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Automated quantification of microvascular perfusion.
McClatchey PM, Mignemi NA, Xu Z, Williams IM, Reusch JEB, McGuinness OP, Wasserman DH
(2018) Microcirculation 25: e12482
MeSH Terms: Animals, Automation, Blood Flow Velocity, Hematocrit, Mice, Microcirculation, Microscopy, Fluorescence, Microscopy, Video, Microvessels, Perfusion, Phenylephrine, Reproducibility of Results, Saline Solution, Software
Show Abstract · Added March 26, 2019
OBJECTIVE - Changes in microvascular perfusion have been reported in many diseases, yet the functional significance of altered perfusion is often difficult to determine. This is partly because commonly used techniques for perfusion measurement often rely on either indirect or by-hand approaches.
METHODS - We developed and validated a fully automated software technique to measure microvascular perfusion in videos acquired by fluorescence microscopy in the mouse gastrocnemius. Acute perfusion responses were recorded following intravenous injections with phenylephrine, SNP, or saline.
RESULTS - Software-measured capillary flow velocity closely correlated with by-hand measured flow velocity (R = 0.91, P < 0.0001). Software estimates of capillary hematocrit also generally agreed with by-hand measurements (R = 0.64, P < 0.0001). Detection limits range from 0 to 2000 μm/s, as compared to an average flow velocity of 326 ± 102 μm/s (mean ± SD) at rest. SNP injection transiently increased capillary flow velocity and hematocrit and made capillary perfusion more steady and homogenous. Phenylephrine injection had the opposite effect in all metrics. Saline injection transiently decreased capillary flow velocity and hematocrit without influencing flow distribution or stability. All perfusion metrics were temporally stable without intervention.
CONCLUSIONS - These results demonstrate a novel and sensitive technique for reproducible, user-independent quantification of microvascular perfusion.
© 2018 John Wiley & Sons Ltd.
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14 MeSH Terms
Photoperiod programs dorsal raphe serotonergic neurons and affective behaviors.
Green NH, Jackson CR, Iwamoto H, Tackenberg MC, McMahon DG
(2015) Curr Biol 25: 1389-94
MeSH Terms: 8-Hydroxy-2-(di-n-propylamino)tetralin, Adrenergic alpha-1 Receptor Agonists, Animals, Dorsal Raphe Nucleus, Dose-Response Relationship, Drug, Female, Male, Mesencephalon, Mice, Inbred C3H, Mice, Knockout, Norepinephrine, Organ Culture Techniques, Phenylephrine, Photoperiod, Receptor, Melatonin, MT1, Serotonergic Neurons, Serotonin, Serotonin Receptor Agonists
Show Abstract · Added March 18, 2020
The serotonergic raphe nuclei of the midbrain are principal centers from which serotonin neurons project to innervate cortical and sub-cortical structures. The dorsal raphe nuclei receive light input from the circadian visual system and indirect input from the biological clock nuclei. Dysregulation of serotonin neurotransmission is implicated in neurobehavioral disorders, such as depression and anxiety, and alterations in the serotonergic phenotype of raphe neurons have dramatic effects on affective behaviors in rodents. Here, we demonstrate that day length (photoperiod) during development induces enduring changes in mouse dorsal raphe serotonin neurons—programming their firing rate, responsiveness to noradrenergic stimulation, intrinsic electrical properties, serotonin and norepinephrine content in the midbrain, and depression/anxiety-related behavior in a melatonin receptor 1 (MT1)-dependent manner. Our results establish mechanisms by which seasonal photoperiods may dramatically and persistently alter the function of serotonin neurons.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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Targeted inhibition of ANKRD1 disrupts sarcomeric ERK-GATA4 signal transduction and abrogates phenylephrine-induced cardiomyocyte hypertrophy.
