Whether EDH is primordial is a difficult one for me to answer personally. Many different mechanisms of EDH have "evolved" which makes it a tricky drugable target globally. We see transferrable factors, such as EETs, H2O2, K+ ions etc, but also the transfer of endothelial hyperpolarization to the smooth muscle via gap junctions. In certain arteries we also see combinations of such mechanisms. Increasingly appreciated is the role of signalling microdomains located in caveolae, at endothelial cell borders, and in EC/SM projections that permeate holes in the IEL to establish close heterocellular contact. 

EDH is largely confined to smaller arteries and the microcirculation, and is not a typical feature of conduit vessels, except under certain disease states where EDH may compensate for the loss of NO. The impact of this in physiology may depend on what mechanism is at work. In human coronary vessels from CAD patients, for example, NO is replaced by H2O2, which almost fully preserves dilator function of the vessel, but it has led some to question the long term benefit because H2O2 is proinflammatory (albeit weaker than superoxide) and NO is anti-inflammatory. 

The reason for such diversity in mechanisms of EDH (interspecies, intraspecies, and along any single vascular bed) is unclear. My personal belief is that local haemodynamic conditions "tune" EDH, because so many EDH genes are upregulated by shear, such as TRPV4, TRPC3, KCa2.3 and KCa3.1, Cxs, some Kir, epoxygenases (many more). Remember, shear increases along the circulation between conduit vessels and microcirculation, and shear is much higher in the aorta, for example, of the mouse compared to human. 

I don't know whether I have helped at all with my answer. If not, please give more specifics because I suspect I may not have fully understood your question.

Dave

Thank you Dave

The EDHF

pathway appears to be additional upregulated factor. We described its role in reduced vasodilatory response to dietary salt loading in SD rats (Sofola et al, J Physiol, 543: 255-260, 2002). When EDRF response is inadequate, it appears EDHF is stimulated. EDHF hardly has expression in conduit arteries and appears to feature in resistance arterioles. Many studies have confirmed this observation.

In our experience EDHF is not visualized in aorta while in carotid arteries and in mesenteric bed in present. It is a key relaxing factor in microcirculation and due to some similarity with hydrogen sulfide we have demonstrated that it could be an EDHF ( Hydrogen sulfide-induced dual vascular effect involves arachidonic acid cascadein rat mesenteric arterial bed. J Pharmacol Exp Ther. 2011 Apr;337(1):59-64. d'Emmanuele di Villa Bianca R et al.,).

An impairment of hydrogen sulphide/EDHF was also observed in hypertension induced by glucocorticoids treatmen (d'Emmanuele di Villa Bianca R, et al., Hydrogen sulfide-induced dual vascular effect involves arachidonic acid cascade in rat mesenteric arterial bed. J Pharmacol Exp Ther. 2011 Apr;337(1):59-64. doi: 10.1124/jpet.110.176016. Epub 2011 Jan 12. PubMed PMID: 21228064)

Yes, it is rarely seen in aorta, except in certain specific disease states, and indeed is rare in many conduits, with some exceptions. I stress again, "EDHF" is too generic a term, and has only been demonstrated fairly conclusively in a handful of studies. David Gutterman has done a good job of demonstrating transferability of EETs and H2O2 (under particular conditions) in the human microcirculation. Bill Campbell notably was the first to demonstrate transferable EDHF type actions of EETs. Several others too. However, many studies use the term EDHF without having gone close to demonstrating it. EDH is term that appreciates both factors and the role of gap junctions. In a general context, the term EDHF is very misleading to the non initiated reader. A consensus on this was reached at the most recent EDHF conference, which Michel Feletou and Paul Vanhoutte published on.

Yes David this is exactly correct.  Things like H202 and EETs are EDHFs and in many cases NO its self acts an EDHF. So when a known factor contributes to EDH you should avoid the term EDHF and use the name of the known factor. EDH is a better term that encompasses the role of factors  Gap junctions and microdomians it describes the entire process involving hyperpolarization that is independent of NO or PGI2. In some vessels under "normal" conditions EDH is not  seen except in disease conditions (e.g. Aorta). In other vessels where it is seen the EDH response seems to be up-regulated in certain disease conditions, or only observed when NOS/COX are blocked which has lead to the idea that it is a "back up" mechanism (e.g. saphenous artery and some mesenteric beds). However EDH responses are functioning in parallel in many vascular beds as can be uncovered by measuring hyperpolarization of smooth muscle in combination with observing relaxation both ex-vivo and in-vivo examples of this include small most small "resistance" sized arteries including mesenteric and cerebral. Indeed there are reports   in small arteries the EDH component seems to dominate relaxation over NO responses. Finally huge sex difference are seen in vascular beds (in general males seem to have a bigger EDH component) and EDH response can be both upregulated or down regulated in disease. Fundamentally I think the lesson is that vascular relaxation is such an important process that it needs multiple mechanisms to ensure it occurs in homoeostasis, pathology and also to fine tune different vascular beds to their different metabolic roles.

As an example, EETs are proposed as an EDHF in some vessels, such as in bovine coronary. However, in the murine carotid artery EDH-type dilation to flow is prevented by agents that prevent EET synthesis and are absent in TRPV4 null mice, with the corollarly that EETs activate TRPV4 to elicit dilation. However in WT there is no TRPV4 expressed in SM, only endothelium. So in this case EETs are not EDHF; instead they promote Can2+ influx and KCa activation in the endothelium. 

For H2O2, EDH-type responses in human gut submucosal microvessels are strongly suppressed by catalase, but in endothelium denuded preparations of these vessels exogenous H2O2 causes only further constriction, and so is promoting EDH via an endothelial action, and not a direct SM action. 

There's two good examples of when two of the most acclaimed "EDHFs" promote EDH via an action distinct from that of an EDHF. 

What would be the cause of relaxation observed in Aorta towards Ach in presence of L-NAME? EDHF is rare in Aorta but how could we describe the relaxation observed here?

Try indomethacin in combination with L-NAME, because it may be PGI2 causing the NO-independent relaxation. If there is a residual relaxation in the presence of both these inhibitors then it is designated EDH-type (not EDHF, or EDHF-type). 

please explain what is proper protocol for using combination of antagonists . like u have suggested L-NAME and Indo.

i think first we have to add indo for 20 minutes and then L-name for 20 minutes .

Thanks. I must have mentioned, Yes, I tried Indomethecin and combinations.

What %relaxation is left after those two inhibitors? Try 60 mM KCl (as an inexpensive, albeit slightly primative, way of doing a preliminary study on EDH) with and without L-NAME+indo. Is it a disease model where this residual response is left?

no one replied my question.

Shahnawaz, you can just add both at the same time. 30 mins is perfectly sufficient.

thanks

reply my message also.