Exercise-induced neuroplasticity in autonomic nuclei restores the cardiac vagal tone and baroreflex dysfunction in aged hypertensive rats.

Aging is accompanied by considerable deterioration of homeostatic systems, such as autonomic imbalance characterized by heightened sympathetic activity, lower parasympathetic tone, and depressed heart rate (HR) variability, which are aggravated by hypertension. Here, we hypothesized that these age-related deficits in aged hypertensive rats can be ameliorated by exercise training, with benefits to the cardiovascular system. Therefore, male 22-mo-old spontaneously hypertensive rats (SHRs) and age-matched Wistar Kyoto (WKY) submitted to moderate-intensity exercise training (T) or kept sedentary (S) for 8 wk were evaluated for hemodynamic/autonomic parameters, baroreflex sensitivity, cardiac sympathetic/parasympathetic tone and analysis of dopamine ß-hydroxylase (DBH+) and oxytocin (OT+) pathways of autonomic brain nuclei. Aged SHR-S versus WKY-S exhibited elevated mean arterial pressure (MAP: +51%) and HR (+20%), augmented pressure/HR variability, no cardiac vagal tone, and depressed reflex control of the heart (HR range, -28%; gain, -49%). SHR-T exhibited a lower resting HR, a partial reduction in the MAP (-14%), in the pressure/HR variabilities, and restored parasympathetic modulation, with improvement of baroreceptor reflex control when compared with SHR-S. Exercise training increased the ascending DBH+ projections conveying peripheral information to the paraventricular nucleus of hypothalamus (PVN), augmented the expression of OT+ neurons, and reduced the density of DBH+ neurons in the rostral ventrolateral medulla (RVLM) of SHR-T. Data indicate that exercise training induces beneficial neuroplasticity in brain autonomic circuitry, and it is highly effective to restore the parasympathetic tone, and attenuation of age-related autonomic imbalance and baroreflex dysfunction, thus conferring long-term benefits for cardiovascular control in aged hypertensive individuals.NEW & NOTEWORTHY Exercise training reduces high blood pressure and cardiovascular autonomic modulation in aged hypertensive rats. The dysfunction in the baroreflex sensitivity and impaired parasympathetic tone to the heart of aged hypertensive rats are restored by exercise training. Exercise induces beneficial neuroplasticity in the brain nuclei involved with autonomic control of cardiovascular function of aged hypertensive rats.

Histidine dipeptides are key regulators of excitation-contraction coupling in cardiac muscle: Evidence from a novel CARNS1 knockout rat model.

Histidine-containing dipeptides (HCDs) are abundantly expressed in striated muscles. Although important properties have been ascribed to HCDs, including H+ buffering, regulation of Ca2+ transients and protection against oxidative stress, it remains unknown whether they play relevant functions in vivo. To investigate the in vivo roles of HCDs, we developed the first carnosine synthase knockout (CARNS1-/-) rat strain to investigate the impact of an absence of HCDs on skeletal and cardiac muscle function. Male wild-type (WT) and knockout rats (4 months-old) were used. Skeletal muscle function was assessed by an exercise tolerance test, contractile function in situ and muscle buffering capacity in vitro. Cardiac function was assessed in vivo by echocardiography and cardiac electrical activity by electrocardiography. Cardiomyocyte contractile function was assessed in isolated cardiomyocytes by measuring sarcomere contractility, along with the determination of Ca2+ transient. Markers of oxidative stress, mitochondrial function and expression of proteins were also evaluated in cardiac muscle. Animals were supplemented with carnosine (1.8% in drinking water for 12 weeks) in an attempt to rescue tissue HCDs levels and function. CARNS1-/- resulted in the complete absence of carnosine and anserine, but it did not affect exercise capacity, skeletal muscle force production, fatigability or buffering capacity in vitro, indicating that these are not essential for pH regulation and function in skeletal muscle. In cardiac muscle, however, CARNS1-/- resulted in a significant impairment of contractile function, which was confirmed both in vivo and ex vivo in isolated sarcomeres. Impaired systolic and diastolic dysfunction were accompanied by reduced intracellular Ca2+ peaks and slowed Ca2+ removal, but not by increased markers of oxidative stress or impaired mitochondrial respiration. No relevant increases in muscle carnosine content were observed after carnosine supplementation. Results show that a primary function of HCDs in cardiac muscle is the regulation of Ca2+ handling and excitation-contraction coupling.