Zhong L, Chiusa M, Cadar AG, Lin A, Samaras S, Davidson JM, Lim CC
(2015) Cardiovasc Res 106: 261-71
MeSH Terms: Animals, Cardiomegaly, Cells, Cultured, GATA4 Transcription Factor, MAP Kinase Signaling System, Mice, Mice, Knockout, Muscle Proteins, Nuclear Proteins, Phenylephrine, Phosphorylation, Repressor Proteins, Signal Transduction
Show Abstract · Added April 24, 2015
AIMS - Accumulating evidence suggest that sarcomere signalling complexes play a pivotal role in cardiomyocyte hypertrophy by communicating stress signals to the nucleus to induce gene expression. Ankyrin repeat domain 1 (ANKRD1) is a transcriptional regulatory protein that also associates with sarcomeric titin; however, the exact role of ANKRD1 in the heart remains to be elucidated. We therefore aimed to examine the role of ANKRD1 in cardiomyocyte hypertrophic signalling.
METHODS AND RESULTS - In neonatal rat ventricular myocytes, we found that ANKRD1 is part of a sarcomeric signalling complex that includes ERK1/2 and cardiac transcription factor GATA4. Treatment with hypertrophic agonist phenylephrine (PE) resulted in phosphorylation of ERK1/2 and GATA4 followed by nuclear translocation of the ANKRD1/ERK/GATA4 complex. Knockdown of Ankrd1 attenuated PE-induced phosphorylation of ERK1/2 and GATA4, inhibited nuclear translocation of the ANKRD1 complex, and prevented cardiomyocyte growth. Mice lacking Ankrd1 are viable with normal cardiac function. Chronic PE infusion in wild-type mice induced significant cardiac hypertrophy with reactivation of the cardiac fetal gene program which was completely abrogated in Ankrd1 null mice. In contrast, ANKRD1 does not play a role in haemodynamic overload as Ankrd1 null mice subjected to transverse aortic constriction developed cardiac hypertrophy comparable to wild-type mice.
CONCLUSION - Our study reveals a novel role for ANKRD1 as a selective regulator of PE-induced signalling whereby ANKRD1 recruits and localizes GATA4 and ERK1/2 in a sarcomeric macro-molecular complex to enhance GATA4 phosphorylation with subsequent nuclear translocation of the ANKRD1 complex to induce hypertrophic gene expression.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
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13 MeSH Terms
Nitric oxide and regulation of heart rate in patients with postural tachycardia syndrome and healthy subjects.
Gamboa A, Okamoto LE, Raj SR, Diedrich A, Shibao CA, Robertson D, Biaggioni I
(2013) Hypertension 61: 376-81
MeSH Terms: Adult, Autonomic Nervous System, Baroreflex, Blood Pressure, Enzyme Inhibitors, Female, Heart Rate, Humans, Male, Nitric Oxide, Nitric Oxide Synthase, Phenylephrine, Postural Orthostatic Tachycardia Syndrome, omega-N-Methylarginine
Show Abstract · Added December 10, 2013
The objective is to study the role of nitric oxide (NO) on cardiovascular regulation in healthy subjects and postural tachycardia syndrome (POTS) patients. Reduced neuronal NO function, which could contribute to a hyperadrenergic state, and increased NO-induced vasodilation, which could contribute to orthostatic intolerance, have been reported in POTS. In protocol 1, 13 healthy volunteers (33 ± 3 years) underwent autonomic blockade with trimethaphan and were administered equipressor doses of Nω-monomethyl-L-arginine (L-NMMA, a NO synthase inhibitor) and phenylephrine to determine the direct chronotropic effects of NO (independent of baroreflex modulation). In protocol 2, we compared the effects of L-NMMA in 9 POTS patients (31 ± 3 years) and 14 healthy (32 ± 2 years) volunteers, during autonomic blockade. During autonomic blockade, L-NMMA and phenylephrine produced similar increases in systolic blood pressure (27 ± 2 versus 27 ± 3 mm Hg). Phenylephrine produced only minimal heart rate changes, whereas L-NMMA produced a modest, but significant, bradycardia (-0.8 ± 0.4 versus -4.8 ± 1.2 bpm; P=0.011). There were no differences between POTS and healthy volunteers in the systolic blood pressure increase (22 ± 2 and 28 ± 5 mm Hg) or heart rate decrease (-6 ± 2 and -4 ± 1 bpm for POTS and controls, respectively) produced by L-NMMA. In the absence of baroreflex buffering, inhibition of endogenous NO synthesis results in a significant bradycardia, reflecting direct tonic modulation of heart rate by NO in healthy individuals. We found no evidence of a primary alteration in NO function in POTS. If NO dysfunction plays a role in POTS, it is through its interaction with the autonomic nervous system.
