Nitrergic inhibition of sympathetic arteriolar constrictions in the female rodent urethra.

During the urine storage phase, tonically contracting urethral musculature would have a higher energy consumption than bladder muscle that develops phasic contractions. However, ischaemic dysfunction is less prevalent in the urethra than in the bladder, suggesting that urethral vasculature has intrinsic properties ensuring an adequate blood supply. Diameter changes in rat or mouse urethral arterioles were measured using a video-tracking system. Intercellular Ca2+ dynamics in arteriolar smooth muscle (SMCs) and endothelial cells were visualised using NG2- and parvalbumin-GCaMP6 mice, respectively. Fluorescence immunohistochemistry was used to visualise the perivascular innervation. In rat urethral arterioles, sympathetic vasoconstrictions were predominantly suppressed by α,ß-methylene ATP (10 µM) but not prazosin (1 µM). Tadalafil (100 nM), a PDE5 inhibitor, diminished the vasoconstrictions in a manner reversed by N-ω-propyl-l-arginine hydrochloride (l-NPA, 1 µM), a neuronal NO synthesis (nNOS) inhibitor. Vesicular acetylcholine transporter immunoreactive perivascular nerve fibres co-expressing nNOS were intertwined with tyrosine hydroxylase immunoreactive sympathetic nerve fibres. In phenylephrine (1 µM) pre-constricted rat or mouse urethral arterioles, nerve-evoked vasodilatations or transient SMC Ca2+ reductions were largely diminished by l-nitroarginine (l-NA, 10 µM), a broad-spectrum NOS inhibitor, but not by l-NPA. The CGRP receptor antagonist BIBN-4096 (1 µM) shortened the vasodilatory responses, while atropine (1 µM) abolished the l-NA-resistant transient vasodilatory responses. Nerve-evoked endothelial Ca2+ transients were abolished by atropine plus guanethidine (10 µM), indicating its neurotransmitter origin and absence of non-adrenergic non-cholinergic endothelial NO release. In urethral arterioles, NO released from parasympathetic nerves counteracts sympathetic vasoconstrictions pre- and post-synaptically to restrict arteriolar contractility. KEY POINTS: Despite a higher energy consumption of the urethral musculature than the bladder detrusor muscle, ischaemic dysfunction of the urethra is less prevalent than that of the bladder. In the urethral arterioles, sympathetic vasoconstrictions are predominately mediated by ATP, not noradrenaline. NO released from parasympathetic nerves counteracts sympathetic vasoconstrictions by its pre-synaptic inhibition of sympathetic transmission as well as post-synaptic arteriolar smooth muscle relaxation. Acetylcholine released from parasympathetic nerves contributes to endothelium-dependent, transient vasodilatations, while CGRP released from sensory nerves prolongs NO-mediated vasodilatations. PDE5 inhibitors could be beneficial to maintain and/or improve urethral blood supply and in turn the volume and contractility of urethral musculature.

The vasoactive effects of bradykinin, vasoactive intestinal peptide, calcitonin gene-related peptide and neuropeptide Y depend on the perivascular tissue in porcine retinal arterioles in vitro.

PURPOSE: The retina contains a number of vasoactive neuropeptides and corresponding receptors, but the role of these neuropeptides for tone regulation of retinal arterioles has not been studied in detail. METHODS: Porcine arterioles with preserved perivascular retinal tissue were mounted in a wire myograph, and the tone was measured after the addition of increasing concentrations of bradykinin, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), substance P (SP), calcitonin gene-related peptide (CGRP) and brain natriuretic peptide (BNP). The experiments were performed during inhibition of the synthesis of nitric oxide (NO), prostaglandins and dopamine and were repeated after removal of the perivascular retinal tissue. RESULTS: Bradykinin, VIP and CGRP induced significant concentration-dependent dilatation and NPY significant concentration-dependent contraction of the arterioles in the presence of perivascular retinal tissue (p < 0.03 for all comparisons) but not on isolated arterioles. BNP and SP had no effect on vascular tone. The NOS inhibitor L-NAME reduced bradykinin- and VIP-induced relaxation (p < 0.001 for both comparisons), whereas none of the other inhibitors influenced the vasoactive effects of the studied neuropeptides. CONCLUSION: The effects of neuropeptides on the tone of retinal arterioles depend on the perivascular retinal tissue and may involve effects other than those mediated by nitric oxide, prostaglandins and adrenergic compounds. Investigation of the mechanisms underlying the vasoactive effect of neuropeptides may be important for understanding and treating retinal diseases where disturbances in retinal flow regulation are involved in the disease pathogenesis.

