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1.
Am J Physiol Heart Circ Physiol ; 327(1): H45-H55, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38700474

RESUMO

Patients with heart failure with reduced ejection fraction (HFrEF) have exaggerated sympathoexcitation and impaired peripheral vascular conductance. Evidence demonstrating consequent impaired functional sympatholysis is limited in HFrEF. This study aimed to determine the magnitude of reduced limb vascular conductance during sympathoexcitation and whether functional sympatholysis would abolish such reductions in HFrEF. Twenty patients with HFrEF and 22 age-matched controls performed the cold pressor test (CPT) [left foot 2-min in -0.5 (1)°C water] alone and with right handgrip exercise (EX + CPT). Right forearm vascular conductance (FVC), forearm blood flow (FBF), and mean arterial pressure (MAP) were measured. Patients with HFrEF had greater decreases in %ΔFVC and %ΔFBF during CPT (both P < 0.0001) but not EX + CPT (P = 0.449, P = 0.199) compared with controls, respectively. %ΔFVC and %ΔFBF decreased from CPT to EX + CPT in patients with HFrEF (both P < 0.0001) and controls (P = 0.018, P = 0.015), respectively. MAP increased during CPT and EX + CPT in both groups (all P < 0.0001). MAP was greater in controls than in patients with HFrEF during EX + CPT (P = 0.025) but not CPT (P = 0.209). In conclusion, acute sympathoexcitation caused exaggerated peripheral vasoconstriction and reduced peripheral blood flow in patients with HFrEF. Handgrip exercise abolished sympathoexcitatory-mediated peripheral vasoconstriction and normalized peripheral blood flow in patients with HFrEF. These novel data reveal intact functional sympatholysis in the upper limb and suggest that exercise-mediated, local control of blood flow is preserved when cardiac limitations that are cardinal to HFrEF are evaded with dynamic handgrip exercise.NEW & NOTEWORTHY Patients with HFrEF demonstrate impaired peripheral blood flow regulation, evidenced by heightened peripheral vasoconstriction that reduces limb blood flow in response to physiological sympathoexcitation (cold pressor test). Despite evidence of exaggerated sympathetic vasoconstriction, patients with HFrEF demonstrate a normal hyperemic response to moderate-intensity handgrip exercise. Most importantly, acute, simultaneous handgrip exercise restores normal limb vasomotor control and vascular conductance during acute sympathoexcitation (cold pressor test), suggesting intact functional sympatholysis in patients with HFrEF.


Assuntos
Exercício Físico , Antebraço , Força da Mão , Insuficiência Cardíaca , Volume Sistólico , Sistema Nervoso Simpático , Vasoconstrição , Humanos , Masculino , Sistema Nervoso Simpático/fisiopatologia , Feminino , Insuficiência Cardíaca/fisiopatologia , Pessoa de Meia-Idade , Antebraço/irrigação sanguínea , Idoso , Fluxo Sanguíneo Regional , Estudos de Casos e Controles , Função Ventricular Esquerda , Temperatura Baixa , Pressão Arterial , Descanso
2.
Am J Physiol Heart Circ Physiol ; 326(5): H1105-H1116, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38391313

