Evidence for a novel intrapituitary autocrine/paracrine feedback loop regulating growth hormone synthesis and secretion in grass carp pituitary cells by functional interactions between gonadotrophs and somatotrophs

Gonadotropin (GTH) and GH released from the pituitary are known to interact at multiple levels to modulate the functions of the gonadotrophic and somatotrophic axes. However, their interactions at the pituitary level have not been fully characterized. In this study, autocrine/paracrine regulation of GH synthesis and secretion by local interactions between gonadotrophs and somatotrophs was examined using grass carp pituitary cells as a cell model. Exogenous GTH and GH induced GH release and GH mRNA expression in carp pituitary cells. Removal of endogenous GTH and GH by immunoneutralization with GTH and GH antisera, respectively, suppressed GH release, GH production, and GH mRNA levels. GH antiserum also blocked the stimulatory effects of exogenous GTH on GH release and GH mRNA levels. In reciprocal experiments, GH release and GH mRNA expression induced by exogenous GH was significantly reduced by GTH antiserum. In addition, exogenous GH was found to be inhibitory to basal GTH release and treatment with GH antiserum elevated GTH secretion at low doses but suppressed GTH production at high doses. These results suggest that local interactions between gonadotrophs and somatotrophs may form an intrapituitary feedback loop to regulate GH release and synthesis. In this model, GTH released from gonadotrophs induces GH release and GH production in neighboring somatotrophs. GH secreted maintains somatotroph sensitivity to GTH stimulation, and at the same time, inhibits basal GTH release in gonadotrophs. This feedback loop may represent a novel mechanism regulating GH release and synthesis in lower vertebrates.     

High plasma growth hormone (GH) levels inhibit expression of GH secretagogue receptor messenger ribonucleic acid levels in the rat pituitary

Synthetic GH secretagogues (GHSs) act via a receptor (GHS-R) distinct from that of GH-releasing hormone. The GHS-R has been cloned from the pituitary and is expressed not only in the pituitary but also in specific areas of the brain, including the hypothalamus. Recent studies suggest that hypothalamic GHS-R expression is regulated by GH. This study was designed to investigate whether pituitary GHS-R expression is modulated by GH. Female Wistar-Furth rats were injected sc with either saline (control) or GC tumor cells (GC) that secrete rat GH. The tumors were allowed to develop for 1-4 weeks. At weeks 1-4, control (n = 4-8) and GC rats (n = 3-8) were killed. Pituitary GHS-R messenger RNA (mRNA) was measured by a quantitative competitive PCR assay. The endogenous GHS-R mRNA levels were measured by determining the amount of competitive template RNA required to produce equimolar amounts of native and competitive template PCR products. The mean log plasma GH levels were significantly greater in the GC rat group than in the control group at weeks 2, 3, and 4. At these times, the mean log pituitary GHS-R mRNA contents were significantly lower in the GC rat group than in the control group. No relationship could be established between log estradiol levels and GHS-R levels. These data indicate that pituitary GHS-R expression is modulated by GH.     

Renovascular hypertension: structural changes in the renal vasculature

Experimental narrowing of the main renal artery to produce hypertension increases the aorta-glomerular capillary pressure difference and vascular resistance. This article examines the hypothesis that hypertension also may be caused by structural changes that narrow intrarenal blood vessels, similarly increasing preglomerular vascular resistance and the aortic-glomerular capillary pressure gradient. There is evidence of both wall hypertrophy and lumen narrowing of the preglomerular arteries in spontaneously hypertensive rats, with increased preglomerular resistance and aortic-glomerular capillary pressure difference. We have also attempted to induce structural changes in renal-preglomerular vessels experimentally by infusing angiotensin II at low doses (0.5 to 4.5 ng/kg per minute) into the renal artery of Sprague-Dawley rats and greyhound dogs for up to 4 weeks. This angiotensin II infusion produced apparent dose-related effects on preglomerular vessel structure and hypertension. The possibility that hypertension may be induced by structural changes in preglomerular resistance vessel walls, by simulation of the hemodynamic effects of main renal artery stenosis, deserves further investigation.     

Anomalous origin of the left coronary artery from the pulmonary trunk. Potential for false negative diagnosis with cross sectional echocardiography.