Zinc-sensing receptor activation induces endothelium-dependent hyperpolarization-mediated vasorelaxation of arterioles.

BACKGROUND: The micronutrient zinc (Zn2+) is critical for cell function as intracellular signaling and endogenous ligand for Zn2+ sensing receptor (ZnR). Although cytosolic Zn2+ (cyt) signaling in the vascular system was studied previously, role of the ZnR has not been explored in vascular physiology. METHODS: ZnR-mediated relaxation response of human submucosal arterioles and the mesenteric arterioles from wide-type (WT), ZnR-/- and TRPV4-/- mice were determined by a Mulvany-style wire myograph. The perfused vessel density (PVD) of mouse mesenteric arterioles was also measured in in vivo study. The expression of ZnR in arterioles and vascular endothelial cells (VEC) were examined by immunofluorescence staining, and its function was characterized in VEC by Ca2+ imaging and patch clamp study. RESULTS: ZnR expression was detected on human submucosal arterioles, murine mesenteric arterioles and VEC but not in ZnR-/- mice. ZnR activation predominately induced endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation of arterioles in vitro and in vivo via Ca2+ signaling, which is totally different from endothelium-dependent vasorelaxation via Zn2+ (cyt) signaling reported previously. Furthermore, ZnR-induced vasorelaxation via EDH was significantly impaired in ZnR-/- and TRPV4-/- mice. Mechanistically, ZnR induced endothelium-dependent vasorelaxation predominately via PLC/IP3/IP3R and TRPV4/SOCE. The role of ZnR in regulating Ca2+ signaling and ion channels on VEC was verified by Ca2+ imaging and patch clamp techniques. CONCLUSION: ZnR activation induces endothelium-dependent vasorelaxation of resistance vessels predominately via TRPV4/Ca2+/EDH pathway. We therefore not only provide new insights into physiological role of ZnR in vascular system but also may pave a potential pathway for developing Zn2+-based treatments for vascular disease.

Scoping Review: Integration of the Major Mechanisms Underlying the Regulation of Arteriolar Tone.

BACKGROUND: Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Arteriolar tone regulation plays a critical role in maintaining appropriate organ blood flow and perfusion distribution, which is vital for both vascular and overall health. SUMMARY: This scoping review aimed to explore the interplay between five major regulators of arteriolar tone: metabolism (adenosine), adrenergic control (norepinephrine), myogenic activation (intravascular pressure), perivascular oxygen tension, and intraluminal flow rates. Specifically, the aim was to address how arteriolar reactivity changes in the presence of other vasoactive stimuli and by what mechanisms. The review focused on animal studies that investigated the impact of combining two or more of these stimuli on arteriolar diameter. Overall, 848 articles were identified through MEDLINE and EMBASE database searches, and 38 studies were included in the final review. KEY MESSAGES: The results indicate that arteriolar reactivity is influenced by multiple factors, including competitive processes, structural limitations, and indirect interactions among stimuli. Additionally, the review identified a lack of research involving female animal models and limited insight into the interaction of molecular signaling pathways, which represent gaps in the literature.

Increased Oxygen Saturation in Retinal Venules During Isometric Exercise Is Accompanied With Increased Peripheral Blood Flow in Normal Persons.

