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Biomedical subjects

M R Warner

Publications and source records attributed to M R Warner.

At least 37 records · Page 2Linked to original sources
PubMed1986

Beat-by-beat modulation of AV conduction. I. Heart rate and respiratory influences.

We examined the integration of heart rate and neural influences at the atrioventricular (AV) node in conscious dogs. Animals were anesthetized and, under sterile conditions, instrumented to chronically record atrial and ventricular electrograms and blood pressure. In the conscious state, electrocardiogram (ECG), respiration, blood pressure, and electrograms were recorded on a beat-by-beat basis, and heart rate and AV interval were plotted graphically as a function of time. Resting animals exhibited both respiratory sinus arrhythmia and marked oscillations in AV conduction time associated with respiration. During inspiration AV interval was shortened, and during expiration AV interval was prolonged. To obviate the effect of cyclic changes in heart rate, atrial pacing was used to increase heart rate over a wide range both abruptly and linearly. Regardless of the pattern of heart rate change, AV interval oscillated at the respiratory frequency at pacing rates 10-100 beats/min above control. Higher levels of atrial pacing resulted in AV conduction patterns that were correlated with changes in blood pressure. Thus in the conscious dog variations in AV conduction time occur on a beat-by-beat basis in conjunction with respiration; oscillatory activity of AV conduction is not dependent on simultaneous changes in heart rate; and during atrial pacing, autonomic neural activity associated with respiration and blood pressure appears to dynamically modulate AV conduction with respiratory effects predominating at low heart rates and blood pressure effects at high heart rates.

Animals↗
PubMed1986

Beat-by-beat modulation of AV conduction. II. Autonomic neural mechanisms.

We examined the mechanism by which autonomic neural activity associated with respiration and blood pressure modulates atrioventricular (AV) conduction in conscious dogs. Mongrel dogs were anesthetized and instrumented under sterile conditions to record atrial and ventricular electrograms and blood pressure. In the conscious state, electrocardiogram (ECG), respiration, blood pressure, and electrograms were recorded continuously, and heart rate and AV interval were plotted graphically as a function of time. To delineate the role(s) of sympathetic and parasympathetic activity, AV conduction was studied during abrupt and linear changes in heart rate after administration of atropine, propranolol, or both. In the basal state and after propranolol, AV interval oscillated with respiration both in the absence of atrial pacing and at pacing rates 10-100 beats/min above control. Following atropine, oscillations in AV interval associated with respiration were abolished; however, linear and abrupt heart rate increases resulted in AV conduction changes that were associated with fluctuations in blood pressure. In contrast, after both atropine and propranolol, alterations in blood pressure or respiration did not influence AV conduction and rate-dependent prolongation of AV conduction occurred. We conclude that in the basal state, AV conduction is influenced predominately by changes in parasympathetic activity which is the major determinant of respiratory-related AV interval oscillations; after atropine, sympathetic activity produces fluctuations in both AV conduction and blood pressure; and intrinsic rate-dependent properties of the AV node are modulated continually by both divisions of the autonomic nervous system.

Animals↗
PubMed1985

Dynamic interactions between heart rate and atrioventricular conduction.

We examined the beat-by-beat alterations in atrioventricular (AV) conduction time that accompany both linear and abrupt changes in heart rate (HR). We used alpha-chloralose-anesthetized and autonomically decentralized dogs (n = 10) and recorded electrocardiogram (ECG), arterial pressure, and electrograms from sinus node, right ventricle, and His bundle. Abrupt or linear HR changes of known slope were generated by computer and displayed graphically with AV interval as a function of time. HR was increased linearly from 10 to 110 beats/min above control over 15, 30, and 60 s and then decreased in a linear fashion. AV interval was dependent on direction of HR change with marked asymmetry between increases and decreases in HR. Similar data were apparent irrespective of whether the decrease followed the increase or vice versa. To study determinants of 1:1 conduction, HR was increased linearly by 200 beats/min above control over 15, 30, and 60 s. As rate of change of HR increased, 1:1 conduction continued to a higher HR; however, the last conducted AV interval was negatively correlated with rate of change of HR. Abrupt sustained increases in HR of 25, 50, 75, and 100% above control resulted in marked accommodation of AV interval only at higher levels of HR. Thus in the absence of autonomic neural tone, 1) cardiac cycle length is not associated with a fixed AV interval but is dependent on magnitude and direction of HR change; and 2) the HR at which 1:1 AV conduction fails is significantly altered by the rate of change of HR.

Animals↗
PubMed1984

Ametantrone inhibits prostaglandin--mediated resorption in bone organ culture.

