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Vascular - Hiley

Bellamy & Garthwaite 2002 YC-1 is used to potentiate s-guanylyl cyclase activation by NO, reduces rate of NO dissociation & can reverse desensitisation caused by haem oxidation. ODQ is an inhibitor, oxidises haem within the sGC, YC1 prevents ODQ's inactivating effects.
Campbell et al 2003 ACh triggers arachidonic acid release to cause endothelium-dep relaxation, KCl inhibits (indicates K+ channels involved). EETs (metabolites of AA) are EDHF in coronary vessels. HEETAs and THETAs are AA metabolites, THETAs seem to be EDHF in rabbit aorta.
Cocks & Angus 1983 NA and 5-HT constrict better without endothelium. Blocking BARs and a1ARs w/ propranolo and prazosin blocked smooth muscle effects of NA. Left endo-dep relaxation blocked by a2 antagonists. 5-HT2 receptor block causes 5-HT to become relaxing.
Garland et al 2011 Review: EDHF uses Kca2.3 & 3.1, Hyperpoln can spread through gap junctions from endo to smooth muscle. TEA & apamin are classic EDHF blockers. K+ release stimulates Na/K ATPase to hyperpolarise. EETs are slightly different, act through BK channels.
Mather et al 2005 Loaded endothelial cells with antibody (fluor tagged to show success) against connexins to block gap junctions. This reduced the dilation induced by an a1 agonist (phenylephrine). Prevented spread of hyperpolarisation from endothelium to muscle.
Hiley 2009 (only author) Review: Cb2R predominates peripherally. ab-cannabidiol effects suggest new receptor, O-1918 is thoguht to antagonise. FAAH mRNA is present in the heart, CB2Rs are thought to mediate remote preconditioning to ischaemia. FAAH null mice protected in old age.
Thillez & Richard 2005 Review: Some B blockers act as NO donors. NO limits expression of inflam adhesion molecules (VCAM-1 etc). Decr No in hypertension, ACE inh potentiate BK to stim release of NO,EDHF&PGI2. Ca channel block seems protective, unknown mechanism.
Perticone et al 2001 Impaired vasodilation to BK and ACh predicts adverse events in hypertension. All patients drug naive. ACh and BK given while measuring forearm blood flow. Cardiovascualar event risk was doubled in the least responsive compared to most responsive.
Zygmunt et al 1999 Anadamide causes an increase in cAMP and CGRP. TRPV1 blocker (capsazepine) reduced the dilatory response to AEA. CGRP receptor blockade also reduces the response.
Alderton et al 2001 Review: 51-57% homology between human NOS isoforms. Zinc needed for NOS dimers but no effect on activity. All 3 isoforms need CaM. Phosphorylation incr ca-ind activity, eNOS phospho under shear stress, phospho'd by Akt. nNOS targetted to synapses by PDZ.
Sugiura et al 2006 Review: 2-AG can be produced from arachidonic acid-containing membrane phosopholipids. FAAH can degrade 2-AG. 2-AG may well be taken up by the putative anandamide transporter (although some results suggest
Beltramo et al 1997 Evidence that AEA is inactivated by cellular uptake via transporter. Uptake was rapid, temperature sensitive and saturable. Blocking the receptor prevented possible internalisation, blocking FAAH prevented degradation, uptake continued despite both.
Glaser et al 2003 'Specific' transport inhibitors found to inhibit FAAH, thus reducing the gradient for AEA diffusion. Used a shorter time scale, showing no saturation (claim due to FAAH in beltramo). Showed that transporter temp sensitivity was similar to that of FAAH.
Batkai et al 2007 Some argument as to whether FAAH acts in the heart, cardioprotective effects of KO in mice suggest it does. Reduced the decr in cardiac output and stroke work. Reduced incr in TNFa, caspases 3 & 9 plus other genes.
Pacher et al 2005 Concentration of AEA is increased in cardiac tissue of FAAH KO mice, 2-AG is unaltered. No effect on normal cardiac function.
Aronow & Cassidy 1974 Showed that marijuana smoking caused angina to develop more rapidly after beginning exercise. First indications of vascular effects of cannabinoids.
Mittleman et al 2001 Showed that inhaled cannabis causes a short-term risk of heart attack. Unsurprising given its effects to incr heart rate and cause both supine hypertension and postural hypotension.
Varga et al 1995 Used spinal cord transection and symp block to find out how much of AEA's effects are central. Both methods had no effect on pressor response to AEA but removed the long term hypotensive effect (phase 3). Vagotomy stopped decr HR in phase 1.
White & Hiley 1997 Claimed that the AEA response was entirely independent of the endothelium, functioning enodothelium tested by carbachol response. Precontraction with KCl nearly blocked all cannabinoid response.
