Arterial Response Research Articles

Exposure to prenatal hypoxia impairs the function and structure of the carotid arteries in the adult offspring.

Prenatal hypoxia, a common pregnancy complication, can lead to vascular dysfunction, thereby increasing the risk of cardiovascular disease in the adult offspring. Carotid arteries are responsible for the majority of the blood flow to the brain/head, and carotid artery dysfunction is associated with life-threating cardiovascular events, such as stroke. However, whether prenatal hypoxia exposure impacts the function of the carotid arteries in the adult offspring is not known. We hypothesize that prenatal hypoxia impairs carotid artery function in the adult male and female offspring. Sprague Dawley rats were exposed to normoxia (21% O2) or hypoxia (11% O2) from gestational day (GD) 15 to 21 (term=22 days; n=9-11/group). Carotid arteries were isolated from the 4-month-old adult male and female offspring. Vasoconstrictor and vasodilatory properties were assessed by wire myography, and biomechanical properties (myogenic tone, circumferential stress and strain) by pressure myography. Collagen deposition (Masson's trichrome stain) and elastin density (Verhoeff stain) were measured in carotid artery cryosections. Prenatal hypoxia did not impact vasoconstriction or vasorelaxation responses in carotid arteries from both offspring. However, in males, prenatal hypoxia reduced carotid artery myogenic tone development and increased circumferential strain, which coincided with a lower collagen deposition and higher elastin density. In females, prenatal hypoxia tended to lower carotid artery circumferential strain (i.e., increased stiffness), without differences in myogenic tone or collagen/elastin density. Altogether, these data show that prenatal hypoxia exposure affects the carotid arteries of the adult offspring in a sex-specific manner, which may impact the blood flow regulation to the brain.

Pregnancy and Postpartum Effects of Electronic Cigarettes on Maternal Health and Vascular Function in the Fourth Trimester.

Pregnancy is a vulnerable time with significant cardiovascular changes that can lead to adverse outcomes, which can extend into the postpartum window. Exposure to emissions from electronic cigarettes (Ecig), commonly known as "vaping," has an adverse impact on cardiovascular function during pregnancy and post-natal life of offspring, but the postpartum effects on maternal health are poorly understood. We used a Sprague Dawley rat model, where pregnant dams are exposed to Ecigs between gestational day (GD)2-GD21 to examine postpartum consequences. Litter and dam health were monitored during the weaning period, and maternal vascular and endocrine function were assessed after weaning.Exposure to Ecig emissions during pregnancy led to fetal losses (i.e., reabsorption in utero) and reduced survival of pups during weaning compared to controls (air-exposed dams). We find that maternal vaping during pregnancy, with or without nicotine (or flavoring) results in maternal vascular and hormonal dysfunction (i.e., reduced prolactin, increased expression of sirtuin 1 deacetylase in the brain). Both5 and 30W Ecig aerosol exposures resulted in significant impairment of middle cerebral artery reactivity to acetylcholine-mediated dilation (decreasing ~ 22 and ~ 50%, respectively).We also observed an increase in the number of extracellular vesicles (EVs)in plasma from 30-W group that persists up to 3-week postpartum and that these EVs impaired endothelial cell function when applied to in vitro and ex vivo assays. Our data suggest (1) Ecig vaping, even without nicotine or flavorings, during pregnancy alters maternal circulating factors that influence maternal and fetal health, (2) circulating EVs may contribute to the etiology of vascular dysfunction, and (3) that the window for recovery from vascular dysfunction in the dam is likely to be longer than the exposure window.

Antenatal betamethasone augments lung perfusion but lowers upper body blood flow and O2 delivery with delayed cord clamping at birth in preterm lambs.

