The endothelial component of cannabinoid‐induced relaxation in rabbit mesenteric artery depends on gap junctional communication

Abstract

An endothelium-derived hyperpolarizing factor (EDHF) is now widely recognized to mediate endothelium-dependent vascular relaxations that are independent of nitric oxide (NO) and prostanoid synthesis (Mombouli & Vanhoutte, 1997). Although the chemical identity of EDHF remains controversial, there is accumulating evidence that this mediator normally effects relaxation following diffusion from the endothelium to smooth muscle via myoendothelial gap junctions rather than the extracellular space Taylor et al. 1998;Dora et al. 1999;Hutcheson et al. 1999). Anatomically, this hypothesis is supported by the demonstration of myoendothelial gap junction plaques in rabbit conduit arteries (Spagnoli et al. 1982), and functional dye transfer experiments confirm direct chemical coupling between endothelium and subjacent smooth muscle (Little et al. 1995). Gap junctions are membrane structural proteins which consist of two hemichannels or connexons contributed by apposing cells, with each connexon being formed from six protein subunits or connexins arranged around an aqueous central pore that permits intercellular transfer of electrical current and molecules < 1 kDa in size (Yeager & Nicholson, 1996). Connexin 43 (Cx43) is present in both endothelial and vascular smooth muscle cells, and EDHFmediated relaxations and hyperpolarizations of rabbit

Characterisation of the vasorelaxant properties of the novel endocannabinoid N‐arachidonoyl‐dopamine (NADA)

“…To characterise the endotheliumderived vasorelaxant involved in the NADA response, experiments were performed in the presence of the nitric oxide synthase inhibitor L-NAME, and after potassium channel blockade, to inhibit EDHF activity. It was found that NADA does not act via the release of NO, which is in agreement with some reports on anandamide in isolated mesenteric vessels (White & Hiley, 1997;Chaytor et al, 1999). However, relaxation to NADA was reduced when potassium channels were inhibited, suggesting that release of EDHF contributes to vasorelaxation to NADA, which is in agreement with findings …”

“…This is in agreement with the findings of Chaytor et al (1999) for anandamide in similar isolated arterial preparations, but contrary to those of White & Hiley (1997). However, it is clear that some other CBs such as abnormal cannabidiol are clearly endothelium-dependent (Ja´rai et al, 1999).…”

“…This is consistent with the notion that CBs may exert their effects through direct activation of potassium channels (Randall & Kendall, 1998) or through mediation via EDHF (Chaytor et al, 1999). Alternatively, the high potassium solution may act on sensory nerves either by rapidly depleting or inhibiting the release of neurotransmitters via a depolarisation-clamp mechanism.…”

“…However, this is complicated by the wide-ranging actions of SR141716A at various concentrations. For example, SR141716A can inhibit myoendothelial gap junctions (Chaytor et al, 1999), which themselves have been implicated in the actions of anandamide via EDHF (Chaytor et al, 1999;Harris et al, 2002). SR141716A may also antagonise the novel non-CB 1 endothelial CB receptor proposed by Kunos and colleagues (Ja´rai et al, 1999;Offerta´ler et al, 2003).…”

“…Although nitric oxide does not appear to mediate responses to anandamide, the vasorelaxation is partly endothelium-dependent, in some, but not all preparations (White & Hiley, 1997;Chaytor et al, 1999;Ja´rai et al, 1999). It is therefore likely that anandamide stimulates the release of the endothelium-derived hyperpolarising factor (EDHF), which is communicated to smooth muscle cells via myoendothelial gap junctions (Chaytor et al, 1999;Harris et al, 2002).…”