoconstriction induced by histamine (10 μg/kg, i.v.) by 20–70%. Maximum bronchodilator effects occurred within 3 min and lasted for as long as 30 min after either route of administration. Both compounds caused a fall in blood pressure after intravenous but not after aerosol administration. AY-22093 relaxed the guinea pig tracheal strip where tone was induced by carbachol. This relaxation was not altered by propranolol. The results indicate that AY-22093 is a bronchodilator qualitatively similar to PGE2, having a direct effect on smooth muscle but less potent than PGE2.

ISSN:0008-4212    

DOI:10.1139/y74-001

出版商:NRC Research Press    

年代:1974

数据来源: NRC

摘要:

The study of the turnover characteristics of adrenocorticotropin (ACTH) has been facilitated by (1) a sensitive bioassay for ACTH in plasma based upon the response of suspended adrenal cells to ACTH and (2) a technique for preserving the ACTH in small plasma samples. The metabolic clearance rate (MCR) of ACTH was determined by intravenous step infusions of ACTH into dogs lightly anesthetized with Nembutal, without blockade of ACTH secretion; in these dogs the endogenous plasma ACTH level was negligible. The infusion rates ranged from 0.25 to 3.0 mU/kg∙min, yielding plasma ACTH plateau concentrations of 1.8 to 37 mU/100 ml. In no dog did the MCR correlate significantly with plasma concentration, nor did the MCR differ significantly from dog to dog. The 34 successful plateaux yielded a mean MCR of 9.54 ± 0.24 ml/kg∙min. Linear regression of MCR versus concentration yielded a correlation coefficient of −0.00026. The findings showed that the disappearance of ACTH from blood is not dose-dependent and varies negligibly with time or among animals. Hence the measured MCR may be used to convert concentrations of ACTH in plasma into turnover ra

ISSN:0008-4212    

DOI:10.1139/y74-002

出版商:NRC Research Press    

年代:1974

数据来源: NRC

摘要:

Impairment of testosterone metabolism or excretion has been found in some patients with essential hypertension (Nowacynskiet al. Can. J. Biochem. (1968),46, 1031–1038). The effects of testosterone (10 mg/kg, intramuscular (i.m.)), methyltestosterone (10 mg/kg, i.m.), and vehicle on heart rate, arterial pressure, and responses of perfused canine hindpaws to intra-arterial norepinephrine (0.1–3.0 μg), tyramine (50 and 200 μg), angiotensin (0.1, 0.3, and 1.0 μg), and nitroglycerin (10 and 100 μg) were studied in three groups of dogs (five per group), 5 days after single doses of androgen or vehicle. Plasma and tibial artery electrolytes were also measured. After testosterone, heart rate (157 ± 5 beats/min) was higher than in control dogs after vehicle (132 ± 6 beats/min). Mean arterial pressure was similar in the two groups. Methyltestosterone-treated dogs had a significantly greater heart rate (160 ± 8 beats/min) than vehicle-treated animals. However, mean arterial pressures were similar in the two groups. A second series of dogs that received propranolol (1 mg/kg) 30 min before evaluation of heart rate showed no significant differences in heart rate among the treatment groups. Mean arterial pressures were similar in the three experimental groups. Pressor responses (expressed as the percentage change in perfusion pressure from the base line) to norepinephrine and tyramine were significantly enhanced after testosterone treatment. Pressor responses to angiotensin- and nitroglycerin-induced vasodilatation were unchanged after testosterone treatment when compared with vehicle controls. Pressor responses to tyramine, but not to norepinephrine, were also enhanced after methyltestosterone when compared with control responses after vehicle. Responses to angiotensin and nitroglycerin were similar in the two groups of animals. Plasma and tibial artery electrolytes were not different in the three experimental groups. These data suggest that single doses of androgen sensitized these animals to exogenously administered and endogenously released catecholamines. The effects were not mediated by sodium retention or altered plasma or tissue calcium concentrations.

ISSN:0008-4212    

DOI:10.1139/y74-003

出版商:NRC Research Press    

年代:1974

数据来源: NRC

摘要:

The inotropic and chronotropic effects of histamine on the isolated perfused guinea pig heart were antagonized by promethazine over a concentration range 4 × 10−6– 16 × 10−6 M. Promethazine (4 × 10−6 M) decreased the ability of histamine (1 μg) to elevate cardiac cyclic AMP. A higher dose of histamine could not overcome the promethazine blockade. Promethazine (4 × 10− 6 M) did not block the inotropic effect of noradrenaline. Higher concentrations of promethazine, particularly 16 × 10−6 Mdid decrease the noradrenaline response. The data indicate that promethazine can interact with cardiac histamine receptors but the interaction is either noncompetitive or competitive non-equilibrium in nature.

