Vasomotor Responses Research Articles

Acid sensing ion channels in rat cerebral arteries: Probing the expression pattern and vasomotor activity

AimsThe recent identification of acid sensing ion channels (ASICs) in vascular beds suggests their possible involvement in modulating vasomotor tone. Therefore, we investigated the gene expression profiles of ASIC subtypes in the middle cerebral artery (MCA) of Wistar rats and the functional implication of ASICs in acidosis-induced relaxation as well as maintenance of resting tension. Main methodsReal time PCR was employed to study the pattern of ASIC mRNA expression in the MCA wall in comparison with (i) matching brain tissue samples and (ii) arteries cultured for 24 h and 48 h. The functional implication regarding vasomotor response to acidosis and maintenance of resting tension was assessed using in vitro myography. Key findingsA robust mRNA expression of ASIC-1, -2 and -4 was found in brain tissue samples and to a lower extent in freshly isolated MCA. In the MCA wall, short term culture induced a down-regulation of ASIC-1 and -2 expression without any remarkable change in ASIC-4 expression. Acidosis induced a pH-related relaxation of freshly isolated MCA ring segments, being more pronounced after short term culture. Incubation with the ASIC blocker amiloride moderately enhanced acidosis-induced relaxation, in cultured MCAs somewhat stronger than in freshly isolated vessels. In addition, amiloride resulted in a decrease of resting tension, albeit only in freshly isolated MCA. SignificanceOur results comprehensively describe ASIC subtype composition in the rat MCA in physiological and pathological conditions and strongly suggest the involvement of ASICs in the modulation of vasomotor responses under conditions of normal or decreased pH values.

Functional Neurosonology Reveals Impaired Cerebrovascular Reactivity in Multiple Sclerosis.

Vascular aspects like global cerebral hypoperfusion are frequently reported in patients with multiple sclerosis (MS). Although mechanistic question remains unanswered, this hemodynamic impairment may be caused by a widespread endothelial dysfunction. Furthermore, impaired cerebrovascular reactivity (CVR) has been described in patients with MS by means of hypercapnic perfusion magnetic resonance imaging (MRI). We sought to further evaluate potential hemodynamic restriction in patients with MS using functional sonographic methods. We evaluated consecutive patients with MS and healthy controls with adequate bilateral transtemporal window. CVR was assessed by bilateral transcranial Doppler monitoring of proximal middle cerebral arteries. Mean flow velocities were recorded before and after 30 seconds of breath holding. Vasomotor response was quantified by breath holding index (BHI). A total of 42 patients with MS (mean age 39 ± 12 years; 69% women) were compared to 31 healthy controls (mean age 35 ± 11 years; 71% women). BHI was lower in patients with MS compared to healthy controls (.70 ± .43 vs. .93 ± .55; P = .006), documenting a lower cerebrovascular response to hypercapnia. There was no correlation between patient age (r = .1254; P = .277), expanded disability status scale (r = .1838; P = .109), and disease duration (r = .1882; P = .101) with BHI in patients with MS. These preliminary sonographic findings appear to independently corroborate the previously reported observation of impaired CVR on brain MRI in patients with MS. However, the underlying pathophysiological mechanisms as well as the clinical impact of this observation remain elusive.

Persistent Dysfunction of Coronary Endothelial Vasomotor Responses is Related to Atheroma Plaque Progression in the Infarct-Related Coronary Artery of AMI Survivors.

Aim: Although coronary endothelial vasomotor dysfunction predicts future coronary events, there are few human studies showing the relationship between endothelial vasomotor dysfunction and atheroma plaque progression in the same coronary artery. This study examined whether endothelial vasomotor dysfunction is related to atheroma plaque progression in the infarct-related coronary artery of ST-segment elevation myocardial infarction (STEMI) survivors using serial assessment of coronary plaque size with intravascular ultrasound (IVUS) and coronary vasomotor responses to acetylcholine (ACh).Methods: This study included 50 patients with a first acute STEMI due to occlusion of the left anterior descending coronary artery (LAD) and successful reperfusion therapy with percutaneous coronary intervention (PCI). IVUS and vasomotor response to ACh in the LAD were measured within two weeks of acute myocardial infarction (AMI) (1st test) and repeated six months (2nd test) after AMI under optimal anti-atherosclerotic therapies.Results: Percent atheroma volume (PAV) and total atheroma volume (TAV) in the LAD progressed over six months of follow-up in 18 and 14 patients, respectively. PAV and TAV progression was significantly associated with persistent impairment of epicardial coronary artery dilation and coronary blood flow increase in response to ACh at both the 1st and 2nd tests. PAV and TAV progression had no significant association with traditional risk factors, PCI-related variables, medications, and the coronary vasomotor responses to sodium nitroprusside, an endothelium-independent vasodilator.Conclusions: Persistent impairment of endothelial vasomotor function in the conduit arterial segment and the resistance arteriole was related to atheromatous plaque progression in the infarct-related coronary arteries of STEMI survivors.

