Changes In Smooth Muscle Tone Research Articles

TRPV6 channel mediates alcohol-induced gut barrier dysfunction and systemic response.

SUMMARYIntestinal epithelial tight junction disruption is a primary contributing factor in alcohol-associated endotoxemia, systemic inflammation, and multiple organ damage. Ethanol and acetaldehyde disrupt tight junctions by elevating intracellular Ca2+. Here we identify TRPV6, a Ca2+-permeable channel, as responsible for alcohol-induced elevation of intracellular Ca2+, intestinal barrier dysfunction, and systemic inflammation. Ethanol and acetaldehyde elicit TRPV6 ionic currents in Caco-2 cells. Studies in Caco-2 cell monolayers and mouse intestinal organoids show that TRPV6 deficiency or inhibition attenuates ethanol- and acetaldehyde-induced Ca2+ influx, tight junction disruption, and barrier dysfunction. Moreover, Trpv6−/− mice are resistant to alcohol-induced intestinal barrier dysfunction. Photoaffinity labeling of 3-azibutanol identifies a histidine as a potential alcohol-binding site in TRPV6. The substitution of this histidine, and a nearby arginine, reduces ethanol-activated currents. Our findings reveal that TRPV6 is required for alcohol-induced gut barrier dysfunction and inflammation. Molecules that decrease TRPV6 function have the potential to attenuate alcohol-associated tissue injury.

Coronary vascular regulation, remodelling, and collateralization: mechanisms and clinical implications on behalf of the working group on coronary pathophysiology and microcirculation.

Histological specimen and textbook schematics evoke static pictures of vascular networks. However, the concept of a static system is grossly misleading as vessels and their arrangement into networks exhibit a high degree of adaptation in vessel tone and vessel wall structure.1–3 These adaptive responses include the fast adjustment of vessel diameter by changes in smooth muscle tone, the slower changes of structural vessel diameter, the addition or removal of vessels by angiogenesis (sprouting/splitting), or vascular pruning ( Figure 1 ). It is relevant to distinguish physiological adaptation, maintaining an adequate state of perfusion as well as perfusion reserve, from mal-adaptation, which may occur in the context of pathological conditions, such as a persistent increase in blood pressure. There are also differences between regulatory mechanisms in larger vessels (e.g. remodelling at the site of epicardial stenosis) and those in the microcirculation. Even within the microcirculation vascular control mechanisms are highly dependent on vessel size and type and the extent of changes in vasomotor tone and structure seem to increase with decreasing vessel size.4,5 Adaptive processes in the microcirculation are increasingly emerging as being crucial for maintenance of physiological function and for the development of relevant pathological conditions. This part of the coronary circulation, exhibiting that functional and structural plasticity requires more attention in both basic and clinical science as the basis to develop improved diagnostic and therapeutic approaches. Consequently, the present review will focus on adaptive events occurring in the coronary microcirculation which is beyond the domain of catheter investigation and intravascular imaging. Figure 1 Dynamics of vascular adaptation at various time scale (angioadaptation).57 While tone provides a rapid mechanism to adjust perfusion …

Inflammation and large arteries: Potential mechanisms for inflammation-induced arterial stiffness

Systemic inflammatory conditions are associated with an increased risk of cardiovascular disease (CVD). How exactly inflammation leads to this is not fully understood, but it has been suggested that arterial stiffening, could provide potential mechanisms to explain it. Chronic, systemic inflammatory conditions, as well as acute-models of inflammation are associated with arterial stiffening. Moreover, aortic stiffness can be reversed with successful immunomodulatory therapy. Although it seems evident that inflammation is involved in the process of aortic stiffening, the precise mechanism responsible for this remains unclear.There are number of possible mechanisms by which inflammation could lead to arterial stiffening. (1) Inflammation is associated with endothelial dysfunction and this can regulate arterial stiffness via changes in smooth muscle tone. (2) Inflammation leads to increased synthesis of matrix metalloproteinases, which can degrade elastin, resulting in stiffening. (3) Several mediators of inflammation may directly stimulate vascular calcification, whereas endogenous inhibitors of vascular calcification are downregulated during inflammation, both of which can lead to stiffening. (4) During inflammation arterial glycosaminoglycan (GAG) synthesis is upregulated. In animal models, an overproduction of certain GAGs in the aorta results in stiffening of the arterial wall by thinning of elastic lamellae. (5) Finally, direct vascular inflammation could lead to arterial stiffening by changing the composition of extracellular matrix. This review aims to discuss potential mechanisms by which inflammation could lead to aortic stiffening.

