Local Regulation Of Blood Flow Research Articles

What Is the Link Between Vascular Dysregulation and Glaucoma?

The need of blood flow to different organs varies rapidly over time which is why there is sophisticated local regulation of blood flow. The term dysregulation simply means that blood flow is not properly adapted to this need. Dysregulative mechanisms can lead to an over- or underperfusion. A steady overperfusion may be less critical for long-term damage. A constant underperfusion, however, can lead to some tissue atrophy or in extreme situations to infarction. Unstable perfusion (underperfusion followed by reperfusion) leads to oxidative stress. There are a number of causes that lead to local or systemic vascular dysregulation. Systemic dysregulation can be primary or secondary of nature. A secondary dysregulation is due to other autoimmune diseases such as rheumatoid arthritis, giant cell arteritis, systemic lupus erythematodes, multiple sclerosis, colitis ulcerosa, or Crohns disease. Patients with a secondary vascular dysregulation normally have a high level of circulating endothelin-1 (ET-1). This increased level of ET-1 leads to a reduction of blood flow both in the choroid and the optic nerve head but has little influence on autoregulation. In contrast, primary vascular dysregulation has little influence on baseline ocular blood flow but interferes with autoregulation. This, in turn, leads to unstable oxygen supply, which seems to be a relevant component in the pathogenesis of glaucomatous optic neuropathy.

Coupling a change in intraluminal pressure to vascular smooth muscle depolarization: still stretching for an explanation

pressure-induced (myogenic) constriction of arterioles is believed to be a fundamental contributor to the local regulation of microvascular blood flow and pressure. Myogenic constriction provides a level of tone upon which vasodilators can act to lower resistance and match blood flow to metabolic

Definitive role for natriuretic peptide receptor-C in mediating the vasorelaxant activity of C-type natriuretic peptide and endothelium-derived hyperpolarising factor

C-type natriuretic peptide (CNP) has recently been suggested to represent an endothelium-derived hyperpolarising factor (EDHF) in the mammalian resistance vasculature and, as such, important in the regulation of local blood flow and systemic blood pressure. Additionally, this peptide has been shown to protect against ischaemia-reperfusion injury and inhibits leukocyte and platelet activation. Herein, we use a novel, selective natriuretic peptide receptor-C (NPR-C) antagonist (M372049) to highlight the pivotal contribution of CNP/NPR-C signalling in the EDHF-dependent regulation of vascular tone and investigate the mechanism(s) underlying the release and biological activity of CNP. In vitro pharmacological investigation was conducted in rat (Sprague-Dawley) aorta and mesenteric resistance arteries. Relaxant responses to CNP, atrial natriuretic peptide (ANP), the nitric oxide donor spermine-NONOate (SPER-NO) and the endothelium-dependent vasodilator, acetylcholine (ACh) were examined in the absence and presence of M372049 or inhibitor cocktails shown previously to block endothelium-dependent dilatation in the resistance vasculature. RT-PCR was employed to characterize the expression of NPR subtypes in the vessels studied. M372049 produced concentration-dependent inhibition of the vasorelaxant activity of CNP in rat isolated mesenteric resistance arteries but not aorta; in contrast, M372049 did not affect relaxations to ANP or SPER-NO in either vessel. M372049 or ouabain alone produced small, significant inhibition of EDHF-dependent relaxations in mesenteric arteries and in combination acted synergistically to abolish such responses. A combination of M372049 with established inhibitors of EDHF-dependent relaxation revealed that multiple, distinct pathways coordinate the bioactivity of EDHF in the resistance vasculature, and that CNP/NPR-C signalling represents a major component. These data substantiate CNP/NPR-C signalling as a fundamental pathway underlying EDHF-dependent regulation of vascular tone in the rat mesenteric resistance vasculature. An increased understanding of the physiological roles of CNP/NPR-C signalling in the vasculature (now facilitated by the identification of a selective NPR-C antagonist) should aid determination of the (patho)physiological importance of EDHF and might provide the rationale for the design of novel therapeutics.

