Constrictor Effect Research Articles

Morphofunctional traits and reactivity of the portal vein

Background: Portal vein is the most enigmatic vessel of our body because it regulates own contractile performances using a special pace-maker mechanism represented by cells of Cajal. The contribution of various metabolic mediators and natural vasotropic agents in the control of the portal blood circuit is much less studied compared to the arterial system in general and the hepatic system in particular. The studies designed on the structure, function, and reactivity of the portal vein in different preconditioning have brought some common but also distinct evidence of the arterial system. Nitric oxide production is higher partly due to reduced arginase expression, but muscular media is thinner. Periodic spontaneous contractions directed towards the liver gate are characteristic for portal vein (PV), and the longitudinal muscle fibers are considered to be responsible for this phenomenon. Spontaneous rhythmic oscillations of the cells of Cajal are triggered by increasing calcium ion concentration leading to their depolarization. PV constrictor effect of phenylephrine is dependent on the activity of receptors to ET-1. For PV is characterized the acetylcholine induced contraction either in vivo or in vitro, and this effect is thought to be dependent on ET-1. Conclusions: The establishment of main particularities of portal vein reactivity of action of different paracrine, endocrine, and hemodynamical stimuli represents an important tool for prediction of contractile disorders leading plausible to portal hypertension. Likewise, a well proven interplay between cholinergic and adrenergic stimulations and on the other hand between Ang II and ET-1 actions must be a support for pharmacological modulating of portal vein reactivity disorders.

Vitamin C Deficiency Exacerbates Dysfunction of Atherosclerotic Coronary Arteries in Guinea Pigs Fed a High-Fat Diet.

Vitamin C (vitC) deficiency has been associated with an increased risk of cardiovascular disease; while several putative mechanistic links have been proposed, functional evidence supporting a causal relationship is scarce. In this study, we investigated how vitC deficiency affects coronary artery vasomotor function and the development of coronary atherosclerotic plaques in guinea pigs subjected to chronic dyslipidemia by a high-fat diet regime. Female Hartley guinea pigs were fed either a control (low-fat diet and sufficient vitC) (N = 8) or a high-fat diet with either sufficient (N = 8) or deficient (N = 10) vitC for 32 weeks. Guinea pigs subjected to the high-fat diet developed significant atherosclerotic plaques in their coronary arteries, with no quantitative effect of vitC deficiency. In isolated coronary arteries, vasomotor responses to potassium, carbachol, nitric oxide, or bradykinin were studied in a wire myograph. Carbachol, bradykinin, and nitric oxide mediated relaxation in the coronary arteries of the control group. While vasorelaxation to carbachol and nitric oxide was preserved in the two high-fat diet groups, bradykinin-induced vasorelaxation was abolished. Interestingly, bradykinin induced a significant contraction in coronary arteries from vitC-deficient guinea pigs (p < 0.05). The bradykinin-induced contraction was unaffected by L-NAME but significantly inhibited by both indomethacin and vitC, suggesting that, during vitC deficiency, increased release of arachidonic acid metabolites and vascular oxidative stress are involved in the constrictor effects mediated by bradykinin. In conclusion, the present study shows supporting evidence that poor vitC status negatively affects coronary artery function.

Novel Smooth Muscle Ca2+-Signaling Nanodomains in Blood Pressure Regulation.