ISSN:0008-4212    

DOI:10.1139/y74-004

出版商:NRC Research Press    

年代:1974

数据来源: NRC

摘要:

An assay procedure for the metabolism of14C-imipraminein vitrois described. Using female mouse liver as the enzyme source, the conditions of the assay have been determined for the formation of 2-hydroxyimipramine, desmethylimipramine, and imipramine-N-oxide. Demethylation was linear up to a substrate concentration of 120 μg/3.5 ml,N-oxidation was linear up to a concentration of imipramine of 70 μg/3.5 ml, and hydroxylation up to 20 μg/3.5 ml of reaction mixture. Desmethylimipramine competitively inhibited both hydroxylation and demethylation, whereas imipramine-N-oxide had no effect. Pretreatment of mice with norethindrone decreased hydroxylation, and increased demethylation. Cytochrome P-450 was also increased by this progestin;N-oxidation was not changed. The effects of concurrent administration of norethindrone with known inducers or inhibitors of drug metabolism have been determined. From these experiments, it was concluded that the induction of cytochrome P-450 by norethindrone is not responsible for the increased demethylation of imipramine. Rather, it appeared that competitive inhibition of hydroxylation of imipramine by the norethindrone allowed more of the drug to be demethylated.

ISSN:0008-4212    

DOI:10.1139/y74-005

出版商:NRC Research Press    

年代:1974

数据来源: NRC

摘要:

Aspartic acid was replaced in position 1 of angiotensin II (ATII) with several amino acids, to assess the possible influence of the N-terminal amino acid for (a) the intrinsic activity, (b) the affinity, and (c) the metabolic degradation of agonist analogues of ATII. Some of the substitutions in position 1 were used in combination with replacement of Phe by Gly or Leu in position 8, to obtain the corresponding antagonist.The compounds were testedin vivo(rat blood pressure) and in twoin vitropreparations (rat stomach and rabbit aorta strips). The oil immersion technique, described by Kalsner and Nickerson (1968) (Can. J. Physiol. Pharmacol.46, 719–730), was used to study the disposition of the peptides by vascular smooth muscles (rabbit aorta strips). Degradation of the peptides by purified aminopeptidases was evaluatedin vitroby measuring the fragments on paper chromatography. Potency of antagonists was estimatedin vivo(ID50) andin vitro(pA2values): duration of action was established by infusing the inhibitors intravenously into anesthetized rats and testing the effect of standard doses of angiotensin before and after.The results indicate that replacement of Asp with other amino acids does not influence the intrinsic activity, but can either increase or decrease the affinityin vitroor the potencyin vivo. 1-Sar-ATII, and 1-D-Ala-ATIIare more potent and longer acting than 1-Asp-ATIIon isolated intestinal and vascular smooth muscles, but notin vivo. On the contrary, 1-β-Asp-ATIIand 1-β-D-Asp-ATIIare more potent than 1-Asp-ATIIin vivo, but not on rabbit aorta strips. Rate of relaxation of rabbit aorta strips suspended in oil, after contraction with submaximal doses of several analogues of ATII, are significantly slower than relaxation after 1-Asn2-ATIIand 1-Asp-ATII. A close parallelism between the diminution of the relaxation rate in oil and the degradation by aminopeptidesesin vitrowas observed, suggesting that metabolic degradation may be the major factor determining relaxation of rabbit aorta in oil after contraction with one of these peptides. Potencies of antagonistsin vivoandin vitroare increased by replacing Asp with Sar. Substitution of Asp with β-Asp or β-D-Asp brings about a slight increase of potencyin vivobut notin vitro. It appears that firm binding and prolonged occupation of receptors by sarcosyl derivatives are the primary factors contributing to increase the potency and to prolong the duration of action of antagonists, while prevention or reduction of metabolic breakdown by aminopeptidases is much less efficient.

ISSN:0008-4212    

DOI:10.1139/y74-006

出版商:NRC Research Press    

年代:1974

数据来源: NRC

摘要:

The action of angiotensin II (ATII) and of several analogues, including antagonists, has been studied on isolated perfused rabbit hearts. Changes of transmembrane potential have been recorded from atrial and ventricular fibers with floating microelectrodes.ATII, heptapeptide (2–8), and 1-Sar-ATIIincrease the amplitude of contraction and prolong the P–R interval of the electrocardiogram. High doses of ATIIand heptapeptide (2–8), but not of 1-Sar-ATII, decrease heart rate. Inhibitory analogues (8-Gly-ATII, 1-Sar,8-Gly-ATII) are inactive on tension but prolong slightly the P–R interval.The plateau phase of the action potential (A.P.) in atrial fibers is significantly prolonged by ATII, heptapeptide (2–8) and 1-Sar-ATII, while antagonists do not produce any change. The plateau phase of ventricular cells is similarly prolonged by ATIIand heptapeptide (2–8); the other analogues were not tested.Hearts taken from reserpinized rabbits respond to ATIIand heptapeptide (2–8) with similar changes of tension and transmembrane potential as the hearts of non-treated rabbits.The effects of ATIIand heptapeptide (2–8) are inhibited by relatively small doses of 8-Gly-ATIIand 1-Sar,8-Gly-ATII; inhibition by 8-Gly-ATIIis surmountable with ATII.The results indicate that (a) ATIIand heptapeptide (2–8) have a direct effect on the myocardium, (b) this effect is antagonized by position 8 substituted analogues of ATIIthat inhibit the action of ATIIon smooth muscles andin vivo, and (c) changes of tension of myocardial fibers are accompanied by an increased duration of A.P. plateau phase.

