RESUMO
AIMS: Anti-inflammatory molecules, such as rose oxide (RO), are likely to exert therapeutic effects in systemic arterial hypertension (SAH), a disease associated with abnormal immune responses. We aimed to investigate acute autonomic effects of RO on hemodynamic parameters of Wistar and spontaneously hypertensive rats (SHR). METHODS: Rats were anesthetized and femoral artery and veins were cannulated. Next day, blood pressure (BP) and heart rate (HR) were recorded. Acute effects of RO (1.25, 2.5, or 5.0 mg/kg; iv) on BP, HR, and variability of systolic arterial pressure (SAP) and pulse interval (PI) were assessed. The effects of RO were also investigated in SHR, which received atropine (2 mg/kg), propranolol (4 mg/kg), or hexamethonium (20 mg/kg) 15 min before receiving RO. Vasorelaxant effects of RO (10-10 to 10-4 M) on aortic rings of rats were also assessed. KEY FINDINGS: In Wistar rats, none of the RO doses evoked significant changes in BP, HR, and variability of SAP and PI. On the other hand, in SHR, RO elicited reduction in mean arterial pressure (MAP), and prevented the increase in the low frequency power (LF) of the SAP spectra. Pretreatment with atropine or propranolol did not alter hypotension, but attenuated RO-induced bradycardia. Hexamethonium prevented RO-induced hypotension and bradycardia. RO exerted vasorelaxant effects on aortic rings with (Wistar and SHR) or without functional endothelium (SHR only). SIGNIFICANCE: Rose oxide, a monoterpene with anti-inflammatory properties, acts as an antihypertensive molecule due to its ability to acutely promote hypotension and bradycardia in spontaneously hypertensive rats.
Assuntos
Monoterpenos Acíclicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Monoterpenos Acíclicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Hipertensivos/farmacologia , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Frequência Cardíaca/fisiologia , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Especificidade da Espécie , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
Systemic arterial hypertension and heart failure are cardiovascular diseases that affect millions of individuals worldwide. They are characterized by a change in the autonomic nervous system balance, highlighted by an increase in sympathetic activity associated with a decrease in parasympathetic activity. Most therapeutic approaches seek to treat these diseases by medications that attenuate sympathetic activity. However, there is a growing number of studies demonstrating that the improvement of parasympathetic function, by means of pharmacological or electrical stimulation, can be an effective tool for the treatment of these cardiovascular diseases. Therefore, this review aims to describe the advances reported by experimental and clinical studies that addressed the potential of cholinergic stimulation to prevent autonomic and cardiovascular imbalance in hypertension and heart failure. Overall, the published data reviewed demonstrate that the use of central or peripheral acetylcholinesterase inhibitors is efficient to improve the autonomic imbalance and hemodynamic changes observed in heart failure and hypertension. Of note, the baroreflex and the vagus nerve activation have been shown to be safe and effective approaches to be used as an alternative treatment for these cardiovascular diseases. In conclusion, pharmacological and electrical stimulation of the parasympathetic nervous system has the potential to be used as a therapeutic tool for the treatment of hypertension and heart failure, deserving to be more explored in the clinical setting.
Assuntos
Insuficiência Cardíaca , Hipertensão , Sistema Nervoso Autônomo , Barorreflexo , Colinérgicos , Estimulação Elétrica , Insuficiência Cardíaca/tratamento farmacológico , Frequência Cardíaca , Humanos , Hipertensão/tratamento farmacológicoRESUMO
NEW FINDINGS: What is the central question of this study? The traditional surgical approach for sino-aortic denervation in rats leads to simultaneous carotid baroreceptor and chemoreceptor deactivation, which does not permit their individual study in different situations. What is the main finding and its importance? We have described a new surgical approach capable of selective denervation of the arterial (aortic and carotid) baroreceptors, keeping the carotid bodies (chemoreceptors) intact. It is understood that this technique might be a useful tool for investigating the relative role of the baro- and chemoreceptors in several physiological and pathophysiological conditions. ABSTRACT: Studies have demonstrated that the traditional surgical approach for sino-aortic denervation in rats leads to simultaneous carotid baroreceptor and chemoreceptor deactivation. The present study reports a new surgical approach to denervate the aortic and the carotid baroreceptors selectively, keeping the carotid bodies (peripheral chemoreceptors) intact. Wistar rats were subjected to specific aortic and carotid baroreceptor denervation (BAROS-X) or sham surgery (SHAM). Baroreflex activation was achieved by i.v. administration of phenylephrine, whereas peripheral chemoreflex activation was produced by i.v. administration of potassium cyanide. The SHAM and BAROS-X rats displayed significant hypertensive responses to phenylephrine administration. However, the reflex bradycardia following the hypertensive response caused by phenylephrine was remarkable in SHAM, but not significant in the BAROS-X animals, confirming the efficacy of the surgical procedure to abolish the baroreflex. In addition, the baroreflex activation elicited by phenylephrine increased carotid sinus nerve activity only in SHAM, but not in the BAROS-X animals, providing support to the notion that the baroreceptor afferents were absent. Instead, the classical peripheral chemoreflex hypertensive and bradycardic responses to potassium cyanide were similar in both groups, suggesting that the carotid body chemoreceptors were preserved after BAROS-X. In summary, we describe a new surgical approach in which only the baroreceptors are eliminated, while the carotid chemoreceptors are preserved. Therefore, it is understood that this procedure is potentially a useful tool for examining the relative roles of the arterial baroreceptors versus the chemoreceptors in several pathophysiological conditions, for instance, arterial hypertension and heart failure.
