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Biomedical subjects

B J Clark

Publications and source records attributed to B J Clark.

179 records · Page 10Linked to original sources
PubMed1971

The hypothalamic neurosecretory pathways for the release of oxytocin and vasopressin in the cat.

1. The neurones of the supraoptic nucleus (SON) and paraventricular nucleus (PVN) were stimulated electrically in lactating cats under chloralose anaesthesia. Milk-ejection responses were used to monitor the release of oxytocin and vasopressin and both hormones were assayed in samples of blood collected during stimulation. The position of the tip of the stimulating electrode was confirmed from brain sections stained selectively for cystine-rich neurosecretory material.2. A previous finding that stimulation of the SON in the cat releases vasopressin without oxytocin was confirmed.3. Stimulation of the PVN caused both hormones to be released. The ratio of their concentrations in blood was variable; this suggests release from separate neurones.4. Both hormones were also released on stimulation of the median eminence but not of the zone lying vertically between this structure and the PVN. No neurosecretory material was detected in this zone. These findings argue against the existence of a direct or medial paraventriculo-hypophysial pathway running downwards along the wall of the third ventricle.5. Study of sections from unstimulated brains confirmed that the tractus paraventricularis cinereus of Greving which runs ventro-laterally from the PVN towards the SON, represents the principal efferent pathway for neurosecretory fibres from the PVN.6. The results are discussed in relation to the problem of the independent release of oxytocin and vasopressin in response to physiological stimulation of the neurohypophysis.

Animals↗
PubMed1970

Some pharmacological properties of a synthetic oxytocin analogue [1-N-carbamoyl-hemicystine-2-O-methyltyrosine]-oxytocin (carbamoyl-methyloxytocin), an antagonist to the neurohypophysial hormones.

1. A synthetic oxytocin analogue, [1-N-carbamoyl-hemicystine-2-O-methyltyrosine]-oxytocin (carbamoyl-methyloxytocin), has been tested as an antagonist to the actions of oxytocin and vasopressin on the uterus, the mammary gland and blood pressure.2. The analogue inhibited the response of the isolated rat uterus to both oxytocin and vasopressin without itself stimulating the uterus to contract. The responses to equipotent doses of oxytocin and vasopressin were inhibited equally. There was little or no inhibition of the response to bradykinin. carbachol, angiotensin or 5-hydroxytryptamine with doses of the analogue up to 160 times that required to inhibit the response to oxytocin by 50%. The analogue caused a parallel displacement of the log dose-response curve for oxytocin; the pA(2) value (2 min contact) varied from 6.4 to 7.1 according to the ionic composition of the solution in the organ bath.3. The analogue inhibited the response of the rat uterus in situ to oxytocin but not to angiotensin or 5-hydroxytryptamine. It did not stimulate the uterus.4. When, in certain experimental conditions, spontaneous activity occurred in the isolated uterus or the uterus in situ, this activity was unaffected by the analogue but the increase in amplitude and frequency of contractions caused by oxytocin was inhibited. The regular rhythm of contractions induced in the quiescent uterus by the intravenous infusion of oxytocin was interrupted by intravenous injections of the analogue.5. The response of the isolated strip of rat mammary gland to the analogue depended on whether or not magnesium was present in the bath solution. In the presence of this ion, the analogue generally caused an increase in tension; in its absence, it acted as a pure antagonist. As on the isolated uterus, oxytocin and vasopressin were equally inhibited, and the analogue caused a parallel displacement of the log dose-response curve for oxytocin. With 0.9 mM Ca and 1.0 mM Mg, the mean pA(2) value (2 min contact) was 6.28 +/- 0.08 (S.E.)6. In the lactating rat, the analogue inhibited the milk-ejection response to oxytocin and vasopressin but not that to acetylcholine, bradykinin or 5-hydroxytryptamine. A milk-ejection response to the analogue itself was seen occasionally with retrograde arterial but not with intravenous injections.7. The analogue inhibited the avian depressor response to oxytocin and the rat pressor response to vasopressin.8. On all assay preparations, the degree of inhibition caused by the analogue was dependent on the dose, and the inhibition could be surmounted by increasing the dose of agonist. Recovery usually occurred within 15 min. These features, together with the parallel displacement of the dose-response curve for oxytocin on the isolated uterus and mammary strip, and the equal inhibition of the responses to oxytocin and vasopressin, suggest that carbamoyl-methyl-oxytocin acts as a specific competitive inhibitor of the neurohypophysial hormones.9. The structure-activity relationships of analogues of oxytocin having substituents in the terminal amino and phenolic hydroxyl groups, and some practical applications of the carbamoyl-methyl analogue, are discussed.

