Aim
During early post‐natal development, arterial contraction depends less on Ca2+‐signalling pathways but more on changes in Ca2+‐sensitivity compared to adult animals. Whether this difference is ...related to Rho‐kinase, one of the major players affecting Ca2+‐sensitivity, is unknown for intact vessels. Thus, we tested the hypothesis that Rho‐kinase critically contributes to the higher Ca2+‐sensitivity of contraction in intact arteries of 1‐week‐old rats.
Methods
We studied 1‐week‐old, 4‐ to 5‐week‐old and 10‐ to 12‐week‐old rats performing isometric myography, Ca2+‐fluorimetry and Western blotting using intact saphenous arteries and arterial pressure measurements under urethane anaesthesia.
Results
In 10‐ to 12‐week‐old rats, methoxamine (MX) produced vasoconstriction associated with an increase in Ca2+i and Ca2+‐sensitivity. In contrast, in 1‐week‐old rats these contractions were accompanied only by an increase in Ca2+‐sensitivity. All MX‐induced effects were reduced by the Rho‐kinase inhibitor Y‐27632; this reduction was complete only in 1‐week‐old rats. The Rho‐kinase specific site Thr855 on MYPT1 was increasingly phosphorylated by MX in vessels of 1‐week‐old, but not 10‐ to 12‐week‐old rats; this effect was also inhibited completely by Y‐27632. The Rho‐kinase inhibitor fasudil in a dose not affecting the pressor response to MX in 4‐ to 5‐week‐old rats reduced it considerably in 1‐week‐old rats.
Conclusion
Our results suggest that the higher Ca2+‐sensitivity of arterial contraction in 1‐week‐old compared to 10‐ to 12‐week‐old rats is due to a greater Rho‐kinase activity. Constitutively active Rho‐kinase contributes to MX‐induced contraction in 10‐ to 12‐week‐old rats. In 1‐week‐old rats, additional Rho‐kinase activation is involved. This remodelling of the Rho‐kinase pathway is associated with its increased contribution to adrenergic arterial pressure responses.
Reactive oxygen species (ROS) have been considered for many years as negative regulators in the cardiovascular system. Indeed, excessive production of ROS characterizes many cardiovascular diseases. ...The damaging effect of ROS can be especially pronounced in a newborn organism, since during this period their vasoconstrictor effect in pulmonary arteries remains as high as in pre-term fetus and the antioxidant systems have not yet formed. Therefore, in the first hours and days of independent life, pulmonary arteries tend to contract, primarily due to the low bioavailability of endothelial NO, which increases the risk of developing pulmonary hypertension in newborns. At the same time, during the perinatal period, ROS play an important role in the adaptive reactions of the circulatory system. ROS provide occlusion of the ductus arteriosus and separation of the pulmonary and systemic circulations soon after birth, and also contribute to the contraction of peripheral vessels during hypoxia, which often accompanies the delivery, and therefore provide priority blood supply to the brain in these conditions. The vasomotor effect of ROS is also pronounced in early postnatal ontogenesis, but it has a different character. In the first weeks of life, the action of ROS serves as one of the mechanisms for increasing endothelium-dependent relaxation of pulmonary vessels. In addition, during early postnatal ontogeny, ROS may play an important role in the regulation of systemic vascular tone. This review outlines the current understanding of the vasomotor role of ROS in the vessels of the pulmonary and systemic circulations and considers the mechanisms of ROS effects on the functioning of vascular endothelial and smooth muscle cells in the perinatal and early postnatal periods.
