Features of microcirculation in psoriatic arthritis

The literature review presents data on features of microcirculation in patients with psoriatic arthritis (PsA). The immune inflammation underlying PsA leads to increased permeability of the vascular wall, deposition of the immune complexes in it, a decreased capillary blood flow, and vascular sensitivity to sympathetic stimulation. In combination with impaired blood rheology during inflammation, these changes have a significant effect on the state of the microvasculature. Increased vascular permeability and a damaged connection between the endothelium and the extracellular matrix in PsA cause the formation of the capillaries with a pathological structure. Microscopic examination of the synovial membrane of patients with PsA shows vascular tortuosity, branching, and elongation. The duration, activity of articular inflammation, as well as severity of psoriasis are associated with the degree of microcirculatory disorders in PsA. The pathomorphological changes in the vessels of patients with PsA are detected not only in the articular tissues but also in the skin, which indicates dysregulation of angiogenesis in general. The mechanisms of the formation of new vessels with a pathological structure are not fully understood. However, most likely, an imbalance of the factors of angiogenesis and antiangiogenesis plays an important role. There is growing evidence that vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-beta) and platelet growth factor (PDGF) are involved in the pathogenesis of PsA. At the moment, the issue of early diagnosis of PsA remains relevant, especially in cases with minor skin changes and rheumatoid-like joint lesions. Information on microcirculation obtained by capillaroscopy, video capillaroscopy, and fluorescence microscopy provides additional opportunities for a differential diagnosis of PsA, a determination of activity, and a prognosis of the disease.

The Impact of Acute Central Hypovolemia on Cerebral Hemodynamics: Does Sex Matter?

Trauma-induced hemorrhage is a leading cause of disability and death due, in part, to impaired perfusion and oxygenation of the brain. It is unknown if cerebrovascular responses to blood loss are differentiated based on sex. We hypothesized that compared to males, females would have reduced tolerance to simulated hemorrhage induced by maximal lower body negative pressure (LBNP), and this would be associated with an earlier reduction in cerebral blood flow and cerebral oxygenation. Methods: Healthy young males (n=29, 26±4 y) and females (n=23, 27±5 y) completed a step-wise LBNP protocol to presyncope. Mean arterial pressure (MAP), stroke volume (SV), middle cerebral artery velocity (MCAv), end-tidal CO2 (etCO2), and cerebral oxygen saturation (ScO2) were measured continuously. Results: Unexpectedly, tolerance to LBNP was similar between the sexes (males, 1604±68 s vs. females, 1453±78 s; P=0.15). Accordingly, decreases (%Δ) in MAP, SV, MCAv, and ScO2 were similar between males and females throughout LBNP and at presyncope (P≥0.20). Interestingly, while decreases in etCO2 were similar between the sexes throughout LBNP (P=0.16), at presyncope, the %Δ etCO2 from baseline was greater in males compared to females (-30.8±2.6% vs. -21.3±3.0%; P=0.02). Conclusion: Contrary to our hypothesis, sex does not influence tolerance, or the central or cerebral hemodynamic responses to simulated hemorrhage. However, the etCO2 responses at presyncope do suggest potential sex differences in cerebral vascular sensitivity to CO2 during central hypovolemia.

Vasoactive Effects of Acute Ergot Exposure in Sheep

Ergotism is a common and increasing problem in Saskatchewan’s livestock. Chronic exposure to low concentrations of ergot alkaloids is known to cause severe arterial vasoconstriction and gangrene through the activation of adrenergic and serotonergic receptors on vascular smooth muscles. The acute vascular effects of a single oral dose with high-level exposure to ergot alkaloids remain unknown and are examined in this study. This study had two main objectives; the first was to evaluate the role of α1-adrenergic receptors in mediating the acute vasocontractile response after single-dose exposure in sheep. The second was to examine whether terazosin (TE) could abolish the vascular contractile effects of ergot alkaloids. Twelve adult female sheep were randomly placed into control and exposure groups (n = 6/group). Ergot sclerotia were collected and finely ground. The concentrations of six ergot alkaloids (ergocornine, ergocristine, ergocryptine, ergometrine, ergosine, and ergotamine) were determined using HPLC/MS at Prairie Diagnostic Services Inc., (Saskatoon, SK, Canada). Each ewe within the treatment group received a single oral treatment of ground ergot sclerotia at a dose of 600 µg/kg BW (total ergot) while each ewe in the control group received water. Animals were euthanized 12 h after the treatment, and the pedal artery (dorsal metatarsal III artery) from the left hind limb from each animal was carefully dissected and mounted in an isolated tissue bath. The vascular contractile response to phenylephrine (PE) (α1-adrenergic agonist) was compared between the two groups before and after TE (α1-adrenergic antagonist) treatment. Acute exposure to ergot alkaloids resulted in a 38% increase in vascular sensitivity to PE compared to control (Ctl EC50 = 1.74 × 10−6 M; Exp EC50 = 1.079 × 10−6 M, p = 0.046). TE treatment resulted in a significant dose-dependent increase in EC50 in both exposure and control groups (p < 0.05 for all treatments). Surprisingly, TE effect was significantly more pronounced in the ergot exposed group compared to the control group at two of the three concentrations of TE (TE 30 nM, p = 0.36; TE 100 nM, p < 0.001; TE 300 nM, p < 0.001). Similar to chronic exposure, acute exposure to ergot alkaloids results in increased vascular sensitivity to PE. TE is a more potent dose-dependent antagonist for the PE contractile response in sheep exposed to ergot compared to the control group. This study may indicate that the dry gangrene seen in sheep, and likely other species, might be related to the activation of α1-adrenergic receptor. This effect may be reversed using TE, especially at early stages of the disease before cell death occurs. This study may also indicate that acute-single dose exposure scenario may be useful in the study of vascular effects of ergot alkaloids.