Ski-Everest (8848 m) Expedition: Digit Skin Temperature Responses to Cold Immersion May Reflect Susceptibility to Cold Injury

We tested the hypothesis that individual susceptibility to freezing cold injury might be reflected in an attenuated cold-induced vasodilatation (CIVD) response by comparing the CIVD responses of an elite alpinist with a history of freezing cold injury in the feet (case alpinist) with those of an age- and ability- matched noninjured alpinists control group (controls). According to this hypothesis, the vasomotor responses to a CIVD test of the case alpinist would represent a pathophysiological response when compared with the normal physiological response of a noninjured cohort. The case alpinist and the controls in the cohort group conducted a cold water immersion test comprising sequential immersion of a hand and foot for 5 min in 35°C water, followed by a 30-min immersion in 8°C water and a 10-min recovery period in room air. During this test we monitored the finger and toe skin temperatures. The case alpinist had a significantly attenuated CIVD response and a lower skin temperature in all injured and noninjured digits during immersion (∼2°C lower than in the control group) and an attenuated recovery of finger skin temperatures (∼6°C lower than in the control group). The attenuated CIVD response of the case alpinist may reflect a previously unrecognized enhanced susceptibility to frostbite. In addition to the poor vasomotor response observed in the injured toes, he also exhibited a poor vasomotor response in his noninjured fingers. The results of the present study indicate that a test of vasomotor activity during thermal stress may identify individuals predisposed to cold injury.

Impact of Intravitreal Dexamethasone Implant on Vessel Diameters in Patients with Retinal Vein Occlusion.

Purpose To investigate the vasomotor responses and diameter of retinal vessels in patients with macular edema secondary to retinal vein occlusion (RVO) who were treated with intravitreal dexamethasone implant. Methods We enrolled 17 eyes of 17 patients with macular edema secondary to RVO. All patients were evaluated through optical coherence tomography and dynamic and static retinal vessel analysis, using the Dynamic Vessel Analyzer (Imedos, Jena, Germany) before administration (baseline) and 1 week, 1 month, and 2 months after administration of intravitreal dexamethasone. Measurements of patients were compared to those of 17 eyes of age- and sex-matched control subjects. Results In static analysis, arteriovenous ratio (AVR) in control subjects was 0.86 (0.80–0.88). In RVO patients, baseline AVR was 0.71 (0.54–0.84) and significantly lower than that in control subjects (p=0.016). Baseline AVR in the RVO group was significantly lower than AVR at month 1 and month 2 (p=0.001 and p < 0.001, respectively). CRVE in healthy control subjects was 183.59 ± 21.79 measurement units (MU) which was significantly different from CRVE of RVO eyes at baseline (207.00 ± 26.35 MU) (p=0.008). Static analysis showed a significant decrease of central retinal vein equivalent (CRVE) from baseline to 1 week, 1 month, and 2 months (p < 0.001, p < 0.001, and p < 0.001, respectively). CRAE in the control group was 176.24 ± 22.45 MU. CRAE in the RVO group was significantly lower at baseline, week 1, month 1, and month 2 compared to that in the control group (p=0.008, p=0.003, p=0.013, and p=0.011, respectively). Dynamic analysis showed that maximum venous and arterial dilations did not statistically differ from baseline to 1 week, 1 month, or 2 months. Conclusion Using the Dynamic Vessel Analyzer, we found that retinal veins in patients with RVO were significantly larger compared to those in the control group, and intravitreal dexamethasone treatment reduced the diameters of these veins.

Deficiency of the transcription factor, Nrf2, impairs vasomotor responses and limits exercise training‐induced adaptations of coronary arterioles

Nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) is a transcription factor that is crucial in maintaining cellular redox homeostasis. Vasomotor responses of the coronary resistance vasculature and regulation of coronary blood flow are closely linked to myocardial metabolism and redox status of the myocardium. We hypothesized that deletion of Nrf2 would alter vascular responses of coronary arterioles and limit exercise training‐induced adaptations of vasomotor function. We exercise trained wild type (WT) Sprague‐Dawley rats, and their littermates that were lacking the Nrf2 gene (Nrf2KO). Rats were either exercise trained (EX) on a motor‐driven treadmill 5 days/wk or remained sedentary (SED) in their cages for 10–12 weeks. A mixed moderate aerobic and high‐intensity interval training protocol was utilized. At the end of the training period, coronary arterioles were isolated for assessment of vasomotor responses to potassium chloride (KCl) and endothelin, as both are considered potential endogenous regulators of coronary vascular resistance. We also evaluated responsiveness of coronary arterioles to increasing intraluminal pressure (the myogenic response). Contractile responses of coronary arterioles to KCl and endothelin were reduced in arterioles from sedentary Nrf2KO rats as compared to arterioles from sedentary WT rats. Low concentrations of KCl induced vasodilation in coronary arterioles from exercise trained WT rats but not in arterioles from sedentary WT rats. Constriction to high concentrations of KCl was reduced in arterioles from exercise trained WT rats as compared to those from sedentary WT (WT EX vs WT SED; P&lt;0.01); however, these adaptations to exercise training were absent in arterioles from Nrf2KO rats (KO EX vs KO SED; P=0.94). Exercise training altered vasoconstrictor responses to endothelin in coronary arterioles from both WT and Nrf2KO rats; however, the effects of exercise training were directionally opposite in arterioles from WT and Nrf2KO rats. In arterioles from WT rats, exercise training reduced vasoconstrictor responses to endothelin, whereas in arterioles from Nrf2KO rats, vasoconstrictor responses to endothelin were increased by exercise training. Myogenic responsiveness was decreased in coronary arterioles from Nrf2KO rats as compared to arterioles from WT rats, but exercise training did not alter myogenic responsiveness in arterioles from either WT or Nrf2KO rats. These data suggest that the contractile responsiveness of coronary arterioles is decreased in the absence of Nrf2. The absence of Nrf2 also limits adaptation of coronary arterioles in response to exercise training. These changes in arteriolar function may be linked to alterations of redox homeostasis and metabolite production in cardiac muscle that is deficient in Nrf2.Support or Funding InformationNIH R15AG055029This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

No significant change of extracranial conduit vessel diameter during cerebral vasomotor reactivity test with moderately‐altered end‐tidal CO2

Cerebral vasomotor reactivity (CVMR) is often assessed using transcranial Doppler (TCD) to measure the cerebral blood flow velocity (CBFV) in the middle cerebral artery (MCA). Recently the validity of this technique has been questioned because of the assumption that MCA diameter does not change. The goal of this work was to test if the extracranial cerebral arteries, i.e. internal carotid and vertebral arteries (ICA and VA), have a significant diameter change during moderate alteration of end‐tidal carbon dioxide (ETCO2). Fifteen healthy subjects (6 males; age: 32±10 yrs) were enrolled. The CBFV at the MCA was continuously recorded with TCD during an 8‐min CVMR test, i.e. 2‐min resting ventilation, 2‐min inspiration of 5% CO2, 21% O2, balance nitrogen, 2‐min recovery, and 2‐min mild hyperventilation. 8 min protocol was repeated on the same subjects, to allow measurement of ICA diameter during one run and VA during the other using high‐frequency ultrasound. CVMR is expressed as the percent change in MCA's CBFV per mmHg change in ETCO2, as quantified by the slope of this relationship. The time‐averaged diameter during each static stage was measured offline with echo‐tracking software. All results presented as Mean ± SD. The experimental protocol resulted in a moderated change of ETCO2 (mmHg) during 5% CO2 inspiration (+6.9±2.0) and mild hyperventilation (−14.8±5.8) relative to the baseline values (34.6±2.7). Both hypercapnic and hypocapnic stages showed no significant changes (relative to the baseline) in blood pressure, heart rate, diameters of ICA (5.23±0.83 and 5.21±0.71, vs. baseline 5.22 ±0.83 mm; P = 0.88 and 0.86) and VA (3.91±0.69 and 3.91±0.72, vs. baseline 3.87±0.65 mm; P = 0.40 and 0.55), except for a slight increase (+7±8 bpm, P &lt; 0.001) of HR during hypocapnia. The individual variation of the diameter response showed no correlation with the concurrent blood pressure, heart rate, and CBFV responses. Based on these results, we concluded that the TCD appears to still be a reliable method to assess the CBF response during CVMR test with a moderate change of ETCO2, as no significant change of the conduit vessel diameter is likely to occur. However, future work is necessary to confirm that flow changes in the extracranial arteries are reflective of relative changes in TCD values.Support or Funding InformationSupported by the Funding from Rutgers University and U.S. Department of Defense.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Prostaglandin E2 at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles: implications for neurovascular coupling responses