The activity of many physiological mechanisms depends on pH; therefore, maintaining a normal pH in the body is one of the important tasks of homeostatic regulation. Shifts in the acid–base balance ...can be associated with both pathological and physiological processes. Physiological acidosis in skeletal muscles appears due to physical exercise as muscle contractions may significantly reduce pH in muscle fibers and interstitium. However, after the cessation of contractions, the pH level rapidly normalizes, which is largely ensured by the work of the circulatory system, which removes metabolic products from the muscle. Acidosis causes vasodilatation by affecting the activities of numerous mechanisms in smooth muscle and endothelial cells and by inhibiting vasoconstrictor nerve influence. Vasodilation and increased muscle blood flow are favorable to recovery of the skeletal muscle performance following intense contractions.
During early post-natal development, arterial contraction depends less on Ca
-signalling pathways but more on changes in Ca
-sensitivity compared to adult animals. Whether this difference is related ...to Rho-kinase, one of the major players affecting Ca
-sensitivity, is unknown for intact vessels. Thus, we tested the hypothesis that Rho-kinase critically contributes to the higher Ca
-sensitivity of contraction in intact arteries of 1-week-old rats.
We studied 1-week-old, 4- to 5-week-old and 10- to 12-week-old rats performing isometric myography, Ca
-fluorimetry and Western blotting using intact saphenous arteries and arterial pressure measurements under urethane anaesthesia.
In 10- to 12-week-old rats, methoxamine (MX) produced vasoconstriction associated with an increase in Ca
and Ca
-sensitivity. In contrast, in 1-week-old rats these contractions were accompanied only by an increase in Ca
-sensitivity. All MX-induced effects were reduced by the Rho-kinase inhibitor Y-27632; this reduction was complete only in 1-week-old rats. The Rho-kinase specific site Thr
on MYPT1 was increasingly phosphorylated by MX in vessels of 1-week-old, but not 10- to 12-week-old rats; this effect was also inhibited completely by Y-27632. The Rho-kinase inhibitor fasudil in a dose not affecting the pressor response to MX in 4- to 5-week-old rats reduced it considerably in 1-week-old rats.
Our results suggest that the higher Ca
-sensitivity of arterial contraction in 1-week-old compared to 10- to 12-week-old rats is due to a greater Rho-kinase activity. Constitutively active Rho-kinase contributes to MX-induced contraction in 10- to 12-week-old rats. In 1-week-old rats, additional Rho-kinase activation is involved. This remodelling of the Rho-kinase pathway is associated with its increased contribution to adrenergic arterial pressure responses.
The ratio of low-frequency (LF, ~0.1 Hz) waves of RR interval duration (RRI) and systolic blood pressure (SAP) reflects the cardiac baroreflex sensitivity (BRS). Gravitational unloading (GU) may ...alter BRS during head-up tilt test (HUT) and lower body negative pressure (LBNP) test. Both effects cause blood redistribution to the lower body, but HUT is accompanied by greater unloading of sinocarotid baroreceptors than LBNP and activation of the vestibulosympathetic reflex. However, GU effects on BRS in these tests have not been directly compared previously. In this study we tested the hypothesis that the effect of dry immersion (DI, on-ground model of GU) on BRS in the same subjects will be more pronounced during HUT than during LBNP, while causing a comparable decrease in stroke volume (SV). Nine healthy men participated in two test sessions (before and after 7-day DI) consisting of five 3-min HUT (65°C) and five 3-min LBNP (–35 mmHg) with data averaging in each test. Wavelet analysis was used to determine the amplitude of the RRI and SAP waves in the 0.05–0.13 Hz range. The amplitude of LF waves of SAP increased in both tests, after DI—more significantly in HUT. The amplitude of LF RRI waves decreased in two tests; the percentage decrease did not differ between tests and did not change under the influence of DI. The α-coefficient (the ratio of RRI and SAP LF wave amplitudes) decreased equally in two tests before DI. After DI, more pronounced α-coefficient reduction was observed in HUT test but not in LBNP test. Thus, the effect of DI on BRS is evident in HUT, but not in LBNP, which may be explained by the more pronounced influence of HUT on the mechanisms of neural control of heart rhythm.
