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Sigma Receptor Agonism by Afobazole Attenuates Lymphatic Pumping in Juvenile Rat Mesenteric Collecting Vessels
Author(s) -
Trujillo Andrea Nichole,
Adderley Shaquria P,
Katnik Christopher P,
Cuevas Javier,
Breslin Jerome W
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.726.2
Subject(s) - receptor , lymphatic system , chemistry , medicine , endocrinology , pharmacology , pathology
The mechanisms that govern tone and phasic contractions of collecting lymphatics are known to involve transient increases in intracellular free Ca 2+ but are still poorly understood. The role of sigma (σ) receptors, chaperone proteins recently identified to modulate intracellular free Ca 2+ has not been previously explored. We studied mesenteric collecting lymphatics isolated from 5–9 week old male Sprague Dawley rats, investigating whether: 1) sigma receptors, are expressed in lymphatic collecting vessels; and 2) Afobazole modulates tone and pumping. Lymphatics were mounted onto resistance‐matched glass micropipettes, in a 37°C albumin physiological salt solution (APSS) bath with 1–2 cm H 2 O luminal pressure. Concentrations of 50, 100 and 150 μM Afobazole were assessed. Video recordings were used to obtain contraction frequency (CF), end diastolic diameter (EDD), end systolic diameter (ESD), phasic contraction amplitude (AMP), tone, and ejection fraction (EF). Ca 2+ ‐free APSS was used to obtain the maximal passive diameter (MaxD) used to normalize EDD, ESD and AMP. Expression of the sigma 1 (σ1) receptor in lymphatics was verified by q‐PCR and western blot. Afobazole (50–150 μM) decreased CF, AMP/MaxD, tone and EF, and increased ESD/MaxD compared to baseline. A 15‐min pre‐treatment with either BD 1047 dihydrobromide or BD 1063 dihydrochloride, both σ1 receptor antagonists, blocked the effects produced by 50 and 100 μM Afobazole. Similar pre‐treatment with SM‐21, a specific antagonist of the σ2 receptor, did not block the responses to Afobazole (50–100 μM). Lastly, using multi‐photon laser‐scanning microscopy, the σ1 receptor was detected in lymphatic collecting vessels, closely associated with the endothelium. This study shows, for the first time, that agonists of the σ1 receptor can negatively modulate juvenile mesenteric lymphatic vessel contractile function. Support or Funding Information Supported by NIH grant L40HL097863