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1.
Skin Pharmacol Physiol ; 36(5): 249-258, 2023.
Article in English | MEDLINE | ID: mdl-37788642

ABSTRACT

INTRODUCTION: Elastic skin fibers lose their mechanical properties during aging due to enzymatic degradation, lack of maturation, or posttranslational modifications. Dill extract has been observed to increase elastin protein expression and maturation in a 3D skin model, to improve mechanical properties of the skin, to increase elastin protein expression in vascular smooth muscle cells, to preserve aortic elastic lamella, and to prevent glycation. OBJECTIVE: The aim of the study was to highlight dill actions on elastin fibers during aging thanks to elastase digestion model and the underlying mechanism. METHODS: In this study, elastic fibers produced by dermal fibroblasts in 2D culture model were injured by elastase, and we observed the action of dill extract on elastic network by elastin immunofluorescence. Then action of dill extract was examined on mice skin by injuring elastin fibers by intradermal injection of elastase. Then elastin fibers were observed by second harmonic generation microscopy, and their functionality was evaluated by oscillatory shear stress tests. In order to understand mechanism by which dill acted on elastin fibers, enzymatic tests and real-time qPCR on cultured fibroblasts were performed. RESULTS: We evidence in vitro that dill extract is able to prevent elastin from elastase digestion. And we confirm in vivo that dill extract treatment prevents elastase digestion, allowing preservation of the cutaneous elastic network in mice and preservation of the cutaneous elastic properties. Although dill extract does not directly inhibit elastase activity, our results show that dill extract treatment increases mRNA expression of the endogenous inhibitor of elastase, elafin. CONCLUSION: Dill extract can thus be used to counteract the negative effects of elastase on the cutaneous elastic fiber network through modulation of PI3 gene expression.


Subject(s)
Anethum graveolens , Elastic Tissue , Mice , Animals , Elastic Tissue/metabolism , Elafin , Anethum graveolens/metabolism , Elastin/metabolism , Pancreatic Elastase/metabolism
2.
J Biomed Mater Res A ; 109(6): 926-937, 2021 06.
Article in English | MEDLINE | ID: mdl-32779367

ABSTRACT

Poly(ethylene glycol) (PEG) hydrogels have been extensively used as scaffolds for tissue engineering applications, owing to their biocompatibility, chemical versatility, and tunable mechanical properties. However, their bio-inert properties require them to be associated with additional functional moieties to interact with cells. To circumvent this need, we propose here to reticulate PEG molecules with poly(L-lysine) dendrigrafts (DGL) to provide intrinsic cell functionalities to PEG-based hydrogels. The physico-chemical characteristics of the resulting hydrogels were studied in regard of the concentration of each component. With increasing amounts of DGL, the cross-linking time and swelling ratio could be decreased, conversely to mechanical properties, which could be tailored from 7.7 ± 0.7 to 90 ± 28.8 kPa. Furthermore, fibroblasts adhesion, viability, and morphology on hydrogels were then assessed. While cell adhesion significantly increased with the concentration of DGL, cell viability was dependant of the ratio of DGL and PEG. Cell morphology and proliferation; however, appeared mainly related to the overall hydrogel rigidity. To allow cell infiltration and cell growth in 3D, the hydrogels were rendered porous. The biocompatibility of resulting hydrogels of different compositions and porosities was evaluated by 3 week subcutaneous implantations in mice. Hydrogels allowed an extensive cellular infiltration with a mild foreign body reaction, histological evidence of hydrogel degradation, and neovascularization.


Subject(s)
Biocompatible Materials/chemistry , Polyethylene Glycols/chemistry , Polylysine/chemistry , Tissue Scaffolds , Animals , Biocompatible Materials/adverse effects , Cell Adhesion , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Cross-Linking Reagents , Foreign-Body Reaction , Humans , Hydrogels , Mechanical Phenomena , Mice , Neovascularization, Physiologic/drug effects , Polyethylene Glycols/adverse effects , Polylysine/adverse effects , Porosity , Tissue Scaffolds/adverse effects
3.
Int J Obes (Lond) ; 43(3): 556-566, 2019 03.
Article in English | MEDLINE | ID: mdl-30006585

ABSTRACT

BACKGROUND/OBJECTIVES: The increased prevalence of obesity has prompted great strides in our understanding of specific adipose depots and their involvement in cardio-metabolic health. However, the impact of obesity on dermal white adipose tissue (dWAT) and dermal microvascular functionality remains unclear. This study aimed to investigate the temporal changes that occur in dWAT and dermal microvascular functionality during the development of diet-induced obesity and type 2 diabetes in mice. METHODS: Metabolic phenotyping of a murine model of hypercaloric diet (HCD)-induced obesity and type 2 diabetes was performed at three time points that reflected three distinct stages of disease development; 2 weeks of HCD-overweight-metabolically healthy, 4 weeks of HCD-obese-prediabetic and 12 weeks of HCD-obese-type 2 diabetic mice. Expansion of dWAT was characterized histologically, and changes in dermal microvascular reactivity were assessed in response to pressure and the vasodilators SNP and Ach. RESULTS: HCD resulted in a progressive expansion of dWAT and increased expression of pro-inflammatory markers (IL1ß and COX-2). Impairments in pressure-induced (PIV) and Ach-induced (endothelium-dependent) vasodilation occurred early, in overweight-metabolically healthy mice. Residual vasodilatory responses were NOS-independent but sensitive to COX inhibition. These changes were associated with reductions in NO and adiponectin bioavailability, and rescued by exogenous adiponectin or hyperinsulinemia. Obese-prediabetic mice continued to exhibit impaired Ach-dependent vasodilation but PIV appeared normalized. This normalization coincided with elevated endogenous adiponectin and insulin levels, and was sensitive to NOS, COX and PI3K, inhibition. In obese-type 2 diabetic mice, both Ach-stimulated and pressure-induced vasodilatory responses were increased through enhanced COX-2-dependent prostaglandin response. CONCLUSIONS: We demonstrate that the development of obesity, metabolic dysfunction and type 2 diabetes, in HCD-fed mice, is accompanied by increased dermal adiposity and associated metaflammation in dWAT. Importantly, these temporal changes are also linked to disease stage-specific dermal microvascular reactivity, which may reflect adaptive mechanisms driven by metaflammation.