Ca2+ signals in smooth muscle cells (SMCs) contribute to vascular resistance and control blood pressure. Increased vascular resistance in hypertension has been attributed to impaired SMC Ca2+ signaling mechanisms. In this regard, transient receptor potential vanilloid 4 (TRPV4SMC) ion channels are a crucial Ca2+ entry pathway in SMCs. However, their role in blood pressure regulation has not been identified. We used SMC-specific TRPV4-/- (TRPV4SMC-/-) mice to assess the role of TRPV4SMC channels in blood pressure regulation. We determined the contribution of TRPV4SMC channels to the constrictor effect of α1 adrenergic receptor (α1AR) stimulation and elevated intraluminal pressure: 2 main physiologic stimuli that constrict resistance-sized arteries. The contribution of spatially separated TRPV4SMC channel subpopulations to elevated blood pressure in hypertension was evaluated in angiotensin II-infused mice and patients with hypertension. We provide first evidence that TRPV4SMC channel activity elevates resting blood pressure in normal mice. α1AR stimulation activated TRPV4SMC channels through PKCα (protein kinase Cα) signaling, which contributed significantly to vasoconstriction and blood pressure elevation. Intraluminal pressure-induced TRPV4SMC channel activity opposed vasoconstriction through activation of Ca2+-sensitive K+ (BK) channels, indicating functionally opposite pools of TRPV4SMC channels. Superresolution imaging of SMCs revealed spatially separated α1AR:TRPV4 and TRPV4:BK nanodomains in SMCs. These data suggest that spatially separated α1AR-TRPV4SMC and intraluminal pressure-TRPV4SMC-BK channel signaling have opposite effects on blood pressure, with α1AR-TRPV4SMC signaling dominating under resting conditions. Furthermore, in patients with hypertension and a mouse model of hypertension, constrictor α1AR-PKCα-TRPV4 signaling was upregulated, whereas dilator pressure-TRPV4-BK channel signaling was disrupted, thereby increasing vasoconstriction and elevating blood pressure. Our data identify novel smooth muscle Ca2+-signaling nanodomains that regulate blood pressure and demonstrate their impairment in hypertension.

Craniofacial reconstructions in children with craniosynostosis

Craniosynostosis is a rare congenital disease of the skull. They arise when one or more cranial sutures ossify prematurely. This causes an obstruction to normal brain growth and leads to specific deformations of the skull, which may result in intracranial hypertension and cognitive delay. We have retrospectively analysed all children treated at the Unit of paediatric neurosurgery of the University Medical Centre Ljubljana between June 2015 and September 2020. The following items have been recorded: affected suture, underlying syndromic condition, hydrocephalus, Chiari malformation, raised intracranial pressure, age at surgery, surgical technique, need for multiple operations and surgical complications. During the study period, 71 children have been treated for craniosynostosis. The median postoperative follow-up was 31 months. There were: 54.9% sagittal, 25.3% metopic, 14.0% unicoronal, 1.4% bicoronal and 1.4% unilateral lambdoid craniosynostosis. Multiple sutures were affected in 2.8% cases. 7.0% of the cases were syndromic. Overall, 74 surgical procedures have been performed: frontoorbital advancement represented 40.5% of them; biparietal remodelling 32.4%: total cranial vault remodelling 22.9%; posterior distraction 2.7%; posterior expansion 1.3%. Median age at surgery was 12.8 months. The treatment of craniosynostosis is surgical and requires a multidisciplinary approach, with expertise in plastic and reconstructive surgery, maxillofacial surgery and neurosurgery. The aim of surgical treatment is to release the constrictive and deformative effect that the synostosis has on skull growth. This requires a remodelling of the neurocranium and, if necessary, of the viscerocranium. Beyond aesthetic purposes, the primary aim of surgical treatment is to permit a normal development of the brain.

Computed tomographic assessment of principal bronchial anatomy in dogs of various thoracic conformations: 93 cases (2012-2017).

To better understand spatial relationships between principal bronchi and other intrathoracic structures by use of CT images of dogs of various somatotypes. 93 dogs that underwent thoracic CT. Information was collected from medical records regarding signalment and physical examination and echocardiographic findings. Two investigators recorded multiple measurements on a thoracic axial CT image from each dog. Thoracic height-to-width ratio (H:W) was associated with left principal bronchus (LPB) and right principal bronchus (RPB) H:W, aortic-LPB separation, focal LPB narrowing, and aortic-vertebral overlap. Thoracic H:W was not associated with dog age, weight, sex, or brachycephalic breed. Twenty-five (27%) dogs had focal LPB narrowing, compared with 5 (5%) dogs with focal RPB narrowing (P < 0.001). Ten of 25 dogs had overlap or contact between vertebrae, aorta, LPB, and heart, suggesting a cumulative compressive effect on the LPB, while 15 had LPB-aorta contact and lack of contact between the aorta and thoracic vertebrae, suggesting an aortic constrictive effect on the LPB. None had LPB narrowing without contact from surrounding structures. Inter-rater agreement was high. In dogs that underwent CT and were not selected for clinical suspicion of bronchial disease, principal bronchial morphology was associated with thoracic conformation. Focal LPB narrowing occurred more often than RPB narrowing. Focal LPB narrowing occurred with evidence of extraluminal compression, with or without contact between aorta and vertebrae. Brachycephalic breed could not be used for predicting thoracic H:W.

Luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, reverses cerebrovascular dysfunction and cognitive impairments in 18-mo-old diabetic animals.

Diabetes mellitus (DM) is a leading risk factor for age-related dementia, but the mechanisms involved are not well understood. We previously discovered that hyperglycemia induced impaired myogenic response (MR) and cerebral blood flow (CBF) autoregulation in 18-mo-old DM rats associated with blood-brain barrier (BBB) leakage, impaired neurovascular coupling, and cognitive impairment. In the present study, we examined whether reducing plasma glucose with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) luseogliflozin can ameliorate cerebral vascular and cognitive function in diabetic rats. Plasma glucose and HbA1c levels of 18-mo-old DM rats were reduced, and blood pressure was not altered after treatment with luseogliflozin. SGLT2i treatment restored the impaired MR of middle cerebral arteries (MCAs) and parenchymal arterioles and surface and deep cortical CBF autoregulation in DM rats. Luseogliflozin treatment also rescued neurovascular uncoupling, reduced BBB leakage and cognitive deficits in DM rats. However, SGLT2i did not have direct constrictive effects on vascular smooth muscle cells and MCAs isolated from normal rats, although it decreased reactive oxygen species production in cerebral vessels of DM rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage.NEW & NOTEWORTHY This study demonstrates that luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, improved CBF autoregulation in association with reduced vascular oxidative stress and AGEs production in the cerebrovasculature of 18-mo-old DM rats. SGLT2i also prevented BBB leakage, impaired functional hyperemia, neurodegeneration, and cognitive impairment seen in DM rats. Luseogliflozin did not have direct constrictive effects on VSMCs and MCAs isolated from normal rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage.

The social psychological dynamics of transgender and gender nonconforming identity formation, negotiation, and affirmation

This study contributes to trans identity affirmation research by exploring transgender and gender nonconforming (GNC) identity formation, negotiation, and affirmation involving self-verification (recognition by others of one’s gender identity and presentation) and validation (accordant treatment by others) in interpersonal relationships and social interactions. Classic symbolic interactionism and social identity theory, with a focus on the self-verification and identity negotiation processes that lie therein, provide the bases for viewing gender-expansive identity within social and interpersonal negotiations. Eighteen interviews were conducted with transgender and GNC participants. Using a grounded theory approach, four key themes emerged: the importance of personal agency in achieving internal and external identity accord, the value of revealing gender histories in interpersonal relationships, the recognition of extant hurdles in navigating intersectional identities, and the constrictive effects of cisgender privilege and binaried views of gender on the gender-expansive individual. In the discussion we address strategies to enhance gender negotiations, and suggest modifications to current views of gender roles and relationships that recognize the value of transgender and GNC individuals as enablers of change within and between gender groups.

Effects of Alpha‐adrenergic Receptors Blockade on Cardiovascular Responses to Acute Exercise and Isolated Metaboreflex in Postmenopausal Women

