Rocuronium-Induced Dilated Nonreactive Pupils in a Patient With Coronavirus Disease 2019: A Case Report.

We report the clinical case of a patient with coronavirus disease 2019 (COVID-19) who had recently undergone neurosurgery and presented with dilated nonreactive pupils during continuous rocuronium infusion, which was reversible with the suspension of the drug. Both the neurosurgical procedure and possible disruption of the blood-brain barrier due to COVID-19 infection may have led to the action of rocuronium in the central nervous system (CNS). Thus, clinicians must remember that neuromuscular blocking agents (NMBAs) can cause dilated nonreactive pupils in patients with COVID-19.

Microvascular Effects of Echinodorus grandiflorus on Cardiovascular Disorders.

Echinodorus grandiflorus is a semiaquatic plant native to Brazil and belongs to the Alismataceae family. Infusion preparations of the leaves of this plant are often used due to its diuretic, blood pressure lowering, and anti-inflammatory properties. Our aim was to investigate the effects of chronic treatment with the crude hydroalcoholic extract of E. grandiflorus on central and peripheral microvascular changes induced in a model of hypertension and diabetes. The hemodynamic and microvascular effects of E. grandiflorus extract (50, 100, or 200 mg/kg/day for 28 days) or the isolated major diterpene from E. grandiflorus (3 to 10 mg/kg i. v.) were evaluated in spontaneously hypertensive rats using tail plethysmography and intravital fluorescence videomicroscopy, respectively, and were compared to vehicle-treated normotensive Wistar-Kyoto rats. We also investigated the protective effects of chronic treatment with E. grandiflorus (100 mg/kg/day) in brain capillary density and leukocyte-endothelium interactions on the brain vessels of DM-spontaneously (DM: diabetes mellitus) hypertensive rats. Chronically treating spontaneously hypertensive rats with increasing doses of crude hydroalcoholic E. grandiflorus extract resulted in significant dose-dependent reductions in systolic blood pressure and an anti-inflammatory effect on the brain microcirculation of DM-spontaneously hypertensive rat animals. Using laser speckle contrast imaging, we observed that intravenous administration of the major isolated clerodane diterpene metabolite (1 - 10 mg/kg) increased microvascular blood flow by 25% in spontaneously hypertensive rat skeletal muscle. The results of this study show that E. grandiflorus extracts can be useful in the prevention and reduction of microcirculatory damage in arterial hypertension and other diseases that involve microvascular dysfunction.

Cerebral microvascular dysfunction in metabolic syndrome is exacerbated by ischemia-reperfusion injury.

BACKGROUND: Metabolic syndrome (MetS) is associated with an increased risk of cerebrovascular diseases, including cerebral ischemia. Microvascular dysfunction is an important feature underlying the pathophysiology of cerebrovascular diseases. In this study, we aimed to investigate the impacts of ischemia and reperfusion (IR) injury on the cerebral microvascular function of rats with high-fat diet-induced MetS. RESULTS: We examined Wistar rats fed a high-fat diet (HFD) or normal diet (CTL) for 20 weeks underwent 30 min of bilateral carotid artery occlusion followed by 1 h of reperfusion (IR) or sham surgery. Microvascular blood flow was evaluated on the parietal cortex surface through a cranial window by laser speckle contrast imaging, functional capillary density, endothelial function and endothelial-leukocyte interactions by intravital videomicroscopy. Lipid peroxidation was assessed by TBARs analysis, the expression of oxidative enzymes and inflammatory markers in the brain tissue was analyzed by real-time PCR. The cerebral IR in MetS animals induced a functional capillary rarefaction (HFD IR 117 ± 17 vs. CTL IR 224 ± 35 capillary/mm2; p < 0.05), blunted the endothelial response to acetylcholine (HFD IR -16.93% vs. CTL IR 16.19% from baseline inner diameter p < 0.05) and increased the endothelial-leukocyte interactions in the venules in the brain. The impact of ischemia on the cerebral microvascular blood flow was worsened in MetS animals, with a marked reduction of cerebral blood flow, exposing brain tissue to a higher state of hypoxia. CONCLUSIONS: Our results demonstrate that during ischemia and reperfusion, animals with MetS are more susceptible to alterations in the cerebral microcirculation involving endothelial dysfunction and oxidative stress events.