Assuntos
Aorta/cirurgia , Artérias/cirurgia , Corpo Carotídeo/cirurgia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Artérias/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Corpo Carotídeo/efeitos dos fármacos , Corpo Carotídeo/fisiologia , Células Quimiorreceptoras/efeitos dos fármacos , Células Quimiorreceptoras/fisiologia , Denervação/métodos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hipertensão/fisiopatologia , Masculino , Fenilefrina/farmacologia , Pressorreceptores/efeitos dos fármacos , Pressorreceptores/fisiologia , Ratos , Ratos WistarRESUMO
Hydrogen sulfide (H2S) is classically known for its toxic effects. More recently H2S has been documented as a neuromodulator. Here we investigated the central effects of aminooxyacetate (AOA; inhibitor of the H2S-synthesizing enzyme cystathionine ß-synthase, CBS) on cardiovascular, respiratory and thermoregulatory responses to hypercapnia in spontaneously hypertensive rats (SHR). To attain this goal we measured mean arterial pressure (MAP), heart rate (HR), ventilation (VE), and deep body temperature (Tb) of SHR and (normotensive) Wistar Kyoto (WKY) rats before and after microinjection of AOA (9 nmol/µL) or saline into the fourth ventricle immediately followed by 30-min hypercapnia exposure (7% inspired CO2). In saline-treated WKY rats, hypercapnia caused an increase in MAP accompanied by bradycardia, an increase in VE, and a drop in Tb. In AOA-treated WKY rats exposed to hypercapnia, the drug did not affect the increased MAP, potentiated the bradycardic response, attenuated the increased VE, and potentiated the drop in Tb. In saline-treated SHR, in comparison to the saline-treated WKY rats, hypercapnia elicited a minor, shorter-lasting increase in MAP with no changes in HR, evoked a greater increase in VE, and did not induce a drop in Tb. In AOA-treated SHR exposed to hypercapnia, the drug did not change the hypercapnia-induced cardiovascular and ventilatory responses while permitted a drop in Tb. Our findings indicate that AOA, an inhibitor of H2S production, modulates cardiorespiratory and thermoregulatory responses to hypercapnia in normotensive rats, whereas hypertension development in SHR is accompanied by suppression of the AOA effect on the cardiovascular and respiratory responses.
Assuntos
Ácido Amino-Oxiacético/farmacologia , Pressão Arterial , Regulação da Temperatura Corporal , Temperatura Corporal , Inibidores Enzimáticos/farmacologia , Frequência Cardíaca , Sulfeto de Hidrogênio/antagonistas & inibidores , Hipercapnia/fisiopatologia , Taxa Respiratória , Ácido Amino-Oxiacético/administração & dosagem , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Regulação da Temperatura Corporal/efeitos dos fármacos , Regulação da Temperatura Corporal/fisiologia , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Taxa Respiratória/efeitos dos fármacos , Taxa Respiratória/fisiologiaRESUMO
Spontaneously hypertensive rats (SHR) display autonomic imbalance and abnormal body temperature (Tb) adjustments. Hydrogen sulfide (H2S) modulates hypoxia-induced hypothermia, but its role in SHR thermoregulation is unknown. We tested the hypothesis that SHR display peculiar thermoregulatory response to hypoxia and that endogenous H2S overproduced in the caudal nucleus of the solitary tract (NTS) of SHR modulates this response. SHR and Wistar rats were microinjected into the fourth ventricle with aminooxyacetate (AOA, H2S-synthezing enzyme inhibitor) or sodium sulfide (Na2S, H2S donor) and exposed to normoxia (21% inspired O2) or hypoxia (10% inspired O2, 30 min). Tb was continuously measured, and H2S production rate was assessed in caudal NTS homogenates. In both groups, AOA, Na2S, or saline (i.e., control; 1 µL) did not affect euthermia. Hypoxia caused similar decreases in Tb in both groups. AOA presented a longer latency to potentiate hypoxic hypothermia in SHR. Caudal NTS H2S production rate was higher in SHR. We suggest that increased bioavailability of H2S in the caudal NTS of SHR enables the adequate modulation of excitability of peripheral chemoreceptor-activated NTS neurons that ultimately induce suppression of brown adipose tissue thermogenesis, thus accounting for the normal hypoxic hypothermia.