Impaired Skin Microvascular Reactivity in Painful Diabetic Neuropathy

The pathogenesis of painful diabetic neuropathy (PDN) is not clear. Following our in vivo observations of increased sural nerve epineurial blood flow in patients with PDN, we investigated the cutaneous microcirculation of the foot by laser Doppler flowmetry to determine if the epineurial findings were just confined to the nerve or more widespread in other vascular beds. We measured foot skin vasodilator responses to acetylcholine (Ach) and sodium nitroprusside (SNP) and vasoconstrictor responses to sympathetic (deepest possible gasp) stimulation in 5 healthy control subjects, 10 non-neuropathic diabetic (NND) patients, 10 diabetic patients with painless neuropathy (PLDN), and 8 diabetic patients with PDN. In PDN, there were significantly reduced responses to Ach (ANOVA P = 0.003) and vasoconstrictor inspiratory gasp (ANOVA P < 0.001) but not to SNP (NS). Post hoc analysis showed significant differences in Ach-induced vasodilation between PDN and nondiabetic control subjects (P < 0.05) as well as between PDN and NND (P < 0.05) but not PDN and PLDN (NS). There were no significant differences for SNP-induced vasodilation. However, there were significant differences in the vasoconstrictor response between PDN and control, NND, and PLDN (P < 0.01). We found an impairment of cutaneous endothelium-related vasodilation and C-fiber-mediated vasoconstriction in PDN. Inappropriate local blood flow regulation may have a role in the pathogenesis of pain in diabetic neuropathy. Prospective studies are required to determine the temporal relationship of these changes in relation to the emergence of neuropathic pain.

Retracted: RhoA activation and interaction with Caveolin-1 are critical for pressure-induced myogenic tone in rat mesenteric resistance arteries

Myogenic tone, which has a major role in the regulation of local blood flow, refers to the ability of vascular smooth muscle to adapt its contractility to changes in transmural pressure. Although Rho-kinase is involved in myogenic tone, the pathway involved remains unclear, especially concerning translocation to the plasma membrane and activation of RhoA. As caveolae have a key role in the signal transduction of membrane-bound proteins, we tested the hypothesis that RhoA might be activated by pressure and that its activation might involve caveolin-1, which has been shown to be involved in vascular functions. Myogenic tone was studied in isolated rat mesenteric resistance arteries (118+/-15 microm internal diameter with a pressure of 75 mmHg) submitted to pressure steps (25, 75, and 150 mmHg). Pharmacological blockade of caveolae or RhoA-Rho-kinase pathway was assessed by confocal microscopy in pressurized arteries to analyze protein co-localization and by co-immunoprecipitation in order to confirm protein interactions. Caveolin-1-deficient mice were used to confirm the role of the protein in myogenic tone. Pressure-induced myogenic tone was significantly reduced by RhoA inactivation with TAT-C3 (90.5% inhibition at 150 mmHg) and by the Rho-kinase inhibitor Y27632 (91.8% inhibition at 150 mmHg). In arteries pressurized at 150 mmHg, RhoA was localized to the plasma membrane (localization by confocal microscopy and increased quantity of RhoA in the membrane fraction after protein extraction). Thus, translocation of RhoA to the plasma membrane was associated with pressure-induced tone. In addition, caveolae disruption with methyl-beta-cyclodextrin reduced myogenic tone by 66% at 150 mmHg. Further, myogenic tone was significantly reduced to 24% of control in caveolin-1-deficient mice (active tone was 32.3+/-2.8 microm and 9.1+/-3.7 microm in +/+ and -/- mice, respectively, n = 5 per group), suggesting a key role of caveolin-1 in myogenic tone. Finally, RhoA and caveolin-1 co-immunoprecipitation and co-localization significantly increased when myogenic tone developed at 150 mmHg (co-localization showed 26+/-13% merging at 25 mmHg versus 97+/-21% at 150 mmHg, n = 5). Co-immunoprecipitation was prevented by TAT-C3 and by methyl beta-cyclodextrin. RhoA activation is critical for the development of myogenic tone in resistance arteries. This activation induced translocation of RhoA to the plasma membrane within caveolae, where the interaction of RhoA with caveolin-1 leads selectively to the activation of a Rho-kinase-dependent force development.