Although the corticosteroid betamethasone is routinely administered to accelerate lung and cardiovascular maturation in the preterm fetus prior to birth, and use of delayed cord clamping (DCC) is recommended at birth by professional bodies, it is unknown whether antenatal betamethasone alters perinatal pulmonary or systemic arterial blood flow accompaniments of DCC. To address this issue, preterm fetal lambs [gestation 127 (1) days, term=147days] with (n=10) or without (n=10) antenatal betamethasone treatment were acutely instrumented under general anaesthesia with flow probes to obtain left (LV) and right ventricular (RV) outputs, major central arterial blood flows and shunt flow across both the ductus arteriosus and foramen ovale (FO). After delivery, lambs underwent initial ventilation for 2min prior to DCC. During initial ventilation and after DCC, betamethasone (1) augmented rises in pulmonary arterial blood flow, with this greater increase supported during initial ventilation by enhanced pulmonary distribution of a higher RV output that was largely underpinned by newly emergent and substantial left-to-right (L→R) shunting across the FO, and after DCC, by an added contribution from more pronounced L→R ductal shunting; (2) increased a redistribution of LV output away from the upper body region, accompanied by lowering of upper body blood flow and O2 delivery; and (3) accentuated a progressive systemic-to-pulmonary arterial shift in the distribution of the combined LV and RV output that occurred in conjunction with more pronounced perinatal L→R shunting. These findings suggest that antenatal betamethasone substantially alters arterial blood flow effects of initial ventilation and DCC in the preterm birth transition. KEY POINTS: Betamethasone is given to increase fetal lung and cardiovascular maturation prior to preterm birth, while delayed cord clamping (DCC) is recommended at birth. Whether antenatal betamethasone alters perinatal arterial blood flow responses to DCC is unknown. Anaesthetized preterm fetal lambs with or without betamethasone pretreatment were instrumented with central arterial flow probes and, at birth, underwent ∼2min of ventilation before DCC. Betamethasone augmented perinatal rises in pulmonary arterial blood flow, related to enhanced pulmonary distribution during initial ventilation of a higher right ventricular output largely underpinned by left-to-right (L→R) shunting across the foramen ovale, with an added contribution from more pronounced L→R ductal shunting after DCC. Betamethasone increased a redistribution of left ventricular output away from the upper body region, with lowering of upper body blood flow and O2 delivery. Betamethasone accentuated a systemic-to-pulmonary arterial shift in the distribution of combined ventricular output occurring with greater perinatal L→R shunting.

Retinal vessel flicker light responsitiviness and its relation to analysis protocols, static and metabolic data in healthy subjects

Aims/Purpose: To assess agreement between different analysis protocols for determination of retinal vessel dilation response to flicker light (FL) and its relation to static‐ and metabolic parameters of retinal vessels in healthy subjects.Methods: 24 right eyes of 24 healthy controls (mean age: 35.87 ±SD 14.20 years), who underwent dynamic‐ and static retinal diameter‐ and oxygen saturation measurements on Retinal Vessel Analyser were included (RVA, Imedos, Jena, Germany). Using repeated video analyses, responses to FL were measured within the superior‐temporal (ST) area. Taking the length and the location into account, the FL data were evaluated in 3 groups: length < 1 optic disc (OD) (group 1); length > 1OD: close to the OD (group 2) and within the VesselMap area (group 3).For comparability, the static‐ (CRA, CRV, AVR) and oxygen saturation parameters (A‐V SO2, V‐SO2, A‐V SO2) were calculated in the ST peripapillary area using the VesselMap tool of RVA and were evaluated in relation to the corresponding dynamic ones (group 3).Results: In all groups, vascular FL response of arteries was less pronounced compared to venules (p = 0.023). Event thought, FL responses (mean ±SD: FL‐A; FL‐V, %) in group 1 to be more pronounced (mean 3.36 ±2.31; 4.42 ±1.69) compared to those in groups 2 (mean: 2.97 ±2.40; 4.08 ±1.55) and 3 (2.84 ±2.29; 4.21± 2.03) they did not reach statistically significant values (p > 0.44).The mean flicker response of venules showed negative correlations to the corresponding static‐ and metabolic parameters: CRV (r = ‐0.489; p = 0.015) and V‐SO2 (r = ‐0.375; p = 0.001).Conclusions: Our study confirms, that flicker light response, even showing slight difference about its length and location, allows agreeable measurements. However, even in healthy subjects, the effect of the static‐ and metabolic retinal vessel measurements on retinal venular flicker response should be taken in consideration.

Retinal vessel flicker light responsitiviness and its relation to analysis protocols, static and metabolic data in healthy subjects