Ethyl Rosmarinate Prevents the Impairment of Vascular Function and Morphological Changes in L-NAME-Induced Hypertensive Rats

Background and Objectives: The potent, endothelium-independent, vasorelaxant effect of ethyl rosmarinate, an ester derivative of rosmarinic acid, makes it of interest as an alternative therapeutic agent for use in hypertension. This study was designed to investigate the effect of ethyl rosmarinate on Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. Materials and Methods: L-NAME was given orally to male Wistar rats for 6 weeks to induce hypertension concurrently with treatment of ethyl rosmarinate at 5, 15, or 30 mg/kgor enalapril at 10 mg/kg Systolic blood pressure (SBP), heart rate, and body weight of all experimental groups were recorded weekly, while the vascular sensitivity and histological changes of the aorta were evaluated at the end of the experiment. Results: For all treatment groups, the data indicated that ethyl rosmarinate significantly attenuated the SBP in hypertensive rats induced by L-NAME, with no significant differences in heart rate and body weight. In addition, the response of vascular sensitivity to acetylcholine (ACh) was improved but there was no significant difference in the response to sodium nitroprusside (SNP). Furthermore, the sensitivity of the aorta to phenylephrine (PE) was significantly decreased. The thickness of the aortic wall did not differ between groups but the expression of endothelial nitric oxide synthase (eNOS) was increased in ethyl rosmarinate- and enalapril-treated groups compared with the hypertensive group. Conclusions: Ethyl rosmarinate is an interesting candidate as an alternative treatment for hypertension due to its ability to improve vascular function and to increase the expression of eNOS similar to enalapril which is a drug commonly used in hypertension.

Attenuation of human hypoxic pulmonary vasoconstriction by acetazolamide and methazolamide

Acetazolamide (AZ), a carbonic anhydrase inhibitor used for preventing altitude illness attenuates hypoxic pulmonary vasoconstriction (HPV) while improving oxygenation. Methazolamide (MZ), an analog of acetazolamide, is more lipophilic, has a longer half-life, and activates a major antioxidant transcription factor. However, its influence on the hypoxic pulmonary response in humans is unknown. The aim of this study was to determine whether a clinically relevant dosing of MZ improves oxygenation, attenuates HPV, and augments plasma antioxidant capacity in men exposed to hypoxia compared with an established dosing of AZ known to suppress HPV. In this double-blind, placebo-controlled crossover trial, 11 participants were randomized to treatments with MZ (100 mg 2× daily) and AZ (250 mg 3× daily) for 2 days before 60 min of hypoxia (FIO2 ≈0.12). Pulmonary artery systolic pressure (PASP), alveolar ventilation (V̇A), blood gases, and markers of redox status were measured. Pulmonary vascular sensitivity to hypoxia was determined by indexing PASP to alveolar PO2. AZ caused greater metabolic acidosis than MZ, but the augmented V̇A and improved oxygenation with hypoxia were similar. The rise in PASP with hypoxia was lower with MZ (9.0 ± 0.9 mmHg) and AZ (8.0 ± 0.7 mmHg) vs. placebo (14.1 ± 1.3 mmHg, P < 0.05). Pulmonary vascular sensitivity to hypoxia (ΔPASP/ΔPAO2) was reduced equally by both drugs. Only AZ improved the nonenzymatic plasma antioxidant capacity. Although AZ had only plasma antioxidant properties, MZ led to similar improvements in oxygenation and reduction in HPV at a dose causing less metabolic acidosis than AZ in humans. NEW & NOTEWORTHY Both acetazolamide and methazolamide are effective in the prevention of acute mountain sickness by inducing an increase in ventilation and oxygenation. Acetazolamide attenuates hypoxic pulmonary vasoconstriction; however, it was previously unknown whether methazolamide has the same effect in humans. This study shows that a dosing of methazolamide causing less metabolic acidosis improves oxygenation while attenuating hypoxic pulmonary vasoconstriction and pulmonary vascular sensitivity to hypoxia. Acetazolamide improved plasma antioxidant capacity better than methazolamide.