There is considerable controversy regarding the vasoactive action of prostaglandin E2 (PGE2). On the one hand, indirect evidence implicates that astrocytic release of PGE2 contributes to neurovascular coupling responses mediating functional hyperemia in the brain. On the other hand, overproduction of PGE2 was also reported to contribute to cerebral vasospasm associated with subarachnoid hemorrhage. The present study was conducted to resolve this controversy by determining the direct vasoactive effects of PGE2 in resistance‐sized human cerebral parenchymal arterioles.To achieve this goal PGE2‐induced isotonic responses were assessed in parenchymal arterioles isolated from fronto‐temporo‐parietal cortical tissues surgically removed from patients and expression of PGE2 receptors were examined.In functionally intact parenchymal arterioles lower concentrations of PGE2 (from 10−8 to 10−6 mol/l) caused significant, endothelium‐independent vasorelaxation, which was inhibited by the EP4 receptor blocker BGC201531. In contrast, higher concentrations of PGE2 evoked significant EP1‐dependent vasoconstriction, which could not be reversed by the EP4 receptor agonist CAY10598. We also confirmed previous observations that PGE2 primarily evokes constriction in intracerebral arterioles isolated from R. norvegicus. Importantly, vascular mRNA expression of vasodilator EP4 receptors was significantly higher than that of vasoconstrictor EP1 receptors in human cerebral arterioles. In contrast, rat vessels expressed predominantly EP1 receptors.PGE2 at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles. This bimodal vasomotor response is consistent with both the proposed vasodilator role of PGE2 during functional hyperemia and its putative role in cerebral vasospasm associated with subarachnoid hemorrhage in human subjects.Support or Funding InformationThis work was supported by grants from the National Research, Development and Innovation Office to PT (NKFI‐FK123798) and AK (K108444), the Hungarian Academy of Sciences Bolyai Research Scholarship BO/00634/15 to PT, the PTE AOK‐KA 3/2016 04.01/F to PT, the ÚNKP‐18‐4‐PTE‐6 New National Excellence Program of the Ministry of Human Capacities, Higher Education Institutional Excellence Programme – Grant No. 20765‐3/2018/FEKUTSTRAT, EFOP‐3.6.2.‐16‐2017‐00008, GINOP‐2.3.2‐15‐2016‐00048 and GINOP‐2.3.3‐15‐2016‐00032 to PT and AB, the Hungarian National Brain Research Program Grant No. 2017‐1.2.1‐NKP‐2017‐00002 to AB; the Marie Curie Actions SMARTER 7th Framework Program of the European Union 606998 to NSz and AK, National Institute of Health R01‐AG055395, R01‐NS100782, R01‐AT006526 to ZU.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Human Coronary Micro‐artery Dysfunction is Associated with Structural and Smooth Muscle Cell Phenotypic Alterations

Autoregulation is compromised in patients with coronary heart disease. A lack of myogenic reactivity and endothelial dysfunction each contribute to a reduced ability to control blood flow within the coronary microcirculation. Little is known how coronary arterial smooth muscle structure and phenotype links to vascular reactivity.Right atrial appendage biopsies from consented patients undergoing valve replacement surgery, and from pigs were collected at clinical standards under general anesthesia. Human and porcine arteries from right atrial appendage samples were isolated and mounted for pressure myography. Confocal imaging established vasomotor responses, cellular viability, and immunohistochemical localization of proteins. The human study complies with the Helsinki Declaration and the animal study complies with the UK Animal (Scientific Procedures) Act, 1986.Here, we compared the structural features of human patient intra‐myocardial coronary arteries (IMCAs) with equivalently handled porcine IMCAs, representing healthy, juvenile controls. More than half the human IMCAs failed to develop ≥10% myogenic tone, even those in which constituent smooth muscle cells (SMCs) could adequately mobilize intracellular Ca2+required for contraction. 3D confocal revealed a novel, distinct layer of longitudinally‐arranged sub‐intimal SMCs (l‐SMCs) between the endothelium and the expected circumferentially‐arranged SMCs responsible for radial contraction (r‐SMC) in the majority of human and porcine IMCAs.Contractile function strongly correlated with SMC phenotype, with the synthetic markers L‐caldesmon and vimentin highly expressed in SMCs with poor contractile function, namely the human r‐SMCs and the porcine l‐SMCs. Thus, we propose that l‐SMCs retain an immature, synthetic phenotype in healthy vessels with functional r‐SMCs but, with loss of r‐SMC function in aged patients, l‐SMCs may play a reparative role and can adopt a contractile phenotype in an attempt to restore function and control myocardial perfusion. The role of l‐SMCs in maintaining the integrity of arterial function warrants further investigation.Support or Funding InformationThis work was supported by the British Heart Foundation (grant numbers FS/08/033/25111, FS/13/16/30199, IG/13/5/30431, PG/18/11/33552) and by the Oxford BHF Centre of Research Excellence (RE/13/1/30181).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Nerve‐Mediated Responses in Isolated Myogenic and Non‐Myogenic Arteries