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14 MeSH Terms
Independent regulation of α1 and α2 adrenergic receptor-mediated vasoconstriction in vivo.
Muszkat M, Kurnik D, Sofowora GG, Wood AJ, Stein CM
(2011) J Hypertens 29: 251-6
MeSH Terms: Adrenergic alpha-1 Receptor Agonists, Adrenergic alpha-2 Receptor Agonists, Adult, Dexmedetomidine, Dose-Response Relationship, Drug, Female, Hand, Humans, Male, Models, Cardiovascular, Phenylephrine, Receptors, Adrenergic, alpha-1, Receptors, Adrenergic, alpha-2, Signal Transduction, Vasoconstriction, Young Adult
Show Abstract · Added December 10, 2013
BACKGROUND - Vascular α1 and α2 adrenergic receptors mediate vasoconstriction and are major determinants of peripheral vascular tone. There is a wide variability in vasoconstrictor sensitivity to α1 and α2 adrenergic receptor agonists among individuals. In previous studies, this variability was not explained by identified α1 and α2 adrenergic receptor genetic variants. Thus, we hypothesized that adrenergic vasoconstrictor sensitivity is determined by shared constrictor mechanisms downstream of the individual receptors and that α1 and α2 adrenergic receptor-mediated vasoconstrictor sensitivity would therefore be correlated.
METHODS - Dorsal hand vein responses to increasing doses of the α1 adrenergic receptor agonist phenylephrine (12-12 000 ng/min) and the α2 adrenergic receptor agonist dexmedetomidine (0.01-100 ng/min) were measured in healthy individuals using a linear variable differential transformer. From individual dose-response curves, we calculated the dose of phenylephrine and dexmedetomidine that produced 50% (ED50) of maximum venoconstriction (Emax) for each patient. We examined the correlation between phenylephrine and dexmedetomidine ED50 and Emax before and after adjustment for covariates (age, sex, ethnicity, BMI, blood pressure, heart rate, and baseline plasma norepinephrine concentrations).
RESULTS - In 62 patients (36 men, 34 African-American, 28 whites), the median ED50 for dexmedetomidine was 1.32 ng/min [interquartile range (IQR) 0.45-5.37 ng/min] and for phenylephrine 177.8 ng/min (IQR 40.7-436.5 ng/min). The Emax for phenylephrine was 90.8% (82.2-99.6%) and for dexmedetomidine 80.0% (64.7-95.2%). There was no correlation between individual sensitivities (ED50) to phenylephrine and dexmedetomidine, before and after adjustment for covariates (P > 0.30).
CONCLUSION - Both phenylephrine and dexmedetomidine produce strong venoconstriction in the dorsal hand vein; however, there is no significant correlation between vascular sensitivity to an α1 and α2 adrenergic receptor agonist. These findings suggest the independent regulation of vascular α1 and α2 adrenergic receptor-mediated responses.
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16 MeSH Terms
O-GlcNAcylation contributes to augmented vascular reactivity induced by endothelin 1.