Personalized Medicine

Personalized medicine merges genetics, physiology, and patient outcome. Loss of physiologic complexity (heart rate [HR] variability) is a bedside biomarker for autonomic nervous system (ANS) dysfunction. We hypothesized that variability in ANS receptor proteins (genetics) and loss of complexity (physiology) are independently associated with mortality in critical illness. Decreased HR complexity has been associated with increased mortality and morbidity in trauma and other critically ill populations. Genetic variations in alpha-1A and beta-2 adrenergic receptors (ADRA1A, ADRB2) have been associated with changes in smooth muscle tone in various tissues, and implicated in bronchial hyper-responsiveness, metabolic syndrome, and other disorders. A cohort of 644 trauma intensive care unit (ICU) admissions had complexity data and genetic samples. Two ANS receptor polymorphisms (rs1048101, Alpha ADRA1A and rs1042714, Beta ADRB2) were genotyped. Physiologic complexity at various points in the ICU stay was measured using previously-studied integer HR multiscale entropy (MSE) over 6-hour intervals (~21,600 HR data points/interval/patient). Logistic regression assessed the concurrent relationship of genotypes, complexity, and probability of survival, an acuity score incorporating age, injury mechanism/severity, and admission vitals, to risk of death. Of total, 96 patients (15%) died. Nonsurvivors had lower complexity at early, middle, and late portions of ICU stay (median MSE at least 25% less in nonsurvivors, P < 0.001) and lower incidence of the GG ADRB2 genotype (7.5% vs. 18.3%, P < 0.001). In multivariable logistic regression, the GG ADRB2 genotype carried ~3-fold decrease in mortality odds (odd ratio [OR] = 0.33, P = 0.01), independent of significant effects in HR MSE (OR = 0.93, P < 0.001), and probability of survival (OR = 0.22, P < 0.001). This first study to simultaneously examine ANS genetics, the biomarker complexity, and mortality concludes: (1) ANS genetics and physiologic complexity are independently related to mortality; (2) Genetics and complexity add information over traditional acuity scoring (probability of survival); and (3) Simultaneous assessment of ANS physiology and genetics may yield novel research, diagnostic, and therapeutic opportunities in critical illness.

T1668 Mast Cell Proteases Stimulate Neurogenic and Non-Neurogenic Mucosal Chloride Secretion in Guinea Pig Distal Ileum

G A A b st ra ct s and involved in the various gut function. However little is known about the subpopulations of TRPV1-expressing nerves and sensory peptidergic nerves in gut. We previously demonstrated that TRPV1-positive nerve fibers in rectum were most abundant among the regions of mouse large intestine. In the present study, we investigated the immunohistochemical distribution of TRPV1 channels and sensory neuropeptides and their co-localization in mouse rectum. METHODS: Extensive TRPV1-immunoreactivity was detected by using immunohistochemical staining with fluorescein-conjugated tyramide amplification. Protein gene product 9.5 (PGP), CGRP, substance P (SP) and neurokinin A (NKA)-immunoreactivity was also detected by indirect staining with their specific antibodies. The longitudinal change in smooth muscle tone was isotonically measured using Magnus apparatus. RESULTS: The localization of TRPV1 was studied at both transverse and horizontal planes of sections in mouse rectum. Numerous TRPV1-immunoreactive nerve fibers were clearly detected in the mucosal, submucosal layer and myenteric plexus. In contrast, TRPV1 nerve fibers were sparsely distributed in circular and longitudinal muscle layers. Next, double labeling studies were carried out. In the mucosal layer, all the TRPV1 nerve fibers were found to colocalize with PGP and CGRP. SP and NKA positive nerve fibers were not observed. TRPV1 nerve fibers containing both CGRP and SP were observed running around blood vessels in the submucosal layer. In the myenteric plexus, most of the TRPV1 axons were found to colocalize with PGP and CGRP. Relatively small numbers of TRPV1 axons were immunopositive for SP. NKA and SP-immunoreactive axons were observed in the circular and longitudinal muscle, and the cell bodies were detected in the myenteric plexus. NKA and SP were almost colocalized at the axons and cell bodies in muscle layer. In the Magnus experiment, capsaicininduced contraction was significantly inhibited by NK1 and NK2 receptor antagonists. DISCUSION: The present results suggest that TRPV1 nerve fibers in mouse rectum are extrinsic primary afferents. TRPV1 fibers containing CGRP are distributed in mucosal, submucosal layer and myenteric plexus and play various roles in rectal function. TRPV1 fibers containing SP and/or NKA are distributed in myenteric plexus and involved in rectal motor function by stimulating intrinsic excitatory motor neurons.

