BACKGROUND AND PURPOSEPerivascular adipose tissue (PVAT) releases adipocyte-derived hyperpolarizing factors (ADHFs) that may partly act by opening myocyte K + channels. The present study in rat and mouse mesenteric arteries aimed to identify the myocyte K + channel activated by PVAT and to determine whether adiponectin contributed to the hyperpolarizing effects of PVAT. EXPERIMENTAL APPROACHMyocyte membrane potential was recorded from de-endothelialized, non-contracted rat and mouse mesenteric arteries in the presence and absence of PVAT. KEY RESULTSThe b3-adrenoceptor agonist, CL-316,243 (10 mM), generated PVAT-dependent, iberiotoxin-sensitive myocyte hyperpolarizations resulting from BKCa channel opening and which were partially blocked by L-NMMA (100 mM). Adiponectin (5 mg·mL -1 ) also produced iberiotoxin-sensitive hyperpolarizations in PVAT-denuded arterioles. Activation of myocyte AMP-activated protein kinase (AMPK) using 5 mM A-769662 also induced BKCa-mediated hyperpolarizations. Dorsomorphin abolished hyperpolarizations to CL-316,243, adiponectin and A-769662. In vessels from Adipo -/-mice, hyperpolarizations to CL-316,243 were absent whereas those to A-769662 and adiponectin were normal. In rat vessels, adipocyte-dependent hyperpolarizations were blocked by glibenclamide and clotrimazole but those to NS1619 (33 mM) were unaltered. CONCLUSIONS AND IMPLICATIONSUnder basal, non-contracted conditions, b3-adrenoceptor stimulation of PVAT releases an ADHF, which is probably adiponectin. This activates AMPK to open myocyte BKCa channels indirectly and additionally liberates NO, which also contributes to the observed PVAT-dependent myocyte hyperpolarizations. Clotrimazole and glibenclamide each reversed hyperpolarizations to adiponectin and A-769662, suggesting the involvement of myocyte TRPM4 channels in the ADHF-induced myocyte electrical changes mediated via the opening of BKCa channels. AbbreviationsA-769662, 4-hydroxy-3-(2′-hydroxybiphenyl-4-yl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile; ADHF, adipocyte-derived hyperpolarizing factor; AMPK, AMP-activated kinase; BKCa, large-conductance Ca 2+

The extracellular calcium-sensing receptor (CaR) was first described in the parathyroid gland. Recent studies have shown that the CaR is also expressed in blood vessels, especially in the endothelial and adventitial layers but its physiological function is still not clear. However, an understanding of its possible role(s) in the vasculature (perivascular-neurones, heart and blood vessels) is important because of the use of synthetic positive allosteric CaR modulators in hyperparathyroidism and the potential importance of negative modulators in the treatment of osteoporosis. In this review, the effects of CaR activation and inhibition are detailed and the possible role of the CaR as both an amplifier and attenuator of myo-endothelial coupling in the vasculature is described.

Familial Adenomatous Polyposis (FAP) is characterised by the development of hundreds to thousands of colorectal adenomas and results from inherited or somatic mosaic variants in the APC gene. Index patients with suspected FAP are usually investigated by APC coding region sequence and dosage analysis in a clinical diagnostic setting. The identification of an APC variant which affects protein function enables predictive genetic testing to guide the management of family members. This report describes a 4-generation family with a phenotype consistent with FAP, but in which an APC variant had not been identified, despite testing. To explore this further, quantitative PCR (qPCR) was employed to assess APC transcription, demonstrating reduced levels of APC RNA. Next generation sequencing (NGS) identified the APC 5 UT'/ E o aria t, c.-190 G>A, that had been reported previously in another FAP family with APC allelic imbalance. Quantitative RNA studies and DNA sequencing of the APC promoters/ Exon 1 may be useful diagnostically for patients with suspected FAP when coding region variants cannot be identified.

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