The Cholinergic Drug Galantamine Alleviates Oxidative Stress Alongside Anti-inflammatory and Cardio-Metabolic Effects in Subjects With the Metabolic Syndrome in a Randomized Trial.

Background: The metabolic syndrome (MetS) is an obesity-associated disorder of pandemic proportions and limited treatment options. Oxidative stress, low-grade inflammation and altered neural autonomic regulation, are important components and drivers of pathogenesis. Galantamine, an acetylcholinesterase inhibitor and a cholinergic drug that is clinically-approved (for Alzheimer's disease) has been implicated in neural cholinergic regulation of inflammation in several conditions characterized with immune and metabolic derangements. Here we examined the effects of galantamine on oxidative stress in parallel with inflammatory and cardio-metabolic parameters in subjects with MetS. Trial Design and Methods: The effects of galantamine treatment, 8 mg daily for 4 weeks or placebo, followed by 16 mg daily for 8 weeks or placebo were studied in randomly assigned subjects with MetS (n = 22 per group) of both genders. Oxidative stress, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities, lipid and protein peroxidation, and nitrite levels were analyzed before and at the end of the treatment. In addition, plasma cytokine and adipokine levels, insulin resistance (HOMA-IR) and other relevant cardio-metabolic indices were analyzed. Autonomic regulation was also examined by heart rate variability (HRV) before treatment, and at every 4 weeks of treatment. Results: Galantamine treatment significantly increased antioxidant enzyme activities, including SOD [+1.65 USOD/mg protein, [95% CI 0.39-2.92], P = 0.004] and CAT [+0.93 nmol/mg, [95% CI 0.34-1.51], P = 0.01], decreased lipid peroxidation [thiobarbituric acid reactive substances [log scale 0.72 pmol/mg, [95% CI 0.46-1.07], P = 0.05], and systemic nitrite levels [log scale 0.83 µmol/mg protein, [95% CI 0.57-1.20], P = 0.04] compared with placebo. In addition, galantamine significantly alleviated the inflammatory state and insulin resistance, and decreased the low frequency/high frequency ratio of HRV, following 8 and 12 weeks of drug treatment. Conclusion: Low-dose galantamine alleviates oxidative stress, alongside beneficial anti-inflammatory, and metabolic effects, and modulates neural autonomic regulation in subjects with MetS. These findings are of considerable interest for further studies with the cholinergic drug galantamine to ameliorate MetS.

Training-Induced Deactivation of the AT1 Receptor Pathway Drives Autonomic Control and Heart Remodeling During the Transition From the Pre- to Hypertensive Phase in Spontaneously Hypertensive Rats.

BACKGROUND: The effects of hypertension and exercise training (T) on the sequential interplay between renin-angiotensin system (RAS), autonomic control and heart remodeling during the development of hypertension in spontaneously hypertensive rats (SHR), was evaluated.Methods and Results:Time course changes of these parameters were recorded in 4-week-old SHR submitted to a T or sedentary (S) protocol. Wistar Kyoto rats served as controls. Hemodynamic recordings were obtained in conscious rats at experimental weeks 0, 1, 2, 4, and 8. The left ventricle (LV) was collected to evaluate RAS gene and protein expression, cardiomyocytes' hypertrophy and collagen accumulation. Pre-hypertensive SHR exhibited augmented AT1R gene expression; at 5 weeks, they presented with elevated pressure, increased LV angiotensinogen and ACE mRNA expression, followed by sympathoexcitation (from the 8thweek onwards). Marked AT1R protein content, myocytes's hypertrophy, collagen deposition and increased pressure variability were observed in 12-week-old sedentary SHR. In addition to attenuating all these effects, T activated Mas receptor expression augmented parasympathetic modulation of the heart, and delayed the onset and reduced the magnitude, but did not block the development of genetic hypertension. CONCLUSIONS: The close temporal relationship between changes in the LV ACE-Ang II-AT1R axis, autonomic control and cardiac remodeling at both the establishment of hypertension and during exercise training reveals the essential role played by the AT1R pathway in driving cardiac remodeling and autonomic modulation during the transition from the pre- to hypertensive phase.