T1667 Canonical Transient Receptor Potential Channels (TRPC Channels) in Regulation of Mucosal Chloride Secretion in Guinea Pig Ileum

G A A b st ra ct s and involved in the various gut function. However little is known about the subpopulations of TRPV1-expressing nerves and sensory peptidergic nerves in gut. We previously demonstrated that TRPV1-positive nerve fibers in rectum were most abundant among the regions of mouse large intestine. In the present study, we investigated the immunohistochemical distribution of TRPV1 channels and sensory neuropeptides and their co-localization in mouse rectum. METHODS: Extensive TRPV1-immunoreactivity was detected by using immunohistochemical staining with fluorescein-conjugated tyramide amplification. Protein gene product 9.5 (PGP), CGRP, substance P (SP) and neurokinin A (NKA)-immunoreactivity was also detected by indirect staining with their specific antibodies. The longitudinal change in smooth muscle tone was isotonically measured using Magnus apparatus. RESULTS: The localization of TRPV1 was studied at both transverse and horizontal planes of sections in mouse rectum. Numerous TRPV1-immunoreactive nerve fibers were clearly detected in the mucosal, submucosal layer and myenteric plexus. In contrast, TRPV1 nerve fibers were sparsely distributed in circular and longitudinal muscle layers. Next, double labeling studies were carried out. In the mucosal layer, all the TRPV1 nerve fibers were found to colocalize with PGP and CGRP. SP and NKA positive nerve fibers were not observed. TRPV1 nerve fibers containing both CGRP and SP were observed running around blood vessels in the submucosal layer. In the myenteric plexus, most of the TRPV1 axons were found to colocalize with PGP and CGRP. Relatively small numbers of TRPV1 axons were immunopositive for SP. NKA and SP-immunoreactive axons were observed in the circular and longitudinal muscle, and the cell bodies were detected in the myenteric plexus. NKA and SP were almost colocalized at the axons and cell bodies in muscle layer. In the Magnus experiment, capsaicininduced contraction was significantly inhibited by NK1 and NK2 receptor antagonists. DISCUSION: The present results suggest that TRPV1 nerve fibers in mouse rectum are extrinsic primary afferents. TRPV1 fibers containing CGRP are distributed in mucosal, submucosal layer and myenteric plexus and play various roles in rectal function. TRPV1 fibers containing SP and/or NKA are distributed in myenteric plexus and involved in rectal motor function by stimulating intrinsic excitatory motor neurons.

Inositol trisphosphate‐dependent Ca2+ stores and mitochondria modulate slow wave activity arising from the smooth muscle cells of the guinea pig prostate gland

Changes in smooth muscle tone of the prostate gland are involved in aetiology of symptomatic prostatic hyperplasia, however the control mechanisms of prostatic smooth muscle are not well understood. Here, we have examined the role of internal Ca(2+) compartments in regulating slow wave activity in the guinea pig prostate. Standard intracellular membrane potential recording techniques were used. The majority (89%) of impaled cells displayed 'slow wave' activity. Cyclopiazonic acid (10 micromol.L(-1)) transiently depolarized (3-9 mV) the membrane potential of the prostatic stroma and transiently increased slow wave frequency. Thereafter, slow wave frequency slowly decreased over 20-30 min. Ryanodine transiently increased slow wave frequency, although after 30 min exposure slow wave frequency and time course returned to near control values. Caffeine (1 mmol.L(-1)) reduced slow wave frequency, accompanied by membrane depolarization of about 8 mV. Blockade of inositol trisphosphate receptor (IP(3)R)-mediated Ca(2+) release with 2-aminoethoxy-diphenylborate (60 micromol.L(-1)) or Xestospongin C (3 micromol.L(-1)) or inhibiting phospholipase C and IP(3) formation using U73122 (5 micromol.L(-1)) or neomycin (1 and 4 mmol.L(-1)) reduced slow wave frequency, amplitude and duration. The mitochondrial uncouplers, p-trifluoromethoxy carbonyl cyanide phenyl hydrazone (1-10 micromol.L(-1)), carbonyl cyanide m-chlorophenylhydrazone (1-3 micromol.L(-1)) or rotenone (10 micromol.L(-1)), depolarized the membrane (8-10 mV) before abolishing electrical activity. These results suggest that slow wave activity was dependent on the cyclical release of Ca(2+) from IP(3)-controlled internal stores and mitochondria. This implies that intracellular compartments were essential in the initiation and/or maintenance of the regenerative contractile activity in the guinea pig prostate gland.

