Vasomotor Responses Research Articles

Seasonal variation of temperature regulation: do thermoregulatory responses “spring” forward and “fall” back?

Seasonal variations in day length and light intensity can affect the circadian rhythm as well as some characteristics of temperature regulation. We investigated characteristics of autonomic (ATR), behavioural (BTR) and nocturnal (NTR) temperature regulation during spring and autumn. Eleven participants underwent experiments in both seasons. To assess ATR, participants performed a 30-min bout of submaximal upright exercise on a cycle ergometer, followed by 100min of water immersion (28°C). Thresholds for the onset of shivering and sweating and vasomotor response were measured. BTR was assessed using a water-perfused suit, with participants regulating the water-perfused suit temperature (Twps) within a range, considered as thermally comfortable. The Twps changed in a saw-tooth manner from 10 to 50°C; by depressing a switch, the direction of the Twps changed, and this limit defined the thermal comfort zone (TCZ) for each participant. A 24-h proximal (calf)-distal (toe) skin temperature gradient (∆Tc-t) was measured to assess NTR. Initiation of vasomotor tone, shivering and sweating was similar between trials. Width of the TCZ was 8.1°C in spring and 8.6°C in autumn (p = 0.1), with similar upper and lower regulated temperatures. ∆Tc-t exhibited a typical circadian rhythm with no difference between seasons. Minor changes in skin temperature and oxygen consumption (p˂0.05) between the seasons may indicate a degree of seasonal adaptation over the course of winter and summer, which persisted in spring and autumn. Other factors, such as country, race, sex and age could however modify the outcome of the study.

Vasomotor reactivity in the ophthalmic artery

Vasomotor reactivity in the ophthalmic artery

Objective Diagnosis of Migraine without Aura with Migraine Vascular Index: A Novel Formula to Assess Vasomotor Reactivity

This pilot study was aimed at developing an objective method to diagnose migraine by measuring the difference in vasomotor reactivity between migraineurs and non-migraineurs. Thirty patients diagnosed with migraine without aura and 30 healthy patients were recruited. Vasomotor reactivity of all patients was then assessed by measuring the breath holding index (BHI), hyperventilation index and a novel formula, the migraine vascular index (MVI), of the middle cerebral artery using transcranial Doppler ultrasonography. Migraineurs were found to have significantly lower BHI and MVI values (p < 0.001). Logistic regression analysis revealed that MVI was a significant independent predictor of migraine (p = 0.007). The sensitivity and specificity of MVI in diagnosing migraine with a cutoff value of 1.035 were 86.7% and 86.7%, respectively. In conclusion, MVI measurement is a reliable method for objectively diagnosing migraine. Further research is needed to validate the usage of MVI for migraine diagnosis.

Effects of Oleamide on the Vasomotor Responses in the Rat

Introduction: Cardiovascular effects of endocannabinoids (eCBs) have generated considerable interest since it has been suggested that the eCB system could become the new pharmacological target, either by blocking its activity or by promoting its effects on several cardiovascular diseases such as hypovolemic and septic shock or hypertension. The purpose of this study was to examine the effects of oleamide on several vasomotor responses in adult rats. Materials and Methods: Blood pressure (BP) was measured both directly and indirectly. Coronary flow was quantified with Langendorf preparation, and the vasomotor responses induced by oleamide were analyzed in the aortic rings. Results: Oleamide induced a decrease in BP, by both direct and indirect methods, which were dose dependent. An increase in coronary flow was observed with Langendorf preparation depending on the dose. Oleamide produced a vasodilator response in aortic rings pre-contracted with phenylephrine (10-5 M), which was concentration and endothelium dependent. This relaxing effect was of minor magnitude than that induced with the same dose on BP. L-NAME did not modify these effects. However, indomethacin induced a shift to the left of the concentration-response curve to oleamide and an increase in the magnitude of maximum vasodilation in rings with endothelium. Oleamide produced the maximal relaxant response at 10-5 M concentration. Conclusions: Oleamide has both in vivo and in vitro vasodilator effects. Vasodilator effects could be mediated by compounds synthesized/released by the endothelium (hyperpolarizing factor) or acting directly on vascular smooth muscle in aortic rings. The TRPV1 and CB1R receptors could mediate these effects. Finally, the results suggest that oleamide probably induces the synthesis/release of a vasoconstrictor prostanoid.