Postmenopausal women (PMW) have higher cardiovascular risk when compared to younger women (YM). Nevertheless, acute response to exercise may characterize an additional risk to PMW. One possible mechanism for an increased cardiovascular risk could be the constrictor effect of the alpha-adrenergic receptors (α-AR). Thus, we aimed to test the hypothesis that the contribution of the α-AR in the cardiovascular responses to exercise is greater in PMW when compared to YW. We measured heart rate (HR), mean arterial pressure (MAP), cardiac output (CO), and total vascular resistance (TVR) in 7 YW (24±5 years;24±2kg∙m-2) and 7 PMW (59±4 years;25±3kg∙m-2), during three-minutes bouts of rest, hand grip exercise, isolated metaboreflex and recovery, respectively, in a control session and after α-AR blockade by oral administration of prazosin. HR increased during exercise in both groups but was blunted in PMW (YW: Δ28±15bpm; PMW: Δ15±7bpm; p<0.05). The α-AR blockade increased HR throughout the protocol (p<0.01), and the response to exercise was similar to the control condition (YW: Δ34±14bpm; PMW: Δ13±9bpm; p<0.05). During metaboreflex activation, HR was similar to resting values in both groups, in the control session (YW: Δ4±5bpm; PMW: Δ2±2bpm; p=0.11) and after the α-AR blockade (YW: Δ7±7bpm; PMW: Δ0±4bpm; p<0.05). MAP increased during exercise in both groups (YW: Δ33±10mmHg; PMW: Δ35±12mmHg; p=0.65). The α-AR blockade decreased MAP throughout the protocol (p<0.05) and the response to exercise was similar to the control session (YW: Δ22±16mmHg; PMW: Δ28±12mmHg; p=0.65). The metaboreflex activation kept the MAP elevated in both groups, in the control session (YW: Δ24±10mmHg; PMW: Δ26±7mmHg; p=0.65), while after the blockade, the increase was blunted when compared to the control session (YW: Δ6±20mmHg; PMW: Δ19±13mmHg; p=0.65). Exercise increased CO only in YW (YW: Δ2.3±1.6 l∙min-1; PMW: Δ0.9±1.4 l∙min-1; p<0.05). The α-AR blockade did not change CO throughout the protocol (p=0.21), with the response to exercise similar to the control condition (YW: Δ2.8±1.0 l∙min-1; PMW: Δ1.0±1.3 l∙min-1; p<0.05). During metaboreflex activation, CO increased only in PMW in the control session (YW: Δ1.1±0.8 l∙min-1; PMW: Δ0.4±0.6 l∙min-1; p<0.05), and after the α-AR blockade (YW: Δ0.4±2.6 l∙min-1; PMW: Δ-0.3±1.7 l∙min-1; p<0.05). Exercise increased TVR only in PMW (YW: Δ0±5mmHg∙l∙min-1; PMW: Δ4±4mmHg∙l∙min-1; p <0.05). The α-AR blockade decreased TVR throughout the protocol (p<0.05), but the response to exercise was similar to the control condition (YW: Δ-2±1mmHg∙l∙min-1; PMW: Δ3±3mmHg∙l∙min-1; p<0.05). The metaboreflex activation increased TVR only in PMW, in the control session, (YW: Δ1±3mmHg∙l∙min-1; PMW: Δ5±3mmHg∙l∙min-1; p<0.05), and after the α-AR blockade (YW: Δ-3±5mmHg∙l∙min-1; PMW: 1±8mmHg∙l∙min-1; p<0.05). We observed that PMW presents a peripheral vasoconstrictor response to exercise and metaboreflex activation when compared to YW, which seemed not to be driven by the α-AR vasoconstriction. Additionally, the adjustments in blood pressure were due to CO in YW and relied on TVR in PMW.

Влияние ФНО-α, ИЛ-2, ИЛ-5, ИЛ-6 на сокращения мышц трахеи и бронхов крысы

The article discusses the role of TNF-α, IL-2, IL-5, IL-6 in the contractile activity of the smooth muscles of the trachea and bronchi of rats. The studies were carried out on isolated preparations using electrical stimulation of postganglionic nerves (frequency - 30 stim / s, duration - 0.5 ms, amplitude - 20 V, duration of stimulation - 10 s). Two groups of animals were formed: a control group (received an intraperitoneal injection of saline) and an experimental group sensitized with ovalbumin (received an intraperitoneal injection of ovalbumin with its repeated administration after 14 days). Further, the assessment of the contraction of the muscles of the trachea and bronchi after repeated administration of ovalbumin and after perfusion with interleukin solutions was carried out. As a result of the study, it was found that TNF-α, IL-2, IL-5, IL-6 lead to a pronounced increase in the contractile responses of the smooth muscle of the trachea and bronchi both in the control group of animals and in the group of animals sensitized with ovalbumin. The greatest constrictor effect on muscle among the studied cytokines belongs to TNF-α and IL-6.