Rebuttal from Drs. Hughes and West

POINT-COUNTERPOINTRebuttal from Drs. Hughes and WestPublished Online:01 May 2008https://doi.org/10.1152/japplphysiol.01092.2007bMoreSectionsPDF (59 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat The areas of agreement in this debate are twofold: 1) mean pulmonary blood flow per horizontal slice [per unit volume or, more accurately, per unit density or “alveolus” (1,6)] increases in the gravity direction, independent (for the most part) of postural orientation, 2) there is considerable inhomogeneity of blood flow within a slice of minimal vertical height. Heterogeneity, whether random or ordered, is inevitable as the spatial resolution increases, just as the length of the shoreline increases indefinitely as the sample size gets smaller. Suffice to say that there are two extremes, 1) a well-expanded, vasodilated lung with low PVR and a mean Ppa level below the top of the lung, and 2) a low volume vasoconstricted lung with high PVR and a Ppa level greater than the lung's vertical height. The effects of gravity will be prominent in the former and largely obscured in the latter.The core of the debate is about the mechanisms responsible for pulmonary blood flow heterogeneity. There has been acceptance (for more than 40 yr) that mean pulmonary blood flow per horizontal slice is influenced by the relations between Ppa, Palv, and Pv (zones I, II, and III) (7), provided the lung is well expanded and PVR is normal. But what determines heterogeneity at the same horizontal level? Between acini, or larger domains, the Seattle group maintains that the architecture of the vascular tree (presumably, arterial) determines local vascular resistance and blood flow by, for example, uneven diameters of the two daughter vessels at a bifurcation. Glenny (5) maintains that this is not random, but forms part of the fractal design of the lung (4). Against this hypothesis is 1) the arterial system contributes only 40% to total PVR (2), and 2) the compliance of the arterial tree means diameters are not fixed, but respond to changes of smooth muscle tone or intra- or extravascular pressures (themselves influenced by gravity from distortion of the lung by its own weight and by other intrathoracic structures).Distal to the arterial tree, at the alveolar septal level, recruitment and distension of vessels occurs (3), independent of arteriolar domains (8), as input pressure increases and exceeds critical opening pressure (9); in the lung periphery, input pressures are a function of vertical height and gravity. So, in subtle ways, gravity may interact with compliant vascular structures to influence local PVR within as well as between horizontal lung slices.REFERENCES1 Anthonisen NR, Milic-Emili J. Distribution of pulmonary perfusion in erect man. J Appl Physiol 21: 760–766, 1966.Link | ISI | Google Scholar2 Dawson CA. Dynamics of blood flow and pressure-volume relationship. In: The Lung: Scientific Foundations, edited by Crystal RG, West JB, et al. Philadelphia: Lippincott-Raven, 1997, p. 1503–1522.Google Scholar3 Glazier JB, Hughes JMB, Maloney JE, West JB. Measurements of capillary dimensions and blood volume in rapidly frozen lungs. J Appl Physiol 26: 65–76, 1969.Link | ISI | Google Scholar4 Glenny RW, Robertson HT. Fractal modelling of pulmonary blood flow inhomogeneity. J Appl Physiol 70: 1024–1030, 1991.Link | ISI | Google Scholar5 Glenny RW. Spatial correlation of regional pulmonary perfusion. J Appl Physiol 72: 2378–2386, 1992.Link | ISI | Google Scholar6 Hughes JMB, Glazier JB, Maloney JE, West JB. Effect of lung volume on the distribution of pulmonary blood flow in man. Respir Physiol 4: 58–72, 1968.Crossref | Google Scholar7 West JB, Dollery CT, Naimark A. Distribution of blood flow in isolated lung; relation to vascular and alveolar pressures. J Appl Physiol 19: 713–724, 1964.Link | ISI | Google Scholar8 Warrell DA, Evans JW, Clarke RO, Kingaby JP, West JB. Pattern of filling in the pulmonary vascular bed. J Appl Physiol 32: 346–356, 1972.Link | ISI | Google Scholar9 West JB, Schneider AM, Mitchell MM. Recruitment in networks of pulmonary capillaries. J Appl Physiol 39: 976–984, 1975.Link | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 104Issue 5May 2008Pages 1535-1535 Copyright & PermissionsCopyright © 2008 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.01092.2007bHistory Published online 1 May 2008 Published in print 1 May 2008 Metrics