CGRP in rat mesenteric artery and vein - receptor expression, CGRP presence and potential roles

CGRP is a potent dilator of arteries and despite rich perivascular CGRP immunoreactivity in both arteries and veins the role of CGRP in veins remains unknown.The aim of the current study was to compare perivascular CGRP immunoreactivity and expression of CGRP receptor mRNA and CGRP receptor immunoreactivity in rat mesenteric arteries and veins. Furthermore, potential vasomotor effects of CGRP were explored in veins.Immunohistochemical studies reproduced rich perivascular CGRP innervation in arteries and in veins. Further, the presence of mRNA encoding the CGRP receptor subunits, CLR and RAMP1, were demonstrated in both arteries and veins using qPCR.Before comparing the vasoactive effects of CGRP in arteries and veins, we aimed to identify an experimental setting where vasomotor responses could be detected. Therefore, a length-tension study was performed in artery and vein segments. Whereas the arteries showed the characteristic monophasic curve with an IC/IC100 value of 0.9, surprisingly the veins showed a biphasic response with two corresponding IC/IC100 values of 0.7 and 0.9, respectively. There was no significant difference between fresh and cultured vasculature segments.To investigate whether a potential tension-dependent CGRP-induced dilation of veins caused the decline between the two IC/IC100 peaks, a second study was performed, with the CGRP receptor antagonist, BIBN4096BS (olcegepant) and the sensory nerve secretagogue, capsaicin. No significant vascular role of endogenous perivascular CGRP in mesenteric veins could be concluded, and a potential role of the rich perivascular CGRP and CGRP receptor abundancy in veins remains unknown.

Targeting the Endothelial Ca2+ Toolkit to Rescue Endothelial Dysfunction in Obesity Associated-Hypertension.

Obesity is a major cardiovascular risk factor which dramatically impairs endothelium- dependent vasodilation and leads to hypertension and vascular damage. The impairment of the vasomotor response to extracellular autacoids, e.g., acetylcholine, mainly depends on the reduced Nitric Oxide (NO) bioavailability, which hampers vasorelaxation in large conduit arteries. In addition, obesity may affect Endothelium-Dependent Hyperpolarization (EDH), which drives vasorelaxation in small resistance arteries and arterioles. Of note, endothelial Ca2+ signals drive NO release and trigger EDH. A structured search of bibliographic databases was carried out to retrieve the most influential, recent articles on the impairment of vasorelaxation in animal models of obesity, including obese Zucker rats, and on the remodeling of the endothelial Ca2+ toolkit under conditions that mimic obesity. Furthermore, we searched for articles discussing how dietary manipulation could be exploited to rescue Ca2+-dependent vasodilation. We found evidence that the endothelial Ca2+ could be severely affected by obese vessels. This rearrangement could contribute to endothelial damage and is likely to be involved in the disruption of vasorelaxant mechanisms. However, several Ca2+-permeable channels, including Vanilloid Transient Receptor Potential (TRPV) 1, 3 and 4 could be stimulated by several food components to stimulate vasorelaxation in obese individuals. The endothelial Ca2+ toolkit could be targeted to reduce vascular damage and rescue endothelium- dependent vasodilation in obese vessels. This hypothesis remains, however, to be probed on truly obese endothelial cells.

Abstract TP436: MyRIAD Mechanisms of Recurrent Stroke in Intracranial Atherosclerotic Disease

