beta-Adrenergic receptors in aged rat brain: reduced number and capacity of pineal gland to develop supersensitivity.

The density but not the affinity of beta-adrenergic receptors declined significantly with age in rat pineal gland, corpus striatum, and cerebellum, as determined by the binding of tritiated dihydroalprenolol. Exposing rats to light for 12 hours increased the binding of this radioligand in 3-month-old but not in 24-month-old rats. The reduced responsiveness to catecholamines seen in aging may be due to a decrease in the number of beta-adrenergic receptors which, in turn, may be caused by an impaired capacity of receptors in aged animals to adapt to changes in adrenergic neuronal input.

Effect of age on the rate of recovery of beta-adrenergic receptors in rat brain following desmethylimipramine-induced subsensitivity.

Brain tissues from aged rats have an impaired ability to increase beta-adrenergic receptors in response to reduced noradrenergic input, but can down-regulate these receptors in response to repeated administration of desmethylimipramine (DMI). In this study we compared the ability of brain tissues from young (3-month) and aged (20- to 26-month) rats to restore their density of beta-adrenergic receptors following desmethylimipramine (DMI)-induced receptor subsensitivity. Either DMI or saline was administered i.p. twice daily for 7 days to groups of young and aged rats. At various times after drug administration [3H]dihydroalprenolol (DHA) binding was determined in homogenates of pineal gland and cerebral cortex. Four hours after the last dose of DMI there was a decrease in DHA binding in both brain areas of young and aged rats. In young rats DHA binding in these tissues returned to control levels by 2 days after DMI administration. In contrast, in aged rats it took 8 and 16 days for DHA binding to recover in cerebrum and pineal, respectively. The concentration and half-life for the disappearance of DMI from serum and cerebrum were significantly greater in aged rats than in young rats, but the differences do not entirely explain the delayed recovery of beta-receptors in the aged rats. The results suggest that beta-adrenergic receptors of brain tissues from aged rats cannot recover from beta-receptor subsensitivity as readily as those from young rats. If this recovery process requires the synthesis of new receptors, then this synthetic mechanism may be impaired with age.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonsurgical management of unruptured ectopic pregnancy: an extended clinical trial.

Unruptured tubal pregnancies diagnosed at laparoscopy were treated with either methotrexate/citrovorum factor (MTX/CF) (n = 21) or observation (n = 5). Entry criteria required that the ectopic pregnancy be visualized, less than or equal to 3 cm in diameter, with intact serosa and no active bleeding. Treatment selection was based upon preoperative levels of beta-human chorionic gonadotropin (beta-hCG), with MTX/CF given to subjects exhibiting a plateaued or rising pattern and observation alone given to those with falling levels. Twenty-five of 26 ectopic pregnancies resolved without need of laparotomy. Two subjects received blood transfusions and one required a second operation for intra-abdominal bleeding. In both cases, fetal cardiac activity was noted pretreatment on ultrasound. The authors conclude the following: (1) MTX/CF may be safely used to treat selected unruptured ectopic pregnancy; (2) many ectopic pregnancies resolve spontaneously; and (3) ectopic pregnancies that form fetal elements, as evidenced on ultrasound, should not be managed medically.

Are human luteinizing granulosa cells a site of action for progesterone and relaxin?

Specific nuclear staining for progesterone receptor (PR) was detected by immunocytochemistry in human granulosa cells (GCs) obtained from in vitro fertilization protocols. The percent of PR-positive cells (60% to 80%) remained unchanged during 7 days of culture in media containing fetal calf serum, in the absence or presence of human chorionic gonadotropin (hCG) or the progesterone antagonist RU486. Progesterone (P) production by GCs cultured on extracellular matrix from bovine corneal endothelial cells was stimulated by hCG and prostaglandin E2 (PGE2). However, addition of RU486 or human relaxin had no effect on control, hCG-, or PGE2-stimulated P production. Thus, the receptor data are consistent with an autocrine action of P in luteinizing GCs, but initial experiments in cell culture did not define a role for P or relaxin in modulating luteal steroidogenesis.