The essential role of hypothalamic paraventricular nucleus nNOS in the modulation of autonomic control in exercised rats.

Nitric oxide (NO), an intercellular signaling molecule is relevant for circulatory autonomic control. Brain NO synthase (NOS) and NO levels were downregulated in pathological conditions, but rescued after exercise training. We hypothesized that exercise training was also able to improve NO modulation within the hypothalamic paraventricular nucleus (PVN) of healthy rats. Male Wistar rats were submitted to two 4-weeks protocols: i) swimming training (T) or kept sedentary (S), ii) l-arginine (62,5 mg/mL, 1 mL/day p. o.) or vehicle supplementation. Rats underwent stereotaxic surgery (PVN bilateral guide cannulas) and chronic catheterization of artery/vein. Arterial pressure (AP), heart rate (HR) and baroreflex sensitivity were recorded in conscious rats at rest and following a selective nNOS inhibitor (Nw-Propyl-l-Arginine, 4 nmol/100 nL) within the PVN. Rats were deeply anesthetized for brain perfusion/harvesting after respiratory arrest. In separate groups (T and S, l-arginine and Vehicle supplemented) not submitted to PVN cannulation, fresh and fixed brains were obtained for gene and protein nNOS expression (qPCR and immunohistochemistry) and nitrite levels (Griess reaction). T and l-arginine treatment were accompanied by resting bradycardia, augmented parasympathetic and reduced sympathetic activity to heart and vessels (power spectral analysis) and increased baroreflex sensitivity (†P < 0.05). In contrast, PVN nNOS inhibition blocked/attenuated these effects in addition to significantly increase in resting MAP and HR (with larger effects in T and l-arginine treated rats vs. respective controls, †P < 0.05). T increased nNOS gene and protein expression within the ventromedial and posterior PVN nuclei (†P < 0.05). PVN nitirite levels were also increased in T and l-arginine groups (†P < 0.05). Data strongly suggest that training by increasing NO availability within PVN preautonomic nuclei favors both the slow down of sympathetic and the augmentation of parasympathetic activity and facilitates baroreflex control, therefore improving autonomic regulation of the heart in healthy rats.

Early Training-Induced Reduction of Angiotensinogen in Autonomic Areas-The Main Effect of Exercise on Brain Renin-Angiotensin System in Hypertensive Rats.

BACKGROUND: Exercise training (T) blunts functional deficits and renin-angiotensin system (RAS) hyperactivity in hypertensive individuals. There is no information on T-induced temporal changes of brain RAS. We evaluate now the simultaneous effects of T on functional responses and time course changes in the expression/activity of brain RAS components in autonomic cardiovascular-controlling areas. METHODS AND RESULTS: Spontaneously hypertensive rats (SHR) and age-matched normotensive controls (WKY) were trained for 0, 1, 2, 4, 8 and 12 weeks. Sedentary (S) groups served as time-controls. After arterial pressure (AP) and heart rate (HR) recordings at rest, fresh and fixed brains were harvested for qPCR and immunofluorescence assays. SHR-S vs. WKY-S exhibited higher mean AP (MAP) and HR, increased pressure variability and sympathetic activity, elevated AT1 receptor (AT1) expression in nucleus tractus solitarii (NTS) and higher Mas receptor expression in the rostroventrolateral medulla (RVLM). In SHR, T promptly (T2 on) reduced sympathetic variability to heart/vessels and largely decreased angiotensinogen expression in the paraventricular hypothalamic nucleus (PVN) and NTS, with a late RVLM reduction (T4). AT1 expression was only reduced at T12 (PVN and NTS) with transient, not maintained Mas receptor changes in PVN and RVLM. These responses were accompanied by baseline MAP and HR reduction in the SHR-T (from T4 on). In the SHR group, PVN angiotensinogen expression correlated positively with sympathetic activity, resting MAP and HR. In WKY-T, a precocious (T2-T12) RVLM AT1 decrease preceded the appearance of resting bradycardia (from T8 on). CONCLUSIONS: Early and maintained reduction of angiotensinogen content in autonomic areas of the SHR is the most prominent effect of training on brain RAS. Down-regulation of PVN RAS expression is an essential factor to drive cardiovascular benefits in SHR-T, while resting bradycardia in WKY-T is correlated to RVLM AT1 reduction.