Potential Roles for Statins in Critically Ill Patients

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most commonly prescribed agents for hypercholesterolemia and have revolutionized the management of hyperlipidemia and the area of cardiovascular risk reduction. However, recent data suggest that their effects go well beyond the lipid lowering seen with long-term use and may include acute antiinflammatory activity, anticoagulation, immunomodulation, as well as promotion of changes in smooth-muscle tone. Because of these data, promising research has begun into the use of these agents in various critical care areas such as the early phases of sepsis, bacteremia, and ischemic stroke. Recent data also show a decrease in cerebral vasospasm after subarachnoid hemorrhage, an area deficient in therapeutic options. More research is necessary to ascertain the true role of statins in the treatment of these various disorders. Nevertheless, the concept of a statin's role as being only a routine preventive therapy with benefits limited to patients undergoing extended treatment is rapidly becoming inaccurate.

Cyclic GMP phosphodiesterases and regulation of smooth muscle function.

Cyclic GMP (cGMP) made in response to atrial natriuretic peptide (ANP) or nitric oxide (NO) is an important regulator of short-term changes in smooth muscle tone and longer-term responses to chronic drug treatment or proliferative signals. The ability of smooth muscle cells (SMCs) to utilize different combinations of phosphodiesterase (PDE) isozymes allows cGMP to mediate these multiple processes. For example, PDE5 as a major cGMP-hydrolyzing PDE effectively controls the development of smooth muscle relaxation. In order for contraction to occur, PDE5 is activated and cGMP falls. Conversely, blockade of PDE5 activity allows the relaxation cycle to be prolonged and enhanced. A recently shown direct activation of PDE5 by cGMP binding to the GAF A domain suggests that this regulatory site might be a target for new drug development. The calcium surge associated with vasoconstrictor initiated contraction also activates a calcium/calmodulin-dependent PDE (PDE1A). Together, PDE5 and PDE1A lower cGMP sufficiently to allow contraction. Longer term, both PDE5 and PDE1A mRNA are induced by chronic stimulation of guanylyl cyclase. This induction is a major cause of the tolerance that develops to NO-releasing drugs. Finally, high levels of cGMP or cAMP also act as a brake to attenuate the proliferative response of SMCs to many mitogens. After vessel damage, in order for SMC proliferation to occur, the levels of cGMP and cAMP must be decreased. In humans, this decrease is caused in large part by induction of another Ca2+/calmodulin-dependent PDE (PDE1C) that allows the brake to be released and proliferation to start.

Airway nerves: neurotransmitter release.

A number of methods exist that allow one to study the pharmacology of neuropeptide release in the airways. Methods include in vitro organ bath techniques to measure neuropeptide release functionally as changes in smooth-muscle tone and direct measurement of neuropeptide release from airway tissue or cultured sensory neurones. The measurement of sensory neuropeptide release from afferent nerves has contributed greatly to our understanding of the role played by these nerves in the control of lung function.

Smooth muscle relaxation and local hydraulic impedance properties of the aorta.