Subject(s)
Adipose Tissue, White , Diabetes Mellitus, Type 2/physiopathology , Inflammation , Obesity/physiopathology , Skin , Adiponectin/metabolism , Adipose Tissue, White/blood supply , Adipose Tissue, White/metabolism , Adipose Tissue, White/pathology , Adipose Tissue, White/physiopathology , Animals , Cytokines/metabolism , Diabetes Mellitus, Experimental , Inflammation/metabolism , Inflammation/pathology , Inflammation/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Microvessels/metabolism , Microvessels/pathology , Microvessels/physiopathology , Skin/blood supply , Skin/metabolism , Skin/physiopathology , Vasodilation/physiology
4.
Mech Ageing Dev ; 166: 48-54, 2017 09.
Article in English | MEDLINE | ID: mdl-28705548

ABSTRACT

INTRODUCTION: The left ventricular hypertrophy (LVH)-ventricular arrhythmias relationship associated with arterial hypertension and aging remains controversial. We aimed to assess the age-dependency of ventricular arrhythmias in spontaneously hypertensive rats (SHRs) and the corresponding ventricular structural and molecular remodeling. MATERIALS AND METHODS: Ventricular arrhythmias were quantified using 24-h radiotelemetry ECG monitoring in eight SHRs and four Wistar-Kyoto (WKY) rats at 14 (young), 24 (adult), and 48 (aging) weeks of age. Left ventricular histology and mRNA expressions of 89 proarrhythmogenic genes were assessed in six additional groups (n=4 each) of young, adult, and aging SHRs and WKYs. RESULTS: Regardless of their age, SHRs presented more premature ventricular contractions (PVCs) than age-matched WKYs (p<0.01). The arrhythmogenicity peak occurred in adult SHRs; ventricular tachycardias only occurred in adult SHRs. Among the SHRs, LV thickness, interstitial fibrosis, and the number of deregulated genes increased with age. Kcnj11 expression was deregulated in adult, but not in young or aging SHRs. DISCUSSION: This study confirms the presence of higher ventricular ectopy in SHRs than in age-matched WKYs. LVH appeared to be an adaptive, antiarrhythmic process. Myocardial energetic changes with advancing age, as reflected by Kcnj11 expression changes, could underlie this age-dependency of ventricular arrhythmias.


Subject(s)
Aging/metabolism , Arrhythmias, Cardiac/metabolism , Gene Expression Regulation , Hypertension/metabolism , Hypertrophy, Left Ventricular/metabolism , Potassium Channels, Inwardly Rectifying/biosynthesis , Ventricular Remodeling , Aging/pathology , Animals , Arrhythmias, Cardiac/pathology , Arrhythmias, Cardiac/physiopathology , Hypertension/pathology , Hypertension/physiopathology , Hypertrophy, Left Ventricular/pathology , Hypertrophy, Left Ventricular/physiopathology , Male , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Risk Factors
5.
Physiol Rep ; 5(4)2017 Feb.
Article in English | MEDLINE | ID: mdl-28242823

ABSTRACT

It has been proposed that sympathoexcitation is responsible for vascular desensitization to α1-adrenoceptor stimulation during lipopolysaccharide (LPS)-induced systemic inflammation. The present study tested this hypothesis by examining the effects of sympatho-deactivation with the α2-adrenoceptor agonist, dexmedetomidine, on mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and vascular reactivity to phenylephrine in conscious rats with cardiac autonomic blockade (methylatropine and atenolol) following LPS administration. In male, adult Sprague-Dawley rats (n = 5 per group), RSNA and MAP were continuously recorded over 1-h periods, before and after LPS administration (20 mg/kg iv), and finally after infusion of either saline or dexmedetomidine (5 µg/kg, then 5 µg/kg/h iv). A full dose-response curve to phenylephrine was constructed under each condition. After pooling data from both groups of rats (n = 10), LPS significantly (P = 0.005) decreased MAP (from 115 ± 1 to 107 ± 2 mmHg), increased RSNA (to 403 ± 46% of baseline values) and induced 4 to 5-fold increases in the half-maximal effective dose (ED50) of phenylephrine (from 1.02 ± 0.09 to 4.76 ± 0.51 µg/kg). During saline infusion, RSNA progressively decreased while vascular reactivity did not improve. Treatment with dexmedetomidine decreased MAP, returned RSNA to near pre-endotoxemic levels, but only partially restored vascular reactivity to phenylephrine (ED50 was still threefold increased as compared with baseline values). These findings indicate that only part of the decrease in vascular reactivity to α1-adrenoceptor stimulation during endotoxemia can be accounted for by sympathetic activation, at least on a short-term basis.


