AMP-activated protein kinase (AMPK) is present in the arterial wall and is activated in response to cellular stressors that raise AMP relative to ADP/ATP. Activation of AMPK in vivo lowers blood pressure but the influence of hyperlipidemia on this response has not been studied. ApoE−/− mice on high fat diet for 6 weeks and age-matched controls were treated with the AMPK activator, AICAR daily for two weeks. Under anesthesia, the carotid artery was cannulated for blood pressure measurements. Aortic tissue was removed for in vitro functional experiments and AMPK activity was measured in artery homogenates by Western blotting. ApoE−/− mice had significantly raised mean arterial pressure; chronic AICAR treatment normalized this but had no effect in normolipidemic mice, whereas acute administration of AICAR lowered mean arterial pressure in both groups. Chronic AICAR treatment increased phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase in normolipidemic but not ApoE−/− mice. In aortic rings, AMPK activation induced vasodilation and an anticontractile effect, which was attenuated in ApoE−/− mice. This study demonstrates that hyperlipidemia dysregulates the AMPK pathway in the arterial wall but this effect can be reversed by AMPK activation, possibly through improving vessel compliance.
Jejunal fluid absorption in vivo was reduced by distension and by hydrostatic pressure and further declined on adding E. coli STa enterotoxin but no net fluid secretion was detected. Luminal atropine reduced pressure mediated reductions in fluid absorption to normal values but intravenous hexamethonium was without effect. A neural component to inhibition of absorption by pressure (though not stretch) may be mediated by axon reflexes within cholinergic neurons. Perfusion of cholinergic compounds also reduced net fluid absorption but did not cause secretion. In order to show that these actions were not secretory processes stimulated by cholinergic compounds that offset normal rates of absorption, these compounds were tested for their ability to cause net secretion in loops that were perfused with solutions in which choline substituted for sodium ion. In addition, these perfusates additionally contained E. coli STa enterotoxin or EIPA (ethyl-isopropylamiloride) to minimize absorption. In these circumstances, where it might be expected to do so if it Original Research Article
Using a recirculation procedure to perfuse anaesthetised rat jejunum, E. coli STa enterotoxin can be shown to inhibit net fluid absorption profoundly, while not causing net fluid secretion, provided fluid measurement is by mass or volume. This observation contradicts many reports of STa causing secretion, implying that the recovered volume technique in the anaesthetised animal over a period of some hours cannot detect secretion because of conjectured or unspecified flaws. Experiments are presented here confirming the viability of the perfusion protocol used in this laboratory but also demonstrate that if secretion were to be occurring, the recovered volume protocol would detect it. It will only return a negative finding, if secretion does not occur. To this end, the effect of two secretory toxins on intestinal fluid movement in a closed loop preparation JAMMR, 28(2): 1-11, 2018; Article no.JAMMR.44118 2 were studied to demonstrate that the anaesthetic, intestinal preparation or perfusion duration did not hinder the demonstration of net secretion when the intestine was exposed to E. coli LT and C. difficile toxin A.. It is evident that STa itself only reduces net absorption but can appear to be secretory if driving forces such as luminal osmotic pressure or capillary hydrostatic pressure through vasodilatation are introduced, as was likely to have occurred with pithing and theophylline. The recognition that STa is a non-secretory enterotoxin necessarily falsifies several alternative methods that claim to demonstrate secretion. Since STa is not secretory many other substances identified by these methods need also not be secretory and alternative explanations must be found to explain their action. The importance of recognising that action on the small intestine cannot be attributed to a secretory mechanism within the enterocyte adds further weight to the concept that where net secretion does occur, the likely mechanism for it is a combination of increased vasodilatation together with increased hydraulic conductivity. Original Research Article
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