Lima VV, Giachini FR, Carneiro FS, Carneiro ZN, Saleh MA, Pollock DM, Fortes ZB, Carvalho MH, Ergul A, Webb RC, Tostes RC
(2010) Hypertension 55: 180-8
MeSH Terms: Acetylglucosamine, Animals, Aorta, Thoracic, Atrasentan, Blood Pressure, Blotting, Western, Desoxycorticosterone, Drug Synergism, Endothelin-1, Glycoproteins, Glycosylation, Hypertension, In Vitro Techniques, Male, N-Acetylglucosaminyltransferases, Phenylephrine, Pyrrolidines, Rats, Rats, Wistar, Time Factors, Vasoconstriction, Vasoconstrictor Agents
Show Abstract · Added July 31, 2014
O-GlcNAcylation augments vascular contractile responses, and O-GlcNAc-proteins are increased in the vasculature of deoxycorticosterone-acetate salt rats. Because endothelin 1 (ET-1) plays a major role in vascular dysfunction associated with salt-sensitive forms of hypertension, we hypothesized that ET-1-induced changes in vascular contractile responses are mediated by O-GlcNAc modification of proteins. Incubation of rat aortas with ET-1 (0.1 mumol/L) produced a time-dependent increase in O-GlcNAc levels and decreased expression of O-GlcNAc transferase and beta-N-acetylglucosaminidase, key enzymes in the O-GlcNAcylation process. Overnight treatment of aortas with ET-1 increased phenylephrine vasoconstriction (maximal effect [in moles]: 19+/-5 versus 11+/-2 vehicle). ET-1 effects were not observed when vessels were previously instilled with anti-O-GlcNAc transferase antibody or after incubation with an O-GlcNAc transferase inhibitor (3-[2-adamantanylethyl]-2-[{4-chlorophenyl}azamethylene]-4-oxo-1,3-thiazaperhyd roine-6-carboxylic acid; 100 mumol/L). Aortas from deoxycorticosterone-acetate salt rats, which exhibit increased prepro-ET-1, displayed increased contractions to phenylephrine and augmented levels of O-GlcNAc proteins. Treatment of deoxycorticosterone-acetate salt rats with an endothelin A antagonist abrogated augmented vascular levels of O-GlcNAc and prevented increased phenylephrine vasoconstriction. Aortas from rats chronically infused with low doses of ET-1 (2 pmol/kg per minute) exhibited increased O-GlcNAc proteins and enhanced phenylephrine responses (maximal effect [in moles]: 18+/-2 versus 10+/-3 control). These changes are similar to those induced by O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate, an inhibitor of beta-N-acetylglucosaminidase. Systolic blood pressure (in millimeters of mercury) was similar between control and ET-1-infused rats (117+/-3 versus 123+/-4 mm Hg; respectively). We conclude that ET-1 indeed augments O-GlcNAc levels and that this modification contributes to the vascular changes induced by this peptide. Increased vascular O-GlcNAcylation by ET-1 may represent a mechanism for hypertension-associated vascular dysfunction or other pathological conditions associated with increased levels of ET-1.
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22 MeSH Terms
Contribution of endothelial nitric oxide to blood pressure in humans.
Gamboa A, Shibao C, Diedrich A, Choi L, Pohar B, Jordan J, Paranjape S, Farley G, Biaggioni I
(2007) Hypertension 49: 170-7
MeSH Terms: Adult, Autonomic Nervous System, Blood Pressure, Cardiotonic Agents, Cardiovascular System, Diastole, Enzyme Inhibitors, Female, Ganglionic Blockers, Humans, Male, Nitric Oxide Synthase Type III, Phenylephrine, Rest, Smoking, Systole, Trimethaphan, omega-N-Methylarginine
Show Abstract · Added December 10, 2013
Impaired endothelial-derived NO (eNO) is invoked in the development of many pathological conditions. Systemic inhibition of NO synthesis, used to assess the importance of NO to blood pressure (BP) regulation, increases BP by approximately 15 mm Hg. This approach underestimates the importance of eNO, because BP is restrained by baroreflex mechanisms and does not account for a role of neurally derived NO. To overcome these limitations, we induced complete autonomic blockade with trimethaphan in 17 normotensive healthy control subjects to eliminate baroreflex mechanisms and contribution of neurally derived NO. Under these conditions, the increase in BP reflects mostly blockade of tonic eNO. N(G)-Monomethyl-l-arginine (250 microg/kg per minute IV) increased mean BP by 6+/-3.7 mm Hg (from 77 to 82 mm Hg) in intact subjects and by 21+/-8.4 mm Hg (from 75 to 96 mm Hg) during autonomic blockade. We did not find a significant contribution of neurally derived NO to BP regulation after accounting for baroreflex buffering. To further validate this approach, we compared the effect of NOS inhibition during autonomic blockade in 10 normotensive individuals with that of 6 normotensive smokers known to have endothelial dysfunction but who were otherwise normal. As expected, normotensive smokers showed a significantly lower increase in systolic BP during selective eNO blockade (11+/-4.5 versus 30+/-2.3 mm Hg in normotensive individuals; P<0.005). Thus, we report a novel approach to preferentially evaluate the role of eNO on BP control in normal and disease states. Our results suggest that eNO is one of the most potent metabolic determinants of BP in humans, tonically restraining it by approximately 30 mm Hg.