Background: The NINDS-funded Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease (MyRIAD) study used a battery of MRI and TCD techniques to discern key pathophysiology leading to a relatively high rate of recurrent stroke. Our study objectives aimed to relate imaging abnormalities of limited arterial blood flow, distal tissue perfusion and artery-to-artery emboli with new infarcts on 6-8 week MRI. Methods: MyRIAD is a prospective, multicenter, observational study of patients with recent (&lt;21 days) ischemic stroke or TIA due to 50-99% ICAD. Quantitative MRA (QMRA), perfusion MRI and TCD vasomotor reactivity (VMR) with emboli detection (ED) were acquired at enrollment. Central adjudication of each imaging modality, clinical events and 6-8 week MRI were independently ascertained. Results: MyRIAD enrolled 105 (mean age 63.7 years, SD 11.8 years; 43% women) patients. Primary outcomes of recurrent stroke in the territory occurred in 9/105 (9%) with secondary outcomes of territorial TIA in 7/105 (7%) and new infarcts on 6-8 week MRI in 22/87 (25%). The limited number of clinical stroke and TIA endpoints precluded definitive analysis of mechanism. Pre-specified Tmax&gt;4s 10 cc lesions on perfusion MRI were noted in 40/92 (43%) but did not predict new infarcts at 6-8 week MRI. New infarcts were noted in 12/44 (27%) of those with Tmax&gt;4s 5 cc lesions at baseline compared to 3/26 (12%) when absent. Abnormal volume flow ratio (VFR) on QMRA was noted in 25/98 (26%), abnormal TCD VMR in 25/76 (33%) and ED in 30/74 (41%). Other pre-specified analyses revealed both abnormal VMR and ED in 21/77 (27%) and both abnormal Tmax&gt;4s perfusion and VFR in 16/99 (16%). Two or more imaging abnormalities were noted at baseline in 49/105 (47%) and stenosis ≥ 70% in 76/91 (84%). New infarcts on 6-8 week MRI were more frequent with ≥ 2 abnormalities (33 vs 18%, p=0.1) and ≥ 70% stenosis (29 vs 7%, p=0.2). Conclusions: Early, recurrent infarction on MRI is common in ICAD. Imaging abnormalities of limited arterial blood flow or distal tissue perfusion and artery-to-artery emboli are frequent and the presence of multiple abnormalities may increase risk. Larger ICAD studies are needed to link routinely acquired imaging with covert infarcts and cognitive impairment.

Gonadal function protects against organ culture-induced vascular damage. Involvement of prostanoids

Androgen deprivation induces vascular dysfunction in which altered release and action of prostanoids has been extensively studied. On the other hand, the vascular organ-culture system has been reported as a valid model for phenotypic changes that occur in several cardiovascular pathologies. Since there are no studies analyzing the impact of androgenic loss on vascular vulnerability during induced vascular damage, the objective of this study was to analyze the possible preventive role of male sex hormones on the organ culture-induced vascular damage in rat aorta. The link to possible changes in gross structure was also analyzed. For this purpose, fresh and 20 h-cultured aortic arterial segments from intact and orchidectomized rats were used to analyze: (i) the release and vasomotor effect of the thromboxane A2 (TXA2), prostaglandin (PG) E2, PGF2α and PGI2; (ii) the vasodilator response induced by acetylcholine (ACh) as well as the involvement of prostanoids, in particular TXA2, in the ACh-induced response; (iii) the effect of activation of thromboxane/prostaglandin (TP) receptors on the ACh-induced response; and (iv) the vascular structure. The results showed that organ culture: i) increased production of prostanoids; ii) increased prostanoids-induced vasomotor responses; iii) decreased ACh-induced relaxation after incubation with indomethacin, a blocker of cyclooxygenases; iv) increased the ACh-induced relaxation after incubation with the TXA2 synthase inhibitor, furegrelate, more in arteries from orchidectomized rats than in those of intact rats; v) diminished ACh-induced relaxation after U-46619 incubation only in arteries from orchidectomized rats; and vi) preserved the integrity of the different vascular layers. These results showed the protective role of male sex hormones against the induced vascular damage, since a decreased deleterious effect of prostanoids, in particular that of TXA2, was observed in arteries from rats with intact gonadal function.

Quantification of dynamic cerebral autoregulation and CO2 dynamic vasomotor reactivity impairment in essential hypertension

The study of dynamic cerebral autoregulation (DCA) in essential hypertension has received considerable attention because of its clinical importance. Several studies have examined the dynamic relationship between spontaneous beat-to-beat arterial blood pressure data and contemporaneous cerebral blood flow velocity measurements (obtained via transcranial Doppler at the middle cerebral arteries) in the form of a linear input-output model using transfer function analysis. This analysis is more reliable when the contemporaneous effects of changes in blood CO2 tension are also taken into account, because of the significant effects of CO2 dynamic vasomotor reactivity (DVR) upon cerebral flow. In this article, we extract such input-output predictive models from spontaneous time series hemodynamic data of 24 patients with essential hypertension and 20 normotensive control subjects under resting conditions, using the novel methodology of principal dynamic modes (PDMs) that achieves improved estimation accuracy over previous methods for relatively short and noisy data. The obtained data-based models are subsequently used to compute indexes and markers that quantify DCA and DVR in each subject or patient and therefore can be used to assess the effects of essential hypertension. These model-based DCA and DVR indexes were properly defined to capture the observed effects of DCA and VR and found to be significantly different (P < 0.05) in the hypertensive patients. We also found significant differences between patients and control subjects in the relative contribution of three PDMs to the model output prediction, a finding that offers the prospect of identifying the physiological mechanisms affected by essential hypertension when the PDMs are interpreted in terms of specific physiological mechanisms.NEW & NOTEWORTHY This article presents novel model-based methodology for obtaining diagnostic indexes of dynamic cerebral autoregulation and dynamic vasomotor reactivity in hypertension.