Acetylcholine↗
PubMed1970

Blood levels of oxytocin and vasopressin during suckling in the rabbit and the problem of their independent release.

1. Oxytocin and vasopressin were assayed in samples of blood collected from conscious rabbits during suckling. The milk yields were determined from the weight gain of the litters.2. With normal milk yields (35-155 g), relatively high concentrations (31-375 muu./ml.) of oxytocin were present in the blood but vasopressin was detected in only one out of eight samples. It is concluded that the release of oxytocin by the milk-ejection reflex is essential for normal milk removal in the rabbit and that this hormone is released independently of vasopressin.3. When the milk yield did not exceed 15 g, an amount which could be removed by passive withdrawal from the mammary gland, vasopressin was detected in four out of five blood samples but none contained a detectable concentration of oxytocin. This result can be explained by the intervention of emotional stress which is known to block the milk-ejection reflex but which acts as a stimulus for the release of vasopressin.4. Emotional stress could inhibit the milk-ejection reflex either centrally by blocking the release of oxytocin, or peripherally by blocking the response of the mammary gland to circulating oxytocin. The absence of the hormone in blood during ineffectual suckling suggests that the block is central.

Animals↗
PubMed1967

An afferent pathway for the selective release of vasopressin in response to carotid occlusion and haemorrhage in the cat.

1. The release of neurohypophysial hormones in response to carotid occlusion and haemorrhage has been studied in anaesthetized cats. Samples of jugular venous blood were extracted with alcohol and the extracts assayed for antidiuretic and milk-ejecting activity.2. The release of vasopressin in response to bilateral occlusion of the common carotid arteries has been confirmed in the cat; this effect was abolished when the sinus nerves were divided.3. Using a new sensitive preparation for the assay of milk-ejecting activity in blood extracts, it has been shown that no oxytocin accompanies the release of vasopressin during carotid occlusion.4. The independent release of vasopressin without oxytocin during haemorrhage has also been confirmed, and the role of the sinus nerves and vagi in this response investigated. Bilateral division of either nerve reduced the response, but the vagus appeared to be of greater importance than the sinus nerve.5. A reflex arc for the selective release of vasopressin has been proposed, of which the fibres of the sinus nerves and vagi form the afferent component and the neurones of the supraoptic nucleus the efferent component.

Animals↗
PubMedDate not supplied

Effect of early furosemide administration in neonates with respiratory distress syndrome.

The effect of early furosemide-induced diuresis was prospectively evaluated in 39 neonates less than 24 hr of age with clinical respiratory distress syndrome (RDS) who received either four doses of furosemide (1 mg/kg) or no diuretic. Measurements of FiO2 alveolar-arterial oxygen gradient (P[A-a]O2), peak inspiratory pressure (PIP), and urine output as a fraction of intake (O/I) were averaged for every 8 hr. The furosemide group overall showed a significant decrease (P less than 0.01) in FiO2, P[A-a]O2, and PIP with an earlier (32 hr vs 52 hr) and more pronounced diuresis (35% greater O/I) when compared to the controls. This effect was accentuated in the subgroup with 1,000-1,500 g birth weight (significantly lower FiO2 and P(A-a)O2 from 16 to 48 hours), while no increase in urine output was observed for the infants weighing less than 1,000 g. A significant reduction in supplemental oxygen and need for ventilatory support at 96 hr of age was observed in the furosemide-treated, less than 1,500-g infants. The incidence of patent ductus arteriosus was not increased following furosemide therapy, and no significant difference in echocardiographic parameters was observed in 21 infants from both groups, who were followed daily during the first week of life. This study suggests that early furosemide-induced diuresis, particularly in infants weighing 1,000-1,500 g at birth, promotes improvement in pulmonary functions in RDS and leads to faster reduction in oxygen and ventilatory support.

Birth Weight↗
PubMedDate not supplied

The determination of the geometric isomers and related impurities of dothiepin in a pharmaceutical preparation by capillary electrophoresis.