The combined effect of betamethasone and ritodrine on the middle cerebral artery in low risk third trimester pregnancies

To evaluate the effect of antenatal betamethasone and ritodrine in third trimester low risk singleton pregnancies by Doppler technology. Eighty-four third trimester pregnant women who received a full course of betamethasone and delivering uneventfully were recruited. The Doppler examination included the assessment of the pulsatility index (PI) of the umbilical artery (UA PI) and the middle cerebral artery (MCA PI) prior to treatment (baseline), and 48, 72 and 96 h after the second dose of betamethasone. No significant difference was found in UA PI and UA/MCA values following betamethasone therapy. In contrast, MCA PI decreased significantly 48 h from the last injection of betamethasone in the whole study group (P<0.001), and returned to basal values at 96 h. We also found that MCA PI was reduced significantly at 48 h in the subgroup under tocolysis (n=41) and in the subgroup not receiving tocolysis (n=43). We compared MCA PI values for both subgroups in the four timings, and found a non-significant difference comparing baseline and 96 h values. However, when comparing MCA PI values after 48 and 72 h, significantly lower differences in PI values in both subgroups were found. In low risk pregnancies, betamethasone therapy in the third trimester is related to a significant but transient reduction of MCA PI, which is more pronounced during tocolytic therapy. Although the physiological basis of this effect is currently unclear, it could be related to the local regulation of intracerebral blood flow.

Reduced Expression of Gi in Erythrocytes of Humans With Type 2 Diabetes Is Associated With Impairment of Both cAMP Generation and ATP Release

Human erythrocytes, by virtue of their ability to release ATP in response to physiological stimuli, have been proposed to participate in the regulation of local blood flow. A signal transduction pathway that relates these stimuli to ATP release has been described and includes the heterotrimeric G protein G(i) and adenylyl cyclase (AC). In this cell, G(i) activation results in increases in cAMP and, ultimately, ATP release. It has been reported that G(i) expression is decreased in animal models of diabetes and in platelets of humans with type 2 diabetes. Here, we report that G(i2) expression is selectively decreased in erythrocytes of humans with type 2 diabetes and that this defect is associated with reductions in cAMP accumulation and ATP release in response to incubation of erythrocytes with mastoparan 7 (10 micromol/l), an activator of G(i). Importantly, this defect in ATP release correlates inversely with the adequacy of glycemic control as determined by levels of HbA(1c) (A1C). These results demonstrate that in erythrocytes of humans with type 2 diabetes, both G(i) expression and ATP release in response to mastoparan 7 are impaired, which is consistent with the hypothesis that this defect in erythrocyte physiology could contribute to the vascular disease associated with this clinical condition.

Contribution of Lipopolysaccharide to Prolylcarboxypeptidase Activation in Endothelial Cells.

Bradykinin (BK) participates in the etiology of vascular inflammation and the regulation of local blood flow and blood pressure by causing a vascular hyperemia. The bradykinin generating pathway of human plasma consists of prolylcarboxypeptidase (PRCP), heat shock protein 90 (HSP90), coagulation factor XII (FXII, Hageman factor), and the heteromer complex of prekallikrein (PK) and high molecular weight kininogen (HK). In the presence of HK, PRCP activates PK to generate kallikrein on endothelial cells. Formed kallikrein then cleaves HK to liberate BK. PRCP-induced PK activation is independent of the activated FXII. The activity of PRCP leads to vasodilation. In inflamed tissues, tissue injury or hypotensive bacteremia, BK has been shown to accumulate in the blood or plasma of these patients. In this investigation, we have assessed the possible contribution of lipopolysaccharide (LPS) to PRCP activation in primary cultures of human umbilical vein endothelial cells (HUVECs) using multiple approaches. The role of LPS in HK binding to HUVECs was assessed. The effect of LPS on the endothelial permeability injury was evaluated by histological changes and analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). The release of von Willebrand factor (VWF), endothelin-1 (ET-1) and intercellular adhesion molecule-1 (ICAM-1) induced by LPS in HUVEC was determined. PK activation on LPS-pretreated endothelial cells was higher than untreated cell. PRCP inhibitor, z-pro-prolinal, inhibited the production of kallikrein from PK compared to the control. These results suggest that LPS contributes to PRCP overactivation which results in the acceleration of the inflammatory process, exerting its effects via PK activation. Inhibiting the activity of PRCP may exert some beneficial therapeutic action in systemic inflammation, at least in part by inhibiting the production of BK and thus preventing vascular dysfunction.