RESUMO

Whether cerebral sympathetic-mediated vasomotor control can be modulated by local brain activity remains unknown. This study tested the hypothesis that the application or removal of a cognitive task during a cold pressor test (CPT) would attenuate and restore decreases in cerebrovascular conductance (CVC), respectively. Middle cerebral artery blood velocity (transcranial Doppler) and mean arterial pressure (finger photoplethysmography) were examined in healthy adults (n = 16; 8 females and 8 males) who completed a control CPT, followed by a CPT coupled with a cognitive task administered either 1) 30 s after the onset of the CPT and for the duration of the CPT or 2) at the onset of the CPT and terminated 30 s before the end of the CPT (condition order was counterbalanced). The major finding was that the CPT decreased the index of CVC, and such decreases were abolished when a cognitive task was completed concurrently and restored when the cognitive task was removed. As a secondary experiment, vasomotor interactions between sympathetic transduction pathways (α1-adrenergic and Y1-peptidergic) and compounds implicated in cerebral blood flow control [adenosine, and adenosine triphosphate (ATP)] were explored in isolated porcine cerebral arteries (wire myography). The data reveal α1-receptor agonism potentiated vasorelaxation modestly in response to adenosine, and preexposure to ATP attenuated contractile responses to α1-agonism. Overall, the data suggest a cognitive task attenuates decreases in CVC during sympathoexcitation, possibly related to an interaction between purinergic and α1-adrenergic signaling pathways.NEW & NOTEWORTHY The present study demonstrates that the cerebrovascular conductance index decreases during sympathoexcitation and this response can be positively and negatively modulated by the application or withdrawal of a nonexercise cognitive task. Furthermore, isolated vessel experiments reveal that cerebral α1-adrenergic agonism potentiates adenosine-mediated vasorelaxation and ATP attenuates α1-adrenergic-mediated vasocontraction.


Assuntos
Trifosfato de Adenosina , Simpatolíticos , Adulto , Masculino , Feminino , Humanos , Animais , Suínos , Velocidade do Fluxo Sanguíneo/fisiologia , Adrenérgicos , Adenosina/farmacologia , Circulação Cerebrovascular/fisiologia , Pressão Sanguínea/fisiologia , Temperatura Baixa
3.
J Appl Physiol (1985) ; 135(2): 279-291, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37348013

RESUMO

Heart failure with reduced ejection fraction (HFrEF) exhibits exaggerated sympathoexcitation and altered cardiac and vascular responses to muscle metaboreflex activation (MMA). However, left ventricular (LV) responses to MMA are not well studied in patients with HFrEF. The purpose of this study was to examine LV function during MMA using cardiac magnetic resonance imaging (MRI) in patients with HFrEF. Thirteen patients with HFrEF and 18 healthy age-matched controls underwent cardiac MRI during rest and MMA. MMA protocol included 6 min of isometric handgrip exercise followed by 6-min of brachial postexercise circulatory occlusion. LV stroke volume index (SVi), end-systolic volume index (ESVi), end-diastolic volume index (EDVi), and global longitudinal strain (GLS) were measured by two- and four-chamber cine images. Volumes were indexed to body surface area. Heart rate (via ECG) and brachial mean arterial pressure (MAP) were recorded. Cardiac output and total peripheral resistance (TPR) were calculated. SVi decreased during MMA in HFrEF (P = 0.037) but not in controls (P = 0.392). ESVi (P = 0.007) and heart rate (P < 0.001) increased during MMA in HFrEF but not controls (P ≥ 0.170). TPR (P = 0.021) and MAP (P < 0.001) increased during MMA in both groups. Cardiac output (P = 0.946), EDVi (P = 0.177), and GLS (P = 0.619) were maintained from rest to MMA in both groups. Despite similarly maintained cardiac output, LV strain, and increased TPR in HFrEF and control groups, SVi decreased, and heart rate increased during MMA in patients with HFrEF. These findings suggest an impaired contractility reserve in response to increased TPR during MMA in HFrEF.NEW & NOTEWORTHY Stroke volume decreases and end-systolic volume increases during muscle metaboreflex activation in patients with heart failure with reduced ejection fraction (HFrEF), suggesting impaired contractile reserve during muscle metaboreflex activation in patients with HFrEF. Total peripheral resistance increases similarly during muscle metaboreflex activation in patients with HFrEF compared to controls, indicating normal levels of peripheral vasoconstriction during muscle metaboreflex activation in patients with HFrEF.