Smooth muscle relaxation is expected to yield beneficial effects on hydraulic impedance properties of large vessels. We investigated the effects of intravenous diltiazem infusion on aortic wall stiffness and local hydraulic impedance properties. In seven anesthetized, closed-chest dogs, instantaneous cross-sectional area and pressure of the descending thoracic aorta were measured using transesophageal echocardiography combined with acoustic quantification and a micromanometer, respectively. Data were acquired during a vena caval balloon inflation, both at the control condition and with diltiazem infusion. At the operating point, diltiazem reduced blood pressure in all dogs but did not alter aortic dimensions or wall stiffness. Over the observed pressure range, aortic area-pressure relationships were linear. Whereas diltiazem affected the slope of this relationship variably (no change in 3 dogs, increase in 1 dog, decrease in 3 dogs), the zero-pressure area intercept was significantly increased in every case such that higher area was observed at any given pressure. When comparisons were made at a common level of wall stress, wall stiffness was either increased or unchanged during diltiazem infusion. In contrast, diltiazem decreased wall stiffness in every case when comparisons were made at a common level of aortic midwall radius. Aortic characteristic impedance and pulse wave velocity, components of left ventricular hydraulic load that are determined by aortic elastic and geometric properties, were affected variably. A comparison of wall stiffness at matched wall stress appears inappropriate for assessing changes in smooth muscle tone. Because of the competing effects of changes in vessel diameter and wall stiffness, smooth muscle relaxation is not necessarily accompanied by the expected beneficial changes in local aortic hydraulic impedance. These results can be reconciled by recognizing that components other than vascular smooth muscle (e.g., elastin, collagen) contribute to aortic wall stiffness.

Modulatory role of endothelial calcium level in vascular tension of canine depolarized coronary arteries.

The vascular tension in the coronary artery is modulated by factors released by endothelial cells. We investigated the relationship between the Ca2+ level in endothelium and endothelium-mediated changes in smooth muscle tone in high K(+)-depolarized canine coronary arteries by measuring intracellular Ca2+ concentration fluorimetrically with the Ca2+ indicator fura 2. Addition of Ca2+ (1 mM) caused an increase in endothelial Ca2+ and relaxed the 30 mM K(+)-depolarized arteries following inhibition of Ca2+ influx in the smooth muscle with diltiazem. This relaxation was inhibited by NG-monomethyl-L-arginine. As extracellular K+ concentration was decreased, increases of endothelial Ca2+ were augmented, whereas the relaxation was decreased. Basal muscle tone was found to be decreased in low K+ by measuring relaxation by sodium nitroprusside. These results suggest the importance of Ca2+ level in the endothelium in playing a modulatory role in coronary tension through the production of nitric oxide. The correlation of extracellular K+ to Ca2+ level in the endothelium indicates a typical characteristic of the passive Ca2+ entry pathway in the endothelium, whereas the resultant relaxation appears to be restricted by the basal muscle tone.

Continuous monitoring of cerebrovascular pressure-reactivity in head injury.

Cerebrovascular vasomotor reactivity reflects changes in smooth muscle tone in the arterial wall in response to changes in transmural pressure or concentration of carbon dioxide in blood. We have investigated whether slow waves in ABP and ICP may be used to derive an index which reflects reactivity of vessels to changes in arterial blood pressure. A method for the continuous monitoring of the association between slow spontaneous waves in ICP and AP has been adopted in a group of 98 head injured patients. ABP, ICP and transcranial Doppler blood flow velocity (FV) in the middle cerebral artery was recorded daily (20 to 120 minutes time periods). A Pressure-Reactivity Index (PRx) was calculated as a moving correlation coefficient between 40 consecutive samples of values for ICP and ABP averaged over 5 seconds. A moving correlation coefficient between spontaneous fluctuations of mean FV and CPP (Mx), which was previously reported to describe cerebral blood flow autoregulation, was also calculated. In an additional 25 patients, PRx was calculated and recorded continuously along with mean ICP, ABP and parameters describing ICP waveform. A positive PRx correlated with high ICP (r = 0.366; p < 0.001), low admission GCS (r = 0.29; p < 0.01), and poor outcome at 6 months after injury (r = 0.48; p < 0.00001). During the first two days following injury, PRx was positive (p < 0.05) in patients with unfavourable outcome. The correlation between PRx and Mx (r = 0.63) was highly significant (p < 0.000001). Continuous recordings demonstrated that PRx was able to indicate individual thresholds of vascular reactivity for CPP, ICP, and ventilation parameters. Computer analysis of slow waves in ABP and ICP is able to provide a continuous index of cerebrovascular reactivity to changes in arterial pressure, which is of prognostic significance.

Continuous assessment of the cerebral vasomotor reactivity in head injury.