Prostaglandins (PG) have been postulated to be involved in both tumor metastases to bone and in tumor-induced bone resorption. The anthracenedione antineoplastic agents ametantrone (HAQ) and mitoxantrone are potent antioxidants and inhibit hydroperoxide-dependent initiation and propagation reactions. Therefore, these compounds may inhibit PG production and could also inhibit tumor metastases and tumor-induced resorption. The ability of HAQ, a prototypic anthracenedione, to inhibit PG synthesis and PG-mediated bone resorption was investigated using neonatal mouse calvaria in organ culture. Epidermal growth factor (EGF) stimulates bone resorption in this tissue by inducing PG synthesis. Consequently, if HAQ inhibits EGF-stimulated PG synthesis, it should also inhibit EGF-stimulated bone resorption. HAQ, at 10 microM, completely abolished EGF-stimulated PG synthesis and calcium release. Moreover, HAQ (1.0-30 microM) inhibition of EGF-stimulated PGE2 synthesis correlated with the inhibition of EGF-stimulated Ca release in a concentration-dependent manner. In contrast to EGF, parathyroid hormone stimulates resorption by a PG-independent pathway. HAQ at 10 microM had no effect on parathyroid hormone stimulated Ca release. These results suggest that HAQ inhibition of bone resorption appears to be primarily mediated by inhibition of PG biosynthesis.

Animals↗
PubMed1983

Blockade of the behavioral effects of lysergic acid diethylamide, 2,5-dimethoxy-4-methylamphetamine, quipazine and lisuride by 5-hydroxytryptamine antagonists.

The effects of lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM), quipazine or lisuride alone and in combination with the 5-hydroxytryptamine antagonist metergoline, pizotifen and cinanserin were studied in rats responding on a fixed-ratio 40 schedule of food presentation. LSD, DOM, quipazine or lisuride produced a similar dose-dependent decrease in the number of food presentations (ED50 values: 81 micrograms/kg, 0.6 mg/kg, 1.6 mg/kg and 31 micrograms/kg, respectively) and a reciprocal increase in the number of pause intervals (IRTs = 10 sec). All three antagonists attenuated the behavioral effects of LSD and DOM for both food presentations and pause intervals. The LSD-response curve for reinforcers was shifted to the greatest degree by pizotifen (1.0 mg/kg), followed by cinanserin (20 mg/kg) and metergoline (1.0 mg/kg). The ED50 values for this effect were 334, 181 and 141 micrograms/kg, respectively. The DOM dose-response pattern for decrease in reinforcers was shifted to the greatest degree by metergoline, followed by pizotifen and cinanserin (ED50 values: 26.5, 3.2 and 1.8 mg/kg, respectively). The effect of quipazine on reinforcers was antagonized by metergoline and pizotifen (ED50 values: greater than 8.0 for both) but not by cinanserin, although all three antagonists attenuated the increase in pause intervals in the same order as they did for DOM. The decrease in reinforcers by lisuride was equally antagonized by metergoline and pizotifen (ED50 values: 58 and 57 micrograms/kg, respectively), whereas cinanserin potentiated the effect of lisuride (ED50: 16 micrograms/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1980

Long term effects of perinatal injection of estrogen and progesterone on the morphological and biochemical development of the mammary gland.

The effects of neonatal injection of estrogen and progesterone on the subsequent in vitro hormone responsiveness of murine mammary glands were determined by a coordinated study of the morphological development and the biochemical response of explants. After daily in vivo pretreatment with estrogen and progesterone, explants were cultured for 5 days in a chemically defined medium containing insulin alone or insulin, cortisol, and PRL. After the culture period, the morphological development of alveoli and lobules was rated. In addition, casein mRNA was quantitated using a specific complementary DNA hybridization probe. Perinatal 17 beta-estradiol exposure was found to increase casein mRNA content as well as lobular development. Conversely, perinatal progesterone treatment inhibited both casein mRNA induction and the formation of lobules. The administration of both estradiol and progesterone to newborns resulted in an antagonistic response between these two steroids, and there was no effect on casein mRNA levels or lobular development in comparison with untreated controls. Mammary tissues of perinatally estrogen-treate mice displayed greater lobular development and contained higher levels of casein mRNA in response to an extension of the duration of in vivo pretreatment from 6 to 9 days. A comparison of the PRL dose response in vitro suggested that exposure to estrogen perinatally sensitized the mammary tissue to the subsequent addition of PRL in culture. These studies indicate that injection of newborns with estrogen may enhance the subsequent hormonally regulated differentiation of the mammary gland. Exposure to progesterone may inhibit later development, and both steroids in combination may exert antagonistic effects. These effects were not mediated solely by alterations in the normal endocrine status of the treated animals but were reflected by the subsequent hormonal response of mammary explants in a defined culture medium. This altered sensitive to hormones may be important in the increased incidence of mammary dysplasias observed in these animals.

Animals↗
PubMed1978

Effect of perinatal oestrogen on the pretreatment required for mouse mammary lobular formation in vitro.