Wagner et al 1999 CB1 receptor agonists had no effect, AEA did. Rimonabant did work but didnt remove all of AEA's effects (only blocked endothelium dep effects, seemingly CBXR as other ants/ags had no effect), indicates a direct action on smooth muscle (not CB1R or CBXR)
Mukhopadhyay et al 2002 Endothelium indep response to AEA is via TRPV1 lcausing CGRP release. indep response blocked by capsazepine (TRPV1), CGRP(8-37) & L-NAME (indicating NO is downstream). Couldnt block endothelium dep relaxation with gap junction blocker
Chaytor et al 1999 Shows that rimonabant blocks gap junctions when given at high concentrations, would explain blockade of endo-dep relaxation if Mukhopadhyay 2002 hadnt shown that specific gap junction blockers dont work.
Baranowska-Kuczko et al 2012 Pulmonary artery. O-1918, L-NAME & COX inh are able to inhibit endo-dep effects of AEA, thought to block CBXR. Abn-cannabidiol & AEA are CBXR agonists of choice. No role for TRPV1 here, AEA may release EDHF (block by apamin & charybdotox). Tissue specific
Randall et al 2004 Review: Magnitude of relaxation to AEA differs between tissues from 0% (rat coronary) - 100% (small mesenteric vessels), 40% in sup mesenteric artery. Sensitivity to L-NAME and TRPV1 antagonists varies between tissues.
Ho & Hiley 2003 Abn cannabidiol not blocked by capsaicin pretreatment or indomethacin (COX inh). Relaxation reduced by precontraction with KCl (relative to precontraction with methoxamine). Thought to block Ca channels, as ionomycin (ionophore) prevented relaxation
AEA Various studies claim it acts directly via CB1, CBX and TRPV1, also indirectly via nitric oxide (NO)/endothelium-derived hyperpolarising factor (EDHF) release, metabolism to vasoactive molecules, opening of K+ channels or the inhibition of Ca2+ channels.
Wagner et al 1997 Transfusion of monocytes & platelets from post-haemorrhagic rats caused CB1 mediated hypotension in recipients. CB1 block has little effect in normal rats, but incr blood pressure post-haemorrhage & decr survival rates. Mass spec showed monocytes make AEA
Varga et al 1998 Showed by mass spec that platelets contain 2-AG, levels of 2-AG incr by exposure to LPS (septic shock). Macrophages make AEA instead. Rimonabant blocked, L-NAME didnt. THC incr survival in septic shock (not all time pts), rimonabant also incr survival.
Wagner et al 2001 CB1 antagonists reduce survival in rats after a myocardial infarction, also reduce responsiveness of endothelium to ACh (may be the cause of mortality). Shows blocking cannabinoids isnt good in cardiogenic shock either.
O'Sullivan et al 2005 (a) THC (exogenous cannabinoid) is able to antagonise AEA at multiple sites. Differences may arise because THC can activate TRPA1. THC constricts the sup mes artery via endothelial facor, unsure what.
O'Sullivan et al 2005 (b) Shows that some of THCs vasorelaxant effects are via activation of PPARy receptors. Used cells transfected with PPARy/RXRa with a PPARy activated luciferase gene. Mimics timescale of rosiglitazone relaxation.
Lepicier et al 2003 Cannabinoids (2-AG & palmitoylethanolamide - low affinity but used here as CB2 agonist) reduce the size of myocardial infarcts. 90-120 mins of low flow ischaemia. Creatine kinase release was reduced. AEA had no effect, may be too quickly degraded/taken up
Lagneux & Lamontagne 2001 CB2 blocker (SR144528) and NOS inhibitor prevented ischaemic preconditioning caused by exposure to LPS. LPS pretreatment normally reduces infarct size, this was prevented. CB1 blocker had no effect
Batkai et al 2001 Endocannabinoids contribute to generalised vasodilation in liver cirrhosis. Used rimonabant (CB1 inh) to raise BP (no effect in normal rats) 3x more CB1Rs on cirrhotic human livers. Blood from cirrhotic rats causes CB1 mediated dilation in recipient rats.
De Petrocellis et al 2001 Entry to cells is needed for AEA to act on TRPV1 receptors, inhibitors of anandamide transporter inhibited TRPV1 response (disproves the transporter blockers as FAAH blockers point made by Glaser 03)
Jarai et al 1999 First description of the CBXR, names AEA as an agonist and rimonabant as an antagonist HU-210, non-specific agonist, fails to cause a response. Response occurred in CB1+2 dbl KO. Effect strongly inh by apamin and charybdotox, indicating EDHF involvement.
Hoi & Hiley 2006 Oleamide has CB-like effects despite low affinity. Blocked by rimonabant, not other antagonists, oleamide=CBXR agonist?. NOS block or apamin+charybdotox blocked effects. No entourage (FAAH blockade potentiating AEA response), FAAH blocker had no effect
Milman et al 2006 Proposed that ARA-S might be an endogenous agonist at the CBXR. Probably not as rimonabant didnt block its effects. O-1918 did, but this persisted when endothelium was removed (odd). Maybe another similar receptor or PPARy?
Created by: Jonmassie



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