We studied the effects of long-term anti-orthostatic hypokinesia (head-down bed rest—BR, a model of gravitational unloading) on the dynamics of orthostasis-induced changes in the content of total ...(THb), deoxygenated (HHb), and oxygenated (OHb) hemoglobin in the calf at the level of the gastrocnemius muscle medial head using near-infrared spectroscopy. In seven young men, 2–4 days before and on the 19th day of BR, a passive head-up tilt test was performed (15 min in the supine position, then 15 min at 65°). After BR, there was an increase in heart rate and a decrease in stroke volume in the supine position, as well as more pronounced changes in these parameters during orthostasis. Blood pressure in the supine position and orthostasis did not change after BR. THb content increased gradually during orthostasis and reached a plateau by the end of the test; after BR, an increase in the half-rise time and a twofold increase in the plateau level were observed. Tissue HHb content by the end of the tilt test also increased after BR. The dynamics of OHb before BR was more complicated: this indicator grew, reached a maximum during a minute, and then gradually decreased to half of the maximum by the end of the test. After BR, the dynamics of OHb changed drastically: the signal increased gradually and reached a level that was twice the peak value of OHb content before BR. The results allow us to conclude that exposure to BR weakens the compensatory constriction of calf vessels during tilt test; consequently, it is followed by higher blood accumulation in calf vascular bed, which, in turn, leads to smaller SV during orthostasis.
Our recent study showed that NO-mediated anticontractile effect of endothelium is absent in coronary arteries of adult rats, which suffered from antenatal/early postnatal hypothyroidism. This study ...tested the hypothesis that exercise training would improve such detrimental consequences of early thyroid deficiency.
Wistar dams received propylthiouracil (PTU, 7 ppm) in drinking water during gestation and two weeks postpartum; control dams received tap water. Six-week-old male offspring of control (CON) and PTU dams was divided into sedentary (CON-Sed, n = 12; PTU-Sed, n = 10) and trained (CON-Tr, n = 12; PTU-Tr, n = 10) groups; the latter had 24-h access to running wheels. Eight weeks later coronary arteries were studied by wire myography. Anticontractile effect of NO was assessed by the effects of NOS inhibitor L-NNA on the basal tone and contractile response to U46619. Oxidative phosphorylation complexes and eNOS were estimated by Western blotting.
T3/T4 and TSH levels (ELISA) were normalized in the progeny of PTU-treated dams at the age of 6 weeks and were not affected by training. Total running distance did not differ between CON-Tr and PTU-Tr. The contents of oxidative phosphorylation complexes were increased post-training in triceps brachii muscle from CON-Tr and PTU-Tr and in heart from PTU-Tr. Coronary arteries of PTU-Sed compared to CON-Sed demonstrated higher basal tone and contractile response to U46619, which were not further increased by L-NNA. The effects of L-NNA on the basal tone and contractile response to U46619 did not differ in CON-Tr and PTU-Tr groups, but were elevated in PTU-Tr compared to PTU-Sed group. PTU-Tr rats in comparison to PTU-Sed group had higher eNOS content in heart. Responses of coronary arteries to DEA/NO did not differ among all experimental groups.
Long-lasting coronary endothelial dysfunction resulted from transient thyroid deficiency during the antenatal/early postnatal period can be corrected by voluntary exercise training.
•Antenatal hypothyroidism weakens NO effects in coronary arteries of adult rats.•Exercise increases OXPHOS and eNOS in myocardium of previously hypothyroid rats.•Exercise improves anticontractile effects of NO in previously hypothyroid rats.