Role of ATP and Cl&lt;sup&gt;–&lt;/sup&gt; transporters in regulation of contractile activity of pulmonary artery smooth muscles in hyposmotic conditions

Objective . The role of Cl – -transport in ATP-dependent regulation of contractile activity of rat pulmonary artery (PA) smooth muscle cells was studied. Design and methods . The study was performed on endotheliumdenuded ring segments of the PA of male Wistar rats. Mechanical tension was measured using organ bath technique. Contractions of the PA segments were induced by high-potassium solution (30 mM KCl), hyposmotic solution (40 mM NaCl), as well as restoration of the medium osmolarity (120 mM NaCl) after incubation in hyposmotic solution. Inhibitor of Na + , K + , 2Cl – cotransport (NKCC) bumetanide (10 μM, 30 minutes preincubation), nonselective Cl – -channel blocker SITS (100 μM) and Ca2 + -activated Cl – channels blocker niflumic acid (NA, 10 μM) were used to modulate the Cl – -transport. Results . ATP (10–500 μM) did not affect vascular tone of PA segments incubated in Krebs solution (120 mM NaCl), while 500 and 1000 μM ATP led to the development of transient contractions, the amplitude of which decreased in the presence of bumetanide, SITS and NA. Incubation of PA segments in a hyposmotic medium (40 mM NaCl) caused the development of transient contraction. Subsequent recovery of the medium osmolarity (120 mM NaCl) induced another transient contraction — isosmotic striction. ATP (500 μM) eliminated the relaxation phase of hyposmotic striction, and completely suppressed the development of isosmotic striction. Bumetanide did not affect the action of ATP during isosmotic striction, but restored the relaxation phase of hyposmotic striction. SITS and NA eliminated the effect of ATP on hypo- and isosmotic striction. Conclusions . The constrictive effect of ATP on the smooth muscle cells of the PA is associated with the activation of mechanisms of transmembrane Cl – -redistribution, in which NKCC and Ca2 + -activated Cl – channels are involved.

B-mode and Doppler Ultrasonographic Assessment of Uterine Involution in Ewes Treated with Two Different Doses of ProstaglandinF2α

Background: Several studies consisted of postmortem evaluations and B-mode ultrasonography have been performed on ovine uterine involution. However, researches with Doppler ultrasonography are very limited in ewes. Doppler ultrasonography is a non-invasive method which provides information about vascular dynamics of the tissues which cannot be examined by B-mode ultrasonography. The aim of the study was to evaluate the effects of two different PGF2α doses on uterine measurements by real time B-mode ultrasonography; and on uterine artery hemodynamics by pulsed-wave Doppler analysis during postpartum uterine involution in ewes.Materials, Methods &amp; Results: The study was conducted with 30 primiparous Kiwircik ewes which lambed singleton without any complication. The ewes were randomly divided into three groups (n= 10 for each group). A single i.m. injection of 125 μg/sheep PGF2α, 75 μg/sheep PGF2α, and 1.0 mL/sheep sterile saline solution were administered to Group 1, 2, and 3, respectively. The day of parturition was considered as the first day of the study. Examinations were performed on days 1, 2, 3, 7, 14, 21 and 28. Diameters of previously gravid horn and caruncles were measured by real time B-mod ultrasonography. Presence of lochia was also noted. Uterine artery pulsatility index (PI), resistance index (RI), systolic/diastolic ratio (S/D) values were measured by pulsed-wave Doppler ultrasonography. The one-way analysis of variance and Duncan’s test were used for statistical analysis. The mean previously gravid horn diameters of ewes were 8.30 ± 0.16 cm and 1.53 ± 0.07 cm on day 1 and day 28, respectively. Previously gravid horn and caruncle diameters had a similar declining pattern in all groups as involution period proceeded. Involution was mostly completed by day 21. More than 50% reduction in uterine size was achieved in prostaglandin administered groups by day 7. Caruncles were not able to be identified after the second week postpartum. Lochia was observed for a longer period in control group. Uterine artery PI and RI showed fluctuations throughout involution period with a similar pattern among groups. S/D values progressively increased until day 14, then showed a decreasing pattern.Discussion: The effects of different PGF2α doses on uterine measurements and uterine artery hemodynamics during postpartum period were compared in ewes for the first time. The uterine size reduction in prostaglandin administered groups suggested that both PGF2α doses were effective in uterine involution. The last observation of lochia in uterine cavity were achieved by day 7 in prostaglandin administered groups, suggesting both PGF2α doses trigger uterine contractions which lead to the removal of uterine content. Automatic measurements by Doppler device were taken in order to provide uniformity and to prevent operator-based bias. The significantly higher uterine artery PI value found in Group 1 on day 1 might suggest the stimulatory effect of PGF2α administration on uterine contractility synergitically with already released endogenous PGF2α. Uterine artery PI and RI showed fluctuations throughout involution period and reached their peak values on day 14. The increasing S/D values up to day 14 indicated increasing diastolic flow, increasing resistance and decreasing blood perfusion in prostaglandin administered groups. Prostaglandin administered groups tended to show higher hemodynamic parameters throughout the study which suggested a vasoconstrictor effect of PGF2α. In conclusion, PGF2α administration on the day of parturition might have constrictor effects both on uterine artery and myometrium which leads to a reduction in uterine blood flow and a rapid decline in uterine size especially during early puerperium even with a reduced dose.

