No abstract

No abstract

Constriction of isolated resistance arteries in response to α -adrenoceptor agonists is limited by reciprocal engagement of inhibitory endothelial mechanisms via myoendothelial feedback. In the current model of feedback, agonist stimulation of smooth muscle cells results in localized InsP -dependent Ca transients that activate endothelial IK channels. The subsequent hyperpolarization of the endothelial membrane potential then feeds back to the smooth muscle to limit further reductions in vessel diameter. We hypothesized that the functional contribution of InsP -IK channel-mediated myoendothelial feedback to limiting arterial diameter may be influenced by the nature of the vasoconstrictor stimulus. To test this hypothesis, we investigated the functional role of myoendothelial feedback in modulating responses of rat mesenteric resistance arteries to the adrenoceptor agonist noradrenaline, the thromboxane A mimetic U46619, increases in intravascular pressure and stimulation of perivascular sympathetic nerves. In isolated arteries, responses to noradrenaline and stimulation of sympathetic nerves, but not to U46619 and increases in intravascular pressure, were modulated by IK channel-dependent myoendothelial feedback. In the intact mesenteric bed perfused under conditions of constant flow, responses to exogenous noradrenaline were modulated by myoendothelial feedback, but shear stress-induced release of NO and activation of endothelial SK channels appeared to be the primary mediators of endothelial modulation of vasoconstriction to agonists and nerve stimulation. Thus, we propose that myoendothelial feedback may contribute to local control of diameter within arterial segments, but at the level of the intact vascular bed, increases in shear stress may be the major stimulus for engagement of the endothelium during vasoconstriction.

With the medical use of cannabis permitted in Canada since 2001, patients seek to use this botanical drug to treat a range of medical conditions. However, many healthcare practitioners express the need for further scientific evidence around the use of medical cannabis. This real-world evidence study aimed to address the paucity of scientific data by surveying newly registered medical cannabis patients, before beginning medical cannabis treatment, and at one follow up 6 weeks after beginning medical cannabis treatment. The goal was to collect data on efficacy, safety and cannabis product type information to capture the potential impact medical cannabis had on patient-reported quality of life (QOL) and several medical conditions over a 6-week period using validated questionnaires. The 214 participants were mainly male (58%) and 57% of the population was older than 50. The most frequently reported medical conditions were recurrent pain, post-traumatic stress disorder (PTSD), anxiety, sleep disorders [including restless leg syndrome (RLS)], and arthritis and other rheumatic disorders. Here we report that over 60% of our medical cannabis cohort self-reported improvements in their medical conditions. With the use of validated surveys, we found significant improvements in recurrent pain, PTSD, and sleep disorders after 6 weeks of medical cannabis treatment. Our findings from patients who reported arthritis and other rheumatic disorders are complex, showing improvements in pain and global activity sub-scores, but not overall changes in validated survey scores. We also report that patients who stated anxiety as their main medical condition did not experience significant changes in their anxiety after 6 weeks of cannabis treatment, though there were QOL improvements. While these results show that patients find cannabis treatment effective for a broad range of medical conditions, cannabis was not a remedy for all the conditions investigated. Thus, there is a need for future clinical research to support the findings we have reported. Additionally, while real-world evidence has not historically been utilized by regulatory bodies, we suggest changes in public policy surrounding cannabis should occur to reflect patient reported efficacy of cannabis from real-world studies due to the uniqueness of medical cannabis's path to legalization.

The trace amine b-phenylethylamine (PEA) is normally present in the body at low nanomolar concentrations but can reach micromolar levels after ingestion of drugs that inhibit monoamine oxidase and primary amine oxidase. In vivo, PEA elicits a robust pressor response, but there is no consensus regarding the underlying mechanism, with both vasodilation and constriction reported in isolated blood vessels. Using functional and biochemical approaches, we found that at low micromolar concentrations PEA (1-30 mM) enhanced nerve-evoked vasoconstriction in the perfused rat mesenteric bed but at a higher concentration (100 mM) significantly inhibited these responses. The a 2 -adrenoceptor antagonist rauwolscine (1 mM) also enhanced nerve-mediated vasoconstriction, but in the presence of both rauwolscine (1 mM) and PEA (30 mM) together, nerveevoked responses were initially potentiated and then showed time-dependent rundown. PEA (10 and 100 mM) significantly increased noradrenaline outflow from the mesenteric bed as determined by high-pressure liquid chromatography coupled with electrochemical detection. In isolated endothelium-denuded arterial segments, PEA (1 mM to 1 mM) caused concentrationdependent reversal of tone elicited by the a 1 -adrenoceptor agonists noradrenaline (EC 50 51.69 6 10.8 mM; n 5 5), methoxamine (EC 50 68.21 6 1.70 mM; n 5 5), and phenylephrine (EC 50 67.74 6 16.72 mM; n 5 5) but was ineffective against tone induced by prostaglandin F 2a or U46619 (9,11-dideoxy-9a,11a-methanoepoxyprostaglandin F 2a H]rauwolscine (K i % 1.2 mM), ligands for a 1 -and a 2 -adrenoceptors, respectively. These data provide the first demonstration that dual indirect sympathomimetic and a 1 -adrenoceptor blocking actions underlie the vascular effects of PEA in resistance arteries.

No abstract

Maintenance of adequate blood flow to tissues and organs requires that endothelial cells dynamically respond in a stimulus-specific manner to elicit appropriate changes in smooth muscle contractility and thus, arterial diameter. Endothelial cells can be stimulated directly by increases in blood flow and by humoral factors acting on surface receptors, as well as through flux of second messengers from smooth muscle cells activated by release of neurotransmitters from perivascular nerves. The ability of endothelial cells to generate stimulus-specific responses to these diverse inputs is facilitated by organization of ion channels and signaling proteins into microdomains that permit finely-tuned, spatially-restricted Ca 2+ events to differentially activate key effectors such as nitric oxide (NO) synthase and Ca 2+-activated K + (K Ca) channels. NO is a diffusible mediator which acts locally to cause vasodilation. Opening of K Ca channels causes hyperpolarization of the endothelial membrane potential which spreads to surrounding smooth muscle cells to also cause local vasodilation. However, once initiated, hyperpolarization also spreads longitudinally through the endothelium to effect coordinated changes in blood flow within multiple arterial segments. Thus, the signaling pathways activated by a particular stimulus determine whether it's effects on arterial diameter are localized or can impact blood flow at the level of the vascular bed.

No abstract