Assuntos
Regulação da Temperatura Corporal , Sulfeto de Hidrogênio/metabolismo , Hipotermia Induzida , Hipóxia/fisiopatologia , Ácido Amino-Oxiacético/administração & dosagem , Ácido Amino-Oxiacético/farmacologia , Animais , Temperatura Corporal/efeitos dos fármacos , Hipóxia/complicações , Masculino , Microinjeções , Ratos , Ratos Endogâmicos SHR , Núcleo Solitário/metabolismo , Núcleo Solitário/fisiopatologia , Sulfetos/administração & dosagem , Sulfetos/farmacologiaRESUMO
Central hydrogen sulfide (H2S) has been reported to act as a gaseous neuromodulator involved in the ventilatory and cardiovascular control of normotensive rats, whereas no information is available in spontaneously hypertensive rats (SHR). We recorded minute ventilation (VE), mean arterial pressure (MAP) and heart rate (HR) before and after blocking of enzyme Cystathionine ß-synthase (CBS) producing H2S in neural tissue by microinjection of aminooxyacetate (inhibitor of CBS) into the fourth ventricle of Wistar normotensive rats (WNR) and SHR followed by 30min of normoxia (21% inspired O2) or hypoxia (10% inspired O2) exposure. Microinjection of AOA or saline (1µL) did not change VE, MAP and HR during normoxia in both WNR and SHR. In WNR, hypoxia caused an increase in VE, HR and a decrease in MAP and these responses were unaltered by AOA. In SHR, hypoxia produced a higher increase of VE, and decrease in MAP and HR when compared to WNR, and these responses were all blunted by AOA. In conclusion, endogenous H2S plays important modulatory roles on hypoxia-induced ventilatory and cardiovascular responses, inhibiting the cardiovascular and stimulating the respiratory systems in SHR.
Assuntos
Fármacos Cardiovasculares/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Hipertensão/fisiopatologia , Hipóxia/fisiopatologia , Respiração/efeitos dos fármacos , Animais , Pressão Arterial/efeitos dos fármacos , Sistema Cardiovascular/fisiopatologia , Modelos Animais de Doenças , Quarto Ventrículo , Frequência Cardíaca/efeitos dos fármacos , Masculino , Ratos Endogâmicos SHR , Ratos Wistar , Volume de Ventilação Pulmonar/efeitos dos fármacosRESUMO
This study examined the relationship between resting heart rate (RHRr) and anthropometric, metabolic and hemodynamic parameters in subjects aged 80 years and over. One hundred thirteen individuals were divided into two groups (RHR:<66 beats/min and ≥66 beats/min). Anthropometric parameters (weight, height, body mass index and waist circumference (WC) were measured. Hemodynamic parameters (systolic (SBP) and diastolic (DBP) pressure) were measured and pulse pressures (PP) were obtained. Metabolic parameters were fasting blood glucose, triglycerides and total cholesterol. In elderly aged 80 and over, RHR influenced the changes observed in DBP, PP and triglycerides. Additionally, subjects with RHR≥66 beats/min had higher DBP, glucose, total cholesterol and lower PP as compared with elderly with RHR<66 beats/min. Men demonstrated greater weight, height, and WC than women while women had higher percentage of body fat, trunk fat, and higher total cholesterol. Thus, subjects with 80 years old and over who present RHR≥66 have higher DBP and lower PP and heart rate variability compared with the elderly with RHR<66.