Subject(s)
Adrenergic alpha-1 Receptor Agonists/pharmacology , Arterial Pressure/drug effects , Heart Rate/drug effects , Kidney/innervation , Lipopolysaccharides/pharmacology , Phenylephrine/pharmacology , Sympathetic Nervous System/drug effects , Animals , Male , Rats , Rats, Sprague-Dawley , Sympathetic Nervous System/physiology
6.
Clin Exp Pharmacol Physiol ; 42(10): 1084-91, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26174159

ABSTRACT

This study examined whether chronic administration of pyridostigmine, a reversible cholinesterase inhibitor, would exacerbate episodes of spontaneous atrial tachyarrhythmia (AT) in conscious, aging, spontaneously hypertensive rats (SHRs). Telemetric recordings of electrocardiogram (ECG, n = 5) and ECG/arterial pressure (n = 3) were performed in male 49-week old SHRs. After a 1-week period of continuous recording under baseline conditions, rats were implanted with osmotic minipumps that delivered pyridostigmine (15 mg/kg/day subcutaneously) for either 1 (n = 8) or 3 (n = 5) weeks. In the latter case, sympathovagal balance was assessed during the last infusion week by measuring heart rate (HR) changes in response to administration of cardiac autonomic blockers. An additional 1-week recording was performed after explantation of minipumps. Significant (P = 0.02) reductions in HR with no consistent changes in arterial pressure were observed. Frequency and duration of AT episodes were increased by pyridostigmine (0.01 ≤ P ≤ 0.07). This increase was sustained across the 3-week treatment period and reversible after cessation of treatment. Autonomic blockade revealed that intrinsic HR was above (P = 0.04) resting HR, pointing to a shift of sympathovagal balance towards vagal predominance. However, the respiratory-related component of HR variability (high-frequency power of RR interval) was lowered (P = 0.01) by pyridostigmine treatment, indicating reduced vagal modulation of HR. The results are consistent with a pathogenic role of the parasympathetic nervous system in the aging SHR model, and raise the possibility that sustained vagal activation may facilitate atrial arrhythmias.


Subject(s)
Aging/physiology , Cholinesterase Inhibitors/pharmacology , Heart Atria/drug effects , Pyridostigmine Bromide/pharmacology , Tachycardia, Supraventricular/physiopathology , Animals , Autonomic Nervous System/drug effects , Autonomic Nervous System/physiopathology , Blood Pressure/drug effects , Electrocardiography , Heart Atria/physiopathology , Heart Rate/drug effects , Male , Motor Activity/drug effects , Rats , Rats, Inbred SHR , Tachycardia, Supraventricular/chemically induced
7.
J Pharmacol Exp Ther ; 346(3): 370-80, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23818682

ABSTRACT

Symptoms of the metabolic syndrome (MetS), such as insulin resistance, obesity, and hypertension, have been associated with sympathetic hyperactivity. In addition, the adiponectin pathway has interesting therapeutic potentials in MetS. Our purpose was to investigate how targeting both the sympathetic nervous system and the adipose tissue (adiponectin secretion) with a drug selective for nonadrenergic I1-imidazoline receptors (I1Rs) may represent a new concept in MetS pharmacotherapy. LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride], a new pyrroline derivative, displaced the specific [(125)I]para-iodoclonidine binding to I1R with nanomolar affinity and had no significant affinity for a large set of receptors, transporters, and enzymes. In addition, it can cross the blood-brain barrier and has good intestinal absorption, permitting oral as well as intravenous delivery. The presence of I1Rs was demonstrated in 3T3-L1 adipocytes; LNP599 had a specific stimulatory action on adiponectin secretion in adipocytes. Short-term administration of LNP599 (10 mg/kg i.v.) in anesthetized Sprague-Dawley rats markedly decreased sympathetic activity, causing hypotension and bradycardia. Long-term treatment of spontaneously hypertensive heart failure rats with LNP599 (20 mg/kg PO) had favorable effects on blood pressure, body weight, insulin resistance, glucose tolerance, and lipid profile, and it increased plasma adiponectin. The pyrroline derivative, which inhibits sympathetic activity and stimulates adiponectin secretion, has beneficial effects on all the MetS abnormalities. The use of one single drug with both actions may constitute an innovative strategy for the management of MetS.


Subject(s)
Aniline Compounds/therapeutic use , Imidazoline Receptors/drug effects , Metabolic Syndrome/drug therapy , Pyrroles/pharmacology , Pyrroles/therapeutic use , 3T3-L1 Cells , Adiponectin/blood , Adiponectin/metabolism , Animals , Blood Pressure/drug effects , Body Weight/drug effects , Glucose Intolerance/drug therapy , Glucose Tolerance Test , Insulin Resistance , Kidney/innervation , Lipids/blood , Male , Mice , Rats , Rats, Inbred SHR , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , Surface Plasmon Resonance , Sympathetic Nervous System/drug effects
8.
Am J Physiol Heart Circ Physiol ; 303(3): H386-92, 2012 Aug 01.
Article in English | MEDLINE | ID: mdl-22661510