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR.

Exercise training (ExT) is recommended to treat hypertension along with pharmaceutical antihypertensive therapies. Effects of ExT in hypothalamic content of high mobility box 1 (HMGB1) and microglial activation remain unknown. We examined whether ExT would decrease autonomic and cardiovascular abnormalities in spontaneously hypertensive rats (SHR), and whether these effects were associated with decreased HMGB1 content, microglial activation, and inflammation in the hypothalamic paraventricular nucleus (PVN). Normotensive Wistar-Kyoto (WKY) rats and SHR underwent moderate-intensity ExT for 2 wk. After ExT, cardiovascular (heart rate and arterial pressure) and autonomic parameters (arterial pressure and heart rate variability, peripheral sympathetic activity, cardiac vagal activity, and baroreflex function) were measured in conscious and freely-moving rats through chronic arterial and venous catheterization. Cerebrospinal fluid, plasma, and brain were collected for molecular and immunohistochemistry analyses of the PVN. In addition to reduced heart rate variability, decreased vagal cardiac activity and increased mean arterial pressure, heart rate, arterial pressure variability, cardiac, and vasomotor sympathetic activity, SHR had higher HMGB1 protein expression, IκB-α phosphorylation, TNF-α and IL-6 protein expression, and microglia activation in the PVN. These changes were accompanied by higher plasma and cerebrospinal fluid levels of HMGB1. The ExT + SHR group had decreased expression of HMGB1, CXCR4, SDF-1, and phosphorylation of p42/44 and IκB-α. ExT reduced microglial activation and proinflammatory cytokines content in the PVN, and improved autonomic control as well. Data suggest that training-induced downregulation of activated HMGB1/CXCR4/microglia/proinflammatory cytokines axis in the PVN of SHR is a prompt neural adaptation to counterbalance the deleterious effects of inflammation on autonomic control.

Influence of aerobic training on the reduced vasoconstriction to angiotensin II in rats exposed to intrauterine growth restriction: possible role of oxidative stress and AT2 receptor of angiotensin II.

Intrauterine growth restriction (IUGR) is associated with impaired vascular function, which contributes to the increased incidence of chronic disease. The aim of this study was to investigate whether aerobic training improves AngII-induced vasoconstriction in IUGR rats. Moreover, we assess the role of superoxide dismutase (SOD) isoforms and NADPH oxidase-derived superoxide anions in this improvement. Female Wistar rats were randomly divided into two groups on day 1 of pregnancy. A control group was fed standard chow ad libitum, and a restricted group was fed 50% of the ad libitum intake throughout gestation. At 8 weeks of age, male offspring from both groups were randomly assigned to 4 experimental groups: sedentary control (SC), trained control (TC), sedentary restricted (SRT), and trained restricted (TRT). The training protocol was performed on a treadmill and consisted of a continuous 60-min session 5 days/week for 10 weeks. Following aerobic training, concentration-response curves to AngII were obtained in endothelium-intact aortic rings. Protein expression of SOD isoforms, AngII receptors and the NADPH oxidase component p47phox was assessed by Western blot analysis. The dihydroethidium was used to evaluate the in situ superoxide levels under basal conditions or in the presence of apocynin, losartan or PD 123,319. Our results indicate that aerobic training can prevent IUGR-associated increases in AngII-dependent vasoconstriction and can restore basal superoxide levels in the aortic rings of TRT rats. Moreover, we observed that aerobic training normalized the increased p47phox protein expression and increased MnSOD and AT2 receptor protein expression in thoracic aortas of SRT rats. In summary, aerobic training can result in an upregulation of antioxidant defense by improved of MnSOD expression and attenuation of NADPH oxidase component p47phox. These effects are accompanied by increased expression of AT2 receptor, which provide positive effects against Ang II-induced superoxide generation, resulting in attenuation of AngII-induced vasoconstriction.