Morphological differentiation was enhanced in mammary glands from mice injected with oestradiol as neonates both in vivo, after 9 days of pretreatment with oestrogen and progesterone, and in vitro, either after 6 or 9 days of pretreatment and on all hormone supplements, or after culture with oestradiol, progesterone, aldosterone, insulin and thyroxine with or without prolactin and growth hormone. These hormone combinations further enhanced development, whereas culture with insulin and thyroxine did not. Differentiation in vitro was least on medium containing insulin + thyroxine, and was greatest on the complete medium (insulin, thyroxine, growth hormone, prolactin, aldosterone, progesterone and oestradiol). An intermediate degree of differentiation occurred when growth hormone and prolactin were omitted from the complete medium. Differences in lobule formation between oestrogen-treated and control mice were probably ovary-dependent at the dose used (25 microgram/day), since pretreatment with oestradiol and progesterone was necessary to reveal them. Enhanced hormone sensitivity of murine mammary tissues exposed to oestradiol early in life may be related to subsequent enhanced dysplastic potential of the tissue and provides a further basis for caution in the administration of steroids to immature individuals.

Aging↗
PubMed1977

Effects of perinatal estrogen on mouse mammary response to corticoids in vitro.

Effects of three adrenal corticoids on in vitro mammary differentiation were compared in neonatally estrogenized (E) and uninjected control (N) BALB/c Crgl female mice. E mice were injected with 10 microgram of 17 beta-estradiol on each of the first 5 days of life. At 4 weeks of age, all mice were pretreated with 1 microgram 17beta-estradiol and 1 mg progesterone for 9 consecutive days. Groups of 10 or more entire mammary glands then were organ-cultured for 5 days at 37 degree C on chemically defined medium in 95% O2/5% CO2 with various combinations of hormones: mammotropin (M), somatotropin (S), insulin (I), thyroxine (T); and corticosterone (B), aldosterone (A), or cortisol (F). Differentiation followed a quantitative pattern of MSIT less than BMSIT less than AMSIT less than FMSIT for both E and N tissues. E tissues formed more alveoli and more lobules in vitro than N tissues with each of the corticoids tested. These findings may have pathologic significance.

Adrenal Cortex Hormones↗
PubMed1976

Age incidence and site distribution of mammary dysplasias in young beagle bitches.

The age incidence and site distribution of 2,142 mammary dysplasias were documented for 39 beagle bitches 6 months to 4 years of age. Lesion onset was at 2-3 years of age, at which time more than 50% of the females had dysplasias. Dysplasias appeared before palpable tumors. Posterior mammae developed more lesions than did anterior mammae. Thus the gradient for early onset of lesions coincided with the gradient for tumor frequency reported previously; a preneoplastic potential is suggested for (some) dysplasias. Problems of defining normal tissue are discussed.

Age Factors↗
PubMed1976

Mammary tumorigenesis in chemical carcinogen-treated mice. IV. Induction of mammary ductal hyperplasias.

BALB/cCrgl, C57BL/Ki, and (C57BL/Ki X DBAf)F1 mice were treated with 7,12-diemthylbenz[a]anthracene (DMBA) or urethan to determine conditions that would induce a high frequency of ductal hyperplasias in the mammary gland. Among virgin BALB/c mice treated with either 3.0 or 4.0 mg DMBA, ductal hyperplasias and mammary tumors were present in 50% and 31% of the mice, respectively. These ductal hyperplasias were characterized by intraluminal epithelial hyperplasia and capped by endbud-like structures that appeared abnormal. Hyperplastic alveolar nodules were not seen. Most mammary tumors were adenocarcinomas rather than the adenocanthomas observed in DMBA-treated, pituitary isograft-bearing BALB/c mice. The predominant mammary lesions in urethan-treated, pituitary isograft-bearing C57BL and (C57BL X DBAf)F1 mice were terminal duct (lobular) hyperplasias characterized by intraluminal epithelial hyperplasia; the urethan-induced mammary tumors were a mixture of adenocarcinomas (36%), adenoacanthomas (5%), and fibroadenomas (59%). The induction by chemical carcinogens of intraductal hyperplasias in a relatively high incidence, with associated mammary neoplasms, provides a system for study of the process of tumor progression in lesions similar to suspected high-risk lesions occurring in human breast cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1976

Effect of various doses of estrogen to BALB/cCrgl neonatal female mice on mammary growth and branching at 5 weeks of age.

High doses of 17beta-estradiol given newborn mice the first 5 days of life had no effect on mammary growth at 3 weeks of age whereas glands measured at 5 weeks of age displayed marked dose-dependent differences in area and branching. The number of duct branches increased significantly as the estrogen dose was raised from the 25 mug threshold to 35 or to 70 mug. Ratios between area and branching remained constant under all experimental conditions. Regional, dose-dependent, differences in gland-pair response were also observed at 5 weeks. Mammary gland pairs differed significantly in several growth parameters. The third gland pair was smaller in area and had fewer branches, but the opposite was true of the second and fourth gland pairs. Systemic injection of high doses of 17beta-estradiol into neonates reduced differences in growth parameters between gland pairs.

Animals↗