Transcranial doppler methods in the assessment of cerebral vasomotor reactivity

Introduction. Transcranial Doppler is the only non-invasive neuroimaging modality in the diagnosis and monitoring of various neurovascular diseases. Apart from assessing cerebral hemodynamics of blood flow in the basal brain arteries, transcranial Doppler provides physiological data and anatomical images. Quantification analysis of vasomotor reactivity. Various transcranial Doppler methods evaluate cerebral vasomotor reactivity, providing important information on the properties of arterioles under induced hemodynamic conditions. Exogenous and endogenous vasoactive stimuli of different potency (apnea, acetazolamide, carbon dioxide, L-arginine) are most commonly used, making transcranial Doppler a prognostic indicator of future ischemic events. This article reviews principles of various transcranial Doppler methods in the evaluation of vasomotor reactivity, emphasizing their advantages and disadvantages. Transcranial Doppler in the field of reduced vasomotor reactivity. Evaluation of vasomotor reactivity has a role in the prediction of future ischemic events, evaluation of revascularization effect after carotid endarterectomy, but also in the increasingly significant choice of the right time to perform it. In recent years, transcranial Doppler methods have found application in other areas of dysfunctional cerebral hemodynamics: dementia, hypertension, migraines, and sepsis. Conclusion. Due to an excellent temporal resolution, non-invasive approach, good cost-benefit ratio, bedside monitoring, relative simplicity in terms of interpretation and performance, and portability, transcranial Doppler in vasomotor reactivity may be the ideal tool in the evaluation of cerebral hemodynamics, arterial perfusion integrity and collateral capacity.

Implementation of home-based health promotion program to improve flow-mediated dilation among patients with subacute stroke.

INTRODUCTION:Stroke causes physiologic functional changes such as vascular resistance and arterial remodeling. This study aimed to explore the effects of 3-month regular home-based exercise rehabilitation on brachial flow-mediated dilation (FMD), daily physical activity, and upper and lower extremity sensorimotor of the acute ischemic stroke patients.MATERIALS AND METHODS:This randomized control trial was done from August 2017 to September 2018. Patients with unilateral ischemic stroke were recruited from inpatient wards at an educational hospital. Patients were randomly assigned to the home-based rehabilitation program (intervention group) or usual care (control group). Fugl-Meyer upper and lower extremity sensorimotor score and Barthel score were evaluated in both the groups before and 3 months after baseline assessment. Furthermore, brachial artery vasomotor reactivity (FMD) hemiparetic arm assessed vascular health. The intervention group received home-based rehabilitation exercise program for 3 months. The control group did not receive home-based rehabilitation program and incentive telephone call. All data were collected and analyzed by SPSS software (version 20) and appropriate statistical tests.RESULTS:Forty ischemic stroke patients (twenty in the intervention group and twenty in the control group) were examined. Results showed that Barthel score and Fugl-Meyer upper and lower extremity score and FMD in the intervention group were significantly higher than the control group after 3-month home-based exercise rehabilitation (P < 0/001).CONCLUSION:Twelve-week regular home-based exercise training was well tolerated by the intervention group. After this period, improvements were reported in brachial FMD as well as daily physical activity and upper and lower extremity functional capacity.

Anti-hypertensive Effect of Hesperidin and Hesperidin-containing Fermented Mikan Tea in Spontaneously Hypertensive Rats

The anti-hypertensive effects of hesperidin and hesperidin-containing fermented Mikan tea were investigated in 8-week-old spontaneously hypertensive rats (SHRs) at a dose of 50 mg/kg body weight for both, over 20 weeks. At the end of the protocol, a significant (P < 0.05) reduction in the systolic blood pressure (SBP) of approximately 60 mmHg was observed in the SHRs with the intake of hesperidin and Mikan tea. No change in the heart rate was observed between groups. Hesperidin altered the impaired vasomotor response in 28-week-old SHRs. Investigation of receptor expression related to mitogen-stimulated vasomotor action revealed that the Mas receptor (MasR) in the aorta of hesperidin-administered SHRs was up-regulated, while no changes in angiotensin II-type 1 and type 2 receptor expressions were observed. An increase in cAMP levels was confirmed in the aorta of hesperidin-administered SHRs, demonstrating that anti-hypertensive hesperidin plays a role in vessel regulation via the upregulated-MasR/cAMP axis.