Assuntos
Insuficiência Cardíaca , Disfunção Ventricular Esquerda , Humanos , Volume Sistólico/fisiologia , Reflexo/fisiologia , Força da Mão , Pressão Arterial/fisiologia , Músculo Esquelético/fisiologia , Função Ventricular Esquerda
4.
Microvasc Res ; 148: 104550, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37230164

RESUMO

Using swine as an experimental model, we examined whether the cannabinoid receptors (CB1R and CB2R) modulated vasomotor tone in isolated pial arteries. It was hypothesized that the CB1R would mediate cerebral artery vasorelaxation in an endothelial-dependent manner. First-order pial arteries were isolated from female Landrace pigs (age = 2 months; N = 27) for wire and pressure myography. Arteries were pre-contracted with a thromboxane A2 analogue (U-46619) and vasorelaxation in response to the CB1R and CB2R receptor agonist CP55940 was examined in the following conditions: 1) untreated; 2) inhibition of the CB1R (AM251); or 3) inhibition of the CB2R receptor (AM630). The data revealed that CP55940 elicits a CB1R-dependent relaxation in pial arteries. CB1R expression was confirmed using immunoblot and immunohistochemical analyses. Subsequently, the role of different endothelial-dependent pathways in the CB1R-mediated vasorelaxation was examined using: 1) denudation (removal of the endothelium); 2) inhibition of cyclooxygenase (COX; Naproxen); 3) inhibition of nitric oxide synthase (NOS; L-NAME); and 4) combined inhibition of COX + NOS. The data revealed CB1R-mediated vasorelaxation was endothelial-dependent, with contributions from COX-derived prostaglandins, NO, and endothelium-dependent hyperpolarizing factor (EDHF). Pressurized arteries underwent myogenic curves (20-100 mmHg) under the following conditions: 1) untreated; 2) inhibition of the CB1R. The data revealed CB1R inhibition increased basal myogenic tone, but not myogenic reactivity. As the vascular responses were assessed in isolated pial arteries, this work reveals that the CB1R modulates cerebrovascular tone independently of changes in brain metabolism.


Assuntos
Cicloexanóis , Óxido Nítrico , Vasodilatação , Animais , Feminino , Artérias Cerebrais/metabolismo , Endotélio Vascular/metabolismo , Óxido Nítrico/metabolismo , Suínos , Cicloexanóis/farmacologia
5.
J Appl Physiol (1985) ; 133(5): 1228-1236, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36227166

RESUMO

Myogenic and flow-induced reactivity contribute to cerebral autoregulation, with potentially divergent roles for smaller versus larger arteries. The present study tested the hypotheses that compared with first-order (1A) branches of the middle cerebral artery, second- and third-order branches (2A and 3A, respectively) exhibit greater myogenic reactivity but reduced flow-induced constriction. Furthermore, nitric oxide synthase (NOS) inhibition may amplify myogenic reactivity and abolish instances of flow-induced dilation. Isolated porcine cerebral arteries mounted in a pressure myograph were exposed to incremental increases in intraluminal pressure (40-120 mmHg; n = 41) or flow (1-1,170 µL/min; n = 31). Intraluminal flows were adjusted to achieve 5, 10, 20, and 40 dyn/cm2 of wall shear stress at 60 mmHg. Myogenic tone was greater in 3A versus 1A arteries (P < 0.05). There was an inverse relationship between myogenic reactivity and passive arterial diameter (P < 0.01). NOS inhibition increased basal tone to a lesser extent in 3A versus 1A arteries (P < 0.01) but did not influence myogenic reactivity (P = 0.49). Increasing flow decreased luminal diameter (P ≤ 0.01), with increased vasoconstriction at 10-40 dyn/cm2 of shear stress (P < 0.01). However, relative responses were similar between 1A, 2A, and 3A arteries (P = 0.40) with and without NOS inhibition conditions (P ≥ 0.29). Whereas NOS inhibition increases basal myogenic tone, and myogenic reactivity was less in smaller versus larger arteries (range = ∼100-550 µM), neither NOS inhibition nor luminal diameter influences flow-induced constriction in porcine cerebral arteries.NEW & NOTEWORTHY This study demonstrated size-dependent heterogeneity in myogenic reactivity in porcine cerebral arteries. Smaller branches of the middle cerebral artery exhibited increased myogenic reactivity, but attenuated NOS-dependent increases in myogenic tone compared with larger branches. Flow-dependent regulation does not exhibit the same variation; diameter-independent flow-induced vasoconstrictions occur across all branch orders and are not affected by NOS inhibition. Conceptually, flow-induced vasoconstriction contributes to cerebral autoregulation, particularly in larger arteries with low myogenic tone.