The application of capillary zone electrophoresis in the assay of the tricyclic antidepressant drug, dothiepin, in tablets is discussed. The method developed for dothiepin which exists as the cis- and trans-isomers and contains two major related impurities, an 11-oxo compound and a propanamine, utilizes inclusion complexation with beta-cyclodextrin. For optimization of the method the structured procedure of factorial design was used; the electrolyte solution was 50 mM disodium hydrogen phosphate with 10 mM beta-cyclodextrin-propan-1-ol(90:10, v/v). Good precision (RSD = 1.06%, n = 6), linearity (y = 26.84x + 2.25), and correlation (r = 0.999, n = 7) was obtained for trans-dothiepin. The reproducibility of tablet extraction was also acceptable (RSD = 0.77%, n = 6); the recovery of the trans-isomer was 98% (w/w) and the level of cis-isomer in tablets of dothiepin (75 mg) was 5.58% (w/w).

Cyclodextrins↗
PubMedDate not supplied

Solid-phase extraction and optimized separation of doxorubicin, epirubicin and their metabolites using reversed-phase high-performance liquid chromatography.

A reversed-phase isocratic high-performance liquid chromatographic method is described in which a formal structured procedure was applied to predict the mobile phase composition giving optimal baseline resolution of the clinically important anticancer agents doxorubicin and 4'-epidoxorubicin (epirubicin), their principal metabolites, and daunorubicin (internal standard). These formal statistical procedures included the simultaneous techniques of solvent selectivity triangle and factorial design for range-finding preliminary studies, followed by use of the modified simplex, a sequential procedure. These were used to select the parameters of organic modifier, buffer strength and pH necessary for use with a Spherisorb ODS 1 column, to achieve optimal separation of eight anthracycline solutes. Ultraviolet and fluorescence detection was used (lambda ex = 254 nm, lambda em = 560 nm), and the latter gave a low detection limit for doxorubicin in serum of 1 ng ml-1. The optimal mobile phase composition was determined to be acetonitrile-0.06 M Na2 HPO4 containing 0.05% (v/v) triethylamine adjusted to pH 4.6 with 0.03 M citric acid (35:65, v/v). A solid-phase extraction method was developed to enable the selective isolation of anthracyclines by adsorption onto C8 Bond-Elut cartridges, and is based on extraction of serum spiked with a mixture of the anthracycline solutes. The anthracyclines were eluted using acetonitrile-0.2 M Na2 HPO4 containing 0.05% (v/v) triethylamine adjusted to pH 3.6 with 0.1 M citric acid (67.5:32.5, v/v). Reproducible recoveries for doxorubicin (94 +/- 8%) and for epirubicin (96 +/- 8%) were obtained (n = 5). In particular, recoveries for the 7-deoxyaglycone metabolite (99%) were higher than other extraction methods cited.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMedDate not supplied

Interaction of thyroid hormone and steroidogenic acute regulatory (StAR) protein in the regulation of murine Leydig cell steroidogenesis.

The steroidogenic acute regulatory (StAR) protein, a novel phosphoprotein, is a crucial factor involved in intramitochondrial cholesterol transportation, the rate-limiting step in steroidogenesis. The present investigations were undertaken to elucidate involvement of thyroid hormone and StAR protein in the regulation of steroidogenesis in mouse Leydig cells. Treatment of cells with triiodothyronine (T(3)) coordinately augmented the levels of StAR protein, StAR mRNA, and steroid production, and these responses were progressively dependent on expression of steroidogenic factor 1 (SF-1). With regard to steroidogenesis and StAR expression, the T(3) response requires both on-going mRNA and protein synthesis. In addition, the effects of T(3) were acutely modulated at the steroidogenic machinery and luteinizing hormone receptor (LHR) function, while these levels were suppressed following longer periods of exposure to T(3). Furthermore, the inhibition of SF-1 expression by DAX-1 markedly abolished T(3)-mediated StAR expression in a time frame, which was consistent with decreased steroid biosynthesis. Specific involvement of SF-1 was further confirmed by assessing the 5'-flanking region of the mouse StAR gene, which identified a region between -254 and -110 bp that was essential for T(3) function. Importantly, it was found that the SF-1 binding site at position -135 bp of the 5'-flanking region was greatly involved in T(3)-mediated reporter activity. Electrophoretic mobility shift assays (EMSA) also demonstrated involvement of SF-1 in T(3) function. The relevance of T(3)-mediated LHR function was investigated in mice rendered hypo-and hyperthyroid, which accounted for up-regulation in the former and down-regulation in the latter group, respectively. These findings demonstrate a key role of thyroid hormone in maintaining mouse Leydig cell function, where thyroid hormone and StAR protein coordinately regulate steroid hormone biosynthesis.