Lactate release from adipose tissue and skeletal muscle in vivo: defective insulin regulation in insulin-resistant obese women

To study the local tissue lactate production in the normal state and its possible disturbances in insulin resistance, rates of lactate release from adipose tissue (AT) and skeletal muscle (SM) were compared postabsorptively and during a hyperinsulinemic euglycemic clamp in 11 healthy nonobese and 11 insulin-resistant obese women. A combination of microdialysis, to measure interstitial lactate, and the 133Xe clearance technique, to determine local blood flow, were used. In the controls, local blood flow increased by 40% in SM (P<0.05) and remained unchanged in AT, whereas the interstitial-plasma difference in lactate doubled in AT (P<0.005) and was unaffected in SM during hyperinsulinemia. In the obese, blood flow and interstitial-plasma difference in lactate remained unchanged in both tissues during hyperinsulinemia. The lactate release (micromol100 g-1min-1) was 1.17+/-0.22 in SM and 0.43+/-0.11 in AT among the controls (P<0.01) and 0.86+/-0.23 in SM and 0.83+/-0.25 in AT among the obese women in the postabsorptive state. During insulin infusion, lactate release in the controls increased to 1.92+/-0.26 in SM (P<0.005) and to 1.14+/-0.22 in AT (P<0.005) but remained unchanged in the obese women. It is concluded that AT and SM are both significant sources of lactate release postabsorptively, and AT is at least as responsive to insulin as SM. The ability to increase lactate release in response to insulin is impaired in AT and SM in insulin-resistant obese women, involving defective insulin regulation of both tissue lactate metabolism and local blood flow.

Nicotinic Acid-Induced Flushing Is Mediated by Activation of Epidermal Langerhans Cells

The antidyslipidemic drug nicotinic acid (niacin) has been used for decades. One of the major problems of the therapeutical use of nicotinic acid is a strong cutaneous vasodilation called flushing, which develops in almost every patient taking nicotinic acid. Nicotinic acid-induced flushing has been shown to be mediated by the nicotinic acid receptor GPR109A and to involve the formation of vasodilatory prostanoids. However, the cellular mechanisms underlying this short-term effect are unknown. Here, we show that epidermal Langerhans cells are essential for the cutaneous flushing response induced by nicotinic acid. Langerhans cells respond with an increase in [Ca(2+)](i) to nicotinic acid and express prostanoid synthases required for the formation of the vasodilatory prostanoids prostaglandin E(2) and prostaglandin D(2). Depletion of epidermal Langerhans cells but not of macrophages or dendritic cells abrogates nicotinic acid-induced flushing. These data unexpectedly identify epidermal Langerhans cells as essential mediators of nicotinic acid-induced flushing and may help to generate new strategies to suppress the unwanted effects of nicotinic acid. In addition, our results suggest that Langerhans cells besides their immunological roles are also involved in the local regulation of dermal blood flow.

Local regulation of skin blood flow during cooling involving presynaptic P2 purinoceptors in rats

1. This study investigated a local effect of cooling on the plantar skin blood flow (PSBF) of tetrodotoxin-treated rats by laser-Doppler flowmetry. 2. When the air temperature around the left foot was locally cooled from 25 to 10 degrees C, the PSBF of the left foot decreased. 3. The response was inhibited by the alpha-adrenoceptor antagonist phentolamine, the alpha1-adrenoceptor antagonist bunazosin, the alpha2-adrenoceptor antagonist RS79948, and bretylium and guanethidine that inhibit noradrenaline release from sympathetic nerves. Adrenalectomy of the rats did not affect the cooling-induced response. 4. The P2 purinoceptor antagonists suramin and PPADS also significantly suppressed the cooling-induced reduction of PSBF. However, the inhibitory effect of PPADS on the cooling-induced response was abolished after the treatment with phentolamine. Intra-arterial injections of ATPgammaS, a stable P2 purinoceptor agonist, at 25 degrees C caused a transient decrease in PSBF in a dose-dependent manner, which was significantly inhibited by phentolamine and guanethidine. 5. These results suggest a novel mechanism for local cooling-induced reduction of skin blood flow in vivo; moderate cooling of the skin induces the release of ATP, which stimulates presynaptic P2 purinoceptors on sympathetic nerve terminals and facilitates the release of noradrenaline, thereby causing contractions of skin blood vessels via the activation of alpha1-and alpha2-adrenoceptors.