Cerebrovascular vasomotor reactivity reflects changes in smooth muscle tone in the arterial wall in response to changes in transmural pressure or the concentration of carbon dioxide in blood. We investigated whether slow waves in arterial blood pressure (ABP) and intracranial pressure (ICP) may be used to derive an index that reflects the reactivity of vessels to changes in ABP. A method for the continuous monitoring of the association between slow spontaneous waves in ICP and arterial pressure was adopted in a group of 82 patients with head injuries. ABP, ICP, and transcranial doppler blood flow velocity in the middle cerebral artery was recorded daily (20- to 120-min time periods). A Pressure-Reactivity Index (PRx) was calculated as a moving correlation coefficient between 40 consecutive samples of values for ICP and ABP averaged for a period of 5 seconds. A moving correlation coefficient (Mean Index) between spontaneous fluctuations of mean flow velocity and cerebral perfusion pressure, which was previously reported to describe cerebral blood flow autoregulation, was also calculated. A positive PRx correlated with high ICP (r = 0.366; P < 0.001), low admission Glasgow Coma Scale score (r = 0.29; P < 0.01), and poor outcome at 6 months after injury (r = 0.48; P < 0.00001). During the first 2 days after injury, PRx was positive (P < 0.05), although only in patients with unfavorable outcomes. The correlation between PRx and Mean index (r = 0.63) was highly significant (P < 0.000001). Computer analysis of slow waves in ABP and ICP is able to provide a continuous index of cerebrovascular reactivity to changes in arterial pressure, which is of prognostic significance.

Physiologic aspects of drug therapy and large artery elastic properties.

Vasoactive drugs alter smooth muscle tone not only in arterial resistance vessels, but also in large conduit arteries. The resultant changes in smooth muscle tone alter both conduit vessel size and stiffness and hence influence pulsatile components of left ventricular afterload. The effects of smooth muscle relaxation and contraction on arterial elastic properties are complex and have not been fully characterized. Several recent studies have utilized a new intravascular ultrasound technique to study the effects of changes in smooth muscle tone on brachial artery elastic mechanics in normal human subjects in vivo. Smooth muscle relaxation with nitroglycerin improves isobaric brachial artery compliance without significantly altering arterial wall stiffness as measured by incremental elastic modulus (Einc). The improvement in compliance with smooth muscle relaxation is the net result of factors that: (1) increase wall stiffness (increased tension in parallel elastin and collagen fibers); (2) decrease wall stiffness (decreased tension in the smooth muscle and its associated series elastic component); and (3) increase vessel lumen size. Using a modified Maxwell model for the arterial wall, smooth muscle relaxation is also shown to shift the predominant elements contributing to wall stress and Einc from smooth muscle and the collagen fibers in series with the smooth muscle to collagen fibers in parallel with the smooth muscle. A better understanding of the mechanisms contributing to changes in arterial elastic mechanics following alterations in smooth muscle tone will help in developing pharmacologic therapies aimed at reducing pulsatile components of left ventricular afterload.

Measuring Forearm Blood Flow and Interpreting the Responses to Drugs and Mediators

Venous occlusion plethysmography has been widely used to study forearm blood flow. The principle of the technique is straightforward: the rate of swelling of the forearm during occlusion of venous return is used to assess the rate of arterial inflow. Provided that perfusion pressure (arterial blood pressure) remains constant, changes in flow reflect changes in smooth muscle tone in small arteries and arterioles. Local infusion into the brachial artery allows assessment of the direct effect of drugs on vascular tone and has been used to probe the roles of endogenous mediators. The technique is at its most powerful when dose-response relationships to different drugs or mediators within a single study are being compared but can also be used for comparison of responses to drugs between healthy control subjects and patient populations. However, when responses between groups are being compared, it is important to take into account the starting conditions of baseline blood flow and pressure. This article describes venous occlusion plethysmography, discusses the presentation and analysis of data (dose of drug or concentration? forearm blood flow or resistance?), and highlights certain potential problems and limitations of the technique as a means of studying disease states.

Sympathetic denervation of resistance arteries increases contraction and decreases relaxation to flow.