Animals↗
PubMedDate not supplied

Expression of the steroidogenic acute regulatory (StAR) protein: a novel LH-induced mitochondrial protein required for the acute regulation of steroidogenesis in mouse Leydig tumor cells.

The acute response of steroidogenic cells to hormone stimulation is the mobilization of cholesterol from cellular stores and the outer mitochondrial membrane to the inner mitochondrial membrane and the cholesterol side-chain cleavage complex (CSCC) where the first enzymatic reaction occurs. It has been well established that the translocation of cholesterol from the outer to the inner mitochondrial membrane requires de novo protein synthesis and that this process is the rate-limiting, regulated step in steroidogenesis. We have purified a novel mitochondrial protein (named StAR) from the MA-10 mouse Leydig tumor cells which we have previously proposed represents a strong candidate for the newly synthesized regulatory protein in steroidogenesis. The cDNA for StAR was cloned and we have demonstrated that expression of the StAR protein in MA-10 cells in the absence of hormone stimulation results in a 3 fold increase in progesterone production compared to mock transfected cells. These studies indicate a direct indicate a direct relationship between StAR expression and steroidogenesis, therefore, we conclude that StAR is required in the acute regulation of steroidogenesis.

Amino Acid Sequence↗
PubMedDate not supplied

Congenital ocular defects associated with an abnormality of the human chromosome 1: trisomy 1q32-qter.

This article describes the detailed ocular pathology found in a premature neonate, born at 34 weeks, with multiple congenital anomalies resulting from de novo trisomy 1q32-qter. The ocular defects include goniodysgenesis, persistent tunica vasculosa lentis and hyaloid vessels, hypopigmentation of the posterior iris epithelium, ectopia of the ciliary processes, and abnormal insertion of the ciliary muscle and cataract. This is the first report of the detailed ocular pathology in a case of trisomy 1q and is also unusual in that the chromosomal defect has apparently arisen de novo in the proband.

Abnormalities, Multiple↗
PubMedDate not supplied

Treatment of heart failure in infants and children.

In its simplest and most succinct definition, heart failure can be defined as an inability of the heart to meet the metabolic demands of the body. Despite the diverse etiologies of heart failure in the pediatric population, the presentation of heart failure represents a common constellation of symptoms, signs, and physical findings. In infants, an inability to maintain growth either secondary to decreased nutritional intake or an increased catabolic state is a hallmark of heart failure. Infants exhibit increased sympathetic tone with excessive diaphoresis and increased heart rate. Physical findings in the infants with congestive heart failure (CHF) include increased work of breathing, tachypnea and hepatomegaly. In older children, in contrast, new onset heart failure may be less overtly symptomatic. Malaise, decrease in the level of daily activity, and weight loss may be present. Symptoms of abdominal pain and nausea and anorexia can be present and sometimes divert attention from the real etiology. Physical findings include rales and peripheral edema. If there is hepatomegaly, there will likely be hepatic tenderness as well. A gallop rhythm and tachycardia are commonly present. The long-term treatment of CHF in children includes digoxin, diuretics and afterload reduction with angiotensin-converting enzyme (ACE) inhibitors. Digoxin decreases sympathetic tone and improves growth in infants. Diuretics should be used to relieve symptoms but may not be necessary in all children. ACE inhibitors are increasingly valuable in maintaining cardiac function long term. New uses of medications include the addition of spironalactone (Aldactone, G. D. Searle & Co., Chicago, IL) which, in adults, has been shown to significantly decrease both the death rate from CHF and the need for hospitalization. Beta-Blockers have been used in children in limited studies and may have a role in the treatment of patients with idiopathic dilated cardiomyopathy. Surgical treatment, such as partial vectriculectomy, has shown short-term benefit and has been used sparingly in infants.

Adrenergic beta-Antagonists↗