Erythrocytes and the regulation of human skeletal muscle blood flow and oxygen delivery: role of erythrocyte count and oxygenation state of haemoglobin

Blood flow to dynamically contracting myocytes is regulated to match O(2) delivery to metabolic demand. The red blood cell (RBC) itself functions as an O(2) sensor, contributing to the control of O(2) delivery by releasing the vasodilators ATP and S-nitrosohaemoglobin with the offloading of O(2) from the haemoglobin molecule. Whether RBC number is sensed remains unknown. To investigate the role of RBC number, in isolation and in combination with alterations in blood oxygenation, on muscle and systemic perfusion, we measured local and central haemodynamics during one-legged knee-extensor exercise ( approximately 50% peak power) in 10 healthy males under conditions of normocythaemia (control), anaemia, anaemia + plasma volume expansion (PVX), anaemia + PVX + hypoxia, polycythaemia, polycythaemia + hyperoxia and polycythaemia + hypoxia, which changed either RBC count alone or both RBC count and oxyhaemoglobin. Leg blood flow (LBF), cardiac output (Q) and vascular conductance did not change with either anaemia or polycythaemia alone. However, LBF increased with anaemia + PVX (28 +/- 4%) and anaemia + PVX + hypoxia (46 +/- 6%) and decreased with polycythaemia + hyperoxia (18 +/- 5%). LBF and Q with anaemia + PVX + hypoxia (8.0 +/- 0.5 and 15.8 +/- 0.7 l min(-1), respectively) equalled those during maximal knee-extensor exercise. Collectively, LBF and vascular conductance were intimately related to leg arterial-venous (a-v) O(2) difference (r(2)= 0.89-0.93; P < 0.001), suggesting a pivotal role of blood O(2) gradients in muscle microcirculatory control. The systemic circulation accommodated to the changes in muscle perfusion. Our results indicate that, when coping with severe haematological challenges, local regulation of skeletal muscle blood flow and O(2) delivery primarily senses alterations in the oxygenation state of haemoglobin and, to a lesser extent, alterations in the number of RBCs and haemoglobin molecules.

Nitric oxide and prostaglandins influence local skeletal muscle blood flow during exercise in humans: coupling between local substrate uptake and blood flow

Synergic action of nitric oxide (NO) and prostaglandins (PG) in the regulation of muscle blood flow during exercise has been demonstrated. In the present study, we investigated whether these vasodilators also regulate local blood flow, flow heterogeneity, and glucose uptake within the exercising skeletal muscle. Skeletal muscle blood flow was measured in seven healthy young men using near-infrared spectroscopy and indocyanine green and muscle glucose uptake using positron emission tomography and 2-fluoro-2-deoxy-D-[(18)F]glucose without and with local blockade of NO and PG at rest and during one-legged dynamic knee-extension exercise. Local blockade was produced by infusing nitro-L-arginine methyl ester and indomethacin directly in the muscle via a microdialysis catheter. Blood flow and glucose uptake were measured in the region of blockade and in two additional regions of vastus lateralis muscle 1 and 4 cm away from the infusion of blockers. Local blockade during exercise at 25 and 40 watts significantly decreased blood flow in the infusion region and in the region 1 cm away from the site of infusion but not in the region 4 cm away. During exercise, muscle glucose uptake did not show any regional differences in response to blockade. These results show that NO and PG synergistically contribute to the local regulation of blood flow in skeletal muscle independently of muscle glucose uptake in healthy young men. Thus these vasodilators can play a role in regulating microvascular blood flow in localized regions of vastus lateralis muscle but do not influence regional glucose uptake. The findings suggest that local substrate uptake in skeletal muscle can be regulated independently of regional changes in blood flow.

