Endothelin-1 plays a major role in portal hypertension of biliary cirrhotic rats through endothelin receptor subtype B together with subtype A in vivo

The potent vasoconstrictor endothelin-1 (ET-1) is a paracrine, but also autocrine, factor for some types of cells. The goal of our study was to evaluate whether the receptor population in cells expressing endothelin receptor subtype A (rat mesangial cells) or endothelin receptor subtype B (human and rat endothelial cells) was affected by the autocrine production of ET-1. We therefore studied maximal binding capacity of 125I-labeled ET-1 in the presence or absence of the metalloprotease inhibitors phosphoramidon, which blocks the intracellular processing of Big ET-1 to ET-1, and thiorphan, which does not block this conversion. Phosphoramidon inhibited the release of ET-1 by human umbilical vein endothelial cells, rat aortic endothelial cells, and rat mesangial cells, and increased 1.4- to 17-fold the maximal binding capacity in the three types of cells. Thiorphan affected neither ET-1 release nor binding. The increase in receptor binding by phosphoramidon was associated with an increase in the functional effect of ET-1, as measured by arachidonic acid release in rat mesangial cells. We conclude that autocrine production of ET-1 decreases, either by binding or by downregulation, the number of binding sites available for ET-1 of paracrine or systemic sources. This aspect of modulation of the vasoconstrictor effect of endothelin should be considered in pathological situations or after endothelin-converting-enzyme inhibition.

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Recombinant subtype A and B human respiratory syncytial virus clinical isolates co-infect the respiratory tract of cotton rats

Journal of General Virology ◽

10.1099/jgv.0.001471 ◽

2020 ◽

Vol 101 (10) ◽

pp. 1056-1068

Author(s):

Linda J. Rennick ◽

Sham Nambulli ◽

Ken Lemon ◽

Grace Y. Olinger ◽

Nicholas A. Crossland ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Respiratory Tract ◽

Reverse Genetics ◽

Fluorescent Protein ◽

Human Respiratory Syncytial Virus ◽

Subtype B ◽

Cotton Rats ◽

Syncytial Virus ◽

Subtype A

Human respiratory syncytial virus (HRSV) is an important respiratory pathogen causing a spectrum of illness, from common cold-like symptoms, to bronchiolitis and pneumonia requiring hospitalization in infants, the immunocompromised and the elderly. HRSV exists as two antigenic subtypes, A and B, which typically cycle biannually in separate seasons. There are many unresolved questions in HRSV biology regarding the interactions and interplay of the two subtypes. Therefore, we generated a reverse genetics system for a subtype A HRSV from the 2011 season (A11) to complement our existing subtype B reverse genetics system. We obtained the sequence (HRSVA11) directly from an unpassaged clinical sample and generated the recombinant (r) HRSVA11. A version of the virus expressing enhanced green fluorescent protein (EGFP) from an additional transcription unit in the fifth (5) position of the genome, rHRSVA11EGFP(5), was also generated. rHRSVA11 and rHRSVA11EGFP(5) grew comparably in cell culture. To facilitate animal co-infection studies, we derivatized our subtype B clinical isolate using reverse genetics toexpress the red fluorescent protein (dTom)-expressing rHRSVB05dTom(5). These viruses were then used to study simultaneous in vivo co-infection of the respiratory tract. Following intranasal infection, both rHRSVA11EGFP(5) and rHRSVB05dTom(5) infected cotton rats targeting the same cell populations and demonstrating that co-infection occurs in vivo. The implications of this finding on viral evolution are important since it shows that inter-subtype cooperativity and/or competition is feasible in vivo during the natural course of the infection.

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Endothelin-1 and pancreatic islet vasculature: studies in vivo and on isolated, vascularly perfused pancreatic islets

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00640.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1616-E1623 ◽

Cited By ~ 22

Author(s):

En Yin Lai ◽

A. Erik G. Persson ◽

Birgitta Bodin ◽

Örjan Källskog ◽

Arne Andersson ◽

...

Keyword(s):

Blood Flow ◽

Pancreatic Islet ◽

Vascular Reactivity ◽

Blood Perfusion ◽

Receptor Subtype ◽

Endothelin 1 ◽

Islet Blood Flow ◽

Endothelin B

Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor, which also stimulates insulin release. The aim of the present study was to evaluate whether exogenously administered ET-1 affected pancreatic islet blood flow in vivo in rats and the islet arteriolar reactivity in vitro in mice. Furthermore, we aimed to determine the ET-receptor subtype that was involved in such responses. When applying a microsphere technique for measurements of islet blood perfusion in vivo, we found that ET-1 (5 nmol/kg) consistently and markedly decreased total pancreatic and especially islet blood flow, despite having only minor effects on blood pressure. Neither endothelin A (ETA) receptor (BQ-123) nor endothelin-B (ETB) receptor (BQ-788) antagonists, alone or in combination, could prevent this reduction in blood flow. To avoid confounding interactions in vivo, we also examined the arteriolar vascular reactivity in isolated, perfused mouse islets. In the latter preparation, we demonstrated a dose-dependent constriction in response to ET-1. Administration of BQ-123 prevented this, whereas BQ-788 induced a right shift in the response. In conclusion, the pancreatic islet vasculature is highly sensitive to exogenous ET-1, which mediates its effect mainly through ETA receptors.

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