Effects of carbenoxolone on flow-mediated vasodilatation in healthy adults

Abstract

Gap junctions play a key role in maintaining the functional integrity of the vascular wall. Using carbenoxolone (CBX) as a gap junction blocker, we aimed to assess the contribution of gap junctions in the vascular wall to flow-mediated vasodilatation (FMD) in healthy adults. Percentage FMD (%FMD) and circulating vasoactive molecules/activity, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), aldosterone, cortisol, plasma renin activity (PRA), and endothelin (ET-1) , were measured in 25 healthy volunteers (mean age: 30.1 Ϯ 5.4 yr; 14 males) before and after oral administration of CBX (100 mg). %FMD decreased after ingestion of CBX (9.71 Ϯ 3.1 vs. 3.40 Ϯ 2.0%; P Ͻ 0.0001). The levels of ANP, BNP, cortisol, and ET-1 remained stationary, while both PRA and aldosterone decreased (P Ͻ 0.005) after CBX ingestion. Blood pressure and heart rate were minimally changed by CBX. Inhibition of gap junctional communication by CBX impairs FMD in healthy persons, suggesting that physiologically, vascular gap junctions participate in the maintenance of FMD. CBX does not induce the release of vasoconstricting molecules or enhance vasoconstriction, suggesting that inhibition of gap junctional communication by CBX underlies the impairment of FMD. Therefore, administering CBX in FMD examination can be a way to follow the effect of gap junctions on endothelial function, but further work remains to verify the specificity of CBX effect. flow-mediated dilation; gap junctions; vasoactive molecules THE VASCULAR ENDOTHELIUM PLAYS a central role in the regulation of vasomotor tone, thrombogenecity, and inflammation (33). Endothelial dysfunction, an indicator of impairment of these regulatory mechanisms, is a systemic disorder and a key early event in the pathogenesis of atherosclerosis (29,44). In fact, endothelial dysfunction can be detected long before the appearance of structural atherosclerotic disease and is associated with increased cardiovascular risk (47). Accumulated data indicated that atherosclerotic cardiovascular disease also affects endothelial gap junctions, which are involved in maintaining functional integrity of the endothelium (21,22,48).Gap junctions are cell membrane protein channels made of connexins. Our previous study showed that downregulation of endothelial gap junctions is a common phenomenon in various disorders that induce and accelerate atherosclerosis (16), such as hypertension (23), hyperlipidemia (49), and diabetes (15) in cases where endothelial dysfunction exists. In addition, we (46) recently reported that in cultured endothelial cells, reduction of gap junctions per se leads to the development of endothelial dysfunction. However, all of this information comes from cell culture and animal experiments; thus, the contribution of gap junctions to the maintenance of endothelial function in humans remains unclear. To clarify the role of gap junctions, we hypothesized that gap junction blockade impairs flow-mediated vasodilatation (FMD), a clinically applicable examination for evaluat...

Vascular Gap Junctions Contribute to Forepaw Stimulation-Induced Vasodilation Differentially in the Pial and Penetrating Arteries in Isoflurane-Anesthetized Rats

“…), which was used to block the gap junctions of blood vessels. The dose and route of CBX administration was determined based on previous studies (Leshchenko et al, 2006; Lan et al, 2011). One study showed that CBX was not detected in the cerebrospinal fluid following systemic administration at a similar dose (50 mg/kg; i.p.…”

“…Hence, our results may suggest that administered CBX did not act on the brain parenchyma, but possibly on the cerebral vasculature. It has been reported that vasodilation induced by ischemia-reperfusion (due to nitric oxide generated from vascular endothelial cells) in the brachial artery is attenuated by systemic administration of CBX (Lan et al, 2011), indicating that systemically administered CBX acts on the vascular endothelium. Therefore, the present study results may support the hypothesis that pial arterial dilation associated with neuronal activity propagates through gap junctions of the cerebral vascular endothelium.…”

“…This administration dose and route was determined based on previous studies showing that CBX was not detected from cerebrospinal fluid following systemic administration (at 50 mg/kg; i.p. ; Leshchenko et al, 2006) whereas vascular endothelium-dependent vasodilation was suppressed (Lan et al, 2011).…”

Endothelium at a Glance

“…To this end, the corresponding channels have been investigated as potential targets to affect EDH [147,149]. Endothelial hyperpolarization can spread via myoendothelial gap junctions to directly induce VSMC hyperpolarization: the role of gap junctions has been implicated also in humans in vitro and in vivo as carbenoxolone, a nonspecific gap junction blocker, diminished conducted vasodilation in isolated human coronary arterioles [150], and, moreover, reduced FMD in the brachial artery of healthy volunteers [151]. The term conducted dilation has been used to denote electrotonic transmission of local hyperpolarization, and may spread several mm upstream independent of alterations in shear stress [116,119,152].…”

Conexinas na epilepsia experimental induzida por pilocarpina: abordagem molecular e eletrofisiológica.

“…Estes autores mostraram que o desacoplamento promovido pelo ácido glicirretínico 18-beta correlacionou-se com redução da forma fosforilada P2 da Cx43 e aumento da forma não fosforilada da proteína (já é conhecido que o estado de fosforilação da Cx43 pode alterar a condutância do canal, sendo que as formas fosforiladas normalmente estão relacionadas com aumento da probabilidade do canal se encontrar no estado aberto - Godwin et al, 1993;Oelze et al, 1995;Cotrina et al, 1998). No entanto, além da Cx43, a CBX também inibe canais de JC compostos por outras Cx (Lan et al, 2011).…”