Histamine-releasing effect of a corticotrophin derivative. II. Mechanism of action of histamine release by C 44 680-Ba, compared with that of Cpd. 48/80, dextran and triton.

The mechanism of the histamine-liberating action of the synthetic polypeptide C 44 680-Ba, an alkyl-prolyl derivative of beta 1-19 corticotrophin, was investigated and compared with those of Compound 48/80, dextran, Melittin and Triton X-100. It was found that the release of histamine from rat peritoneal cells induced by the polypeptide is dependent on temperature, pH, calcium ions and energy-providing processes. In regard to these criteria, the mode of action of this histamine liberator resembles that of Compound 48/80 but is quite distinct from that of the unspecific substance Triton X-100.     

The effects of histamine liberators and exogenous histamine on wound healing in rat.

The effects of compound 48/80, adenosine-5-triphosphate (ATP) and exogenous histamine (Hi) on the healing of excised surface wound and tensile strength of surgical skin wound in rat were studied. The chemicals were injected directly into the wound area. 48/80, ATP and exogenous Hi were found to stimulate the wound healing as measured by collagen formation, tensile strength examination and a measurement of the surface circular wound. When given separately, the order of activities was: 48/80 is greater than ATP is greater than Hi; when administered together as a mixture, compound 48/80, ATP and exogenous Hi also accelerated the wound healing. The mixture shortened the healing process by about 5 days as compared with 17 days in control.     

The mast cells of the newborn rat diaphragm and their response to histamine liberators.

The mast cell population of rat diaphragm was estimated between birth and adulthood and found to rise with an increase in the age of rat studied. Degranulation of these cells was observed in rats from all age groups, following treatment with compound 48/80 and dextran. The association of mast cells with the blood vessel wall in adult rat diaphragm was not observed in the comparable tissues of newborn rats. These findings are discussed in relationship to the poor vascular permeability reactions exhibited by newborn and young rats.     

Cardiac versus vascular effects of a new dihydropyridine derivative, CV-4093. In vitro comparison with other calcium antagonists

The effects of CV-4093, a new dihydropyridine derivative, on isolated cardiovascular tissues were compared with those of several dihydropyridine and non-dihydropyridine calcium antagonists. CV-4093 effectively inhibited the contractions induced in canine femoral arteries by high [K+]0 and Bay K 8644, but incompletely relaxed those induced by norepinephrine. CV-4093, 10(-6) M, abolished the electrically induced slow action potentials in guinea-pig papillary muscles partially depolarized by 25 mM K+ solution and attenuated those induced by isoproterenol, histamine and Bay K 8644. The rank order of potency of dihydropyridine and non-dihydropyridine calcium antagonists in canine femoral arteries and veins precontracted with 120 mM [K+]0 was as follows: nisoldipine greater than nicardipine greater than or equal to nifedipine greater than or equal to CV-4093 greater than verapamil greater than or equal to diltiazem. Nisoldipine was the most potent and CV-4093 was the least potent among these drugs in terms of negative inotropic effect in normally polarized papillary muscles and negative chronotropic effect in right atria of guinea pigs. The rank order of potency for these cardiodepressant actions was nisoldipine greater than or equal to nifedipine greater than nicardipine greater than verapamil greater than diltiazem greater than or equal to CV-4093. The duration of action potential in guinea-pig papillary muscles was shortened by nisoldipine and nifedipine, unchanged by nicardipine and CV-4093 and was slightly prolonged by verapamil and diltiazem. These results suggest that CV-4093 is a calcium antagonist with a highly selective vascular effect and little cardiodepressant action, and could be of value for the treatment of hypertension.     

Inhibitory effect of beta-adrenergic stimulants on the histamine reaction in human skin. I. Studies with fenoterol.

In 20 volunteers histamine inhibition by fenoterol (Th 1165 a) was studied. The wheal and erythema reaction caused by intracutaneous application of 5 mug histamine can be inhibited by applying fenoterol in doses from 100--400 mug in form of a metered aerosol on the skin 5 min before the injection of histamine. In this study the dose-reaction effect yielded on ED50 of 140 mug fenoterol.     

Acetylation phenotype status in a Bangladeshi population and its comparison with that of other Asian population data

The objective of the present study was to determine the acetylator status of the Bangladeshi population and to compare the findings with the acetylator status of other Asian populations. The acetylator phenotype was determined in 517 unrelated healthy Bangladeshi subjects. The phenotyping procedure was done according to Price Evans' method using the NAT2 specific probe drug--sulphadimidine. The Bangladeshi population showed a bimodal distribution of fast and slow acetylators. Of a total of 517 healthy Bangladeshi, 79.5% (n=411) were fast acetylators and the rest 20.5% (n=106) were slow acetylators. The high frequency of the fast acetylators in the population of Bangladesh was comparable to other populations in East Asia. When this acetylator status was compared with other Asian data, the Asian population showed a positive correlation between the acetylator status and the geographical longitude (r=0.919; t=7.37; p>0.001; d.f.=10). The regression line of the scatter diagram showed that the frequency of acetylating capacity increasingly occurred in the populations towards eastern Asia (regression coefficient=0.54; constant=52.36). This line was termed as the Asian fast acetylator longitude (AFAL). Thus the AFAL was able to predict the acetylator status of the Asian population by the east-west geographical longitude. The AFAL could be a useful prognosticator in the disposition for the effective and safe use of numerous drugs and xenobiotic compounds in humans.     