Neoatherosclerosis - Long-Term Assessment of Bioresorbable Vascular Scaffold.

Although metallic stents improved the safety and efficacy of percutaneous coronary intervention (PCI), even the latest generation of drug-eluting stents (DES) is still limited by several factors. The limitations of DES are mainly related to the permanent metallic caging in vessel, chronic inflammatory response to the polymer and adverse effects of antiproliferative drug on endothelial tissue, leading to impaired physiological vasomotor response and late stent-related adverse events such as stent thrombosis and neoatherosclerosis. Bioresorbable vascular scaffold (Absorb BVS; Abbott Vascular) was designed to overcome these drawbacks of DES by disappearing from the vessel wall. Absorb BVS, however, was withdrawn from the world market because of increased incidence of scaffold thrombosis compared with DES. Importantly, only very limited long-term post-BVS implantation data are available, especially with regard to neoatherosclerosis, which can lead to very late adverse events even after resorption of the scaffold. Therefore, the goal of this review was to highlight the mid to long term clinical outcomes published to date, and to describe the features of the intimal healing process and neoatherosclerosis in the 5 years following Absorb BVS implantation, mainly based on our previous study. This may provide important information on the pathophysiology of the scaffolded vessel for clinicians, and promote identification of future bioresorbable materials for PCI that will minimize the stimulus for neoatherosclerosis.

Relationship of a thinned medial layer to the attenuated contractile response in atherosclerotic coronary arteries.

Coronary arteries with advanced atherosclerosis do not necessarily have greater contractile responses than those with early atherosclerosis. This study aimed to clarify the relationship between thickness of the medial layer and the contractile response to acetylcholine (ACh) in coronary artery using optical coherence tomography (OCT). The OCT and the vasomotor response to ACh in the left anterior descending coronary artery were assessed in 32 patients with previous myocardial infarction. The intimal and medial layer areas were measured by planimetric analysis of the OCT images. The coronary contractile response to ACh had a positive linear relationship with medial area (r = 0.61, P < 0.001). In contrast, the relationship between the coronary contractile response to ACh and intimal area was described by an inverted U-shaped curve that was fitted to a quadratic regression model (R2 = 0.35, P = 0.002, y-axis, contraction; x-axis, intimal area). The contractile response increased as the intimal layer thickened up to the inflection point; thereafter, the contractile response declined. The relationship between medial area and intimal area was also described by an inverted U-shaped curve that was fitted to a quadratic regression model (R2 = 0.41, P < 0.01, y-axis, medial area; x-axis, intimal area). The medial area increased as the intimal area thickened up to the inflection point; thereafter, the medial area thinned. In conclusion, the thinned medial layer was associated with the attenuated contractile response in a coronary artery with greater atherosclerosis.NEW & NOTEWORTHY This is the first clinical study to show the relationship between the contractile response and the thickness of medial smooth muscle layer in coronary artery of patients with previous myocardial infarction using OCT. The contractile response to acetylcholine was attenuated, and medial layer area was thinned in coronary artery with greater atherosclerosis compared with those in coronary artery with mild or moderate atherosclerosis. The coronary contractile response was positively correlated with thickness of the medial layer in coronary arteries with either mild or greater atherosclerosis. Thus, coronary arteries with advanced atherosclerosis do not necessarily have greater contractile responses than those with early atherosclerosis, which could be related to the thinned medial layer.

Ischemia and No Obstructive Coronary Artery Disease: Prevalence and Correlates of Coronary Vasomotion Disorders.