Saphenous Vein Vasa Vasorum as a Potential Target for Perivascular Fat-Derived Factors.

Perivascular adipose tissue (PVAT) is a source of factors affecting vasomotor tone with the potential to play a role in the performance of saphenous vein (SV) bypass grafts. As these factors have been described as having constrictor or relaxant effects, they may be considered either beneficial or detrimental. The close proximity of PVAT to the adventitia provides an environment whereby adipose tissue-derived factors may affect the vasa vasorum, a microvascular network providing the vessel wall with oxygen and nutrients. Since medial ischaemia promotes aspects of graft occlusion the involvement of the PVAT/vasa vasorum axis in vein graft patency should be considered.

Role of Carbon Monoxide in the Mechanisms of Action of Extracellular ATP on Contractile Activity of Vascular Smooth Muscle Cells.

We studied the role of carbon monoxide (CO) in the effect of P2X and P2Y receptor agonist ATP on the tone of rat aorta segments with intact endothelium. ATP (1-1000 μM) and P2X receptor agonist α,β-MeATP (100 μM) relaxed segments precontracted with phenylephrine (10 μM), while UTP (100-1000 μM) increased the amplitude of phenylephrine-induced contraction. The relaxing effect of ATP was enhanced by CORM II (100 μM), NO synthase inhibitor L-NAME, and guanylate cyclase inhibitor ODQ and attenuated by ZnPP IX (100 μM). The constrictive effect of UTP was weakened by CORM II (100 μM), but was not changed by ZnPP IX (100 μM). ZnPP IX (100 μM) weakened the relaxation response to α,β-MeATP. Thus, ATP involves the CO-dependent signaling cascade through P2X receptors.

Evaluating the effectiveness of multimodal low – opioid anesthesia during cardiac surgery with cardiopulmonary bypass

The work is devoted to research of the effectiveness of the application of low-opioid anesthesia during cardiac surgery with cardiopulmonary bypass. The examinations included 32 patients who, on the basis of the State Institution “Heart Institute of the Ministry of Health of Ukraine”, underwent coronary artery bypass surgery (CABG) under conditions of artificial blood circulation (CI) using the multimodal low-anesthetic technique. The average age of the patients was 69,5 ± 6,2 years, the average weight - 89,6 ± 13,9 kg. As a result of the research, it was determined that the multimodal low-opioid method of anesthesia is effective and provides an adequate analgesic effect, it allows refusing the intraoperative usage of routine doses of fentanyl in the performance of highly traumatic operations, as indicated by the absence of hemodynamic and endocrine-metabolic changes. This technique did not affect the dynamics of cardiospecific enzymes, nor was there any negative dynamics on the ECG, which indicated the absence of a coronary – constrictor effect of this method of anesthesia.

Increase in the constrictor effects of Rho-kinase in skeletal muscle and coronary arteries of rats with chronic hypothyroidism

Aim. The deficit of thyroid function is known to be accompanied by an increase in the overall peripheral vascular resistance. This work tested the hypothesis that long-term hypothyroidism leads to an increase in the vasoconstrictor effect of Rho-kinase in skeletal muscle and heart resistance arteries of adult rats.Materials and methods.Male Wistar rats consumed the antithyroid drug propylthiouracil (PTU) in drinking water (0.025%), starting at 10 weeks of age. The rats of the control group received PTU-free water. After 14 weeks, the contractile responses of the gastrocnemius muscle arteries (to the α1-adrenoceptor agonist methoxamine) and the septal coronary artery (to the thromboxane A2 receptor agonist U46619) were isometrically recorded. The contribution of the Rho-kinase to the arterial contractile responses was assessed using inhibitor Y27632 (3 μM).Results.The consumption of propylthiouracil was accompanied by a marked decrease of thyroid hormone concentrations and an increase in total cholesterol serum level as well as a decrease in body weight. Maximal contractile responses of studied arteries were also reduced in hypothyroid rats. However, basal tone and reactivity to the moderate concentrations of agonists in arteries of hypothyroid rats were increased compared to control animals. Y27632 significantly weakened the contractile responses of the arteries and negated the differences between the two groups of rats.Conclusion.Chronic hypothyroidism leads to an increase in the activity of the Rho-kinase signaling pathway in the arteries of the gastrocnemius muscle and heart, which results in the increase of the spontaneous tone of the arteries and their reactivity to agonists.