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18 MeSH Terms
Resuscitation with pressors after traumatic brain injury.
Feinstein AJ, Patel MB, Sanui M, Cohn SM, Majetschak M, Proctor KG
(2005) J Am Coll Surg 201: 536-45
MeSH Terms: Analysis of Variance, Animals, Arginine Vasopressin, Blood Pressure, Brain Injuries, Crystalloid Solutions, Isotonic Solutions, Phenylephrine, Plasma Substitutes, Random Allocation, Resuscitation, Shock, Hemorrhagic, Statistics, Nonparametric, Swine, Vasoconstrictor Agents
Show Abstract · Added June 14, 2016
BACKGROUND - The purpose of the study was to compare initial resuscitation with arginine vasopressin (AVP), phenylephrine (PE), or isotonic crystalloid fluid alone after traumatic brain injury and vasodilatory shock.
STUDY DESIGN - Anesthetized, ventilated swine (n = 39, 30 +/- 2 kg) underwent fluid percussion traumatic brain injury followed by hemorrhage (30 +/- 2mL/kg) to a mean arterial pressure < 30mmHg, then were randomized to 1 of 5 groups to maintain mean arterial pressure > 60mmHg for 30 to 60minutes, then cerebral perfusion pressure > 60mmHg for 60 to 300minutes, either unlimited crystalloid fluid only (n = 9), arginine vasopressin + fluid (n = 9), phenylephrine + fluid (n = 9), arginine vasopressin only (n = 5), or phenylephrine only (n = 5). Heterologous transfusions were administered if hematocrit was < 13, and mannitol was administered if intracranial pressure was > 20 mmHg. Cerebrovascular reactivity was evaluated with serial CO(2) challenges.
RESULTS - In all groups, physiologic variables were similar at baseline and at the end of shock. On resuscitation, all achieved mean arterial pressure and cerebral perfusion pressure goals. Brain tissue PO(2)s were similar. With fluid only, more blood and mannitol were required, intracranial pressure and peak inspiratory pressure were higher, and cerebrovascular reactivity was decreased (all p < 0.05 versus pressor + fluid). With either pressor + fluid, cardiac output, heart rate, lactate, and mixed venous O(2) saturation were similar to fluid only, but total fluid requirements and urine output were both reduced (p < 0.05). With either pressor only, intracranial pressure remained low, but mixed venous O(2) saturation, cardiac output, and urine output were decreased (all p < 0.05 versus other groups).
CONCLUSIONS - To correct vasodilatory shock after traumatic brain injury, a resuscitation strategy that combined either phenylephrine or arginine vasopressin plus crystalloid was superior to either fluid alone or pressor alone.
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15 MeSH Terms
Beta2-adrenoceptor Thr164Ile polymorphism is associated with markedly decreased vasodilator and increased vasoconstrictor sensitivity in vivo.
Dishy V, Landau R, Sofowora GG, Xie HG, Smiley RM, Kim RB, Byrne DW, Wood AJ, Stein CM
(2004) Pharmacogenetics 14: 517-22
MeSH Terms: Adrenergic alpha-1 Receptor Agonists, Adrenergic beta-2 Receptor Agonists, Adult, Female, Heterozygote, Homozygote, Humans, Isoleucine, Isoproterenol, Phenylephrine, Polymorphism, Genetic, Receptors, Adrenergic, alpha-1, Receptors, Adrenergic, beta-2, Threonine, Vasoconstriction, Vasoconstrictor Agents, Vasodilation, Vasodilator Agents, Veins
Show Abstract · Added December 10, 2013
BACKGROUND - The uncommon Thr164Ile polymorphism of the beta2-adrenoceptor is associated with profoundly altered responses to agonist in vitro; however its effects on vascular responses in vivo are not known. Altered adrenergic vascular sensitivity may contribute to the decreased survival observed in patients with congestive heart failure carrying the Ile164 allele.