Purpose: A recent study has shown that an increase in the arterial blood pressure of approximately 10 mm Hg in healthy persons can increase the oxygen saturation in venules from the retinal periphery but not from the macular area. The purpose of the present study was to investigate whether a higher increase in blood pressure has further effects on oxygen saturations and whether this is accompanied with changes in retinal blood flow. Methods: In 30 healthy persons, oxygen saturation, diameter, and blood flow were measured in arterioles to and venules from the retinal periphery and the macular area. The experiments were performed before and during an experimental increase in arterial blood pressure of (mean ± SD) 18.3 ± 6.2 mm Hg. Results: A higher number of venules than arterioles branching from the temporal vascular arcades to the macular area was balanced by a smaller diameter of the venules. Isometric exercise induced significant contraction of both peripheral and macular arterioles (P < 0.01 for both comparisons) and significant increase in oxygen saturation in both peripheral and macular venules (P < 0.001 for both comparisons). This was accompanied with a significant increase in the blood flow in the peripheral arterioles and venules (P = 0.4 for both comparisons), but not in their macular counterparts (P > 0.06 for both comparisons). Conclusions: Increased systemic blood pressure leading to arterial contraction and increased venous oxygen saturation in the retina in normal persons can increase peripheral blood flow without significant effects on macular blood flow. This may contribute to explaining regional differences in the response pattern of retinal vascular disease.

Regulation of Skeletal Muscle Resistance Arteriolar Tone: Integration of Multiple Mechanisms.

INTRODUCTION: Physiological system complexity represents an imposing challenge to gaining insight into how arteriolar behavior emerges. Further, mechanistic complexity in arteriolar tone regulation requires that a systematic determination of how these processes interact to alter vascular diameter be undertaken. METHODS: The present study evaluated the reactivity of ex vivo proximal and in situ distal resistance arterioles in skeletal muscle with challenges across the full range of multiple physiologically relevant stimuli and determined the stability of responses over progressive alterations to each other parameter. The five parameters chosen for examination were (1) metabolism (adenosine concentration), (2) adrenergic activation (norepinephrine concentration), (3) myogenic activation (intravascular pressure), (4) oxygen (superfusate PO2), and (5) wall shear rate (altered intraluminal flow). Vasomotor tone of both arteriole groups following challenge with individual parameters was determined; subsequently, responses were determined following all two- and three-parameter combinations to gain deeper insight into how stimuli integrate to change arteriolar tone. A hierarchical ranking of stimulus significance for establishing arteriolar tone was performed using mathematical and statistical analyses in conjunction with machine learning methods. RESULTS: Results were consistent across methods and indicated that metabolic and adrenergic influences were most robust and stable across all conditions. While the other parameters individually impact arteriolar tone, their impact can be readily overridden by the two dominant contributors. CONCLUSION: These data suggest that mechanisms regulating arteriolar tone are strongly affected by acute changes to the local environment and that ongoing investigation into how microvessels integrate stimuli regulating tone will provide a more thorough understanding of arteriolar behavior emergence across physiological and pathological states.

Dilation of porcine retinal arterioles to nobiletin, a polymethoxyflavonoid: Roles of nitric oxide and voltage-dependent potassium channel.

We examined the effects of nobiletin, a polymethoxyflavonoid, on the retinal microvascular diameter to determine if they depend on the endothelium and/or smooth muscle to reveal the signaling mechanisms involved in this vasomotor activity. Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded diametric responses to nobiletin. The retinal arterioles dilated in a nobiletin concentration-dependent (100 pM-10 µM) manner and decreased by 50% after endothelial removal. The nitric oxide (NO) synthase inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME), reduced nobiletin-induced vasodilation comparable to denudation. Blockade of soluble guanylyl cyclase by 1H-[1,2,4] oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) produced a similar inhibitory effect as that by L-NAME. Nobiletin-induced vasodilation was also inhibited by the nonselective potassium channel inhibitor, tetraethylammonium (TEA), and the voltage-gated K (Kv) inhibitor, 4-aminopyridine. Co-administration of L-NAME and TEA almost eliminated nobiletin-induced vasodilation. Nobiletin elicits both endothelium-dependent and -independent dilation of retinal arterioles mediated by NO release and Kv channel activation, respectively.

5-HT7 receptors mediate dilation of rat cremaster muscle arterioles in vivo.