Are complicated monochorionic twins more susceptible to indomethacin-induced fetal ductal constriction? Two cases of laser surgery for Twin-Twin Transfusion syndrome

Indomethacin is a commonly used medication against preterm delivery. Several reports of fetal ductal constriction have been described after indomethacin use in the literature; however, there are no previously documented reports describing an association between Twin-Twin Transfusion syndrome and a constrictor effect of indomethacin on the ductus arteriosus. Two patients were referred to our department for Twin-Twin Transfusion syndrome and each underwent placental laser surgery. Constriction of the ductus arteriosus occurred as early as 20 and 24 weeks’ gestation following maternal use of indomethacin after laser surgery. Spontaneous amelioration was observed after discontinuation of the drug. The constrictor effect of indomethacin on the ductus arteriosus can be observed even after a single dose and as early as 20 weeks of gestation in complicated monochorionic twin pregnancies. We emphasize meticulous use of indomethacin in complicated monochorionic twin pregnancies because the constrictive effect seems to be independent of gestational age.

Systemic microvascular dysfunction in microvascular and vasospastic angina.

AimsCoronary microvascular dysfunction and/or vasospasm are potential causes of ischaemia in patients with no obstructive coronary artery disease (INOCA). We tested the hypothesis that these patients also have functional abnormalities in peripheral small arteries.Methods and resultsPatients were prospectively enrolled and categorised as having microvascular angina (MVA), vasospastic angina (VSA) or normal control based on invasive coronary artery function tests incorporating probes of endothelial and endothelial-independent function (acetylcholine and adenosine). Gluteal biopsies of subcutaneous fat were performed in 81 subjects (62 years, 69% female, 59 MVA, 11 VSA, and 11 controls). Resistance arteries were dissected enabling study using wire myography. Maximum relaxation to ACh (endothelial function) was reduced in MVA vs. controls [median 77.6 vs. 98.7%; 95% confidence interval (CI) of difference 2.3–38%; P = 0.0047]. Endothelium-independent relaxation [sodium nitroprusside (SNP)] was similar between all groups. The maximum contractile response to endothelin-1 (ET-1) was greater in MVA (median 121%) vs. controls (100%; 95% CI of median difference 4.7–45%, P = 0.015). Response to the thromboxane agonist, U46619, was also greater in MVA (143%) vs. controls (109%; 95% CI of difference 13–57%, P = 0.003). Patients with VSA had similar abnormal patterns of peripheral vascular reactivity including reduced maximum relaxation to ACh (median 79.0% vs. 98.7%; P = 0.03) and increased response to constrictor agonists including ET-1 (median 125% vs. 100%; P = 0.02). In all groups, resistance arteries were ≈50-fold more sensitive to the constrictor effects of ET-1 compared with U46619.ConclusionsSystemic microvascular abnormalities are common in patients with MVA and VSA. These mechanisms may involve ET-1 and were characterized by endothelial dysfunction and enhanced vasoconstriction.Clinical trial registrationClinicalTrials.gov registration is NCT03193294.

Effects of standardized extracts of Lamium album and Urtica dioica on rat tracheal smooth muscle contraction.