METHODS AND RESULTS - We used the linear variable differential transformer dorsal hand vein technique to compare vasodilation in response to the beta-adrenergic receptor agonist, isoproterenol, and vasoconstriction in response to the alpha-adrenergic receptor agonist, phenylephrine, in healthy homozygous (Thr164/Thr164) (n = 21) and heterozygous Thr164/Ile164 (n = 5) women. The dose of isoproterenol required to achieve 50% venodilation (geometric mean; 95% CI) was significantly higher in women with the Ile164 allele (82.5 ng/min; 17.3-394 ng/min) than those without (15.8 ng/min; 11-25 ng/min; P = 0.004). The maximum response to isoproterenol was not different (102 +/- 1% and 102 +/- 3%, respectively, P = 0.9). The dose of phenylephrine needed to induce 50% venoconstriction was significantly lower in women with the Ile164 allele (151 ng/min; 42-543 ng/min) than those without (540 ng/min; 350-835 ng/min; P = 0.02).
CONCLUSIONS - The Thr164Ile polymorphism of the beta2-adrenergic receptor is associated with a five-fold reduction in sensitivity to beta2 receptor agonist-mediated vasodilation; vasoconstrictor sensitivity is increased. The overall effect of the Thr164Ile polymorphism is to shift the balance of adrenergic vascular tone toward vasoconstriction. This suggests a mechanistic explanation for the clinical observation of decreased survival in patients with congestive heart failure heterozygous for the Thr164Ile polymorphism.
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19 MeSH Terms
Alpha 1A-adrenergic receptor polymorphism and vascular response.
Sofowora GG, Dishy V, Landau R, Xie HG, Prasad HC, Byrne DW, Smiley RM, Kim RB, Wood AJ, Stein CM
(2004) Clin Pharmacol Ther 75: 539-45
MeSH Terms: Adrenergic alpha-1 Receptor Agonists, Adult, Analysis of Variance, Dose-Response Relationship, Drug, Female, Humans, Male, Muscle, Smooth, Vascular, Phenylephrine, Polymorphism, Genetic, Receptors, Adrenergic, alpha-1, Vasoconstriction
Show Abstract · Added December 10, 2013
OBJECTIVE - The alpha(1A)-adrenergic receptor is highly expressed in human vasculature including resistance arteries and veins, and its stimulation is primarily responsible for adrenergically mediated smooth muscle contraction. Variability in sensitivity to phenylephrine, an alpha(1A) adrenergic agonist, has a large genetic component. We examined the hypothesis that a common polymorphism of alpha(1A)-adrenergic receptor (Arg347Cys) affects in vivo response.
METHODS - We measured vascular sensitivity to phenylephrine using the dorsal hand vein linear variable differential transformer technique and determined alpha(1A)-adrenergic receptor genotype in 74 healthy, nonsmoking adults (28 Arg/Arg, 30 Arg/Cys, and 16 Cys/Cys).
RESULTS - Sensitivity to phenylephrine, expressed as the dose of phenylephrine resulting in 50% venoconstriction (Phe(50)), was not significantly different in subjects with the 3 alpha(1A) adrenergic receptor genotypes: Phe(50) geometric mean (95% confidence interval) was 513 ng/min (287-918 ng/min) for Arg/Arg, 431 ng/min (274-680 ng/min) for Arg/Cys, and 471 ng/min (197-1124 ng/min) for Cys/Cys (P =.90).
CONCLUSION - We conclude that the Arg347Cys receptor polymorphism does not alter agonist-mediated venoconstriction in vivo.
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12 MeSH Terms