Changes in gene expression of serotonin 5НТ2А-R and endothelin ETA-R receptors as markers for early aging of rat aorta

Возраст является основным фактором риска развития сердечно-сосудистых заболеваний. Однако механизмы влияния старения на развитие заболеваний до сих пор не понятны. Цель исследования - изучение влияния старения на функциональную активность и экспрессию рецепторов эндогенных вазоконстрикторов в аорте крысы. Методы. Исследования проводили на беспородных крысах-самцах в возрасте 4 и 12 мес. Силу сокращения изолированных фрагментов грудного отдела аорты измеряли в изометрическом режиме по методу Мульвани. Выделение РНК из аорты проводили с помощью набора GeneJET, синтез кДНК - используя набор RevertAid H Minus First Strand cDNA Synthesis Kit («Thermo Fisher Scientific», США), ПЦР-РВ проводили с помощью набора qPCRmix-HS («Евроген», Россия), используя праймеры и флуоресцентные зонды («ДНК-синтез», Россия), согласно протоколам производителей. Результаты. Ранними признаками старения сосудов является их сенситизация к вазоконстрикторному действию серотонина (5НТ), обусловленная гиперэкспрессией гена рецепторов 5HT2A-типа (194% от уровня в сосудах 4-мес. крыс). Чувствительность аорты по отношению к воздействию норадреналина, ангиотензина II, аргининвазопрессина и эндотелина-1 у крыс в возрасте 12 мес. остается такой же, как у молодых животных. Установлено, что в аорте стареющих крыс значительно снижается уровень мРНК эндотелиновых рецепторов ETA-типа (55%). Сохранение чувствительности сосудов к вазоконстрикторному действию ET1 при двукратном снижении экспрессии гена ETA-R косвенно свидетельствует об участии данных рецепторов не только в поддержании тонуса сосудов, но и в реализации других эффектов ET1. Заключение. Таким образом, повышение функциональной активности и экспрессии серотониновых 5HT2A-R, а также гипоэкспрессия эндотелиновых ETA-R являются ранними проявлениями старения аорты крыс и могут рассматриваться как маркеры возрастных изменений сосудов. Age is the major risk factor for cardiovascular disease. However, mechanisms of the effect of aging on the disease development are still unclear. The aim of this study was to investigate the effect of aging on functional activity and expression of endogenous vasoconstrictor receptors in the rat aorta. Methods. The study was performed on mongrel male rats aged 4 and 12 months. Contraction force of fragments isolated from the thoracic aorta i was measured in an isometric mode using the Mulvani method. RNA was isolation from the aorta using the GeneJET kit; cDNA synthesis was measured using the RevertAidTM H Minus First Strand cDNA Synthesis Kit (Thermo Fisher Scientific, USA); PCR-RT was performed using the qPCRmix-HS kit (Evrogen, Russia) with primers and fluorescent probes (DNA synthesis, Russia) according to manufacturer’s protocols. Results. Early signs of vascular aging included blood vessel sensitization to the vasoconstrictor effect of serotonin (5HT) due to overexpression of 5HT2A-type receptors (194% of the level in blood vessels of 4-month old rats). The aorta sensitivity to norepinephrine, angiotensin II, arginine vasopressin, and endothelin-1 in 12-month old rats remained the same as in younger animals. The level of ETA-type endothelin receptor mRNA was significantly reduced in the aorta of aging rats (55%). Preservation of vascular sensitivity to the vasoconstrictor action of ET1 with a twofold decrease in the expression of the ETA-R gene indirectly indicated an involvement of these receptors not only in maintaining the vascular tone but also in mediating other ET1 effects. Conclusion. Therefore, increases in the functional activity and expression of serotonin 5HT2A-R along with the hypoexpression of endothelin ETA-R are early manifestations of rat aorta aging and can be considered as markers for age-related changes in blood vessels.