ObjectiveDiseases of the respiratory system are one of the main causes of death and include situation such as chronic obstructive pulmonary disease, pneumonia or asthma. Medicinal plants have beneficial effects on multiple diseases include respiratory disorders like asthma and bronchitis. The aim of this study was to evaluate the effects of U. dioica and L. Album on tracheal smooth muscle contraction.Material and methodsHydroalcoholic extracts of L. Album and U. Dioica aerial parts were prepared by maceration method and standardized based on their total phenol content. The effect of the extracts on the KCl-induced contraction of rat trachea was examined in an organ bath chamber. Data was analyzed with spss software 22.ResultsThe extract of L. Album (5 mg/ml), similar to theophylline (20 mM), significantly reduced the KCl-induced tracheal contraction. On the other hand, U. Dioica (1 mg/ml and 5 mg/ml) augmented the KCl-induced contraction.ConclusionThe relaxant effect of L. Album on the trachea makes it as a candidate for the managing patients with asthma and obstructive pulmonary diseases. But because of U. Dioica potential constrictive effect on the trachea it is suggested that patients avoid consuming it.

Dilatation of the ductus arteriosus by diazoxide in fetal and neonatal rats.

Diazoxide, an ATP-sensitive potassium channel opener, is the main therapeutic agent for treating hyperinsulinemic hypoglycemia. The aim of this study was to determine the invivo ductus arteriosus (DA)-dilating effects of diazoxide in fetal and neonatal rats. Near-term rat pups delivered via cesarean section were housed at 33°C. After rapid whole-body freezing, the ductus arteriosus (DA) diameter was measured using a microscope and a micrometer. Full-term pregnant rats (gestational day 21) were injected i.p. with diazoxide (10 and 100mg/kg) 4h before delivery,and the neonatal DA diameter was measured at 0, 30, or 60min after birth. The newborn rats were also injected i.p. with diazoxide (10 and 100mg/kg) at birth or 60min after birth. DA was measured at 0, 30, or 60min after injection. In the fetal investigation, the effect of diazoxide was studied via simultaneous application of indomethacin (10mg/kg) and L-nitroarginine methyl ester (L-NAME) on gestational days 21 and 19. The control rats had rapid postnatal DA constriction (diameter, 0.80 and 0.08mm at 0 and 60min after birth, respectively). Diazoxide had a dose-dependent inhibitory effect on postnatal DA constriction. Prenatal diazoxide (10mg/kg) inhibited postnatal DA closure (0.20mm at 60min after birth). The diazoxide injection (10mg) at birth inhibited postnatal DA closure (0.14mm at 60min after birth). Diazoxide injection in 60-min-old rats dilated the constricted DA at 60min (0.10mm vs. 0.02mm in the controls). In the fetal investigation, diazoxide inhibited the fetal DA constrictive effect of indomethacin and L-NAME. Diazoxide attenuates postnatal DA constriction and dilates a closing DA in fetal and neonatal rats.

Probenecid Inhibits α-Adrenergic Receptor-Mediated Vasoconstriction in the Human Leg Vasculature.

Coordination of vascular smooth muscle cell tone in resistance arteries plays an essential role in the regulation of peripheral resistance and overall blood pressure. Recent observations in animals have provided evidence for a coupling between adrenoceptors and Panx1 (pannexin-1) channels in the regulation of sympathetic nervous control of peripheral vascular resistance and blood pressure; however, evidence for a functional coupling in humans is lacking. We determined Panx1 expression and effects of treatment with the pharmacological Panx1 channel inhibitor probenecid on the vasoconstrictor response to α1- and α2-adrenergic receptor stimulation in the human forearm and leg vasculature of young healthy male subjects (23±3 years). By use of immunolabeling and confocal microscopy, Panx1 channels were found to be expressed in vascular smooth muscle cells of arterioles in human leg skeletal muscle. Probenecid treatment increased (P<0.05) leg vascular conductance at baseline by ≈15% and attenuated (P<0.05) the leg vasoconstrictor response to arterial infusion of tyramine (α1- and α2-adrenergic receptor stimulation) by ≈15%, whereas the response to the α1-agonist phenylephrine was unchanged. Inhibition of α1-adrenoceptors prevented the probenecid-induced increase in baseline leg vascular conductance, but did not alter the effect of probenecid on the vascular response to tyramine. No differences with probenecid treatment were detected in the forearm. These observations provide the first line of evidence in humans for a functional role of Panx1 channels in setting resting tone via α1-adrenoceptors and in the constrictive effect of noradrenaline via α2-adrenoceptors, thereby contributing to the regulation of peripheral vascular resistance and blood pressure in humans.