Determine the prevalence and correlates of microvascular and vasospastic angina in patients with symptoms and signs of ischemia but no obstructive coronary artery disease (INOCA). Three hundred ninety-one patients with angina were enrolled at 2 regional centers over 12 months from November 2016 (NCT03193294). INOCA subjects (n=185; 47%) had more limiting dyspnea (New York Heart Association classification III/IV 54% versus 37%; odds ratio [OR], 2.0 [1.3-3.0]; P=0.001) and were more likely to be female (68% INOCA versus 38% in coronary artery disease; OR, 1.9 [1.5 to 2.5]; P<0.001) but with lower cardiovascular risk scores (ASSIGN score median 20% versus 24%; P=0.003). INOCA subjects had similar burden of angina (Seattle Angina Questionnaire) but reduced quality of life compared with coronary artery disease; subjects (EQ5D-5 L index 0.60 versus 0.65 units; P=0.041). An interventional diagnostic procedure with reference invasive tests including coronary flow reserve, microvascular resistance, and vasomotor responses to intracoronary acetylcholine (vasospasm provocation) was performed in 151 INOCA subjects. Overall, 78 (52%) had isolated microvascular angina, 25 (17%) had isolated vasospastic angina, 31 (20%) had both, and 17 (11%) had noncardiac chest pain. Regression analysis showed inducible ischemia on treadmill testing (OR, 7.5 [95% CI, 1.7-33.0]; P=0.008) and typical angina (OR, 2.7 [1.1-6.6]; P=0.032) were independently associated with microvascular angina. Female sex tended to associate with a diagnosis of microvascular angina although this was not significant (OR, 2.7 [0.9-7.9]; P=0.063). Vasospastic angina was associated with smoking (OR, 9.5 [2.8-32.7]; P<0.001) and age (OR, 1.1 per year, [1.0-1.2]; P=0.032]. Over three quarters of patients with INOCA have identifiable disorders of coronary vasomotion including microvascular and vasospastic angina. These patients have comparable angina burden but reduced quality of life compared to patients with obstructive coronary artery disease. Microvascular angina and vasospastic angina are distinct disorders that may coexist but differ in associated clinical characteristics, symptoms, and angina severity. URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193294.

Contactless Monitoring of Microcirculation Reaction on Local Temperature Changes

Assessment of skin blood flow is an important clinical task which is required to study mechanisms of microcirculation regulation including thermoregulation. Contactless assessment of vasomotor reactivity in response to thermal exposure is currently not available. The aim of this study is to show the applicability of the imaging photoplethysmography (IPPG) method to measure quantitatively the vasomotor response to local thermal exposure. Seventeen healthy subjects aged 23 ± 7 years participated in the study. A warm transparent compress applied to subject’s forehead served as a thermal impact. A custom-made IPPG system operating at green polarized light was used to monitor the subject’s face continuously and simultaneously with skin temperature and electrocardiogram (ECG) recordings. We found that the thermal impact leads to an increase in the amplitude of blood pulsations (BPA) simultaneously with the skin temperature increase. However, a multiple increase in BPA remained after the compress was removed, whereas the skin temperature returned to the baseline. Moreover, the BPA increase and duration of the vasomotor response was associated with the degree of external heating. Therefore, the IPPG method allows us to quantify the parameters of capillary blood flow during local thermal exposure to the skin. This proposed technique of assessing the thermal reactivity of microcirculation can be applied for both clinical use and for biomedical research.

Prostaglandin E2, a postulated mediator of neurovascular coupling, at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles

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 vasomotor 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 and protein expression of vasodilator EP4 receptors was significantly higher than that of vasoconstrictor EP1 receptors in human cerebral arterioles.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 patients.

Differential vasomotor responses to isocapnic hyperoxia: cerebral versus peripheral circulation.

Isocapnic hyperoxia (IH) evokes cerebral and peripheral hypoperfusion via both disturbance of redox homeostasis and reduction in nitric oxide (NO) bioavailability. However, it is not clear whether the magnitude of the vasomotor responses depends on the vessel network exposed to IH. To test the hypothesis that the magnitude of IH-induced reduction in peripheral blood flow (BF) may differ from the hypoperfusion response observed in the cerebral vascular network under oxygen-enriched conditions, nine healthy men (25 ± 3 yr, mean ± SD) underwent 10 min of IH during either saline or vitamin C (3 g) infusion, separately. Femoral artery (FA), internal carotid artery (ICA), and vertebral artery (VA) BF (Doppler ultrasound), as well as arterial oxidant (8-isoprostane), antioxidant [ascorbic acid (AA)], and NO bioavailability (nitrite) markers were simultaneously measured. IH increased 8-isoprostane levels and reduced nitrite levels; these responses were followed by a reduction in both FA BF and ICA BF, whereas VA BF did not change. Absolute and relative reductions in FA BF were greater than IH-induced changes in ICA and VA perfusion. Vitamin C infusion increased arterial AA levels and abolished the IH-induced increase in 8-isoprostane levels and reduction in nitrite levels. Whereas ICA and VA BF did not change during the vitamin C-IH trial, FA perfusion increased and reached similar levels to those observed during normoxia with saline infusion. Therefore, the magnitude of IH-induced reduction in femoral blood flow is greater than that observed in the vessel network of the brain, which might involve the determinant contribution that NO has in the regulation of peripheral vascular perfusion.