Aims/Purpose: To assess agreement between different analysis protocols for determination of retinal vessel dilation response to flicker light (FL) and its relation to static‐ and metabolic parameters of retinal vessels in healthy subjects.Methods: 24 right eyes of 24 healthy controls (mean age: 35.87 ± SD 14.20 years), who underwent dynamic‐ and static retinal diameter‐ and oxygen saturation measurements on Retinal Vessel Analyser were included (RVA, Imedos, Jena, Germany). Using repeated video analyses, responses to FL were measured within the superior‐temporal (ST) area. Taking the length and the location into account, the FL data were evaluated in 3 groups: length < 1 optic disc (OD) (group 1); length > 1OD: close to the OD (group 2) and within the VesselMap area (group 3).For comparability, the static‐ (CRA, CRV, AVR) and oxygen saturation parameters (A‐V SO2, V‐SO2, A‐V SO2) were calculated in the ST peripapillary area using the VesselMap tool of RVA and were evaluated in relation to the corresponding dynamic ones (group 3).Results: In all groups, vascular FL response of arteries was less pronounced compared to venules (p = 0.023). Event thought, FL responses (mean ± SD: FL‐A; FL‐V, %) in group 1 to be more pronounced (mean 3.36 ± 2.31; 4.42 ± 1.69) compared to those in groups 2 (mean: 2.97 ± 2.40; 4.08 ± 1.55) and 3 (2.84 ± 2.29; 4.21 ± 2.03) they did not reach statistically significant values (p > 0.44).The mean flicker response of venules showed negative correlations to the corresponding static‐ and metabolic parameters: CRV (r = ‐0.489; p = 0.015) and V‐SO2 (r = ‐0.375; p = 0.001).Conclusions: Our study confirms, that flicker light response, even showing slight difference about its length and location, allows agreeable measurements. However, even in healthy subjects, the effect of the static‐ and metabolic retinal vessel measurements on retinal venular flicker response should be taken in consideration.

Intrauterine growth restriction does not lead to pronounced changes in the regulation of arterial contractile responses in rats in the early postnatal period

Intrauterine growth retardation (IUGR) is one of the most common pathologies of pregnancy. As a result of this pathology, the functioning of many systems, including the cardiovascular system, is disrupted. In adult animals who have suffered IUGR, the contribution of procontractile mechanisms regulating vascular tone (for example, the Rho-kinase signaling pathway) increases, and the contribution of anticontractile mechanisms (for example, endothelial NO), on the contrary, decreases, which can lead to vasospasm and impaired blood supply to organs. Since NO and Rho-kinase have a pronounced vasomotor role in early postnatal ontogenesis, the purpose of this work was to assess the influence of IUGR on the contribution of these mechanisms to the regulation of arterial contractile responses in early postnatal ontogenesis. IUGR was modeled by limiting the amount of food consumed by females (by 50%) from the 11th day of pregnancy until birth. In offspring aged 11 - 12 days, the reactions of the isolated saphenous artery were studied in isometric mode, and the content of mRNA and proteins of interest in this artery was also assessed. IUGR did not lead to a change in the reactivity of the arteries of the offspring to the α1-adrenergic receptor agonist methoxamine. The increase in contractile responses to methoxamine in the presence of the NO-synthase inhibitor L-NNA, as well as the expression levels of eNOS (mRNA and protein) and arginase-2 (mRNA) were not changed in the arteries of IUGR rats, while the sensitivity of the arteries to the exogenous NO donor DEA /NO was higher in IUGR compared to control rat pups. Despite the relatively low content of RhoA and Rho-kinase II proteins in the arterial tissue of rat pups from the IUGR group, the decrease in contractile responses under the influence of the Rho-kinase inhibitor Y27632 was equally pronounced in the arteries of rat pups from two experimental groups. Thus, IUGR, caused by maternal nutritional restriction during pregnancy, does not lead to pronounced changes in the regulation of systemic vascular tone in the early postnatal period.

Computational modelling of cardiac control following myocardial infarction using an in silico patient cohort.

Loss of cardiac physiological function following myocardial infarction (MI) is accompanied by neural adaptations in the baroreflex that are compensatory in the short term, but then become associated with long-term disease progression. One marker of these adaptations is decreased baroreflex sensitivity, a strong predictor of post-MI mortality. The relative contributions of cardiac remodelling and neural adaptation in the sensory, central brainstem and peripheral ganglionic loci to baroreflex sensitivity changes remain underexplored. We used a computational model-based approach that accounts for the short-term dynamics of closed-loop human cardiac control to integrate disparate experimental studies on neural adaptation following MI into a unified quantitative framework. We developed an ensemble of 59 distinct model parameterizations that account for the clinically observed heterogeneity of cardiac control in healthy individuals. We simulated an in silico cohort of 35,400 patients with MI, corresponding to six scenarios of one or more loci of neural adaptation coupled with cardiac remodelling. We evaluated the range of MI-induced shifts in arterial pressure, heart rate and baroreflex curve responses. Our results show that adaptation in any single neural locus coupled with cardiac remodelling is sufficient to account for the MI-induced haemodynamic and autonomic changes observed experimentally. Of the adaptation pathways, we found that individuals with central or peripheral vagal efferent adaptation and preserved baroreceptor gain could maintain high baroreflex sensitivity after ischaemic injury. These results suggest that there are a multitude of adaptive pathways for tuning the baroreflex circuit to shift cardiac control physiology, potentially explaining patient heterogeneity post-MI. KEY POINTS: Baroreflex sensitivity is a strong indicator of post-myocardial ischaemia survival and is variable among individuals. We fine-tuned a computational model ensemble based on physiological observations to develop an in silico patient cohort consistent with the range of baroreflex responses observed experimentally. Simulation and analysis of the in silico cohort show that individuals with a functional afferent pathway and the ability to adapt along the vagal efferent pathway can maintain baroreflex sensitivity post-cardiac ischaemia.