ABSTRACT

Experimental models of unprovoked atrial tachyarrhythmias (AT) in conscious, ambulatory animals are lacking. We hypothesized that the aging, spontaneously hypertensive rat (SHR) may provide such a model. Baseline ECG recordings were acquired with radiotelemetry in eight young (14-wk-old) and eight aging (55-wk-old) SHRs and in two groups of four age-matched Wistar-Kyoto (WKY) rats. Quantification of AT and heart rate variability (HRV) analysis were performed based on 24-h ECG recordings in unrestrained rats. All animals were submitted to an emotional stress protocol (air-jet). In SHRs, carbamylcholine injections were also performed. Spontaneous AT episodes were observed in all eight aging SHRs (median, 91.5; range, 4-444 episodes/24 h), but not in young SHRs or WKY rats. HRV analysis demonstrated significantly decreased low frequency components in aging SHRs compared with age-matched WKY rats (P < 0.01) and decreased low/high frequency ratios in both young (P < 0.01) and aging (P = 0.01) SHRs compared with normotensive controls. In aging SHRs, emotional stress significantly reduced the number of arrhythmic events, whereas carbamylcholine triggered AT and significantly increased atrial electrical instability. This study reports the occurrence of unprovoked episodes of atrial arrhythmia in hypertensive rats, and their increased incidence with aging. Our results suggest that autonomic imbalance with relative vagal hyperactivity may be responsible for the increased atrial arrhythmogenicity observed in this model. We also provide evidence that, in this model, the sympatho-vagal imbalance preceded the occurrence of arrhythmia. These results indicate that aging SHRs may provide valuable insight into the understanding of atrial arrhythmias.


Subject(s)
Aging , Autonomic Nervous System/physiopathology , Heart Rate , Hypertension/complications , Tachycardia, Supraventricular/etiology , Age Factors , Animals , Autonomic Nervous System/drug effects , Blood Pressure , Carbachol/administration & dosage , Cholinergic Agonists/administration & dosage , Disease Models, Animal , Electrocardiography, Ambulatory , Heart Rate/drug effects , Hypertension/physiopathology , Injections, Subcutaneous , Male , Phenotype , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Stress, Psychological/complications , Stress, Psychological/physiopathology , Sympathetic Nervous System/physiopathology , Tachycardia, Supraventricular/physiopathology , Tachycardia, Supraventricular/prevention & control , Telemetry , Time Factors , Vagus Nerve/physiopathology
9.
Exp Physiol ; 97(5): 564-71, 2012 May.
Article in English | MEDLINE | ID: mdl-22308161

ABSTRACT

The role of sympathetic innervation in the control of spontaneous fluctuations of cerebral blood flow is still poorly understood. In conscious, unrestrained rats, blood flow velocity (pulsed Doppler) was measured in both internal carotid arteries 1 week after either excision of the right superior cervical ganglion (n = 8) or sham surgery (n = 6). Using Fourier-based techniques, spectral power of each carotid blood flow (CBF) was computed over the whole recording period (246 min), which was segmented into nine consecutive 27.3 min periods. Variability of CBF (spectral power) was ∼40% higher (P < 0.02) on the denervated than on the intact side at frequencies <1 Hz. Coherence between left and right CBFs was similar in the two groups of rats, except in the 0.01-0.1 Hz frequency range where it was lower (P < 0.05) in rats with unilateral sympathectomy (0.54 ± 0.03) than in intact rats (0.74 ± 0.06). In this frequency range, mathematically removing the influence of arterial pressure had little effect on coherence between CBFs in both groups of rats, so that coherence remained significantly lower in rats with unilateral sympathectomy (0.52 ± 0.03) than in intact rats (0.70 ± 0.06). This study indicates that sympathetic innervation has an overall buffering influence on CBF variability. This modulatory role is especially important in a frequency range corresponding to slow fluctuations of CBF (lasting from 10 to 100 s), which are essentially unrelated to fluctuations of arterial pressure.


Subject(s)
Blood Flow Velocity/physiology , Carotid Artery, Internal/physiology , Superior Cervical Ganglion/physiology , Animals , Cerebrovascular Circulation/physiology , Ganglionectomy , Hemodynamics , Male , Rats
10.
Stress ; 15(1): 115-20, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21790485

ABSTRACT

This study examined the role of sympathetic nerves in the control of cerebral hemodynamics during air-jet stress. In adult male Sprague-Dawley rats, blood flow velocity (pulsed Doppler) was measured in both internal carotid arteries 1 week after excision of one superior cervical ganglion. Blood pressure (BP) and carotid blood flows (CBFs) were simultaneously recorded during exposure to air-jet stress. In 5 out of 13 rats, stress was applied after ß(2)-adrenoceptor blockade with ICI 118551 (0.4 mg/kg, then 0.2 mg/kg/h, i.v). Stress evoked an immediate rise in BP, CBFs, and vascular conductances. Vasodilatation was much larger on the denervated side than on the intact side (mean ± SEM: 78 ± 7 versus 19 ± 4%; P < 0.02) and lasted about 10 s. Thereafter, blood flows returned to or near normal and showed parallel variations while BP remained elevated. There was, therefore, a net vasoconstriction on both sides. In ICI 118551-treated rats, the initial vasodilatation was not significantly reduced on the denervated side (64 ± 4%), but the subsequent vasoconstriction was enhanced (P < 0.05) on both sides. In conclusion, air-jet stress evokes an immediate, short-lasting vasodilatation through a mechanism unrelated to ß(2)-adrenoceptor stimulation. Sympathetic nerves powerfully limit this phenomenon, and thus contribute to protect the cerebral circulation from stress-induced BP surges.