Assuntos
Artéria Cerebral Média , Óxido Nítrico , Suínos , Animais , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase , Vasoconstrição/fisiologia
6.
Artigo em Inglês | MEDLINE | ID: mdl-35151870

RESUMO

Full-term low birthweight (LBW) offspring exhibit peripheral vascular dysfunction in the postnatal period; however, whether such impairments extend to the cerebrovasculature remains to be elucidated. We used a swine model to test the hypothesis that LBW offspring would exhibit cerebrovascular dysfunction at later stages of life. Offspring from 14 sows were identified as normal birthweight (NBW) or LBW and were assessed at 28 (similar to end of infancy) and 56 (similar to childhood) days of age. LBW swine had lower absolute brain mass, but demonstrated evidence of brain sparing (increased brain mass scaled to body mass) at 56 days of age. The cerebral pulsatility index, based on transcranial Doppler, was increased in LBW swine. Moreover, arterial myography of isolated cerebral arteries revealed impaired vasoreactivity to bradykinin and reduced contribution of nitric oxide (NO) to vasorelaxation in the LBW swine. Immunoblotting demonstrated a lower ratio of phosphorylated-to-total endothelial NO synthase in LBW offspring. This impairment in NO signaling was greater at 28 vs. 56 days of age. Vasomotor responses to sodium nitroprusside (NO-donor) were unaltered, while Leu31, Pro34 neuropeptide Y-induced vasoconstriction was enhanced in LBW swine. Increases in total Y1 receptor protein content in the LBW group were not significant. In summary, LBW offspring displayed signs of cerebrovascular dysfunction at 28 and 56 days of age, evidenced by altered cerebral hemodynamics (reflective of increased impedance) coupled with endothelial dysfunction and altered vasomotor control. Overall, the data reveal that normal variance in birthweight of full-term offspring can influence cerebrovascular function later in life.


Assuntos
Artérias , Vasodilatação , Animais , Peso ao Nascer , Encéfalo , Feminino , Nitroprussiato , Suínos
7.
Nat Neurosci ; 23(9): 1090-1101, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32661394

RESUMO

While the neuronal underpinnings of autism spectrum disorder (ASD) are being unraveled, vascular contributions to ASD remain elusive. Here, we investigated postnatal cerebrovascular development in the 16p11.2df/+ mouse model of 16p11.2 deletion ASD syndrome. We discover that 16p11.2 hemizygosity leads to male-specific, endothelium-dependent structural and functional neurovascular abnormalities. In 16p11.2df/+ mice, endothelial dysfunction results in impaired cerebral angiogenesis at postnatal day 14, and in altered neurovascular coupling and cerebrovascular reactivity at postnatal day 50. Moreover, we show that there is defective angiogenesis in primary 16p11.2df/+ mouse brain endothelial cells and in induced-pluripotent-stem-cell-derived endothelial cells from human carriers of the 16p11.2 deletion. Finally, we find that mice with an endothelium-specific 16p11.2 deletion (16p11.2ΔEC) partially recapitulate some of the behavioral changes seen in 16p11.2 syndrome, specifically hyperactivity and impaired motor learning. By showing that developmental 16p11.2 haploinsufficiency from endothelial cells results in neurovascular and behavioral changes in adults, our results point to a potential role for endothelial impairment in ASD.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Células Endoteliais/patologia , Acoplamento Neurovascular/fisiologia , Animais , Transtorno Autístico , Circulação Cerebrovascular/fisiologia , Deleção Cromossômica , Transtornos Cromossômicos , Cromossomos Humanos Par 16 , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Deficiência Intelectual , Masculino , Camundongos , Neovascularização Fisiológica/genética
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