OBJECTIVE: Serotonin (5-HT) infusion in vivo causes hypotension and a fall in total peripheral resistance. However, the vascular segment and the receptors that mediate this response remain in question. We hypothesized that 5-HT7 receptors mediate arteriolar dilation to 5-HT in skeletal muscle microcirculation. METHODS: Cremaster muscles of isoflurane-anesthetized male Sprague-Dawley rats were prepared for in vivo microscopy of third- and fourth-order arterioles and superfused with physiological salt solution at 34°C. Quantitative real-time PCR (RT-PCR) was applied to pooled samples of first- to third-order cremaster arterioles (2-4 rats/sample) to evaluate 5-HT7 receptor expression. RESULTS: Topical 5-HT (1-10 nmols) or the 5-HT1/7 receptor agonist, 5-carboxamidotryptamine (10-30 nM), dilated third- and fourth-order arterioles, responses that were abolished by 1 µM SB269970, a selective 5-HT7 receptor antagonist. In contrast, dilation induced by the muscarinic agonist, methacholine (100 nmols) was not inhibited by SB269970. Serotonin (10 nmols) failed to dilate cremaster arterioles in 5-HT7 receptor knockout rats whereas arterioles in wild-type litter mates dilated to 1 nmol 5-HT, a response blocked by 1 µM SB269970. Quantitative RT-PCR revealed that cremaster arterioles expressed mRNA for 5-HT7 receptors. CONCLUSIONS: 5-HT7 receptors mediate dilation of small arterioles in skeletal muscle and likely contribute to 5-HT-induced hypotension, in vivo.

A tight squeeze: how do we make sense of small changes in microvascular diameter?

The brain is an energetically demanding tissue which, to function adequately, requires constant fine tuning of its supporting blood flow, and hence energy supply. Whilst blood flow was traditionally believed to be regulated only by vascular smooth muscle cells on arteries and arterioles supplying the brain, recent work has suggested a critical role for capillary pericytes, which are also contractile. This concept has evoked some controversy, especially over the relative contributions of arterioles and capillaries to the control of cerebral blood flow. Here we outline why pericytes are in a privileged position to control cerebral blood flow. First we discuss the evidence, and fundamental equations, which describe how the small starting diameter of capillaries, compared to upstream arterioles, confers a potentially greater control by capillary pericytes than by arterioles over total cerebral vascular resistance. Then we suggest that the faster time frame over which low branch order capillary pericytes dilate in response to local energy demands provides a niche role for pericytes to regulate blood flow compared to slower responding arterioles. Finally, we discuss the role of pericytes in capillary stalling, whereby pericyte contraction appears to facilitate a transient stall of circulating blood cells, exacerbating the effect of pericytes upon cerebral blood flow.

Impaired dynamics of precapillary sphincters and pericytes at first-order capillaries predict reduced neurovascular function in the aging mouse brain.

The microvascular inflow tract, comprising the penetrating arterioles, precapillary sphincters and first-order capillaries, is the bottleneck for brain blood flow and energy supply. Exactly how aging alters the structure and function of the microvascular inflow tract remains unclear. By in vivo four-dimensional two-photon imaging, we reveal an age-dependent decrease in vaso-responsivity accompanied by a decrease in vessel density close to the arterioles and loss of vascular mural cell processes, although the number of mural cell somas and their alpha smooth muscle actin density were preserved. The age-related reduction in vascular reactivity was mostly pronounced at precapillary sphincters, highlighting their crucial role in capillary blood flow regulation. Mathematical modeling revealed impaired pressure and flow control in aged mice during vasoconstriction. Interventions that preserve dynamics of cerebral blood vessels may ameliorate age-related decreases in blood flow and prevent brain frailty.

Intraluminal pressure elevates intracellular calcium and contracts CNS pericytes: Role of voltage-dependent calcium channels.