Subject(s)
Cerebrovascular Circulation/physiology , Stress, Psychological/physiopathology , Sympathetic Nervous System/physiology , Adrenergic beta-2 Receptor Antagonists/pharmacology , Animals , Blood Flow Velocity/physiology , Blood Pressure , Cerebrovascular Circulation/drug effects , Laser-Doppler Flowmetry , Male , Propanolamines/pharmacology , Rats , Rats, Sprague-Dawley , Superior Cervical Ganglion/physiology , Vasoconstriction
11.
Auton Neurosci ; 152(1-2): 55-9, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-19783485

ABSTRACT

The aim of this study was to examine whether multifibrenal sympathetic nerve activity (RSNA) of conscious rats contains frequency components of biological interest at frequencies above 25Hz. RSNA was recorded in 10 conscious Sprague-Dawley rats under baseline conditions and during infusion of vasoactive drugs that reflexly altered the mean RSNA level. The RSNA signal was band-pass filtered (300-3000Hz) before being sampled at 10,000Hz. The analytic envelope of this raw signal was then extracted using the Hilbert transform, and 132-s periods were submitted to Fourier transform analysis. Spectral power was computed from 0 to 25Hz and from 25 to 3000Hz (P(25-3000)). P(25-3000) was reduced by about 80% after either ganglionic blockade or euthanasia, which indicated that it was of biological origin and derived from the activity of postganglionic sympathetic neurons. After subtraction of post-mortem spectral power, basal P(25-3000) contributed 59.8+/-2.4% of total power. P(25-3000) was strongly barosensitive and thus, accounted for a major part of the reflex changes in total power. In each of the 10 rats, P(25-3000) was linearly correlated with the mean RSNA level (0.984+/-0.003) and even more so with the spectral power in the 0-25Hz frequency range (0.994+/-0.001). In conclusion, the RSNA of conscious rats contains very high frequency components that account for about 60% of the total spectral power and are modulated by the baroreceptor reflex. A reasonable approximation of this power can be obtained by computing spectra up to 25Hz.


Subject(s)
Kidney/innervation , Neurons/physiology , Sympathetic Nervous System/physiology , Vasoconstriction , Vasodilation , Action Potentials/drug effects , Animals , Baroreflex/drug effects , Electrochemical Techniques/methods , Fourier Analysis , Hemodynamics , Kidney/drug effects , Male , Nerve Fibers/physiology , Neurons/drug effects , Rats , Rats, Sprague-Dawley , Signal Processing, Computer-Assisted , Sympathetic Fibers, Postganglionic/drug effects , Sympathetic Fibers, Postganglionic/physiology , Sympathetic Nervous System/drug effects , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacology , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Wakefulness
12.
Am J Physiol Regul Integr Comp Physiol ; 295(1): R8-R14, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18448616

ABSTRACT

This study compared the baroreflex control of lumbar and renal sympathetic nerve activity (SNA) in conscious rats. Arterial pressure (AP) and lumbar and renal SNA were simultaneously recorded in six freely behaving rats. Pharmacological estimates of lumbar and renal sympathetic baroreflex sensitivity (BRS) were obtained by means of the sequential intravenous administration of sodium nitroprusside and phenylephrine. Sympathetic BRS was significantly (P < 0.05) lower for lumbar [3.0 +/- 0.4 normalized units (NU)/mmHg] than for renal (7.6 +/- 0.6 NU/mmHg) SNA. During a 219-min baseline period, spontaneous lumbar and renal BRS were continuously assessed by computing the gain of the transfer function relating AP and SNA at heart rate frequency over consecutive 61.4-s periods. The transfer gain was considered only when coherence between AP and SNA significantly differed from zero, which was verified in 99 +/- 1 and 96 +/- 3% of cases for lumbar and renal SNA, respectively. When averaged over the entire baseline period, spontaneous BRS was significantly (P < 0.05) lower for lumbar (1.3 +/- 0.2 NU/mmHg) than for renal (2.3 +/- 0.3 NU/mmHg) SNA. For both SNAs, spontaneous BRS showed marked fluctuations (variation coefficients were 26 +/- 2 and 28 +/- 2% for lumbar and renal SNA, respectively). These fluctuations were positively correlated in five of six rats (R = 0.44 +/- 0.06; n = 204 +/- 8; P < 0.0001). We conclude that in conscious rats, the baroreflex control of lumbar and renal SNA shows quantitative differences but is modulated in a mostly coordinated way.