The role of the dorsomedial hypothalamus in the cardiogenic sympathetic reflex in the Sprague Dawley rat.

Myocardial ischemia causes the production and release of metabolites such as bradykinin, which stimulates cardiac spinal sensory afferents, causing chest pain and an increase in sympathetic activity referred to as the cardiogenic sympathetic afferent reflex. While the brain stem nuclei, such as the nucleus tractus solitarius and rostral ventrolateral medulla, are essential in the cardiogenic sympathetic afferent reflex, the role of other supramedullary nuclei in the cardiogenic sympathetic afferent reflex are not clear. The dorsomedial hypothalamic nucleus (DMH) is involved in cardiovascular sympathetic regulation and plays an important role in the sympathetic response to stressful stimuli. In this study, we determined the role of DMH in the cardiogenic sympathetic afferent reflex. To do this we measured arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA) responses to epicardial bradykinin (10 μg/mL) in anesthetized Sprague Dawley rats before and after bilateral DMH microinjection (50 nL) of either the GABAA agonist muscimol (0.5 nmol) to inhibit or the antagonist bicuculline (40 pmol) to disinhibit activity. Muscimol inhibition elicited a modest, albeit significant, reduction in basal arterial pressure and heart rate and attenuated the arterial pressure and heart rate reflex response to epicardial bradykinin. However, it did not change the magnitude of the reflex. Bicuculline disinhibition of the DMH increased basal arterial pressure, heart rate, and RSNA but did not augment the response to epicardial bradykinin. These results suggest that sympathetic activity derived from the DMH does not play an important role in the cardiogenic sympathetic afferent reflex in Sprague Dawley rats.

Long-term egg-protein hydrolysate consumption improves endothelial function: a randomized, double-blind, placebo-controlled trial in older adults with overweight or obesity.

The dietary egg-protein hydrolysate Newtricious (NWT)-03 has previously demonstrated improvements in blood pressure and metabolic profiles. However, the long-term effects on vascular function and cardiometabolic risk markers are unknown. Forty-four older (aged 60-75) adults with overweight/obesity experiencing elevated Subjective Cognitive Failures (SCF) were randomized into a 36-week, double-blind, placebo-controlled trial. Participants either consumed 5.7g of an egg-protein hydrolysate (NWT-03) or maltodextrin placebo. Endothelial function (brachial artery flow-mediated vasodilation [FMD] and carotid artery reactivity [CAR] responses after a cold pressor test), arterial stiffness (carotid-to-femoral pulse wave velocity [PWVc-f]), retinal microvascular calibers, and cardiometabolic risk markers (insulin sensitivity using a 7-point oral glucose tolerance test, serum lipid profiles, and blood pressure) were evaluated. FMD observed a non-significant trend towards a 0.3 percentage point (pp) increase in the intervention compared to the placebo group (95% CI: [0.0, 0.7]; p = 0.08), and a significant intervention effect was observed on CAR responses based on a 0.7pp improvement after a cold pressor test (95% CI: [0.1, 1.3]; p = 0.03). No significant overall changes were observed for arterial stiffness as measured by PWVc-f. Retinal microvascular calibers and cardiometabolic parameters also did not change. Long-term supplementation with 5.7g of the egg-protein hydrolysate NWT-03 for 36weeks improved vascular endothelial function in older adults with overweight/obesity experiencing elevated SCF, which may benefit cardiovascular disease risk. No overall changes in other vascular function markers, retinal microvascular calibers or cardiometabolic risk markers were observed. The study was registered at ClinicalTrials.gov in January 2021 as NCT04831203: https://clinicaltrials.gov/study/NCT04831203.

LPS Increases Artery but Not Airway Contraction in Precision Cut Lung Slices from a Mouse Model of ARDS.