Small arteries and arterioles of the resistance vasculature can exhibit a basal level of vasoconstriction, or myogenic tone, in response to an increase in intraluminal pressure. Myogenic tone occurs without influence from perivascular nerves and the endothelium, and is most likely dependent on stretch‐activated receptors which mediate smooth muscle depolarization and contraction. The aim of the current investigation was to compare nerve‐mediated responses in myogenic and non‐myogenic arteries, as data on modulation of myogenic tone by neurotropic factors is lacking.To address this aim, rat mesenteric and cremasteric arteries were excised and studied as non‐myogenic and myogenic arteries, respectively. A combination of immunohistochemistry, wire and pressure myography was employed to evaluate the effect of perivascular nerve activation by electrical field stimulation (EFS).Both artery types are innervated by sympathetic nerve fibres, as confirmed with staining for tyrosine hydroxylase observed only in the adventitial layer. Furthermore, both mesenteric and cremasteric arteries exhibited vasomotor responses to exogenously added norepinephrine (NE, 1 nM – 10 μM), phenylephrine (10 nM – 10 μM), and adenosine triphosphate (ATP, 10 nM – 10 μM). The sensitivity of the tissue to these agents was greater in the pressure myograph compared with the wire myograph, indicating the importance of considering data using EFS in pressurized arteries as well as from arteries under isometric tension.EFS (10 V, 50 pulses, 7 Hz, 1 ms pulse width) caused vasoconstriction of mesenteric arteries at 70 mmHg (27.5 ± 1.3%) which was attenuated by the voltage‐gated Na+ channel blocker tetrodotoxin (TTX, 1 μM, 6.6 ± 0.8%). Furthermore, EFS‐induced vasoconstriction was reduced by the α1‐adrenoceptor antagonist prazosin (1 μM, 18.7 ± 1.5%), the P2X1receptor antagonist NF 449 (10 μM, 17.5 ± 3.5%), and a combination of the two (10.9 ± 1%). The L‐type Ca2+ channel blocker nifedipine also attenuated the response (1 μM, 11.0 ± 2.8%), and in combination with TTX almost completely abolished it (1.4 ± 1.0%). Propranolol had no effect on the vasoconstriction (1 μM, 25.3 ± 2.9%) despite the presence of β‐adrenoceptors mediating vasodilation to exogenous NE. Most interestingly, EFS failed to elicit any response in cremasteric arteries at 80 mmHg with 47.4 ± 1.1% tone.This investigation highlights the importance of conducting experiments with EFS on pressurized arteries. EFS of mesenteric arteries confirmed a synergistic role for NE and ATP released from perivascular nerves and suggests an additional direct effect on L‐type voltage‐gated Ca2+ channels. Our data raise the question, why are arteries with a basal level of spontaneous tone insensitive to EFS, while non‐myogenic arteries are activated? Explaining these observations may be important for our understanding of neural control of blood flow in vivo.Support or Funding InformationThis research was supported by a British Heart Foundation PhD Studentship awarded to Hamish A L Lemmey.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Subchronic stress effects on vascular reactivity in C57BL/6 strain mice

Background and aimsThere is a close relationship between psychosocial stress and the development of cardiovascular diseases. It has been reported that there are different alterations in endothelial function in this relationship. However, results obtained in different experimental stress models are controversial. Herein, we studied the effects of subchronic stress induced by movement restraint on several cardiovascular responses and plasma corticosterone concentration in male adult mice. MethodsExperiments were performed in adult male mice of C57BL/6 strain. Animals were allocated into three groups: Control group A, without manipulation; Control group B, with manipulation (quantitation of blood pressure); and Experimental group, with quantitation of blood pressure and exposure to movement restraint. In vivo, heart rate and blood pressure were registered. In vitro, in aortic rings, vascular reactivity was analyzed. Additionally, plasma corticosterone concentration was quantified. ResultsIn vivo, subchronic stress did not produce changes on heart rate either on blood pressure. In vitro, aortic rings with and without endothelium from control group B and experimental group showed: 1) a significant decrease in the maximal tension developed in response to phenylephrine; 2) this decrease was reverted by L-NAME. However, aortic rings from all groups, developed the same tension in response to high K+ solution. In aortic rings from animals of the experimental group, an increase in the maximal relaxation induced by carbachol was observed. This relaxation was prevented and/or reversed by L-NAME. Plasma corticosterone concentration was higher in the experimental group than that in the control group A. ConclusionsExposition to subchronic movement restraint did not produce alterations in neurovegetative responses in this strain mice. But according to vasomotor responses observed, the results suggest that this subchronic stress model induces an increase in the synthesis/release of nitric oxide, both from endothelial cells and vascular smooth muscle. In accordance with the aforementioned results, we propose that C57BL/6 mice strain is sensitive to subchronic movement restraint stress model.

Cerebral vasomotor reactivity during hypo- and hypercapnia across the adult lifespan

Age is the strongest risk factor for cerebrovascular disease; however, age-related changes in cerebrovascular function are still not well understood. The objective of this study was to measure cerebral vasomotor reactivity (CVMR) during hypo- and hypercapnia across the adult lifespan. One hundred fifty-three healthy participants (21–80 years) underwent measurements of cerebral blood flow velocity (CBFV) via transcranial Doppler, mean arterial pressure (MAP) via plethysmograph, and end-tidal CO2 (EtCO2) via capnography during hyperventilation (hypocapnia) and a modified rebreathing protocol (hypercapnia). Cerebrovascular conductance (CVCi) and resistance (CVRi) indices were calculated from the ratios of CBFV and MAP. CVMRs were assessed by the slopes of CBFV and CVCi in response to changes in EtCO2. The baseline CBFV and CVCi decreased and CVRi increased with age. Advanced age was associated with progressive declines in CVMR during hypocapnia indicating reduced cerebral vasoconstriction, but increases in CVMR during hypercapnia indicating increased vasodilation. A negative correlation between hypo- and hypercapnic CVMRs was observed across all subjects (CBFV%/ EtCO2: r = −0.419, CVCi%/ EtCO2: r = −0.442, P < 0.0001). Collectively, these findings suggest that aging is associated with decreases in CBFV, increases in cerebrovascular resistance, reduced vasoconstriction during hypocapnia, but increased vasodilatory responsiveness during hypercapnia.