Superoxide released to asymmetric dimethylarginine (ADMA) interferes with the vasomotor responses of isolated arterioles

Nitric oxide (NO) is produced by NO synthase (NOS) from L-arginine. In hyperhomocysteinemia, diabetes mellitus and hypertension there is an increase in serum levels of methylated L-arginine, such as ADMA, which cannot be used by NOS to produce NO. Thus we hypothesized that elevated levels of ADMA interfere with the endothelial regulation of arteriolar tone. In the presence of indomethacin, isolated arterioles from rat gracilis muscle (~150 μm at 80 mmHg) were incubated with ADMA (10-4 mol/L). ADMA eliminated the dilations to increases in intraluminal flow (control: from 164±5.4 to 188±3.8 μm vs. ADMA: from 171±6.1 to 173±6.3 μm at 20 μL/min), but did no affect dilations to nifedipine (10-6 M, control: 63.4±2% ADMA: 65.8±3%). In addition, ADMA (10-4 M) elicited significant constrictions of arterioles (from 173±17 μm to 138±16 μm at 80 mmHg), which was inhibited by prior incubation of arterioles with superoxide dismutase (SOD 200 U/ml, control: 155±11 μm vs. ADMA: 150±14 μm). Correspondingly, ADMA, in a SOD reversible manner, increased the production of arterial superoxide assessed by lucigenin-enhanced chemiluminescence. We suggest that increased levels of ADMA, not only result in a reduced release of NO, but also elicit production of superoxide, which could lead to increases in arteriolar tone and disturbances in the local regulation of blood flow. (Grants: Hungarian Nat. Sci. Res. Funds, OTKA T-48376 and NIH HL46813, HL43023 AHA NE Aff. 0555897T)

Local control of pulmonary blood flow and lung structure in reptiles: Implications for ventilation perfusion matching

Lung structure of reptiles is very diverse ranging from single chambered lungs with a simple structure to more complex and multi-chambered lungs. Increased structural complexity resulted from the evolution of smaller gas exchange units and larger surface area, which increases the pulmonary diffusive capacity for O(2). However, increased structural complexity probably also increases the possibilities for ventilation-perfusion (V /Q ) heterogeneity, which exerts significant constraints on gas exchange. In most reptiles, the ventricle is anatomically and functionally undivided so blood pressures are equal in the systemic and pulmonary circulations. In these species, blood flow distribution between pulmonary and systemic circulations are primarily determined by pulmonary and systemic vascular resistances. Thus, increased pulmonary resistance lowers pulmonary blood flow through increasing cardiac right-to-left shunt decreasing systemic oxygen levels. It has been proposed that local mechanisms regulating pulmonary blood flow are more pronounced in reptiles with complex lungs as they are more prone to V /Q heterogeneity. However, local control of pulmonary blood flow has also been suggested to primarily exist when hearts are functionally divided because altered pulmonary vascular resistance does not affect cardiac shunt patterns. Data suggest that, while there seems to be a general trend of increased local regulation of pulmonary blood flow in species with structurally complex lungs and divided hearts, it is also possible that other factors, such as breathing pattern, have been important for the evolutionary development of local regulatory mechanisms in the lungs.

Reduced Nitric Oxide Concentration in the Renal Cortex of Streptozotocin-Induced Diabetic Rats

Nitric oxide (NO) regulates vascular tone and mitochondrial respiration. We investigated the hypothesis that there is reduced NO concentration in the renal cortex of diabetic rats that mediates reduced renal cortical blood perfusion and oxygen tension (P O2). Streptozotocin-induced diabetic and control rats were injected with l-arginine followed by Nomega-nitro-L-arginine-metyl-ester (L-NAME). NO and P O2 were measured using microsensors, and local blood flow was recorded by laser-Doppler flowmetry. Plasma arginine and asymmetric dimethylarginine (ADMA) were analyzed by high-performance liquid chromatography. L-Arginine increased cortical NO concentrations more in diabetic animals, whereas changes in blood flow were similar. Cortical P O2 was unaffected by L-arginine in both groups. L-NAME decreased NO in control animals by 87 +/- 15 nmol/l compared with 45 +/- 7 nmol/l in diabetic animals. L-NAME decreased blood perfusion more in diabetic animals, but it only affected P O2 in control animals. Plasma arginine was significantly lower in diabetic animals (79.7 +/- 6.7 vs. 127.9 +/- 3.9 mmol/l), whereas ADMA was unchanged. A larger increase in renal cortical NO concentration after l-arginine injection, a smaller decrease in NO after L-NAME, and reduced plasma arginine suggest substrate limitation for NO formation in the renal cortex of diabetic animals. This demonstrates a new mechanism for diabetes-induced alteration in renal oxygen metabolism and local blood flow regulation.