Acute respiratory distress syndrome (ARDS) results in decreased quality of life, including increased risk of pulmonary hypertension (PH). In animal models, ARDS can be induced by lipopolysaccharide (LPS), which can disrupt the pulmonary endothelium and epithelium and induce inflammation. We tested whether in vivo administration or ex vivo treatment with LPS alters the reactivity of intrapulmonary arteries and airways to constrictors relevant to both ARDS and PH, using the precision cut lung slice (PCLS) technique. Mice were administered LPS (10μg/50μl, intranasal) or saline daily for 4d before collection of bronchoalveolar lavage fluid (BALF) or preparation of PCLS. Alternatively, PCLS from naïve mice were left untreated or treated ex vivo with LPS (10μg/mL) or tumour necrosis factor (TNF, 10ng/mL) for 18h. Contraction to endothelin-1 (ET-1), U46619 (a stable mimetic of TXA2) or serotonin (5HT) were quantified. In vivo LPS administration increased BAL total inflammatory cells 5-fold, neutrophils 125-fold and protein 2-fold, as well as the thickness of the pulmonary arterial smooth muscle layer. After in vivo LPS, contraction of intrapulmonary arteries in PCLS to ET-1 and U46619, but not 5HT, increased, while bronchoconstrictor responses were unchanged. In PCLS treated with LPS ex vivo, these differential effects on pulmonary artery and airway contraction were maintained. While LPS increased TNF secretion from PCLS, TNF treatment only increased U46619-induced vasoconstriction. This study demonstrates the potential contributions of LPS-induced inflammation and vascular remodelling to altered intrapulmonary artery reactivity to specific agonists with implications for ARDS-associated PH.

Features of isolated systolic and resistant arterial hypertension in patients with type 2 diabetes mellitus

Hypertension and type 2 diabetes mellitus (DM) are often combined and mutually enhance the adverse effects on vascular and renal prognosis. One of the features of hypertension in type 2 diabetes is the frequent occurrence of isolated systolic hypertension (ISG) and resistant hypertension (RH). Objective. To study the features of the structure and function of the left ventricle (LV), categories of circadian rhythm during outpatient blood pressure monitoring (OBPM), as well as the structure and function of blood vessels in people with type 2 diabetes, depending on the presence or absence of ISG and RH. Materials and methods. An observational descriptive one-step study was conducted 139 patients with hypertension in combination with type 2 diabetes (64 men and 75 women aged 73.9±11.7 years). ISAG was isolated if systolic blood pressure (BP) exceeded 140 mmHg, and diastolic blood pressure was less than 90 mmHg. RH was determined if, despite lifestyle changes and taking three classes of antihypertensive drugs, it was not possible to achieve target blood pressure levels. All patients underwent OBPM, echocardiography, ultrasound examination of the brachiocephalic arteries and a reactive hyperemia test. Results. Among 139 patients with hypertension in combination with type 2 DM, systolic-diastolic hypertension was present in 80 (57.6%) cases, ISG in 59 (42.4%), RH in 57 (41.0%), hypertension without resistance to antihypertensive treatment in 82 (59.0%). Conclusions. Patients with ISG characterized by more pronounced and eccentric LV hypertrophy (LVH), types II and III of LV diastolic dysfunction (DD), the "non-dipper" category in OBPM, as well as a significant thickening of the intima-media complex (IMC) of the common carotid artery (CCA). Patients with RH characterized by more pronounced and concentric LVH, types II and III of LV DD, the "night-peaker" category in OBPM, significant thickening of the IMC CCA and impaired brachial artery response in the reactive hyperemia test.

Effects of Hydrogen Sulfide at Normal Body Temperature and in the Cold on Isolated Tail and Carotid Arteries from Rats and TRPA1 Knockout and Wild-Type Mice.

Background: Hydrogen sulfide (H2S) is a gasotransmitter that modulates vascular tone, causing either vasodilation or vasoconstriction depending on the vascular bed, species, and experimental conditions. The cold-sensitive transient receptor potential ankyrin-1 (TRPA1) channel mediates H2S-induced effects; however, its contribution to the vasomotor responses of different arteries at different temperatures has remained unclear. Here, we aimed to fill this gap by comparing the effects of sodium sulfide (Na2S), which is a fast-releasing H2S donor, on the isolated carotid and tail skin arteries of rats and mice at cold and normal body temperature with wire myography. Under the same circumstances, we also aimed to compare the effects of the canonical endothelium-dependent and -independent vasodilators, acetylcholine and sodium nitroprusside, respectively. Methods: We isolated the carotid and tail arteries from 32 adult Wistar rats and 64 TRPA1 knockout and wild-type mice, and then we studied their vasomotor responses to increasing doses (10-6-10-3 M) of Na2S as well as to acetylcholine and sodium nitroprusside (10-5 M for both) at 37 °C and in cold (17 or 20 °C). Results: In rat vessels, Na2S caused constriction of the carotids and relaxation of the tail arteries, which were not influenced by temperature. In mouse carotids, Na2S caused vasorelaxation, which was more pronounced in the cold at a lower dose (10-4 M). At a higher dose (10-3 M), the dilation was markedly attenuated in the absence of the TRPA1 channel. In the mouse tail arteries, Na2S caused vasorelaxation at 37 °C and vasocontraction in the cold. The genetic blockade of TRPA1 channels did not influence the vasomotor responses of the mouse tail arteries. Sodium nitroprusside-induced vasorelaxation was not influenced by any of the investigated factors, while acetylcholine-induced dilation decreased in the cold in all vessel types. Conclusions: Our results reveal the function of TRPA1 in the H2S-induced dilation of carotid arteries in mice. We also highlight interspecies differences in the vasomotor responses between rats and mice, as well as the importance of the effect of temperature on vascular responses. The implementation of the identified variables in future research can advance our understanding of cardiovascular physiology, especially in conditions with hypothermia (either accidental or therapeutic).