ISSN:0008-4212    

DOI:10.1139/y74-007

出版商:NRC Research Press    

年代:1974

数据来源: NRC

摘要:

The effect of potassium replacement by cesium in the rat diaphragm preparations has been investigated using conventional intracellular recording techniques; end-plate potentials (EPP's) recorded in modified Krebs' solution with lowered Ca2+and high Mg2+were increased until twitching in response to indirect stimulation was restored. This increase in amplitude of the EPP was not acccompanied by any change in the magnitude or frequency of miniature end-plate potentials (MEPP's) suggesting that Cs+is acting presynaptically to increase evoked release of transmitter. Similar augmentations of EPP's were observed in preparations paralyzed withd-tubocurarine, gallamine, pancuronium, or decamethonium. Parallel studies showed that the mechanical response of the preparations returned towards control values after K+substitution by Cs+in diaphragms that were blocked by the above agents but not those blocked by hemicholinium.The results are consistent with the conclusion that the presynaptic action of cesium can overcome directly any effect that the clinically used blocking agents may have on presynaptic sites and that the increased release of transmitter by cesium is sufficient to overcome indirectly the depressant effects of the blocking agents at postsynaptic end-plate receptors.

ISSN:0008-4212    

DOI:10.1139/y74-008

出版商:NRC Research Press    

年代:1974

数据来源: NRC

摘要:

Determinations of noradrenaline (NA) content and observations of histochemical fluorescence were carried out on the axillary brown fat pad of ground squirrelsCitellus richardsoniikept at two temperatures, 20 °C and 5 °C. For comparison, NA content of hearts and intrathoracic brown adipose tissue were also determined. Like interscapular brown adipose tissue from cold-acclimated rats, the axillary brown fat of cold-acclimated ground squirrels contained a high level of NA. The NA content of the fat pad from ground squirrels living at 20 °C, however, though somewhat lower was not statistically different from that of the fat pad from the cold-acclimated animals. Fine adrenergic nerve fibers were observed between the adipocytes and more intense and extensive networks were present around arterioles. The density of adrenergic innervation appeared similar in the axillary brown fat of the two groups. The NA content of the hearts of ground squirrels living at 5 °C was lower than that for hearts from animals at 20 °C. Intrathoracic brown fat tissue from both groups of animals showed large variation.

ISSN:0008-4212    

DOI:10.1139/y74-009

出版商:NRC Research Press    

年代:1974

数据来源: NRC

摘要:

In order to investigate the phenomenon of "tubal locking" of ova, thein vitrocontractility of circular rings from the rabbit oviductal isthmus was examined in different hormonal states. Both alpha and beta adrenergic receptors were found to be present in this preparation with predominance of the alpha receptors when the tissues were from either estrogen- or progesterone-dominant animals.Progesterone treatment of estrogen-primed, immature females influenced the dose–response curve of the circular oviductal muscle to norepinephrine, significantly shifting it to the right, in comparison with tissues from animals that had been treated with estrogen only. There was less of a shift when dose–response relations were determined for phenylephrine after beta receptor blocked with propranolol, suggesting that progesterone enhanced the responses of beta compared with alpha receptors. However, there was still a small difference between responses of estrogen- and progesterone-dominated tissue, at least at low concentrations. Since beta receptor activity had been effectively eliminated, this tendency suggests that progesterone's effect on the response to norepinephrine is not completely due to a modification in beta receptor activity.The spontaneous contractility of tissues from estrogen-treated animals was characterized by a series of rapid spike-like contractions with fairly consistent shape and frequency. Additional treatment with progesterone modified the pattern to an irregular one. Moreover, the total spontaneous activity of muscle from estrogen-dominant animals (as measured by the area under the contractility curve) was significantly reduced, and the rate of tension increase was considerably slower than that from animals with progesterone as the dominant hormone. This indicated a form of antagonism to estrogen by progesterone not involving adrenergic receptors.Maximal excitation of the strips with nonspecific agents or adrenergic agonists resulted in significantly less activity in tissues from progesterone-treated animals. The mechanism of action of progesterone to produce this effect probably involves a step or steps in the excitation–contraction process beyond the adrenergic receptors.

ISSN:0008-4212    

DOI:10.1139/y74-010

出版商:NRC Research Press    

年代:1974

数据来源: NRC