The effect of chronic sympathetic and possibly sensory denervation on flow-induced changes in smooth muscle tone was examined in a branch of the rabbit ear artery (200-400 microns ID). The superior cervical ganglion and 1-cm portions of the greater and anterior auricular nerves were removed from 4-wk-old rabbits while under general anesthesia, and arterial segments were studied 21 days later. Efficacy of denervation was assessed by catecholamine histochemistry and by absence of a constrictor response to transmural electrical field stimulation. Intraluminal flow of physiological saline solution was made through a pipette into matched-innervated and -denervated segments. Flow-induced contraction was increased in the denervated compared with the contralateral innervated segments. At the lowest flow rate studied (1 microliters/min), the contraction increased more than six times. This is consistent with the previously described nonspecific, nondeviational hypersensitivity of denervated vascular smooth muscle to constrictor influences. By contrast flow-related dilation at 10 and 20 microliters/min was significantly diminished. An intraluminal flow rate could be found that resulted in dilation in innervated but not the matched-denervated segments. Endothelial-mediated dilation to acetylcholine was also impaired. Chronic sympathetic denervation increased the magnitude of flow contraction and decreased that of flow relaxation.

The non-adrenergic, non-cholinergic response counteracts changes in guinea-pig airway tone with and without sympathetic activation.

1. We examined whether the non-adrenergic, non-cholinergic (NANC) neural response can counteract changes in smooth-muscle tone with and without simultaneous sympathetic activation in guinea-pig airways. 2. Isolated airway preparations were pretreated with indomethacin (10 microM) and incubated with either atropine (1 microM) and guanethidine (10 microM) or atropine (1 microM) alone. The response to electrical field stimulation (EFS: 1200 mA, 0.5 ms, 3 Hz for 240 s) was studied at various levels of tone prior to EFS: first without induced tone, then at a moderate tone induced by histamine (0.3 microM) and finally at a high tone induced by histamine (6 microM). 3. The response to EFS was a contraction when the tone prior to EFS was low and a relaxation when the tone prior to EFS was high. These responses converged towards a similar level of tone, in the distal trachea and in the main bronchus, with and without guanethidine. 4. The mean (s.e. mean) level of tone towards which the responses to EFS converged was lower after incubation with atropine alone compared with incubation with atropine and guanethidine, both in the distal trachea [8 (1)% compared with 30 (6)% of maximum tone] and in the main bronchus [28 (4)% compared with 57 (2)% of maximum tone]. In separate experiments, the guanethidine-induced effect on the responses to EFS was imitated by propranolol (1 microM) but not by prazosin (0.3 microM) and yohimbine (1 microM). 5. These findings indicate that the NANC neural response can counteract changes in airway smooth-muscle tone via a contraction or via a relaxation, depending on the tone prior to activation.This stabilizing effect on tone does not appear to depend upon adrenergic activation per se. The level of tone towards which the NANC responses converge can, however, be reduced by beta-adrenoceptor activation, thus suggesting an interaction which provides protection from severe airway smooth-muscle contraction.

Smooth muscle tone and rapid resetting of rat aortic baroreceptors.

Changes in conditioning mean arterial pressure (cMAP) selectively alter the set point of arterial baroreceptors and baroreflexes without affecting gain. Changes in smooth muscle tone at constant cMAPs shift the pressure-discharge curves of aortic baroreceptors in a similar manner. Using an in vitro preparation of the rat aortic arch, we tested whether near maximal changes in smooth muscle tone affect rapid resetting in single regularly discharging aortic baroreceptors. Discharge, pressure, and aortic diameter were simultaneously measured. By using vasoactive drugs (phenylephrine, angiotensin II, Bay K 8644, and nitroprusside), rapid resetting to cMAP changes was tested during different smooth muscle tone conditions (control, constricted, and dilated). Baroreceptor discharge-response curves were periodically assessed with slow ramps of increasing pressure at each of three different cMAP levels (10-15 minutes each). Rapid resetting relations were constructed for pressure threshold (Pth) and diameter threshold (Dth) plotted against cMAP and conditioning diameter (cD), respectively. Vasoconstriction decreased Pth in all baroreceptors (n = 13, p less than 0.05). Baroreceptor resetting ability as indicated by the slopes of the resetting relations (pressure- or diameter-resetting ratios, delta Pth/delta cMAP or delta Dth/delta cD, respectively) was unaffected by large increases in smooth muscle tone (p greater than 0.12). Vasoconstriction, however, offset the pressure-resetting relation, shifting the linear relation in a parallel manner to higher Pth values. In contrast, Dth values during vasoconstriction were not offset but instead fell along a single diameter-resetting relation coincident with the control relation for each baroreceptor. This last result suggests that acute alteration of vessel mechanics by vasoconstriction does not alter the basic rapid resetting process.(ABSTRACT TRUNCATED AT 250 WORDS)