Recovery of blood flow regulation in microvascular resistance networks during regeneration of mouse gluteus maximus muscle

Skeletal muscle regenerates after injury, however the recovery of its microvascular supply is poorly understood. We injured the gluteus maximus muscle in mice aiming to investigate the recovery of blood flow regulation in microvascular resistance networks. We hypothesized that blood flow regulation recovers in concert with myofibre regeneration. Microvascular perfusion ceased within 1day post injury and was restored at 5days coincident with the appearance of new myofibres; however, the resistance network was dilated and unresponsive to vasoactive agents. Spontaneous vasomotor tone, endothelium-dependent dilatation and adrenergic vasoconstriction increased at 10days in concert with myofibre regeneration. Vasomotor control recovered at 21days, when regenerated myofibres matured and active force production stabilized. Functional vasodilatation in response to muscle contraction recovered at 35days. Physiological integrity of microvascular smooth muscle and endothelium recovers in parallel with myofibre regeneration. Additional time is required to restore the efficacy of signalling between myofibres and microvascular networks controlling their oxygen supply. Myofibre regeneration after skeletal muscle injury is well-studied, although little is known about how microvascular perfusion is restored. The present study aimed to evaluate the recovery of blood flow regulation during skeletal muscle regeneration. In anaesthetized male C57BL/6J mice (aged 4 months), the gluteus maximus muscle (GM) was injured by local injection of barium chloride solution (1.2%, 75μL). Functional integrity of the resistance network was evaluated at 5, 10, 21 and 35 days post-injury vs. Control by measuring internal diameter of feed arteries, first-, second- and third-order arterioles supplying the GM using intravital microscopy. The resting diameters of all branch orders were significantly greater (P<0.05) than Control at 5 and 10days and recovered to Control by 21days, as did spontaneous vasomotor tone. Vasodilatation to ACh and vasoconstriction to phenylephrine (10-9 to 10-5 m) were absent at 5days, increased at 10days and recovered to Control by 21days; reactivity improved in a distal-to-proximal gradient. Across branch orders, functional vasodilatation to single tetanic contraction (100Hz, 500ms) and to rhythmic twitch contractions (4Hz, 30s) was impaired at 5days, improved through 21days and was not different from Control at 35days. Peak force development (g) was 60% of Control at 10days and recovered by 21days. Diminished vasomotor tone during the initial stages of regeneration promotes tissue perfusion as myofibre recovery begins. Recovery of tone and vasomotor responses to agonists occur in concert with myofibre regeneration. Delayed recovery of functional vasodilatation indicates that additional time is required to restore signalling between contracting myofibres and their vascular supply.

An assessment of KIR channel function in human cerebral arteries.

In the rodent cerebral circulation, inward rectifying K+ (KIR) channels set resting tone and the distance over which electrical phenomena spread along the arterial wall. The present study sought to translate these observations into human cerebral arteries obtained from resected brain tissue. Computational modeling and a conduction assay first defined the impact of KIR channels on electrical communication; patch-clamp electrophysiology, quantitative PCR, and immunohistochemistry then characterized KIR2.x channel expression/activity. In keeping with rodent observations, computer modeling highlighted that KIR blockade should constrict cerebral arteries and attenuate electrical communication if functionally expressed. Surprisingly, Ba2+ (a KIR channel inhibitor) had no effect on human cerebral arterial tone or intercellular conduction. In alignment with these observations, immunohistochemistry and patch-clamp electrophysiology revealed minimal KIR channel expression/activity in both smooth muscle and endothelial cells. This absence may be reflective of chronic stress as dysphormic neurons, leukocyte infiltrate, and glial fibrillary acidic protein expression was notable in the epileptic cortex. In closing, KIR2.x channel expression is limited in human cerebral arteries from patients with epilepsy and thus has little impact on resting tone or the spread of vasomotor responses. NEW & NOTEWORTHY KIR2.x channels are expressed in rodent cerebral arterial smooth muscle and endothelial cells. As they are critical to setting membrane potential and the distance signals conduct, we sought to translate this work into humans. Surprisingly, KIR2.x channel activity/expression was limited in human cerebral arteries, a paucity tied to chronic brain stress in the epileptic cortex. Without substantive expression, KIR2.x channels were unable to govern arterial tone or conduction.

Cerebral Hemodynamic Changes During Migraine Attacks and After Triptan Treatments.