Arteriolar smooth muscle cells (SMCs) and capillary pericytes dynamically regulate blood flow in the central nervous system in the face of fluctuating perfusion pressures. Pressure-induced depolarization and Ca2+ elevation provide a mechanism for regulation of SMC contraction, but whether pericytes participate in pressure-induced changes in blood flow remains unknown. Here, utilizing a pressurized whole-retina preparation, we found that increases in intraluminal pressure in the physiological range induce contraction of both dynamically contractile pericytes in the arteriole-proximate transition zone and distal pericytes of the capillary bed. We found that the contractile response to pressure elevation was slower in distal pericytes than in transition zone pericytes and arteriolar SMCs. Pressure-evoked elevation of cytosolic Ca2+ and contractile responses in SMCs were dependent on voltage-dependent Ca2+ channel (VDCC) activity. In contrast, Ca2+ elevation and contractile responses were partially dependent on VDCC activity in transition zone pericytes and independent of VDCC activity in distal pericytes. In both transition zone and distal pericytes, membrane potential at low inlet pressure (20 mmHg) was approximately -40 mV and was depolarized to approximately -30 mV by an increase in pressure to 80 mmHg. The magnitude of whole-cell VDCC currents in freshly isolated pericytes was approximately half that measured in isolated SMCs. Collectively, these results indicate a loss of VDCC involvement in pressure-induced constriction along the arteriole-capillary continuum. They further suggest that alternative mechanisms and kinetics of Ca2+ elevation, contractility, and blood flow regulation exist in central nervous system capillary networks, distinguishing them from neighboring arterioles.

The post-arteriole transitional zone: a specialized capillary region that regulates blood flow within the CNS microvasculature.

The brain is an energy hog, consuming available energy supplies at a rate out of all proportion to its relatively small size. This outsized demand, largely reflecting the unique computational activity of the brain, is met by an ensemble of neurovascular coupling mechanisms that link neuronal activity with local increases in blood delivery. This just-in-time replenishment strategy, made necessary by the limited energy-storage capacity of neurons, complicates the nutrient-delivery task of the cerebral vasculature, layering on a temporo-spatial requirement that invites - and challenges - mechanistic interpretation. The centre of gravity of research efforts to disentangle these mechanisms has shifted from an initial emphasis on astrocyte-arteriole-level processes to mechanisms that operate on the capillary level, a shift that has brought into sharp focus questions regarding the fine control of blood distribution to active neurons. As these investigations have drilled down into finer reaches of the microvasculature, they have revealed an arteriole-proximate subregion of CNS capillary networks that serves a regulatory function in directing blood flow into and within downstream capillaries. They have also illuminated differences in researchers' perspectives on the vascular structures and identity of mural cells in this region that impart the vasomodulatory effects that control blood distribution. In this review, we highlight the regulatory role of a variably named region of the microvasculature, referred to here as the post-arteriole transition zone, in channeling blood flow within CNS capillary networks, and underscore the contribution of dynamically contractile perivascular mural cell - generally, but not universally, recognized as pericytes - to this function.

Spontaneous vasomotion propagates along pial arterioles in the awake mouse brain like stimulus-evoked vascular reactivity.

Sensory stimulation evokes a local, vasodilation-mediated blood flow increase to the activated brain region, which is referred to as functional hyperemia. Spontaneous vasomotion is a change in arteriolar diameter that occurs without sensory stimulation, at low frequency (∼0.1 Hz). These vessel diameter changes are a driving force for perivascular soluble waste clearance, the failure of which has been implicated in neurodegenerative disease. Stimulus-evoked vascular reactivity is known to propagate along penetrating arterioles to pial arterioles, but it is unclear whether spontaneous vasomotion propagates similarly. We therefore imaged both stimulus-evoked and spontaneous changes in pial arteriole diameter in awake, head-fixed mice with 2-photon microscopy. By cross-correlating different regions of interest (ROIs) along the length of imaged arterioles, we assessed vasomotion propagation. We found that both during rest and during visual stimulation, one-third of the arterioles showed significant propagation (i.e., a wave), with a median (interquartile range) wave speed of 405 (323) µm/s at rest and 345 (177) µm/s during stimulation. In a second group of mice, with GCaMP expression in their vascular smooth muscle cells, we also found spontaneous propagation of calcium signaling along pial arterioles. In summary, we demonstrate that spontaneous vasomotion propagates along pial arterioles like stimulus-evoked vascular reactivity.

K+ channels in the coronary microvasculature of the ischemic heart.