Involvement of RhoA/Rho Kinase Pathway in Myogenic Tone in the Rabbit Facial Vein

Myogenic tone (MT), a fundamental stretch-sensitive vasoconstrictor property of resistance arteries and veins, is a key determinant of local blood flow regulation. We evaluated the pathways involved in MT development. The role of the RhoA/Rho kinase, p38 MAP kinase, and HSP27 in MT was investigated in the rabbit facial vein (RFV), previously shown to possess MT at a pressure level equivalent to 20 mm Hg. Venous MT is poorly understood, although venous diseases affect a large proportion of the population. Stretched RFV are characterized by a temperature-sensitive MT, which is normal at 39 degrees C but fails to develop at 33 degrees C. This allows for the discrimination of the pathways involved in MT from the multiple pathways activated by stretch. Isolated RFV segments were mounted in organ baths and stretched. Temperature was then set at 33 degrees C or 39 degrees C. MT was associated to the translocation of RhoA to the plasma membrane and the Rho kinase inhibitor Y27632 decreased stretch-induced MT by 93.1+/-4.9%. MT was also associated to an increase in p38 (131.0+/-12.5% at 39 degrees C versus 100% at 33 degrees C) and HSP27 phosphorylation (196.1+/-13.3% versus 100%), and the p38 MAP kinase inhibitor SB203580 decreased MT by 36.5+/-8.1%. (39 degrees C, compared with RFV stretched at 33 degrees C). Finally, phosphorylation of p38 was blocked by Y27632 and HSP27 phosphorylation was inhibited by SB203580 and Y27632. Thus, MT and the associated p38 and HSP27 phosphorylation seem to depend on RhoA/Rho kinase activation in stretch RFV.

Comparison of cardiovascular responses between lower body negative pressure and head-up tilt

To investigate local blood-flow regulation during orthostatic maneuvers, 10 healthy subjects were exposed to -20 and -40 mmHg lower body negative pressure (LBNP; each for 3 min) and to 60 degrees head-up tilt (HUT; for 5 min). Measurements were made of blood flow in the brachial (BF(brachial)) and femoral arteries (BF(femoral)) (both by the ultrasound Doppler method), heart rate (HR), mean arterial pressure (MAP), cardiac stroke volume (SV; by echocardiography), and left ventricular end-diastolic volume (LVEDV; by echocardiography). Comparable central cardiovascular responses (changes in LVEDV, SV, and MAP) were seen during LBNP and HUT. During -20 mmHg LBNP, -40 mmHg LBNP, and HUT, the following results were observed: 1) BF(brachial) decreased by 51, 57, and 41%, and BF(femoral) decreased by 40, 53, and 62%, respectively, 2) vascular resistance increased in the upper limb by 110, 147, and 85%, and in the lower limb by 76, 153, and 250%, respectively. The increases in vascular resistance were not different between the upper and lower limbs during LBNP. However, during HUT, the increase in the lower limb was much greater than that in the upper limb. These results suggest that, during orthostatic stimulation, the vascular responses in the limbs due to the cardiopulmonary and arterial baroreflexes can be strongly modulated by local mechanisms (presumably induced by gravitational effects).

Hypoxia/reoxygenation reduces microvascular endothelial cell coupling by a tyrosine and MAP kinase dependent pathway