Migraine has been known for many years, but its mechanism remains unclear. Different cerebral hemodynamic changes have been observed at different stages of a migraine attack. Published results on cerebral hemodynamics are contradictory. For this reason, we aimed to investigate cerebral hemodynamic changes during attacks as well as the effects of frovatriptan and rizatriptan. Forty migraine patients with aura using rizatriptan (n=20) and frovatriptan (n=20) and 20 healthy individuals were included in our study. Cerebral blood flow velocities and breath-holding indices were recorded bilaterally from middle and posterior cerebral arteries. All procedures were repeated one hour after treatments and one week after attacks. We observed similar values of cerebral blood flow velocities and breath holding indices in all patients with migraine during the attack-free period compared to the control group. All cerebral vascular structures in migraine patients had significantly lower cerebral blood flow velocities and higher values in breath-holding indices during attacks. After taking rizatriptan and frovatriptan for an attack, the changes in hemodynamics disappeared. During attacks of migraineurs with aura, vasodilatation develops. In addition, higher vasomotor reactivity during attacks supports hypersensitivity in migraine pathophysiology. Triptans, acting as vasoconstrictor agents, were able to stop over-vasodilatation during attacks. In other words, it is possible that triptans show their effects by eliminating vascular hypersensitivity during acute attacks.

Transcranial Doppler assessment of patients with cerebral small vessel disease

Background Cerebral small vessel disease (SVD) refers to any pathology in all vascular structures (small arteries, arterioles, capillaries, venules, and small veins). Transcranial Doppler is a bedside, inexpensive, noninvasive technique that can assess intracerebral circulation in real time and can be used for continuous monitoring. Aim of the work Our study tried to detect the pathogenesis of cerebral SVD, especially the implication of the cerebral large artery disease. Moreover, it assessed the ability of transcranial Doppler in evaluating the severity of cerebral SVD and people who are at risk. Patients with cardioembolic risk were excluded. Patients and methods A cross-sectional study was conducted including 50 patients recruited from El-Sahel Teaching Hospitals, either inpatient or outpatient clinic departments. Results We proved a relation between cerebral large artery disease and severity of cerebral SVD but not embolic in nature. Conclusion There is a relationship between cerebral large artery disease and severity of cerebral SVD, but we cannot hold microemboli as a pathogenesis of cerebral SVD. In addition, cerebral SVD affects cerebral vasomotor reactivity especially in hypertensive patients, so we can use Breath-Holding Index (BHI) for prediction of occurrence of cerebral SVD in high-risk people, especially hypertensive.

Autonomic control of cardiovascular adjustments associated with orthostasis in the scansorial snake Boa constrictor.

Orthostatic hypotension is a phenomenon triggered by a change in the position or posture of an animal, from a horizontal to a vertical head-up orientation, characterised by a blood pooling in the lower body and a reduction in central and cranial arterial blood pressure (PA). This hypotension elicits systemic vasoconstriction and tachycardia, which generally reduce blood pooling and increase PA Little is known about the mediation and importance of such cardiovascular adjustments that counteract the haemodynamic effects of orthostasis in ectothermic vertebrates, and some discrepancies exist in the information available on this subject. Thus, we sought to expand our knowledge on this issue by investigating it in a more elaborate way, through an in vivo pharmacological approach considering temporal circulatory changes during head-up body inclinations in unanaesthetised Boa constrictor To do so, we analysed temporal changes in PA, heart rate (fH) and cardiac autonomic tone associated with 30 and 60deg inclinations, before and after muscarinic blockade with atropine, double blockade with atropine and propranolol, and α1-adrenergic receptor blockade with prazosin. Additionally, the animals' fH variability was analysed. The results revealed that, in B. constrictor: (1) the orthostatic tachycardia is initially mediated by a decrease in cholinergic tone followed by an increase in adrenergic tone, a pattern that may be evolutionarily conserved in vertebrates; (2) the orthostatic tachycardia is important for avoiding an intense decrease in PA at the beginning of body inclinations; and (3) α1-adrenergic orthostatic vasomotor responses are important for the maintenance of PA at satisfactory values during long-term inclinations.

Anatomical landmarks for localizing the otic ganglion: A possible new treatment target for headache disorders

Background: The otic ganglion (OG) is a cranial parasympathetic ganglion located in the infratemporal fossa under the foramen ovale (FO) and adjacent to the medial part of the mandibular nerve. Parasympathetic innervation of intracranial vessels from the OG has been shown both in animal and human models and evidence suggests that the OG plays an important role in the cranial vasomotor response. We review the evidence that positions the OG as a viable target for headache disorders. The OG is a small structure and not detectable on medical imaging. The FO is easily identifiable on CT scans and the mandibular nerve on MRI, hence, the position of the OG may be predicted if the mean distance from the FO is known. Objective: The objective is to describe the average distance between the FO and the OG in a sample of 18 infratemporal fossae from 21 cadavers. Methods: A total of 21 high definition photographs of 21 infratemporal fossae from 18 cadavers were analyzed. The distance between the inferior edge of the medial part of the FO to the OG was measured. Results: Four photographs of infratemporal fossae of four cadavers were excluded due to the inability to localize the inferior edge of the FO. A total of 15 infratemporal fossae from 17 cadavers were measured. The mean distance from the FO to the OG was 4.5 mm (SD 1.7), range 2.1–7.7 mm. Conclusions: We have described the average distance from the OG to an easily identifiable anatomical landmark that is visible in CT scans, the FO. This anatomical study may aid in the development of strategies to localize the OG in order to explore its role as a therapeutic target for headache disorders.