Atividade nervosa simpática e desenvolvimento de lesões de órgãos-alvo na hipertensão arterial: benefícios autonômicos induzidos pelo treinamento aeróbio / Sympathetic nerve activity and development of end-organ injury in hypertension: autonomic benefits induced by aerobic training

A disfunção autonômica encontra-se estreitamente associada ao estabe- lecimento da hipertensão arterial, sendo caracterizada por aumento da atividade simpática, redução do tônus vagal e disfunção barorreflexa, contribuindo para a instalação da insuficiência cardíaca, do infarto do miocárdio, do acidente vascular cerebral, entre outras comorbidades. Remodelamento hipertrófico de arteríolas cerebrais, ativação de quimiorreceptores, anormalidades na barreira hematoencefálica e aumento da atividade neuronal determinam a geração de espécies reativas de oxigênio e citocinas pró-inflamatórias em áreas de controle cardiovascular, as quais, em associação com a hiperativação do sistema renina-angiotensina, perpetuam a disfunção autonôrnica e favorecem a manutenção da hipertensão arterial crônica. Além disto, a disfunção barorreflexa aumenta a variabilidade da pressão arterial, predispondo à rarefação capilar e determinando a progressão de lesões de órgãos-alvo. Por sua vez, a maior disponibilidade de angiotensina li nos diferentes tecidos é um importante estímulo para a inflamação tecidual e hipertrofia de artérias/arteríolas periféricas, potencializando os efeitos deletérios desencadeados pela hiperatividade simpática e disfunção barorreflexa. A hipertensão, uma vez estabelecida, é uma doença crônica que exige tratamento continuado, o qual pode reduzir os níveis pressóricos, mas não curá-Ia. Um importante avanço no controle da hipertensão foi a constatação de que o treinamento aeróbio, mesmo não normalizando a pressão arterial, reduz acentuadamente o estresse oxidativo e a in- flamação em áreas autonômicas, corrigindo prontamente a disfunção barorreflexa, aumentando o tônus vaga I e reduzindo a atividade simpá- tica. Estas adaptações autonôrnicas, em associação com a reversão do remodelamento hipertrófico arteriolar em tecidos exercitados, reduzem a resistência vascular periférica e a pressão arterial.

Autononic dysfunction is closely related to the development of hypertension, being characterized by increased sympathetic activity, decreased vagal tonus and baroreflex dysfunction. These autonornic adaptations contribute to heart failure, myocardial infarction and stroke as well. Hypertrophic remodeling ofbrain arterioles, chemoreceptors activation, blood-brain barrier abnormalities determine reactive oxygen species and pro-inflammatory cytokines production and increased neuronal activity within autonornic brain areas controlling the cardiovascular system. These responses associated with hyperactivation ofthe renin-angiotensin system allow the maintenance of chronic hypertension. Furthermore, baroreflex dysfunction increases arterial pressure variability that causes capillary rarefaction and end-organs injuries. On several tissues, increased Angiotensin li production is an important stimulus for tissue inflammation and arteries/arterioles hypertrophy, thus potentiating the deleterious effects of sympathetic hyperactivity and baroreflex dysfunction. Once established, hypertension is a chronic disease that needs continuous treatment. Chronic pharmacological interventions are able to decrease arterial pressure, but not cure it. An important advance on hypertension control was our recent finding that aerobic training, even not normalizing arterial pressure, sharply decreases oxidative stress and inflammation into autonornic control areas and promptly corrects baro- reflex dysfunction and cardiac vagal activity. Theses training-induced autonomic adaptations associated with reversion ofhypertrophic arteriole remodeling contribute to decrease peripheraJ vascular resistance and arterial pressure in hypertensive subjects.

Training-induced pressure fall in spontaneously hypertensive rats is associated with reduced angiotensinogen mRNA expression within the nucleus tractus solitarii.