Ischemic heart disease is the leading cause of death and a major public health and economic burden worldwide with expectations of predicted growth in the foreseeable future. It is now recognized clinically that flow-limiting stenosis of the large coronary conduit arteries as well as microvascular dysfunction in the absence of severe stenosis can each contribute to the etiology of ischemic heart disease. The primary site of coronary vascular resistance, and control of subsequent coronary blood flow, is found in the coronary microvasculature, where small changes in radius can have profound impacts on myocardial perfusion. Basal active tone and responses to vasodilators and vasoconstrictors are paramount in the regulation of coronary blood flow and adaptations in signaling associated with ion channels are a major factor in determining alterations in vascular resistance and thereby myocardial blood flow. K+ channels are of particular importance as contributors to all aspects of the regulation of arteriole resistance and control of perfusion into the myocardium because these channels dictate membrane potential, the resultant activity of voltage-gated calcium channels, and thereby, the contractile state of smooth muscle. Evidence also suggests that K+ channels play a significant role in adaptations with cardiovascular disease states. In this review, we highlight our research examining the role of K+ channels in ischemic heart disease and adaptations with exercise training as treatment, as well as how our findings have contributed to this area of study.

Shear stress and intravascular pressure effects on vascular dynamics: two-phase blood flow in elastic microvessels accounting for the passive stresses.

We study the steady hemodynamics in physiological elastic microvessels proposing an advanced fluid-structure interaction model. The arteriolar tissue is modeled as a two-layer fiber-reinforced hyperelastic material representing its Media and Adventitia layers. The constitutive model employed (Holzapfel et al. in J Elast 61:1-48, 2000) is parametrized via available data on stress-strain experiments for arterioles. The model is completed by simulating the blood/plasma flow in the lumen, using the thixotropic elasto-viscoplastic model in its core, and the linear Phan-Thien and Tanner viscoelastic model in its annular part. The Cell-Free Layer (CFL) and the Fåhraeus and Fåhraeus-Lindqvist effects are considered via analytical expressions based on experimental data (Giannokostas et al. in Materials (Basel) 14:367, 2021b). The coupling between tissue deformation and blood flow is achieved through the experimentally verified pressure-shear hypothesis (Pries et al. Circ Res 77:1017-1023, 1995). Our calculations confirm that the increase in the reference inner radius produces larger expansion. Also, by increasing the intraluminal pressure, the thinning of the walls is more pronounced and it may reach 40% of the initial thickness. Comparing our predictions with those in rigid-wall microtubes, we conclude that apart from the vital importance of vasodilation, there is an up to 25% reduction in wall shear stress. The passive vasodilation contributes to the decrease in the tissue stress fields and affects the hemodynamic features such as the CFL thickness, reducing the plasma layer when blood flows in vessels with elastic walls, in quantitative agreement with previous experiments. Our calculations verify the correctness of the pressure-shear hypothesis but not that of the Laplace law.

Quantification of hypoxic regions distant from occlusions in cerebral penetrating arteriole trees.

The microvasculature plays a key role in oxygen transport in the mammalian brain. Despite the close coupling between cerebral vascular geometry and local oxygen demand, recent experiments have reported that microvascular occlusions can lead to unexpected distant tissue hypoxia and infarction. To better understand the spatial correlation between the hypoxic regions and the occlusion sites, we used both in vivo experiments and in silico simulations to investigate the effects of occlusions in cerebral penetrating arteriole trees on tissue hypoxia. In a rat model of microembolisation, 25 µm microspheres were injected through the carotid artery to occlude penetrating arterioles. In representative models of human cortical columns, the penetrating arterioles were occluded by simulating the transport of microspheres of the same size and the oxygen transport was simulated using a Green's function method. The locations of microspheres and hypoxic regions were segmented, and two novel distance analyses were implemented to study their spatial correlation. The distant hypoxic regions were found to be present in both experiments and simulations, and mainly due to the hypoperfusion in the region downstream of the occlusion site. Furthermore, a reasonable agreement for the spatial correlation between hypoxic regions and occlusion sites is shown between experiments and simulations, which indicates the good applicability of in silico models in understanding the response of cerebral blood flow and oxygen transport to microemboli.

Blockade of endothelial Mas receptor restores the vasomotor response to phenylephrine in human resistance arterioles pretreated with captopril and exposed to propofol.