Communication of electrical signals along the microvascular endothelium plays a key role in integrating microvascular function required for local regulation of blood flow. The aim of the present study was to examine the effect of a short-term hypoxia (0.1% O(2), 1 h) plus reoxygenation (H/R) on electrical coupling in cultured monolayers of microvascular endothelial cells (rat skeletal muscle origin). To assess coupling, we used a current injection technique and a Bessel function model to compute the intercellular resistance (an inverse measure of coupling) and cell membrane resistivity (a measure of resistance to current leakage across the cell membrane). H/R resulted in rapid (within 4 min after reoxygenation) and sustained (up to 100 min) reduction in intercellular coupling, but it did not alter membrane resistivity. H/R did not alter gap junction protein connexin 43 expression nor its tyrosine phosphorylation as determined by immunoblot and immunoprecipitation analyses. Inhibition of mitochondrial respiration (1 mM NaCN) did not mimic the effect of H/R. However, pre-treatment of monolayers with tyrphostin A48 (1.5 microM), PP2 (10 nM) (tyrosine kinase inhibitors), U 0126 (20 microM), and PD 98059 (5 microM) (MEK1/2 inhibitors) inhibited the H/R-induced reduction in coupling. These results indicate that endothelial cell coupling was reduced quickly after reoxygenation, via activation of a tyrosine and MAP kinase dependent pathway. We predict that a short-term H/R can rapidly compromise microvascular function in terms of reduced cellular communication along the vascular wall.

Commentary

HIGHLIGHTED TOPICSSkeletal and Cardiac Muscle Blood FlowCommentaryGary C. SieckGary C. SieckJournal of Applied Physiology September 2004, Volume 97Published Online:01 Sep 2004https://doi.org/10.1152/japplphysiol.00635.2004MoreSectionsPDF (9 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Reactive oxygen species are generally thought to play a role only in pathological conditions. However, recent studies have suggested that reactive oxygen species may play a physiological role in the modulation of vascular tone. In the first featured article, entitled “Biphasic effect of hydrogen peroxide on skeletal muscle arteriolar tone via activation of endothelial and smooth muscle signaling pathways,” Dr. C. Cseko and colleagues (1) examined the role of H2O2 in local regulation of skeletal muscle blood flow. These investigators provide further evidence supporting concentration-dependent effects of H2O2 on vasomotor tone of arterioles mediated by prostanoids, nitric oxide, and potassium channels. The findings of this study are important because in various physiological and/or pathological conditions, endothelial or smooth muscle cells may release H2O2 during increased oxidative metabolism. Under physiological conditions, H2O2 may provide a feedback signal to locally couple tissue metabolism to blood supply. Under pathological conditions, circulating leukocytes or macrophages that are in or near the vascular wall may produce significant amounts of H2O2, which may then modulate arteriolar diameter and locally increase blood flow, thereby ensuring that all necessary components of inflammation are present in the microcirculation. Together, these findings emphasize that the role of reactive oxygen species, such as H2O2, should be considered when attempting to explain the multifactorial nature of local regulation of blood flow.In the second featured article, entitled “Downhill running: a model of exercise hyperemia in the rat spinotrapezius muscle,” Dr. Y. Kano and colleagues (2) hypothesized that downhill treadmill running recruits the spinotrapezius muscle, as evidenced by the exercise hyperemia. Investigating the processes of blood-muscle exchange requires in vivo observations of capillary hemodynamics via intravital microscopy techniques. Visualization with transmission light microscopy requires that muscle tissue possess excellent optical properties and can be accessed without disturbing neural or vascular supplies. These criteria limit the selection of candidate muscles and impose a difficult challenge to investigation of microvascular adaptations to exercise training. The validity of swimming and uphill and flat running protocols used to train the cremaster and spinotrapezius muscles, respectively, has been questioned on the basis of their effectiveness in inducing physiological hyperemia. In a rat model, these investigators used radioactive microsphere techniques and demonstrated an approximate threefold increase in spinotrapezius blood flow during downhill running. These findings provide a physiological paradigm for the investigation of the microcirculatory basis of enhanced blood-muscle exchange and muscle performance after training.REFERENCES1 Cseko C, Bagi Z, and Koller A. Biphasic effect of hydrogen peroxide on skeletal muscle arteriolar tone via activation of endothelial and smooth muscle signaling pathways. J Appl Physiol 97: 1130–1137, 2004.Google Scholar2 Kano Y, Padilla D, Hageman KS, Poole DC, and Musch TI. Downhill running: a model of exercise hyperemia in the rat spinotrapezius muscle. J Appl Physiol 97: 1138–1142, 2004.Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 97Issue 3September 2004Pages 1129-1129 Copyright & PermissionsCopyright © 2004 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00635.2004History Published online 1 September 2004 Published in print 1 September 2004 Metrics