Male-female comparison of vasomotor effects of circulating hormones in human intracranial arteries

BackgroundThe purpose of this study was to examine whether there are sex differences in vasomotor responses and receptor localization of hormones and neuropeptides with relevance to migraine (vasopressin, oxytocin, estrogen, progesterone, testosterone, amylin, adrenomedullin and calcitonin gene-related peptide (CGRP)) in human intracranial arteries.MethodsHuman cortical cerebral and middle meningeal arteries were used in this study. The tissues were removed in conjunction with neurosurgery and donated with consent. Vasomotor responses of arteries, after exposure to hormones or neuropeptides, were recorded using a wire myograph. Immunohistochemistry was performed to examine the expression and localization of their receptors within human intracranial arteries.ResultsVasopressin showed the strongest contractile responses, followed by oxytocin and progesterone. CGRP displayed the strongest vasodilatory response when compared to adrenomedullin, amylin, testosterone and estrogen. No significant differences were observed in vasomotor responses between male and female arteries. The vasomotor effects were supported by the presence of corresponding receptors in the vascular smooth muscle cells. Estrogen receptors (ERα and ERβ), progesterone receptor (PR), vasopressin 1a receptor (V1aR), and the oxytocin receptor (OTR) were expressed in the walls of both cerebral arteries overlying the cerebral cortex and intracranial arteries of the dura mater. ERα, V1aR, and PR were found to be localized in both smooth muscle cells and endothelium, whereas OTR was exclusively located within the smooth muscle cells.ConclusionsHypothalamic, sex hormones and the pancreas hormone (amylin) receptors are expressed in the human intracranial artery walls. The vasomotor responses revealed no sex differences, however contractile responses to vasopressin was higher and more potent in MMA compared to CCA when pooling data from both sexes. Overall, the hormones estrogen, progesterone and oxytocin, which drop in circulating levels at onset of menstruation, only showed modest vasomotor responses as compared to CGRP. This suggests that their role in inducing menstrual migraine attacks is not directly related to vasomotor responses.Graphical

Effect of Empagliflozin on Reactivity of Mesenteric Arteries and Skin Microvessels in Rats Treated with Doxorubicin

Effect of Empagliflozin on Reactivity of Mesenteric Arteries and Skin Microvessels in Rats Treated with Doxorubicin

Vasorelaxant effect of fennel seeds (Foeniculum vulgare Mill) extracts on rat mesenteric arteries: Assessment of phytochemical profiling and antioxidant potential.

Hypertension is a serious health problems and a leading cause of adult mortality worldwide. Foeniculum. vulgare Mill, a plant traditionally used for various ailments, including cardiovascular disorders such as hypertension. The objective of the study is to verify the vasorelaxant effect of fennel seeds on the isolated and perfused mesenteric vascular beds in rats. The vasorelaxant effect of the aqueous extract of F. vulgare (AEFv) seeds was tested on mesenteric arteries, both intact and denuded, precontracted with phenylephrine. Extracts from liquid-liquid extraction of F. vulgare were screened to find the active fraction. The mechanism of action of the active butanolic fraction (BFFv) was studied using inhibitors like L-NAME (nitric oxide synthase inhibitor), ODQ (guanylate cyclase inhibitor), indomethacin (cyclooxygenase inhibitor), potassium channel blockers (tetraethylammonium TEA, and glibenclamide), and atropine (a muscarinic receptor antagonist). Moreover, the antioxidant properties of AEFv and BFFv were evaluated using DPPH radical scavenging, β-carotene linoleic acid, and ferric-reducing power assays; total flavonoids and phenolics of AEFv and BFFv were measured using Folin-Ciocalteu and aluminum chloride colorimetric assays; HPLC-DAD analysis and acute toxicity of BFFv in mice were also performed. AEFv caused a concentration-dependent vasodilatory response in intact mesenteric arteries (Emax = 81.73 ± 0.36 %). This effect was significantly reduced after endothelium removal. The butanolic fraction showed the highest vasorelaxant effect. The vasodilatory effect was attenuated by L-NAME, ODQ, indomethacin, TEA, glibenclamide, and atropine, indicating involvement of the NO/GMPc pathway, potassium channels, and muscarinic receptors. Additionally, fennel extracts demonstrated excellent antioxidant activity and high concentrations of flavonoids and phenolic compounds. HPLC-DAD analysis of the butanolic fraction revealed an abundance of phenolic acids. Acute toxicity studies of BFFv showed no toxic effects. Our findings support the traditional use of Foeniculum vulgare seeds for preventing cardiovascular disorders associated with vascular dysfunction, highlighting their vasorelaxant and antioxidant properties.