Knowing that exercise training reduces arterial pressure in hypertensive individuals and that pressure fall is accompanied by blockade of brain renin-angiotensin system, we sought to investigate whether training (T) affects central renin-angiotensin system. Spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto controls (WKY) were submitted to training or kept sedentary (S) for 3 months. After functional recordings, brain was removed and processed for autoradiography (brain stem sequential slices hybridized with (35)S-oligodeoxynucleotide probes for angiotensinogen [Aogen] and angiotensin II type 1 [AT(1A)] receptors). Resting arterial pressure and heart rate were higher in SHR(S) (177+/-2 mm Hg, 357+/-12 bpm versus 121+/-1 mm Hg, 320+/-9 bpm in WKY(S); P<0.05). Training was equally effective to enhance treadmill performance and to cause resting bradycardia (-10%) in both groups. Training-induced blood pressure fall (-6.3%) was observed only in SHR(T). In SHR(S) (versus WKY(S)) AT(1A) and Aogen mRNA expression were significantly increased within the NTS and area postrema (average of +67% and +41% for AT(1A) and Aogen, respectively; P<0.05) but unchanged in the gracilis nucleus. Training did not change AT(1A) expression but reduced NTS and area postrema Aogen mRNA densities specifically in SHR(T) (P<0.05 versus SHR(S), with values within the range of WKY groups). In SHRs, NTS Aogen mRNA expression was correlated with resting pressure (y=5.95x +41; r=0.55; P<0.05), with no significant correlation in the WKY group. Concurrent training-induced reductions of both Aogen mRNA expression in brain stem cardiovascular-controlling areas and mean arterial pressure only in SHRs suggest that training is as efficient as the renin-angiotensin blockers to reduce brain renin-angiotensin system overactivity and to decrease arterial pressure.

The NTS and integration of cardiovascular control during exercise in normotensive and hypertensive individuals.

Due to upward resetting of baroreceptors, tachycardia coexists with increased pressure during dynamic exercise. This review critically evaluates current knowledge of proposed mechanisms to explain the continuous resetting of baroreflex control of heart rate and sympathetic nerve activity during and after exercise and exercise training. Of interest is the exercise-induced upward resetting that occurs in hypertensive and normotensive individuals. Accumulated evidence indicates that not only somatosensory afferents, but also inputs from central command projecting to the nucleus tractus solitarius (NTS) in the dorsal brainstem may mediate inhibition of excitatory neurotransmission on barosensitive neurons. Specific coordinated activation of vasopressinergic and oxytocinergic projections to the NTS is essential to tonically maintain baroreflex sensitivity and to adjust heart rate and cardiac output to circulatory demand at rest and during exercise in both sedentary and trained individuals. These findings reinforce the paramount importance of the NTS in integration of cardiovascular control during exercise.

Differential effects of vasopressinergic and oxytocinergic pre-autonomic neurons on circulatory control: reflex mechanisms and changes during exercise.

1. The role of vasopressinergic and oxytocinergic (VPergic and OTergic, respectively) projections to the brain stem in the modulation of heart rate control is discussed on the basis of both changes in the peptide content of the dorsal brain stem (DBS) and functional effects following reflex- and exercise-induced activation in the presence and/or absence of receptor blockade within the nucleus tractus solitarius (NTS) and/or peripheral autonomic block. 2. Experimental data showed a dual effect of NTS VPergic projections on reflex control: (i) to maintain tonically the reflex sensitivity; and (ii) to reset reflex bradycardia towards higher heart rate values when transiently activated. The VPergic drive causes less sympathetic inhibition during pressure increases, mainly by reducing peripheral information going to NTS second-order neurons. Treadmill running increases the vasopressin content within the DBS. This activates NTS V(1) receptors to cause a significant improvement of exercise tachycardia in both sedentary and trained rats. 3. The OTergic drive to DBS areas (NTS/dorsal motor nucleus of the vagus) is also tonic for baroreceptor reflex control: it improves reflex bradycardia by facilitating vagal outflow to the heart. An acute bout of exercise increases DBS oxytocin (OT) content in trained rats, causing a significant blunting of exercise tachycardia only in this group. In both sedentary and trained groups, basal heart rate varies inversely with DBS OT content, the resting bradycardia of trained rats being associated with higher OT content. 4. Specific coordinated activation of VPergic and OTergic suprabulbar pathways is essential to adjust heart rate and cardiac output to circulatory demand at rest and during exercise in both sedentary and trained individuals.

