Glucagon-like peptide-1 (GLP-1) receptor activation dilates cerebral arterioles, increases cerebral blood flow, and mediates remote (pre)conditioning neuroprotection against ischaemic stroke

Stroke remains one of the most common causes of death and disability worldwide. Several preclinical studies demonstrated that the brain can be effectively protected against ischaemic stroke by two seemingly distinct treatments: remote ischaemic conditioning (RIC), involving cycles of ischaemia/reperfusion applied to a peripheral organ or tissue, or by systemic administration of glucagon-like-peptide-1 (GLP-1) receptor (GLP-1R) agonists. The mechanisms underlying RIC- and GLP-1-induced neuroprotection are not completely understood. In this study, we tested the hypothesis that GLP-1 mediates neuroprotection induced by RIC and investigated the effect of GLP-1R activation on cerebral blood vessels, as a potential mechanism of GLP-1-induced protection against ischaemic stroke. A rat model of ischaemic stroke (90 min of middle cerebral artery occlusion followed by 24-h reperfusion) was used. RIC was induced by 4 cycles of 5 min left hind limb ischaemia interleaved with 5-min reperfusion periods. RIC markedly (by ~ 80%) reduced the cerebral infarct size and improved the neurological score. The neuroprotection established by RIC was abolished by systemic blockade of GLP-1R with a specific antagonist Exendin(9–39). In the cerebral cortex of GLP-1R reporter mice, ~ 70% of cortical arterioles displayed GLP-1R expression. In acute brain slices of the rat cerebral cortex, activation of GLP-1R with an agonist Exendin-4 had a strong dilatory effect on cortical arterioles and effectively reversed arteriolar constrictions induced by metabolite lactate or oxygen and glucose deprivation, as an ex vivo model of ischaemic stroke. In anaesthetised rats, Exendin-4 induced lasting increases in brain tissue PO2, indicative of increased cerebral blood flow. These results demonstrate that neuroprotection against ischaemic stroke established by remote ischaemic conditioning is mediated by a mechanism involving GLP-1R signalling. Potent dilatory effect of GLP-1R activation on cortical arterioles suggests that the neuroprotection in this model is mediated via modulation of cerebral blood flow and improved brain perfusion.

Veinplicity versus heat treatment for vein dilation: A randomised cross-over study

Background: Peripheral intravenous cannulation is one of the most common invasive procedures for hospitalised patients. Patients with difficult venous access require special measures to facilitate cannulation. Veinplicity applies mild electrical stimulation to forearm veins to aid vessel dilation. To assess this new technique, we compared its effect on the veins to that of standard heat treatment. Methods: In all, 20 volunteers were randomised to receive either application of heat packs to the forearm and later stimulation with Veinplicity or the same two treatments in reverse order. Ultrasound measurements of the basilic, cephalic and brachial veins were taken at intervals during and after treatment and compared with baseline values. Results: The mean maximum vein diameter increase from baseline was significantly higher with Veinplicity than with heat packs (49.94% ± 23.55% vs 36.26% ± 23.09%, p = 0.021). In addition, the mean duration of the dilatory effect was significantly longer with Veinplicity than with heat packs (9.7 ± 3.9°min vs 4.9 ± 2.2°min, p < 0.001). Conclusion: Veinplicity dilates forearm veins more effectively and for a longer time than commonly used heat packs. This new treatment option appears to be a valuable addition to the vascular access toolkit, with the potential to improve first-attempt cannulation rates and spare patients from discomfort, pain and iatrogenic vessel trauma.