Regulation of brain adrenergic receptors during aging.

Recent studies in our laboratory suggest that the synthesis of alpha- and beta-adrenergic receptors in certain tissues from brain and pineal gland may be impaired with age. This decreased ability of the aged brain to synthesize adrenergic receptors may explain the loss of these receptors in selected brain regions during the aging process, as well as the reduced capacity of aged brain tissue to increase or up-regulate the density of these receptors in response to reduced noradrenergic activation of the tissues or to reduced estrogen levels. The reduced adaptability of brain adrenergic receptors, in turn, may account for the decreased ability of aged individuals to adjust their physiological responses to a changing environment.

Modulation of beta-adrenergic receptors and calmodulin following acute and chronic treatment with neuroleptics.

Neuroleptic drugs have several acute and chronic actions on biochemical mechanisms of brain: (a) Acutely they block the action of catecholamines on the adrenergic receptor-adenylate cyclase complex, thereby preventing the catecholamine-induced rise in cyclic AMP. (b) With long-term treatment they appear to produce a compensatory induction of these adrenergic receptors. (c) Neuroleptics also bind to an endogenous calcium-dependent protein, termed calmodulin, whichis found in high concentrations in the CNS. This binding is relatively specific for clinically-effective neuroleptics of diverse chemical structure. (d) The binding of neuroleptics to calmodulin can explain several of their biochemical actions and suggests that some of the pharmacological and clinical effects of neuroleptics may also be explained by this same common mechanism.

Ability of aged rats to alter beta adrenergic receptors of brain in response to repeated administration of reserpine and desmethylimipramine.

Repeated administration of reserpine to 3-month-old rats produced dose-related increases in [3H]dihydroalprenolol (DHA) binding in pineal gland, cerebral cortex and cerebellum. Reserpine increased DHA binding by increasing the density of beta adrenergic receptors. Brain tissue from 24-month-old rats, however, had an impaired ability to increase receptor density in response to reserpine treatment, even in the pineal gland where the concentration of reserpine was nearly 7 times that found in the glands of young rats given the same dose on the basis of body weight. Repeated administration of desmethylimipramine decreased DHA binding in pineal glands by about 50% and in cerebral cortices by about 25%, but did not alter DHA binding in the cerebellum. The magnitude of these changes was similar in the 3- and 24-month-old rats, although the concentration of desmethylimipramine in the pineal glands and cerebral cortices of the aged rats was significantly higher than that of the young animals. The results indicate that the reserpine-induced decrease in noradrenergic input causes a compensatory increase in beta adrenergic receptor density in rat brain. They suggest further that although aged rats can decrease receptor density in response to increased adrenergic input, they have an impaired ability to increase beta adrenergic receptor density in response to decreased adrenergic input. This finding may explain the decreased density of beta adrenergic receptor found in aged rat brain.

Fluoroscopic radiation measurement in Saskatchewan.

A mail-out thermoluminescent dosimeter (TLD) system has been used to measure fluoroscopic surface dose rates very 8 weeks in Saskatchewan hospitals since 1976. Incentive for the program came from Saskatchewan radiologists. The mean of the annual dose rates for all units was 30.8 mGy/min (3.08 rads/min). Each year, 30% of the machines varied in output by 100% or more, 8% by 200% or more, and one machine's output increased by 800%. These measurements have allowed prompt correction of excessive dose levels or replacement of offending machines when the dose rate could be lowered sufficiently. No significant difference in surface dose rates between manually controlled units and units with automatic brightness control was found.

Ovarian response in superovulated cycles after suppression with oral contraceptive steroids.