In vitro optimization and comparison of CT angiography versus radial cardiovascular magnetic resonance for the quantification of cross-sectional areas and coronary endothelial function

BackgroundOur objectives were first to determine the optimal coronary computed tomography angiography (CTA) protocol for the quantification and detection of simulated coronary artery cross-sectional area (CSA) differences in vitro, and secondly to quantitatively compare the performance of the optimized CTA protocol with a previously validated radial coronary cardiovascular magnetic resonance (CMR) technique.Methods256-multidetector CTA and radial coronary CMR were used to obtain images of a custom in vitro resolution phantom simulating a range of physiological responses of coronary arteries to stress. CSAs were automatically quantified and compared with known nominal values to determine the accuracy, precision, signal-to-noise ratio (SNR), and circularity of CSA measurements, as well as the limit of detection (LOD) of CSA differences. Various iodine concentrations, radiation dose levels, tube potentials, and iterative image reconstruction algorithms (ASiR-V) were investigated to determine the optimal CTA protocol. The performance of the optimized CTA protocol was then compared with a radial coronary CMR method previously developed for endothelial function assessment under both static and moving conditions.ResultsThe iodine concentration, dose level, tube potential, and reconstruction algorithm all had significant effects (all p < 0.001) on the accuracy, precision, LOD, SNR, and circularity of CSA measurements with CTA. The best precision, LOD, SNR, and circularity with CTA were achieved with 6% iodine, 20 mGy, 100 kVp, and 90% ASiR-V. Compared with the optimized CTA protocol under static conditions, radial coronary CMR was less accurate (− 0.91 ± 0.13 mm2 vs. -0.35 ± 0.04 mm2, p < 0.001), but more precise (0.08 ± 0.02 mm2 vs. 0.21 ± 0.02 mm2, p < 0.001), and enabled the detection of significantly smaller CSA differences (0.16 ± 0.06 mm2 vs. 0.52 ± 0.04 mm2; p < 0.001; corresponding to CSA percentage differences of 2.3 ± 0.8% vs. 7.4 ± 0.6% for a 3-mm baseline diameter). The same results held true under moving conditions as CSA measurements with CMR were less affected by motion.ConclusionsRadial coronary CMR was more precise and outperformed CTA for the specific task of detecting small CSA differences in vitro, and was able to reliably identify CSA changes an order of magnitude smaller than those reported for healthy physiological vasomotor responses of proximal coronary arteries. However, CTA yielded more accurate CSA measurements, which may prove useful in other clinical scenarios, such as coronary artery stenosis assessment.

Impaired hypoxic pulmonary vasoconstriction in a mouse model of Leigh syndrome.

Hypoxic pulmonary vasoconstriction (HPV) is a physiological vasomotor response that maintains systemic oxygenation by matching perfusion to ventilation during alveolar hypoxia. Although mitochondria appear to play an essential role in HPV, the impact of mitochondrial dysfunction on HPV remains incompletely defined. Mice lacking the mitochondrial complex I (CI) subunit Ndufs4 (Ndufs4−/−) develop a fatal progressive encephalopathy and serve as a model for Leigh syndrome, the most common mitochondrial disease in children. Breathing normobaric 11% O2 prevents neurological disease and improves survival in Ndufs4−/− mice. In this study, we found that either genetic Ndufs4 deficiency or pharmacological inhibition of CI using piericidin A impaired the ability of left mainstem bronchus occlusion (LMBO) to induce HPV. In mice breathing air, the partial pressure of arterial oxygen during LMBO was lower in Ndufs4−/− and in piericidin A-treated Ndufs4+/+ mice than in respective controls. Impairment of HPV in Ndufs4−/− mice was not a result of nonspecific dysfunction of the pulmonary vascular contractile apparatus or pulmonary inflammation. In Ndufs4-deficient mice, 3 wk of breathing 11% O2 restored HPV in response to LMBO. When compared with Ndufs4−/− mice breathing air, chronic hypoxia improved systemic oxygenation during LMBO. The results of this study show that, when breathing air, mice with a congenital Ndufs4 deficiency or chemically inhibited CI function have impaired HPV. Our study raises the possibility that patients with inborn errors of mitochondrial function may also have defects in HPV.