Treinamento físico na insuficiência cardíaca: ajustes na musculatura esquelética / Physical training in heart failure: adaptations of the skeletal muscle

A insuficiência cardíaca é uma síndrome complexa, associada à redução da capacidade física. Nos últimos anos, porém, tem sido demonstrado que a intolerância ao esforço não pode ser explicada somente por alterações cardíacas e pulmonares, uma vez que existe falta de correlação entre as alterações hemodinâmicas (centrais) e a incapacidade de executar exercícios na insuficiência cardíaca. Diversos pesquisadores têm se empenhado em definir as alterações presentes na periferia, mais especificamente na musculatura esquelética, e os mecanismos intrínsecos da musculatura responsáveis pela intolerância ao esforço. Dentre as alterações observadas têm-se descrito deficiências no fluxo sanguíneo periférico, assim como na morfologia, no metabolismo e na função muscular. Por outro lado, o treinamento físico tem mostrado ser uma conduta segura e tem sido utilizado como coadjuvante no tratamento de pacientes com insuficiência cardíaca, uma vez que as alterações presentes na musculatura esquelética são muito semelhantes àquelas presentes no processo de descondicionamento. Esta revisão tem por objetivo discutir algumas questões pertinentes às alterações instrínsecas da musculatura esquelética, como elas afetam o desempenho de pacientes com insuficiência cardíaca e como o treinamento físico pode reverter essas alterações.

Training-induced, pressure-lowering effect in SHR: wide effects on circulatory profile of exercised and nonexercised muscles.

We showed that the training-induced, pressure-lowering effect correlates with decreased arteriole wall/lumen ratio and venule growth in the gracilis muscle. To investigate whether these beneficial changes are tissue-specific or occur in other muscles and tissues, we analyzed the effects of hypertension and training on microcirculatory profile of locomotor/nonlocomotor muscles and another nonmuscular tissue. Spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats were submitted to low-intensity training (50% to 60% maximal exercise capacity, 13 weeks); age-matched control rats were kept sedentary. Trained and sedentary rats were instrumented for pressure and heart rate measurements at rest. Morphometric analyses (arterioles, capillaries, venules) were performed in all tissues. Training attenuated pressure and heart rate only in SHR. Arterioles (inner diameter <30 microm) were markedly hypertrophied in sedentary SHR, but wall/lumen ratio was equally reduced (approximately 30%) and normalized by training in locomotor (soleus, gastrocnemius, gracilis) and nonlocomotor skeletal muscles (temporalis) in the myocardium and diaphragm, without changes in the renal cortex. Training also increased venule density (approximately 2-fold) only in locomotor and nonlocomotor muscles of SHR. Capillary density was similarly increased in all exercised muscles of both groups, with no change in temporalis and kidneys. Data suggest that growth/proliferation of small venules and regression of hypertrophied arteriole wall/lumen ratio are generalized tissue-specific (skeletal muscle) and group-specific (SHR) adjustments to training to reduce local resistance and augment physical capacity of circulation, thus contributing to training-induced pressure-lowering effect. They are accompanied by remodeling of myocardium (cardiac output) and diaphragm arterioles (ventilatory adjustments), stressing the importance of training as a nonpharmacological therapy to control pressure levels in hypertension.

Fisiopatologia da hipertensão: o que avançamos? / Pathogenesis of hypertension: what is new?

A hipertensão arterial é uma doença poligênica, que resulta de anormalidades dos mecanismos de controle da pressão arterial. Grande número de substâncias biologicamente ativas pode interagir com diferentes sistemas fisiológicos de maneira complexa e com redundância para garantir a homeostasia cardiovascular. Nesta revisão é descrito o papel do sistema nervoso simpático na gênese e na manutenção da hipertensão e o papel dos pressorreceptores e quimiorreceptores arteriais e os receptores cardiopulmonares no controle da pressão arterial pela modulação da atividade simpática. Influências hormonais, como o sistema renina-angiotensina, e outros peptídeos vasoativos, como as cininas e a vasopressina, são também considerados. Além disso, destacam-se influência de substâncias vasodilatadoras e vasoconstritoras derivadas do endotélio e a disfunção endotelial na hipertensão, bem como as modificações associadas a outros fatores, como o conteúdo de sal na dieta, a obesidade e a inatividade física. Finalmente, com o advento das técnicas de biologia molecular e as abordagens da genética molecular, discute-se a possibilidade de se estabelecer estratégias para estudar e identificar os determinantes genéticos da hipertensão essencial. Além disso, comenta-se a abertura de novas oportunidades no estudo da fisiologia em que um novo campo, a genômica fisiológica, pode ser aplicado no entendimento da genética da hipertensão e das doenças cardiovasculares...