Time-Dependent Relationship Between Endothelial Dysfunction and High Blood Pressure in Fructose Drinking Rats.

This study aims to investigate the duration required for endothelium dysfunction to develop in the fructose drinking-induced hypertension and examine the relative contributions of endothelium-dependent relaxing factors to changes in mesenteric arterial reactivity in male Wistar Albino rats. Metabolic parameters (water intake and food consumption) and hemodynamic parameters systolic blood pressure (SBP) and diastolic blood pressure (DBP)-were monitored in vivo. Vascular reactivity was examined in the isolated organ bath. Endothelium-dependent relaxation (EDR) to acetylcholine was observed in the absence and presence of pharmacological inhibitors of endothelial nitric oxide (NO) synthase, cyclooxygenase, and KCa2.3 channels. Contractile responses to phenylephrine and relaxation of sodium nitroprusside (SNP) were also determined. A significant increase in daily water intake and decrease in food consumption were typically observed in rats treated with 10% fructose for 4 weeks (p < 0.05). SBP and DBP increased significantly as early as 2 weeks of induction and continued to rise gradually throughout the induction period (p < 0.05). Fructose consumption significantly impaired EDR at week 3 and worsened at week 4 (p < 0.05). Impairment of the KCa3.1 channel-mediated component of endothelium-dependent hyperpolarisation (EDH)-type relaxation contributed to worsening EDR, whereas the contribution of NO-mediated relaxation was not apparent compared with the controls. The reduction in EDH-type relaxation in fructose-fed rats appears to be partially compensated by increased NO sensitivity in the smooth muscle region, as fructose induction increased SNP relaxation compared with the control. These data provide evidence of early endothelial dysfunction developing concurrently with increased blood pressure in 10% fructose-fed rats. Decreased KCa3.1-mediated part of EDH-type relaxation appears to contribute to the impairment of endothelium-dependent vasorelaxation over time in this model.

Characterising the Time Course of the Dilatory Response of Healthy Retinal Arteries during Flicker-Light Provocation

Introduction: The dilatory response of healthy retinal arterioles to flicker-light (FL) provocation appears to be biphasic. The vessel diameter rapidly increases (acute phase) over 5–10 s, then barely increases thereafter (maintenance phase) until FL cessation. This reaction is usually characterised at a single point by two parameters: maximum dilation (MD) relative to baseline diameter (MD, %) and time to MD (RT, s). This paper describes the biphasic reaction of retinal arteries during FL provocation using a bi-linear function. Methods: Retinal arterioles from 45 adults were examined during flicker provocation. Each individual time course of arterial diameter change during FL provocation was characterised by a bi-linear equation and compared with MD and RT. Results: Slopes of the acute phase were 0.506%/s, and the maintenance phase was nearly flat (0.012%/s). The mean time at which the reaction changed from acute to maintenance phase was 7.4 s which is significantly different from RT (16.0 s). Mean dilation at this point (2.987%) was significantly different from MD (3.734%), but it was still 80% of MD in less than half of RT. Conclusion: Bi-linear fitting parameters better characterises the arterial dilatory response than MD and RT. Further stratification of clinical groups using bi-linear fitting may provide insight of the underlying physiology of vessel dilation for different pathologies.