BACKGROUND: Hypotension that is resistant to phenylephrine is a complication that occurs in anesthetized patients treated with angiotensin converting enzyme (ACE) inhibitors. We tested the hypothesis that Ang 1-7 and the endothelial Mas receptor contribute to vasodilation produced by propofol in the presence of captopril. METHODS: The internal diameters of human adipose resistance arterioles were measured before and after administration of phenylephrine (10-9 to 10-5 M) in the presence and absence of propofol (10-6 M; added 10 min before the phenylephrine) or the Mas receptor antagonist A779 (10-5 M; added 30 min before phenylephrine) in separate experimental groups. Additional groups of arterioles were incubated for 16 to 20 h with captopril (10-2 M) or Ang 1-7 (10-9 M) before experimentation with phenylephrine, propofol, and A779. RESULTS: Propofol blunted phenylephrine-induced vasoconstriction in normal vessels. Captopril pretreatment alone did not affect vasoconstriction, but the addition of propofol markedly attenuated the vasomotor response to phenylephrine. A779 alone did not affect vasoconstriction in normal vessels, but it restored vasoreactivity in arterioles pretreated with captopril and exposed to propofol. Ang 1-7 reduced the vasoconstriction in response to phenylephrine. Addition of propofol to Ang 1-7-pretreated vessels further depressed phenylephrine-induced vasoconstriction to an equivalent degree as the combination of captopril and propofol, but A779 partially reversed this effect. CONCLUSIONS: Mas receptor activation by Ang 1-7 contributes to phenylephrine-resistant vasodilation in resistance arterioles pretreated with captopril and exposed to propofol. These data suggest an alternative mechanism by which refractory hypotension may occur in anesthetized patients treated with ACE inhibitors.

Stress adaptation in rats associate with reduced expression of cerebrovascular Kv7.4 channels and biphasic neurovascular responses.

Neurovascular coupling ensures rapid and precise delivery of O2 and nutrients to active brain regions. Chronic stress is known to disturb neurovascular signaling with grave effects on brain integrity. We hypothesized that stress-induced neurovascular disturbances depend on stress susceptibility. Wistar male rats were exposed to 8 weeks of chronic mild stress. Stressed rats with anhedonia-like behavior and with preserved hedonic state were identified from voluntary sucrose consumption. In brain slices from nonstressed, anhedonic, and hedonic rats, neurons and astrocytes showed similar intracellular Ca2+ responses to neuronal excitation. Parenchymal arterioles in brain slices from nonstressed, anhedonic, and hedonic rats showed vasodilation in response to neuronal excitation. This vasodilation was dependent on inward rectifying K+ channel (Kir2) activation. In hedonic rats, this vasodilation was transient and followed by vasoconstriction insensitive to Kir2 channel inhibition with 100 µM BaCl2. Isolated arteries from hedonic rats showed increased contractility. Elevation of bath K+ relaxed isolated middle cerebral arteries in a concentration-dependent and Kir2-dependent manner. The vasorelaxation to 20-24 mM K+ was reduced in arteries from hedonic rats. The expression of voltage-gated K+ channels, Kv7.4, was reduced in the cerebral arteries from hedonic rats, whereas the expression of arterial inward-rectifying K+ channels, Kir2.1 was similar to that of nonstressed and anhedonic rats. We propose that preserved hedonic state is associated with increased arterial contractility caused by reduced hyperpolarizing contribution of Kv7.4 channels leading to biphasic cerebrovascular responses to neuronal excitation. These findings reveal a novel potential coping mechanism associated with altered neurovascular signaling.

Modeling of vasomotion in arterioles.

We consider the flow of blood, treated as an incompressible Newtonian fluid, through vessels undergoing periodic oscillations. As remarked by many authors, in the absence of valves oscillations hinder the flow because of the lumen reduction. The underlying biological mechanism is the so-called vasomotion, observed long ago in small blood vessels. Here, we study the vasomotion in arterioles and provide its theoretical justification by analyzing the effect when the network of vessels downstream of the arterioles is considered. We thus explain both quantitatively and qualitatively, why the oscillations of the arteriole walls, a phenomenon that undoubtedly reduces blood flow at the level of the single arteriole, play a fundamental role in microcirculation. In "large" arterioles we analyze also the coupling between the vasomotion and the Fåhræus-Lindqvist effect (the tendency of the erythrocytes to accumulate towards the center). In particular, we prove that the presence of a cell depleted layer close to the vessel walls mitigates the disadvantage caused by the lumen reduction.