Subject(s)
Adrenergic Fibers/physiology , Baroreflex/physiology , Kidney/innervation , Lumbosacral Region/innervation , Sympathetic Nervous System/physiology , Animals , Blood Pressure/physiology , Kidney/physiology , Lumbosacral Region/physiology , Male , Rats , Rats, Sprague-Dawley
13.
Am J Physiol Regul Integr Comp Physiol ; 293(5): R1938-46, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17804584

ABSTRACT

The present study examined whether the gain of the transfer function relating cardiac-related rhythm of renal sympathetic nerve activity (RSNA) to arterial pressure (AP) pulse might serve as a spontaneous index of sympathetic baroreflex sensitivity (BRS). AP and RSNA were simultaneously recorded in conscious rats, either baroreceptor-intact (control, n = 11) or with partial denervation of baroreflex afferents [aortic baroreceptor denervated (ABD; n = 10)] during 1-h periods of spontaneous activity. Transfer gain was calculated over 58 adjacent 61.4-s periods (segmented into 10.2-s periods). Coherence between AP and RSNA was statistically (P < 0.05) significant in 90 +/- 3% and 56 +/- 10% of cases in control and ABD rats, respectively. Transfer gain was higher (P = 0.0049) in control [2.39 +/- 0.13 normalized units (NU)/mmHg] than in ABD (1.48 +/- 0.22 NU/mmHg) rats. In the pooled study sample, transfer gain correlated with sympathetic BRS estimated by the vasoactive drug injection technique (R = 0.75; P < 0.0001) and was inversely related to both time- (standard deviation; R = -0.74; P = 0.0001) and frequency-domain [total spectral power (0.00028-2.5 Hz); R = -0.82; P < 0.0001] indices of AP variability. In control rats, transfer gain exhibited large fluctuations (coefficient of variation: 34 +/- 3%) that were not consistently related to changes in the mean level of AP, heart rate, or RSNA. In conclusion, the transfer function method provides a continuous, functionally relevant index of sympathetic BRS and reveals that the latter fluctuates widely over time.


Subject(s)
Baroreflex/physiology , Kidney/innervation , Kidney/physiology , Sympathetic Nervous System/physiology , Animals , Blood Pressure/physiology , Data Interpretation, Statistical , Denervation , Heart Rate/physiology , Kidney Function Tests , Male , Rats , Rats, Sprague-Dawley
14.
Am J Physiol Regul Integr Comp Physiol ; 292(1): R362-7, 2007 Jan.
Article in English | MEDLINE | ID: mdl-16973933

ABSTRACT

The effects of acute emotional stress on the sympathetic component of the arterial baroreceptor reflex have not yet been described in conscious animals and humans. Arterial pressure (AP) and renal sympathetic nerve activity (RSNA) were simultaneously recorded in 11 conscious rats before and during exposure to a mild environmental stressor (jet of air). Baroreflex function curves relating AP and RSNA were constructed by fitting a sigmoid function to RSNA and AP measured during sequential nitroprusside and phenylephrine administrations. Stress increased mean AP from 112 +/- 2 to 124 +/- 2 mmHg, heart rate from 381 +/- 10 to 438 +/- 18 beats/min, and RSNA from 0.80 +/- 0.14 to 1.49 +/- 0.23 microV. The RSNA-AP relationship was shifted toward higher AP values, and its maximum gain was significantly (P < 0.01) increased from 9.0 +/- 1.3 to 16.2 +/- 2.1 normalized units (NU)/mmHg. The latter effect was secondary to an increase (P < 0.01) in the range of the RSNA variation from 285 +/- 33 to 619 +/- 59 NU. In addition, the operating range of the reflex was increased (P < 0.01) from 34 +/- 2 to 41 +/- 3 mmHg. The present study indicates that in rats, the baroreflex control of RSNA is sensitized and operates over a larger range during emotional stress, which suggests that renal vascular tone, and possibly AP, are very efficiently controlled by the sympathetic nervous system under this condition.


Subject(s)
Baroreflex/physiology , Kidney/physiology , Stress, Psychological/physiopathology , Sympathetic Nervous System/physiology , Animals , Blood Pressure/physiology , Heart Rate/physiology , Male , Nitroprusside/pharmacology , Phenylephrine/pharmacology , Physical Stimulation , Rats , Rats, Sprague-Dawley , Renal Circulation/physiology , Vascular Resistance/physiology , Vasoconstrictor Agents/pharmacology , Vasodilator Agents/pharmacology
15.
J Appl Physiol (1985) ; 102(3): 1034-40, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17122372

ABSTRACT

This study examined the possible influence of changes in heart rate (HR) on the gain of the transfer function relating renal sympathetic nerve activity (RSNA) to arterial pressure (AP) at HR frequency in rats. In seven urethane-anesthetized rats, AP and RSNA were recorded under baseline conditions (spontaneous HR = 338 +/- 6 beats/min, i.e., 5.6 +/- 0.1 Hz) and during 70-s periods of cardiac pacing at 6-9 Hz applied in random order. Cardiac pacing slightly increased mean AP (0.8 +/- 0.2 mmHg/Hz) and decreased pulse pressure (-3.6 +/- 0.3 mmHg/Hz) while leaving the mean level of RSNA essentially unaltered (P = 0.680, repeated-measures ANOVA). The gain of the transfer function from AP to RSNA measured at HR frequency was always associated with a strong, significant coherence and was stable between 6 and 9 Hz (P = 0.185). The transfer function gain measured under baseline conditions [2.44 +/- 0.28 normalized units (NU)/mmHg] did not differ from that measured during cardiac pacing (2.46 +/- 0.27 NU/mmHg). On the contrary, phase decreased linearly as a function of HR, which indicated the presence of a fixed time delay (97 +/- 6 ms) between AP and RSNA. In conclusion, the dynamic properties of arterial baroreflex pathways do not affect the gain of the transfer function between AP and RSNA measured at HR frequency in the upper part of the physiological range of HR variations in the rat.