Alanine mutation of the targeting subunit of the myosin phosphatase, MYPT1 at threonine 696 reduces cGMP responsiveness of mouse femoral arteries

The femoral artery (FA) is the largest vessel in the hindlimb circulation and its proper tone regulation ensures adequate blood supply to muscle tissue. We investigated whether an alanine mutation of the targeting subunit of myosin-light-chain-phosphatase (MLCP), MYPT1, at threonine 696 (MYPT1-T696A/+), decisive for enzyme acivity, affects the responsiveness of young and old FAs (y-FAs and o-FAs) to activation of nitric-oxide/soluble-guanylate-cyclase/protein-kinase-G cascade (NO/sGC/PKG). Contractile responses of the vessels were measured by wire myography. Phosphorylation of the regulatory myosin-light-chain at serine 19 (MLC20-S19), the myosin-light-chain-phosphatase targeting subunit, MYPT1-T696, the PKG-sensitive site of MYPT1 at S695 (MYPT1-S695) and S668 (MYPT1-S668), and the regulatory phosphorylation of eNOS at S1177 (eNOS-S1177) were determined in arterial homogenates by Western blot. In FAs of all ages, the MYPT1-T696A-mutation did not alter vessel diameter and the contractile reactivity to the thromboxaneA2-analogue, U46619 and the RhoA kinase inhibitor, Y27632. In contrast, the mutation T696 into alanine attenuated the relaxing effect of exogenous NO (DEA-NONOate) in y-FAs. The effect of a direct sGC activation by cinaciguat was also attenuated in both age groups of MYPT1-T696A/+, but strongly in o-FA . The MYPT1-T696A-mutation also attenuated acetylcholine-induced relaxation, but only in o-FAs. Similary, the alanine mutation attenuated the acetylcholine effect on MLC20-S19- and MYPT1-T696 only in WT o-FAs. Interestingly, neither eNOS-S1177 nor the phosphorylation of the PKG phosphospecific sites, MYPT1-S695 and MYPT1-S668 were altered by MYPT1-T696A-mutation or aging. These findings suggest that the alanine mutation of MYPT1-T696 reduces the ability of the NO/cGMP/PKG-system to relax FAs in aging.

Cerebral blood flow and arterial transit time responses to exercise training in older adults

Brain vascular health worsens with age, as is made evident by resting grey matter cerebral blood flow (CBFGM) reductions and lengthening arterial transit time (ATTGM). Exercise training can improve aspects of brain health in older adults, yet its effects on CBFGM and ATTGM remain unclear. This randomised controlled trial assessed responses of CBFGM and ATTGM to a 26 week exercise intervention in 65 healthy older adults (control: n = 33, exercise: n = 32, aged 60–81 years), including whether changes in CBFGM or ATTGM were associated with changes in cognitive functions. Multiple-delay pseudo-continuous arterial spin labelling data were used to estimate resting global and regional CBFGM and ATTGM. Results showed no between-group differences in CBFGM or ATTGM following the intervention. However, exercise participants with the greatest cardiorespiratory gains (n = 17; ∆V̇O2peak >2 mL/kg/min) experienced global CBFGM reductions (-4.0 [-7.3, -0.8] mL/100 g/min). Cognitive functions did not change in either group and changes were not associated with changes in CBFGM or ATTGM. Our findings indicate that exercise training in older adults may induce global CBFGM reductions when high cardiorespiratory fitness gains are induced, but this does not appear to affect cognitive functions.

Dehydroepiandrosterone (DHEA), a circulating steroid hormone precursor produced potent vasorelaxation in rat aorta and mesenteric arteries through blockade of L-type voltage-dependent calcium channels

Dehydroepiandrosterone (DHEA) is known for potent cardioprotective properties and diminished DHEA level in plasma is often associated with hypertension and age-related anomalies. However, putative ex-vivo vasorelaxation potential of DHEA in systemic resistance vessels like mesenteric arteries and conduit arteries like aorta are still to be worked out. The study aimed to explore vasorelaxation potential of DHEA in superior and resistance mesenteric arteries and aorta in rats and to determine the contribution L-type Voltage dependent calcium channel (L-VDCC) in the relaxation response in these arterial tissues. Ex-vivo vasorelaxation potential of DHEA in isolated arterial tissues were evaluated and the mechanism of vasorelaxation induced by DHEA was characterized by contraction experiment in isolated arterial tissue and in-vitro calcium imaging assay using Fluo-4 in primary vascular smooth muscle cells derived from aorta. In the current study, DHEA was found to exhibit potent concentration dependent, endothelium and potassium channel independent vasorelaxation response in conduit and resistance arteries. The block of L-type VDCCs was evident from the findings that DHEA in a concentration-dependent manner inhibited both BAY K-8644 and CaCl2-induced contractions. The results of the contraction experiment were further substantiated by Fluo-4 mediated calcium imaging assay in primary rat vascular smooth muscle wherein DHEA concentration dependently blocked noradrenaline and BAY K-8644-induced rise in intracellular calcium fluorescence. The present study showed potent endothelium and potassium channel independent vasorelaxation properties of DHEA in aorta, superior and resistance mesenteric artery mediated predominantly through blockade of L-VDCC.