Cross sectional echocardiography can identify anomalous origin of the left coronary artery from the pulmonary trunk. It has been suggested that identification of the left coronary artery arising from the aorta using this technique excludes the diagnosis. In three such infants the anomalous origin of the left coronary artery was identified in each by cross sectional echocardiography. In all three cases, however, an echo free linear structure apparently arising from the aorta, resembling a normal left coronary artery, was imaged. Anatomical sections in one patient, simulating cross sectional echocardiographic cuts, showed that this structure was almost certainly the transverse sinus of the pericardium. False positive cross sectional echocardiographic diagnosis of this condition is also possible because of the failure to image a normally arising left coronary artery. Thus identification of the anomalous origin of the left coronary artery from the pulmonary trunk appears to be the only reliable echocardiographic finding in this condition, and contrast cineaortography remains necessary in patients in whom the diagnosis is suspected clinically or electrocardiographically.     

A search for heterogeneity in insulin dependent diabetes mellitus (IDDM): HLA and autoimmune studies in simplex, multiplex and multigenerational families

HLA antigens (A, B, C and DR loci), serum islet cell antibodies, thyrogastric antibodies, and insulin antibodies were studied in 77 families (25 simplex, 42 multiplex, and 10 multigenerational). In order to test for intrafamilial constancy and intergroup variation, we compared simplex with multiplex families, HLA identical and non identical siblings within families, as well as groups of families characterized by different DR alleles (DR3, DR4, and DR3/DR4) for various immunologic and clinical characteristics. These comparisons did not reveal all the distinct subgroups suggested by different cross-sectional population studies, but did provide evidence for a compound form having an aggregation of different high risk alleles. This study suggests that in many cases (and possibly especially in families with multiple affected individuals), there are several different genetic influences leading to IDDM.     

The effect of terbutaline in exercise-induced asthma.

A double blind study of 5 asthmatic subjects in remission demonstrated that the severity of bronchoconstriction after exercise was decreased by a single oral dose of 5 mg of terbutaline. The effect lasted for at least 6 hours and was significantly better than the protection afforded by 20 mg of metaproterenol, which was itself more effective than a placebo. In these doses, neither terbutaline nor metaproterenol affected heart rate or blood pressure at rest or in exercise, and no drug-induced side effects were found.     

Meobentine sulfate: antiarrhythmic and electrophysiologic effects assessed by programmed electrical stimulation and ambulatory monitoring in patients with complex ventricular tachyarrhythmia. Report of a multicenter evaluation

Five cardiology centers conducted open-label prospective trials of meobentine sulfate, an intravenously and orally available analog of bethanidine, to assess its potential for treatment of recurrent, drug refractory ventricular tachycardia (VT) or fibrillation (VF), and complex ventricular arrhythmias. The study population comprised 26 patients (mean age, 61 years); 18 were men. Coronary artery disease was present in 15, cardiomyopathy in six, and valvular heart disease in three. Patients presented with both VT and VF (seven), sustained VT alone (12), or frequent ventricular ectopy (PVCs) and nonsustained VT (seven). Of the 26 patients, 5 were enrolled in antiarrhythmic studies (chronic PVC suppression) and 21 were enrolled in programmed electrical stimulation (PES) studies. Two of five in the chronic PVC study showed greater than 75% arrhythmia suppression. Among 21 patients in PES studies, there were eight intravenous (16 mg/kg) and 19 oral trials (400 to 1000 mg every 6 hours, 3 days/dose interval). Five of 22 patients showed efficacy at repeat PES study (neither VT nor VF), one showed partial efficacy, and four were not restudied because of clinical arrhythmia (three) and/or adverse effects (two). Overall, three patients (12%) were continued on the drug for an extended period of time. Adverse experience included hypotension in 50% and gastrointestinal effects (nausea, vomiting, or diarrhea) in 56% (oral trials only). Adverse reactions led to drug discontinuation in six and dosage reduction in eight patients. Thus, meobentine may prevent induction of VT or VF or reduce frequency of complex PVCs in selected patients refractory to other antiarrhythmic agents, but the response rate is relatively low. Symptomatic hypotension or gastrointestinal adverse effects are common and may limit utility of meobentine as a chronic oral antiarrhythmic agent.     

Multiple myeloma in a patient with sickle cell anemia: Interacting effects on blood viscosity

Described here is a case of multiple myeloma in a patient with sickle cell anemia. Viscometric studies were made by comparing the patient's whole blood, plasma and washed red blood cells with those of a normal control subject and a patient with sickle cell anemia. Results showed that the increased viscosity of the patient's whole blood as compared with that of the control patient with sickle cell anemia was mainly due to erythrocytic Interaction with the circulating abnormal immunoglobulin. It is postulated that the increased frequency of vaso-occlusive crisis that occurred in our patient in the months before the diagnosis and treatment of multiple myeloma, was due to this cell-protein interaction with the resulting enhancement of whole blood viscosity and the sickling phenomena.