The use of a stent-retriever to cause mechanical dilatation of a vasospasm secondary to iatrogenic subarachnoid haemorrhage

Objective To report the use of a stent-retriever in the management of vasospasm secondary to craniopharyngioma resection. Postoperative improvement was seen both clinically and on perfusion imaging. Methods A patient was admitted for resection of a large craniopharygioma. On day 6 postoperatively the patient had an acute hemiparesis. A computed tomography angiogram and perfusion scan demonstrated acute right-sided cerebral vasospasm and a perfusion defect in the territory of the middle cerebral artery (MCA). Results A pREset 4 × 20 mm stent-retriever was used to dilate the M1 and proximal M2 segments of the right MCA mechanically. This resulted in immediate dilatation of the spastic segment and improvement in the transit time on the angiogram. There was an improvement in the clinical status post-procedure and a computed tomography perfusion performed 24 hours after the procedure showed symmetrical perfusion. A computed tomography angiogram and magnetic resonance imaging performed 1 week later showed a symmetrical appearance to the MCA and no evidence of restricted diffusion. Conclusion The use of commercially available stent-retrievers can cause mechanical dilatation of vasospastic vessels. The stents do not need to be deployed for a prolonged period nor do they need to be implanted to have a prolonged dilatory effect on the spastic vessels.

Abstract P177: The Myotrophoblast of the Rat Placenta Ex Vivo Study of Nitric Oxide Synthase Inhibition

In pregnancy spiral arteries, are invaded by endovascular trophoblasts (EVT) and remodeled. Previously, NOS, and of smooth muscle proteins expression in EVT, and endothelin-1 (ET1) ex-vivo contraction of the remodeled artery were demonstrated, mediated by ET1 receptors A and B (ETA, ETB) Placentas on gestational day 21, were dissected, spiral artery rings devoid of smooth muscle were fixed to a silicon-coated 8-well chamber slide in oxygenated solution. Rings cut surface area (CSA) was observed under laser scanning confocal microscope. Following baseline, L-NAME and 10- 5 M, ET-1 10-7 M were added to some chambers. In other wells, also with ETA antagonist at 10-6 M (BQ-123). CSA was measured using ImageJ software. L-NAME alone, reduced CSA by 2.5% p=0.002. Addition of ET-1 to L-NAME, reduced CSA area immediately, compared with a plateau at 60min by ET1 p=0.001 .L-NAME, followed by ET-1 and ETA antagonist, the isolated constrictive effect of ET-1 via ETB, 7.2%, was earlier and stronger n than via ETA, 6.1% p< 0.001 (figure). L-NAME + ET-1 causes contraction of the arterial ring via ETA and ETB, without the dilatory effect of NO. ET-1 alone shows an earlier, immediate CSA reduction, compared to that of ET-1 without L-NAME, achieved at 40-60 minutes. This is in accordance with the instantaneous NO effect through ETB, compared with the gradual ET-1 induced CSA reduction .To isolate the contracting effect via ETB, we added L-NAME + ETA+ ET-1. The ETB contraction is earlier and stronger than that via ETA. Thus, EVT of the rat remodeled spiral artery react to ET-1 like vascular smooth muscle of non-modified arteries: contraction via receptors A and B and relaxation via receptor B through NOS.

Identification and function of adenosine A3 receptor in afferent arterioles

Adenosine plays an important role in regulation of renal microcirculation. All receptors of adenosine, A1, A2A, A2B, and A3, have been found in the kidney. However, little is known about the location and function of the A3 receptor in the kidney. The present study determined the expression and role of A3 receptors in mediating the afferent arteriole (Af-Art) response and studied the interaction of A3 receptors with angiotensin II (ANG II), A1 and A2 receptors on the Af-Art. We found that the A3 receptor expressed in microdissected isolated Af-Art and the mRNA levels of A3 receptor were 59% of A1. In the isolated microperfused Af-Art, A3 receptor agonist IB-MECA did not have a constrictive effect. Activation of A3 receptor dilated the preconstricted Af-Art by norepinephrine and blunted the vasoconstrictive effect of both adenosine A1 receptor activation and ANG II on the Af-Art, respectively. Selective A2 receptor antagonist (both A2A and A2B) had no effect on A3 receptor agonist-induced vasodilation, indicating that the dilatory effect of A3 receptor activation is not mediated by activation of A2 receptor. We conclude that the A3 receptor is expressed in the Af-Art, and activation of the A3 receptor dilates the Af-Art.