Assuntos
Humanos , Masculino , Feminino , Idoso de 80 Anos ou mais , Pressão Arterial , Frequência Cardíaca/fisiologia , GlucoseRESUMO
OBJECTIVE: The effect of chronic ethanol exposure on chemoreflexes has not been extensively studied in experimental animals. Therefore, this study tested the hypothesis that known ethanol-induced autonomic, neuroendocrine and cardiovascular changes coincide with increased chemoreflex sensitivity, as indicated by increased ventilatory responses to hypoxia and hypercapnia. METHODS: Male Wistar rats were subjected to increasing ethanol concentrations in their drinking water (first week: 5% v/v, second week: 10% v/v, third and fourth weeks: 20% v/v). At the end of each week of ethanol exposure, ventilatory parameters were measured under basal conditions and in response to hypoxia (evaluation of peripheral chemoreflex sensitivity) and hypercapnia (evaluation of central chemoreflex sensitivity). RESULTS: Decreased respiratory frequency was observed in rats exposed to ethanol from the first until the fourth week, whereas minute ventilation remained unchanged. Moreover, we observed an increased tidal volume in the second through the fourth week of exposure. The minute ventilation responses to hypoxia were attenuated in the first through the third week but remained unchanged during the last week. The respiratory frequency responses to hypoxia in ethanol-exposed rats were attenuated in the second through the third week but remained unchanged in the first and fourth weeks. There was no significant change in tidal volume responses to hypoxia. With regard to hypercapnic responses, no significant changes in ventilatory parameters were observed. CONCLUSIONS: Our data are consistent with the notion that chronic ethanol exposure does not increase peripheral or central chemoreflex sensitivity.
Assuntos
Etanol/farmacologia , Hipercapnia/fisiopatologia , Hipóxia/fisiopatologia , Ventilação Pulmonar/efeitos dos fármacos , Animais , Frequência Cardíaca/efeitos dos fármacos , Masculino , Modelos Animais , Ratos Wistar , Reflexo/fisiologia , Mecânica Respiratória/efeitos dos fármacos , Volume de Ventilação Pulmonar/efeitos dos fármacos , Fatores de TempoRESUMO
OBJECTIVE: The effect of chronic ethanol exposure on chemoreflexes has not been extensively studied in experimental animals. Therefore, this study tested the hypothesis that known ethanol-induced autonomic, neuroendocrine and cardiovascular changes coincide with increased chemoreflex sensitivity, as indicated by increased ventilatory responses to hypoxia and hypercapnia. METHODS: Male Wistar rats were subjected to increasing ethanol concentrations in their drinking water (first week: 5% v/v, second week: 10% v/v, third and fourth weeks: 20% v/v). At the end of each week of ethanol exposure, ventilatory parameters were measured under basal conditions and in response to hypoxia (evaluation of peripheral chemoreflex sensitivity) and hypercapnia (evaluation of central chemoreflex sensitivity). RESULTS: Decreased respiratory frequency was observed in rats exposed to ethanol from the first until the fourth week, whereas minute ventilation remained unchanged. Moreover, we observed an increased tidal volume in the second through the fourth week of exposure. The minute ventilation responses to hypoxia were attenuated in the first through the third week but remained unchanged during the last week. The respiratory frequency responses to hypoxia in ethanol-exposed rats were attenuated in the second through the third week but remained unchanged in the first and fourth weeks. There was no significant change in tidal volume responses to hypoxia. With regard to hypercapnic responses, no significant changes in ventilatory parameters were observed. CONCLUSIONS: Our data are consistent with the notion that chronic ethanol exposure does not increase peripheral or central chemoreflex sensitivity. .
Assuntos
Animais , Masculino , Hipóxia/fisiopatologia , Etanol/farmacologia , Hipercapnia/fisiopatologia , Ventilação Pulmonar/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Modelos Animais , Ratos Wistar , Reflexo/fisiologia , Mecânica Respiratória/efeitos dos fármacos , Fatores de Tempo , Volume de Ventilação Pulmonar/efeitos dos fármacosRESUMO
We evaluated the effects of parasympathetic activation by pyridostigmine (PYR) on chemoreflex sensitivity in a rat model of heart failure (HF rats). HF rats demonstrated higher pulmonary ventilation (PV), which was not affected by PYR. When HF and control rats treated or untreated with PYR were exposed to 15% O2, all groups exhibited prompt increases in respiratory frequency (RF), tidal volume (TV) and PV. When HF rats were exposed to 10% O2 they showed greater PV response which was prevented by PYR. The hypercapnia triggered by either 5% CO2 or 10% CO2 promoted greater RF and PV responses in HF rats. PYR blunted the RF response in HF rats but did not affect the PV response. In conclusion, PYR prevented increased peripheral chemoreflex sensitivity, partially blunted central chemoreflex sensitivity and did not affect basal PV in HF rats.