Subject(s)
Baroreflex/physiology , Blood Pressure/physiology , Heart Rate/physiology , Kidney/innervation , Sympathetic Nervous System/physiology , Animals , Cardiac Pacing, Artificial , Kidney/physiology , Male , Rats , Rats, Sprague-Dawley
16.
Am J Physiol Regul Integr Comp Physiol ; 291(3): R736-41, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16513767

ABSTRACT

Previous studies have shown that the sympathetically mediated oscillations of arterial pressure (AP), the so-called Mayer waves, are shifted from 0.4 to 0.6 Hz after acute alpha-adrenoceptor blockade in conscious rats. This raises the possibility that, under physiological conditions, Mayer waves are mediated by the conjoint action of norepinephrine and other sympathetic cotransmitters. To evaluate the possible role of the cotransmitter ATP in determining the frequency of Mayer waves, AP and renal sympathetic nerve activity (RSNA) were simultaneously recorded in 10 conscious rats with cardiac autonomic blockade before and after acute blockade of P2 receptors with pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid. P2 receptor blockade did not alter the mean level and overall variability of AP and RSNA but shifted peak coherence between AP and RSNA from 0.43 +/- 0.02 to 0.22 +/- 0.01 Hz. A model of the sympathetic limb of the arterial baroreceptor reflex was designed to simulate Mayer waves at 0.2 and 0.6 Hz, with norepinephrine and ATP, respectively, acting as the sole sympathetic cotransmitter. When both cotransmitters acted in concert, a single oscillation was observed at 0.4 Hz when the gain ratio of the adrenergic to the purinergic components was set at 15. The model thus accounted for an important role for ATP in determining Mayer wave frequency, but not in sustaining the mean level of AP or controlling its overall variability.


Subject(s)
Blood Pressure/physiology , Receptors, Purinergic P2/metabolism , Adrenergic Fibers/physiology , Animals , Kidney/innervation , Male , Purinergic P2 Receptor Antagonists , Pyridoxal Phosphate/analogs & derivatives , Pyridoxal Phosphate/pharmacology , Rats , Rats, Sprague-Dawley
17.
Am J Physiol Regul Integr Comp Physiol ; 289(4): R1074-82, 2005 Oct.
Article in English | MEDLINE | ID: mdl-15932970

ABSTRACT

The present study examined the effects of baroreceptor loading and unloading on the various rhythms present in the renal sympathetic nerve activity (RSNA) of 10 conscious rats. Short-lasting (4-5 min), steady-state decreases (from -10 to -40 mmHg) and increases (from 5 to 30 mmHg) in arterial pressure (AP) were induced by the intravenous infusion of sodium nitroprusside and phenylephrine, respectively. The relationship between changes in AP level and RSNA total power (fast Fourier transform analysis; 0-25 Hz) was characterized by an inverse sigmoid function. Basal AP was located 6.3 mmHg above AP at the midrange of the curve, that is, near the lower plateau. Sigmoid relationships were also observed for spectral powers in the low (LF, 0.030-0.244 Hz), respiratory (0.79-2.5 Hz) and high-frequency (HF, 2.5-25 Hz) bands. In contrast, in the MF band (0.27-0.76 Hz) containing oscillations associated with Mayer waves, the AP-RSNA power relationship showed a bell curve shape with a maximum at 21 mmHg below basal AP. Similarly, changes in RSNA power at the frequency of the heart beat were well characterized by a bell curve reaching a maximum at 22 mmHg below basal AP. Under baseline conditions, LF, MF, respiratory and HF powers contributed approximately 3, 10, 18, and 69% of the total RSNA power, respectively. The pulse-synchronous oscillation of RSNA accounted for only 11 +/- 1% of HF power. The contribution of HF power to total power did not change consistently with AP changes. Therefore, most of the baroreflex-induced changes in RSNA are mediated by changes in the amplitude of fast, irregular fluctuations.


Subject(s)
Baroreflex/physiology , Blood Pressure/physiology , Consciousness/physiology , Heart Rate/physiology , Kidney/innervation , Kidney/physiology , Models, Cardiovascular , Sympathetic Nervous System/physiology , Adaptation, Physiological/physiology , Animals , Computer Simulation , Kidney/blood supply , Male , Rats , Rats, Sprague-Dawley
18.
J Physiol ; 559(Pt 2): 639-49, 2004 Sep 01.
Article in English | MEDLINE | ID: mdl-15235092

ABSTRACT

The objective of the present study was to examine whether a simple linear feedback model of arterial pressure (AP) control by the sympathetic nervous system would be able to reproduce the characteristic features of normal AP variability by using AP and renal sympathetic nerve activity (RSNA) data collected in conscious sinoaortic baroreceptor denervated (SAD) rats. As compared with baroreceptor-intact rats (n=8), SAD rats (n=10) had increased spectral power (+ 680%) of AP in the low frequency range (LF, 0.0003-0.14 Hz) and reduced power (-19%) in the mid-frequency range (MF, 0.14-0.8 Hz) containing Mayer waves. In individual SAD rats, RSNA data were translated into 'sympathetic' AP time series by using the RSNA-AP transfer function that had been previously characterized in anaesthetized rats. AP 'perturbation' time series were then calculated by subtracting 'sympathetic' from actual AP time series. Actual RSNA and AP 'perturbation' time series were introduced in a reflex loop that was closed by using the previously identified baroreflex transfer function (from baroreceptor afferent activity to RSNA). By progressively increasing the open-loop static gain, it was possible to compute virtual AP power spectra that increasingly deviated from their progenitor spectra, with spectral power decreasing in the LF range (as a result of baroreflex buffering of haemodynamic perturbations), and increasing in the MF band (as a result of increasing transients at the resonance frequency of the loop). The most accurate reproduction of actual AP and RSNA spectra observed in baroreceptor-intact rats was obtained at 20-30% of the baroreflex critical gain (open-loop static gain resulting in self-sustained oscillations at the resonance frequency). In conclusion, while the gain of the sympathetic component of the arterial baroreceptor reflex largely determines its ability to provide an efficient correction of slow haemodynamic perturbations, this is achieved at the cost of increasing transients at higher frequencies (Mayer waves). However, the system remains fundamentally stable.