The endocrine response to controlled ovarian hyperstimulation was reviewed in 94 women undergoing in vitro fertilization during 114 cycles. The purpose of this review was to evaluate the effect of short-term oral contraceptive suppression on the recovery of pituitary gonadotropin function and subsequent controlled ovarian hyperstimulation. Seventy-three cycles (64%) were adequate for oocyte retrieval. In 41 cycles (36%) hyperstimulation was discontinued. The serum 17 beta-estradiol value in women with a poor response was 57 +/- 50 pg/ml on day 8 compared with 376 +/- 334 pg/ml in the women who completed in vitro fertilization (p less than 0.05). The majority of women (84.2%) had a prompt response to controlled ovarian hyperstimulation after short-term oral contraceptive suppression. Most discontinuations were due to dominant follicle selection or luteinizing hormone surge and not to oversuppression by short-term oral contraceptives. Clinical pregnancies occurred in 15 women (20.5% of harvests).

Denervation supersensitivity and beta-adrenergic receptors as a function of age.

The density and ontogenetic development of beta-adrenergic receptors varies in the different brain areas. The density of receptors in pineal gland, which at maturity is the highest of the brain areas studied, increases rapidly soon after birth, whereas the density of beta-receptors in cerebellum does not increase from birth. This development of beta-receptors in pineal gland is temporally related to the development of the sensitivity of adenylate cyclase to norepinephrine. Preventing the sympathetic innervation to the pineal gland before it has ever been innervated does not impede development of beta-adrenergic receptors. That is, the beta-receptors can develop in the absence of sympathetic input to the gland. In fact, reducing sympathetic input, particularly after the receptors have developed, causes an increase in the number of beta-adrenergic receptors and a concomitant increase in the response of adenylate cyclase to norepinephrine. With advanced age the number of beta-adrenergic receptors declines in several areas of the brain. This reduction may explain the reduced ability of aged tissue to respond to adrenergic agonists. The mechanism for this decrease in beta-adrenergic receptors with age may be related to a reduced ability of aged tissues to produce compensatory increases in their receptor density in the face of decreased sympathetic input.

Impaired recovery of alpha 1- and alpha 2-adrenergic receptors in brain tissue of aged rats.

The influence of age on the rate of recovery of alpha 1- and alpha 2-adrenergic receptors was determined in rat brain following their irreversible inhibition by phenoxybenzamine (PBZ). Fischer 344 rats (3- or 24-months old) were administered two doses of vehicle or PBZ at 12-hour intervals. At various times after the last dose of PBZ, alpha-adrenergic receptors were quantified in washed membranes of cerebral cortex and hypothalamus, using [3H]prazosin and [3H]rauwolscine to label alpha 1- and alpha 2-adrenergic receptors, respectively. Recovery of prazosin binding sites in cortex and hypothalamus and of rauwolscine binding sites in cortex was significantly delayed in aged versus young rats. Administration of [3H]PBZ to young and aged rats revealed no apparent differences in the concentration or rate of disappearance of PBZ or its metabolites that could account for these age-related changes. These data suggest that the synthesis of both alpha 1- and alpha 2-adrenergic receptors is impaired in brain tissue from aged rats.

Nonsurgical management of unruptured isthmic ectopic pregnancy: preliminary experience.

Five unruptured isthmic tubal pregnancies diagnosed at laparoscopy were treated with either methotrexate/citrovorum factor rescue (MTX/CF) (n = 4) or observation alone (n = 1). Entry criteria required that the ectopic be fully visualized, no greater than 3 cm in diameter, with intact serosa, and without active bleeding. Treatment selection was based upon preoperative levels of beta-hCG with MTX/CF given to subjects exhibiting a plateaued or rising pattern and observation alone given those with falling levels. Subjects were followed with serial measurements of beta-hCG, complete blood counts, and liver function tests. In all subjects the ectopic pregnancy resolved without further surgery. Time to resolution (first day of treatment to undetectable beta-hCG) ranged from 12 to 55 days. Of the five subjects studied, follow-up hysterosalpingograms in four demonstrated tubal patency on the side of the ectopic gestation.