Neurotransmitter mechanism of the tropoxin effect in comparison with other antimigraine preparations

The results of experiments on cats showed that tropoxin produces no adreno- and cholinoblocking action and possesses no antihistamine properties. A comparative study of the antiserotonin cerebrovascular effect of tropoxin and some other well-known antimigraine drugs showed that tropoxin not only attenuates cerebrovascular constriction response to serotonin, but distorts these reactions so as to reduce the tone of cerebral vessels. An analogous antiserotonin activity was also observed for methysergide, dihydroergotamine, nicergoline, and (to a lower extent) tolfenamic acid, while propranolol inhibited serotonin reactions only in 50% of cases. The 5HT2 receptor blocker ketanserin significantly reduces the cerebrovascular effects of serotonin, while the 5HT3 receptor blocker tropisetron shows no such activity.     

The role of histamine in wound healing I. The effect of high doses of histamine on collagen and glycosoaminoglycan content in wounds.

The effect of high doses of histamine (Hi) on collagen and glycosoaminoglycan (GAG) content in skin wounds of rats was studied on days 1, 3, 5, 10 and 14 after wounding. Injection of high doses of Hi into the wounded area inhibited colagen production, collagen polymerization and GAG synthesis; levels of chondroitin sulphates (chondroitin-4,6-sulphate and dermatan sulphate) and hyaluronic acid were decreased.     

Inhibitory effect of egualen sodium: a new stable derivative of azulene on histamine release from mast cell-like cells in the stomach.

We studied the inhibitory effect of egualen sodium (ES) (sodium 3-ethyl-7-isopropyl-1-azulenesulfonate 1/3 hydrate, KT1-32), a new derivative and more stable compound than azulene, on histamine release from the mucosal histaminocytes and elucidated the mechanism for this action. ES prevented the histamine release from isolated mast cell-like cells of the guinea pig stomach induced by A23187 in a dose-dependent fashion. ES dose-dependently inhibited the histamine release from lung pieces of sensitized guinea pigs induced by an antigen-antibody reaction. ES also inhibited histamine release from rat peritoneal mast cells induced by compound 48/80 or antigen-antibody reaction. ES exhibited the membrane stabilizing activity on DPPC liposomes. These findings suggest that ES may prevent histamine release from histaminocytes induced by various stimuli and the stabilizing action of the cell membrane may be responsible for the inhibition of histamine release.     

Evidence for a PCN-P450 enzyme in chickens and comparison of its development with that of other phenobarbital-inducible forms

Of four monoclonal antibodies to purified rat liver cytochrome P450s, including those from 3-methylcholanthrene-, phenobarbital-, ethanol-, and pregnenolone-16-alpha-carbonitrile-treated rats, only the monoclonal antibody against pregnenolone-16-alpha-carbonitrile-inducible P450 immunodetected proteins in chicken liver microsomes after blotting from sodium dodecyl sulfate-polyacrylamide gels. This protein migrated identically with the pregnenolone-16-alpha-carbonitrile-inducible P450 detected in microsomes from dexamethasone-treated rats. It was most predominant in liver microsomes from chickens at 1 day posthatching, whereas much lower levels were observed in the embryo and at 36 days posthatch. Phenobarbital and dexamethasone were both effective inducers of this protein. The developmental profile and induction by phenobarbital and dexamethasone of several cytochrome P450-associated catalytic activities were compared with those of the immunodetected protein. Chicken liver microsomal erythromycin demethylase, a characteristic activity of rat pregnenolone-16-alpha-carbonitrile-inducible P450, was similar in developmental profile and induction to the immunodetected protein, with a high degree of augmentation at 1 day posthatch compared with that in the embryo and at 36 days posthatch; aldrin epoxidase, benzphetamine demethylase, ethylmorphine demethylase, and aminopyrine demethylase were more similar to each other in development and induction and were less well correlated with the immunodetected protein. This evidence suggests the presence in chicken liver of at least two types of P450, one a form related to the pregnenolone-16-alpha-carbonitrile-inducible P450 family. All of the catalytic activities were induced after pretreatment of chickens with phenobarbital but aldrin epoxidase was most effectively induced. Aldrin epoxidase was also detected in microsomes from untreated embryos as early as 7 days of incubation. Erythromycin demethylase was the only catalytic activity induced by dexamethasone. There was a trend of increased specific activity toward all the substances after hatching, indicating a more efficient P450 system, possibly due to a sharp increase in some isozymes, including the form from the pregnenolone-16-alpha-carbonitrile-inducible P450 family. This evidence for a pregnenolone-16-alpha-carbonitrile-inducible P450 in chickens agrees with sequence information that suggests the early evolution of this form and demonstrates the suitability of the chicken for studies of P450 evolution.