Cognition and cerebrovascular function in primary hyperparathyroidism before and after parathyroidectomy.

There are cognitive changes in primary hyperparathyroidism (PHPT) that improve with parathyroidectomy, but the mechanism of cognitive dysfunction has not been delineated. We assessed if cerebrovascular function is impaired in PHPT, improves post-parathyroidectomy and is associated with PTH level and cognitive dysfunction. This is an observational study of 43 patients with mild hypercalcemic or normocalcemic PHPT or goiter. At baseline, cerebrovascular function (dynamic cerebral autoregulation and vasomotor reactivity) by transcranial Doppler and neuropsychological function were compared between all three groups. A subset underwent parathyroidectomy or thyroidectomy, and was compared 6months post-operatively. Mean cerebrovascular and neuropsychological function was normal and no worse in PHPT compared to controls preoperatively. Higher PTH was associated with worse intracerebral autoregulation (r = - 0.43, p = 0.02) and worse cognitive performance on some tests. Post-parathyroidectomy, mood improved significantly, but changes did not differ compared to those having thyroidectomy (p = 0.84). There was no consistent improvement in cognition or change in vascular function in either surgical group. Although higher PTH was associated with worse intracerebral autoregulation, cerebrovascular function, cognition and mood were normal in mild PHPT. PTX did not improve vascular or cognitive function. The observed improvement in mood cannot be clearly attributed to PTX. Notwithstanding the small sample size, the results do not support changing current criteria for parathyroidectomy to include cognitive complaints. However, the associations between PTH, cognition and cerebral autoregulation merit future studies in those with more severe hyperparathyroidism.

Persistent insulin signaling coupled with restricted PI3K activation causes insulin-induced vasoconstriction.

Insulin modulates vasomotor tone through vasodilator and vasoconstrictor signaling pathways. The purpose of the present work was to determine whether insulin-stimulated vasoconstriction is a pathophysiological phenomenon that can result from a combination of persistent insulin signaling, suppressed phosphatidylinositol-3 kinase (PI3K) activation, and an ensuing relative increase in MAPK/endothelin-1 (ET-1) activity. First, we examined previously published work from our group where we assessed changes in lower-limb blood flow in response to an oral glucose tolerance test (endogenous insulin stimulation) in lean and obese subjects. The new analyses showed that the peak rise in vascular resistance during the postprandial state was greater in obese compared with lean subjects. We next extended on these findings by demonstrating that insulin-induced vasoconstriction in isolated resistance arteries from obese subjects was attenuated with ET-1 receptor antagonism, thus implicating ET-1 signaling in this constriction response. Last, we examined in isolated resistance arteries from pigs the dual roles of persistent insulin signaling and blunted PI3K activation in modulating vasomotor responses to insulin. We found that prolonged insulin stimulation did not alter vasomotor responses to insulin when insulin-signaling pathways remained unrestricted. However, prolonged insulinization along with pharmacological suppression of PI3K activity resulted in insulin-induced vasoconstriction, rather than vasodilation. Notably, such aberrant vascular response was rescued with either MAPK inhibition or ET-1 receptor antagonism. In summary, we demonstrate that insulin-induced vasoconstriction is a pathophysiological phenomenon that can be recapitulated when sustained insulin signaling is coupled with depressed PI3K activation and the concomitant relative increase in MAPK/ET-1 activity.NEW & NOTEWORTHY This study reveals that insulin-induced vasoconstriction is a pathophysiological phenomenon. We also provide evidence that in the setting of persistent insulin signaling, impaired phosphatidylinositol-3 kinase activation appears to be a requisite feature precipitating MAPK/endothelin 1-dependent insulin-induced vasoconstriction.