Subject(s)
Baroreflex/physiology , Blood Pressure/physiology , Linear Models , Adrenergic Fibers/physiology , Animals , Rats
19.
Auton Neurosci ; 111(2): 80-8, 2004 Apr 30.
Article in English | MEDLINE | ID: mdl-15182737

ABSTRACT

The effects of sedation with pentobarbital sodium (15 mg/kg followed by 15.9+/-1.2 mg/kg/h, i.v.) on arterial pressure (AP) Mayer waves and accompanying oscillations of renal sympathetic nerve activity (RSNA) were examined in rats (n=8). As compared with values observed in the conscious state, pentobarbital significantly (P<0.05) decreased AP (from 119+/-2 to 93+/-3 mm Hg), heart rate (HR; from 427+/-11 to 355+/-11 beats/min) and RSNA (from 1.20+/-0.27 to 0.62+/-0.13 microV). The baroreflex control of RSNA was analyzed by fitting a sigmoid logistic function to changes in RSNA and AP observed during nitroprusside and phenylephrine administrations. During pentobarbital infusion, the RSNA-AP relationship was reset towards lower AP values, but neither its maximum gain nor its gain at resting AP were significantly altered (from 6.3+/-1.0 to 5.8+/-1.4 and from 3.2+/-0.5 to 3.8+/-1.3 normalized units (n.u.)/mm Hg, respectively). Spectral power in the frequency band containing Mayer waves (0.29-0.73 Hz) was significantly decreased by pentobarbital for both AP (from 4.65+/-0.90 to 0.95+/-0.25 mm Hg2) and RSNA (from 1437+/-245 to 488+/-79 n.u.2). This effect was mainly secondary to the attenuation of strongly coherent oscillations of both variables at approximately 0.4 Hz. Although previous experimental evidence points to a major involvement of the sympathetic limb of the arterial baroreceptor reflex in the genesis of Mayer waves, the present study indicates that the amplitude of these oscillations cannot be used as a quantitative index of sympathetic baroreflex sensitivity.


Subject(s)
Baroreflex/physiology , Blood Pressure/physiology , Kidney/innervation , Sympathetic Nervous System/physiology , Animals , Baroreflex/drug effects , Blood Pressure/drug effects , Hypnotics and Sedatives/pharmacology , Male , Pentobarbital/pharmacology , Rats , Rats, Sprague-Dawley , Sympathetic Nervous System/drug effects
20.
Kidney Int ; 63(4): 1276-84, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12631344

ABSTRACT

BACKGROUND: Endothelins (ET) have diuretic and natriuretic actions via ETB receptors that are found in most renal tubular segments, although the thin limbs have not been studied. Data also suggest that dysfunction of the renal ET system may be important in the pathogenesis of hypertension. The present study was aimed at determining the presence and nature of ET receptors in the thin limbs of Henle's loop and their ability to activate a Ca2+-dependent signaling pathway, as well as whether ET-induced Ca2+ signals are altered in hypertension. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and Fura 2 fluoreselected strains of Lyon rats with low-normal (LL), normal (LN), and high (LH) blood pressure. RESULTS: In SD rats, ET induced Ca2+ signals in DTL of long-looped nephrons, but not in DTL of short loops, or in ascending thin limbs. Ca2+ increases were abolished by BQ123, an antagonist of the ETA receptor, but not by BQ788, an antagonist of the ETB subtype. Endothelin-3 and sarafotoxin 6c, two ETB receptor agonists, were both inactive. RT-PCR showed the presence of both ETA and ETB receptor mRNA. Ca2+ signals measured scence measurements of [Ca2+]i were made to characterize ET receptors in descending thin limbs (DTL) of Sprague-Dawley rats, spontaneously hypertensive (SH) rats, and control Wistar-Kyoto (WKY) rats, and the three in DTL of WKY LL and LN rats were similar to those in Sprague-Dawley rats, but were significantly diminished (LH) or abolished (SH) in hypertensive rats. CONCLUSION: A functional ETA receptor activating a Ca2+-dependent pathway is expressed in DTL. This ETA-induced calcium signaling is impaired in two strains of genetically hypertensive rats.


Subject(s)
Calcium Signaling/physiology , Hypertension/genetics , Hypertension/metabolism , Loop of Henle/metabolism , Receptor, Endothelin A/metabolism , Animals , Disease Models, Animal , Endothelin B Receptor Antagonists , Endothelin-1/metabolism , Epithelial Cells/physiology , Kidney Tubules, Collecting/metabolism , Male , RNA, Messenger/analysis , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Rats, Sprague-Dawley , Receptor, Endothelin A/genetics
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