Functional and molecular characterization of prostaglandin E2 dilatory receptors in the rat craniovascular system in relevance to migraine

Introduction: Migraine pain is thought to involve an increase in trigeminal nerve terminal activity around large cerebral and meningeal arteries, leading to vasodilatation. Because prostaglandin E2 (PGE2) is elevated in cephalic venous blood during migraine attacks, and is also capable of inducing headache in healthy volunteers, we hypothesize that PGE2 dilatory receptors, EP2 and EP4, mediate the response. Materials and methods: By the use of specific agonists and antagonists, the dilatory effect of PGE2 was characterized in rat cranial arteries by use of in vivo and in vitro methods. Furthermore, EP2 and EP4 quantitative messenger RNA (mRNA) receptor expression was studied in the rat craniovascular system. Results: Our results suggest that EP4, and to a lesser degree EP2, receptors mediate the dilatory effect of PGE2 in the craniovascular system in rats. Thus, antagonism of these receptors might be of therapeutic relevance in migraine.

Nitric oxide-epoxygenase interactions and arachidonate-induced dilation of rat renal microvessels

Nitric oxide (NO) is an inhibitor of hemoproteins including cytochrome P-450 enzymes. This study tested the hypothesis that NO inhibits cytochrome P-450 epoxygenase-dependent vascular responses in kidneys. In rat renal pressurized microvessels, arachidonic acid (AA, 0.03–1 μM) or bradykinin (BK, 0.1–3 μM) elicited NO- and prostanoid-independent vasodilation. Miconazole (1.5 μM) or 6-(2-propargyloxyphenyl)hexanoic acid (30 μM), both of which are inhibitors of epoxygenase enzymes, or the fixing of epoxide levels with 11,12-epoxyeicosatrienoic acid (11,12-EET; 1 and 3 μM) inhibited these responses. Apamin (1 μM), which is a large-conductance Ca2+-activated K+ (BKCa) channel inhibitor, or 18α-glycyrrhetinic acid (30 μM), which is an inhibitor of myoendothelial gap junctional electromechanical coupling, also inhibited these responses. NO donors spermine NONOate (1 and 3 μM) or sodium nitroprusside (0.3 and 3 μM) but not 8-bromo-cGMP (100 μM), which is an analog of cGMP (the second messenger of NO), blunted the dilation produced by AA or BK in a reversible manner without affecting that produced by hydralazine. However, the non-NO donor hydralazine did not affect the dilatory effect of AA or BK. Spermine NONOate did not affect the dilation produced by 11,12-EET, NS-1619 (a BKCa channel opener), or cromakalim (an ATP-sensitive K+ channel opener). AA and BK stimulated EET production, whereas hydralazine had no effect. On the other hand, spermine NONOate (3 μM) attenuated basal (19 ± 7%; P < 0.05) and AA stimulation (1 μM, 29 ± 9%; P < 0.05) of renal preglomerular vascular production of all regioisomeric EETs: 5,6-; 8,9-; 11,12-; and 14,15-EET. These results suggest that NO directly and reversibly inhibits epoxygenase-dependent dilation of rat renal microvessels without affecting the actions of epoxides on K+ channels.

Localization of the Bronchodilatory Effects of Isoproterenol and Aminophylline in Patients with Bronchial Asthma: An Investigation Using Selective Alveolobronchography

The effect of isoproterenol (isoprenaline) and aminophylline on airway calibre in 18 adult patients with bronchial asthma was measured directly using selective alveolobronchography. Isoproterenol caused a significant dilation in the maximal calibre of the central airway from bifurcation numbers 1 – 5 ( P < 0.05) and number 6 ( P < 0.01). There was no change in bifurcation number 0 (trachea). Aminophylline caused a significant dilatation in bifurcation numbers 3 and 4 ( P < 0.01), with no change in bifurcation numbers 0–2 and 5 – 6. In the minimal calibre of the central airway, both drugs displayed a significant dilatory effect only at bifurcation number 3 ( P < 0.05). These results indicate that the central airway is the main site of the dilatory effects of these drugs. Although their precise mechanisms of action are not known, these results suggest that mechanisms of action of the two drugs are different. Isoproterenol acts on the whole region of the central airway, while the action of aminophylline tends to be limited to bifurcation numbers 3 and 4.