The change in the diameter of small arteries and arterioles is a key mechanism for regulating the resistance of the vascular bed and blood pressure and blood flow in organs and tissues. The tone of ...arterial smooth muscle cells (SMC) depends on the level of membrane potential (MP), which, in turn, is determined by the balance of depolarizing and hyperpolarizing currents. The main hyperpolarizing current of SMC is the outward potassium current. Activation and opening of potassium channels counteract depolarization and inhibit calcium entry into the cell and contraction. Thus, potassium channels play an anticonstrictor role in the arteries. TASK-1 channels, members of the two-pore domain potassium channel family (K
2P
), have relatively recently been described in the vasculature. It is known that TASK-1 channels mediate outward potassium leakage current in arterial SMC. In addition, TASK-1 channels are regulated by a number of stimuli: their activity augments with an increase of extracellular pH, decreases in hypoxia, and can also change under the influence of inhalation/local anesthetics and vasoactive substances. TASK-1 channels play an important role in the regulation of arterial tone in pulmonary circulation; their dysfunction is one of the causes of arterial pulmonary hypertension development. In systemic arteries of adult animals, the influence of TASK-1 channels under normal pH is small or absent, but it can manifest itself under conditions of extracellular alkalosis. In addition, the anticontractile role of TASK-1 channels is more pronounced at the early stages of postnatal development. This review outlines the current understanding of the functional role and regulation of TASK-1 channels in the vascular system.
Gold complexes Ph
3
PR
+
Au(CN)
2
I
2
-
trans
−
, where R = Et
(1)
, CH
2
Ph
(2)
, Ph
(3)
, were synthesized by the reaction of potassium dicyanodiiodoaurate with tetraorganylphosphonium chlorides ...in acetonitrile and were structurally characterized. The phosphorus atoms in the cations are in a tetrahedral environment. In the centrosymmetric square Au(CN)
2
I
2
−
anions of complexes
1–3
, the Au—I distances have similar values (2.617(2), 2.623(2), and 2.611(2) Å, respectively); the largest bond length is observed in complex
2.
The Au-C and C≡N bond lengths in complexes
1–3
are 1.993(5), 2.002(4), 2.003(19) Å and 1.130(6), 1.074(7), 1.12(2) Å, respectively. In the tetrahedral Ph
3
PR
+
cations (C-P-C angles, 105.5(10)–111.2(7)°), the P-C distances vary in the range of 1.797(4)–1.816(4) Å. The structural organization of the crystals of compounds
1–3
is due mainly to weak N⋯H-C hydrogen bonds (2.44–2.74 Å) between hydrogen atoms of the cations and nitrogen atoms of the anions.
—
The nongenomic effects of thyroid hormones (THs) develop within minutes or hours and do not depend on the binding of the hormone to the transcriptionally active nuclear receptors TRα and TRβ. These ...effects are characterized by a variety of receptors and signaling pathways involved, which may be distinct in different cell types. Thyroxin (T
3
) or triiodthyronine (T
4
) can induce a nongenomic effect by association with transcriptionally inactive TRα and TRβ in the cell cytoplasm, their truncated isoforms, or αvβ3 integrin. With nongenomic action, as well as with genomic action, T
3
and T
4
can alter gene transcription, but their influence is extended to a wider spectrum of genes in this case. The nongenomic effects of THs often complement the genomic ones, causing similar changes in cell activity, or enhance them by providing TRα and TRβ translocation into the nucleus or their posttranslational modification. The nongenomic effects of THs on the vasculature include angiogenesis and rapid vasodilation. The key signaling cascade mediating angiogenesis includes αvβ3 integrin, protein kinase D, and histone deacetylase 5. The mechanisms of rapid vasodilation are still poorly understood and may vary in different regions of the vascular bed. In cytoplasm of endothelial cells, the nongenomic effect of THs is mediated by TRα1, PI3K, and NO synthase, although this mechanism is not universal. TH-induced vasodilation of skeletal muscle arteries includes the participation of αvβ3 integrin located in smooth muscle cells, but the signaling cascades triggered by it have not yet been studied. Knowledge of the molecular mechanisms of the nongenomic effect of thyroid hormones is important for the development of new methods of pharmacological correction of vascular pathologies, which are usually associated with thyroid disorders.