Aerobic exercise training induces superior cardioprotection following myocardial ischemia reperfusion injury than a single aerobic exercise session in rats

Abstract AIM To compare the amount of cardioprotection induced by a single exercise session with those achieved after an 8-week aerobic exercise training following ischemia reperfusion injury in rats. METHODS Twenty-five male Wistar rats (250-300g) were assigned into a group submitted to physical training (TR; n=12) or a single maximal exercise session (EXE; n=13). Following sedentarism or physical training (8 weeks, 5 sessions/wk, 1h/session at 70% of maximal speed) both groups performed a maximal exercise test. Then, groups were submitted to ischemia reperfusion injury (30 min/1h) through an isolated heart protocol, in which left ventricle developed pressure was measured. RESULTS The TR group presented greater maximal oxygen consumption compared to the EXE group (77.25±20.41 vs 41.32±25.86 ml/Kg/min; P=0.003). Regarding left ventricle developed pressure, no differences were detected between groups at baseline (TR: 89.78±24.40 vs EXE: 81.37±31.84 mmHg; P=0.48). However, after reperfusion, the TR group presented superior intraventricular pressure than EXE group (37.94±18.34 vs 21.59±13.67 mmHg; P=0.03). CONCLUSION Eight-week aerobic training induced greater cardioprotection against ischemia reperfusion injury in rats compared to a single exercise session, due to an increased cardiac function. This suggests that exercise-induced cardioprotection is a multifactorial process that may involve different mediators according to the exercise duration.(AU)

Effect of continuous and interval aerobic exercise training on baroreflex sensitivity in heart failure.

INTRODUCTION: The ability of continuous aerobic exercise training (AET) to increase baroreflex control and cardiac function in heart failure (HF) has been well described, but the comparison between continuous and interval AET on these functions is inconclusive. OBJECTIVES: To compare the effects of continuous and interval AET on cardiac function and baroreflex sensitivity (BrS) in an experimental model of HF. METHODS: Rats were divided into the following groups: continuous training (HF-CT), intense interval training (HF-IIT), moderate interval training (HF-MIT), sedentary group (HF-SED), and sham sedentary (SHAM-SED). Animals underwent surgery to induce HF by ligation of the interventricular coronary artery. Six weeks after surgery, AET was started (8weeks, 3sessions/week). Echocardiography studies to assess cardiac function were performed before and after AET. At the end of the training protocols, the BrS index was assessed by stepwise intravenous infusions of sodium nitroprusside and phenylephrine. RESULTS: All methods of exercise prevented the HF-induced increase in left ventricular diameter in diastole observed in the HF-SED rats (0.88±0.09 vs. 1.03±0.09cm; P<0.05), but only the HF-CT (28.5±6.3 vs. 39.2±12.7%; P<0.05) and HF-MIT (31.0±8.5 vs. 42.0±10.3%; P<0.05) groups exhibited an increase in ejection fraction. Nevertheless, the HF-CT group was the only group that showed a tachycardia reflex higher than that of the HF-SED group (0.87±0.34 vs. 0.20±0.05bpm/mmHg; P<0.05) and similar to that of the SHAM-SED group (1.04±0.11bpm/mmHg). CONCLUSIONS: These results suggest that continuous and moderate interval training induced similar improvements in cardiac function but that only continuous training induced higher BrS in HF rats.

Derivados canabinóides e o tratamento farmacológico da dor / Cannabinoid derivatives and the pharmacological management of pain

RESUMO JUSTIFICATIVA E OBJETIVOS: As propriedades medicinais da Cannabis sativa têm sido relatadas por muitos séculos para o tratamento de diversos distúrbios e, mais recentemente, para o tratamento da dor. O objetivo deste estudo foi revisar os principais avanços na farmacologia do sistema endocanabinóide e no potencial uso terapêutico de alguns compostos canabinóides no tratamento de diversas formas de dor. CONTEÚDO: Foi realizada uma busca nos bancos de dados Pubmed, Scielo e Lilacs, identificando-se estudos e revisões da literatura sobre a farmacologia e o uso terapêutico de substâncias canabinóides em dor. Nessa busca foram utilizadas as seguintes palavras-chaves: Cannabis sativa, tetra-hidrocanabinol, canabidiol, sativex®, cannador®, canabinóides, endocanabinóide, dor e dor neuropática. Os canabinóides sintéticos e os extratos de Cannabis sativa apresentaram efeito analgésico em diversos ensaios clínicos, sugerindo um potencial papel no tratamento da dor, em particular naquela de origem neuropática. Os canabinóides sintéticos e os extratos de Cannabis sativatambém apresentaram efeitos ansiolíticos quando usados como adjuvantes no tratamento da dor no câncer, na artrite reumatoide e na esclerose múltipla. Porém, efeitos adversos significativos, como euforia, depressão e sedação limitam o uso clínico desses agentes canabinóides. CONCLUSÃO: Um melhor conhecimento sobre a farmacologia do sistema endocanabinóide, juntamente com os resultados dos estudos envolvendo o tratamento da dor com substâncias de natureza canabinóide, podem ser de grande valor para o desenvolvimento de fármacos que permitam um avanço significativo na terapêutica de pacientes portadores de síndromes dolorosas, em particular nos casos de difícil controle. Porém, mais estudos são necessários para confirmar esses resultados e determinar a segurança desses compostos.

ABSTRACT BACKGROUND AND OBJECTIVES: Medical properties of Cannabis sativa have been reported for centuries for the treatment of diff ent disorders and, more recently, to manage pain. Th study aimed at reviewing major pharmacological advances of the endocannabinoid system and the potential therapeutic use of some cannabinoid compounds to manage diff ent types of pain. CONTENTS: A search was carried out in Pubmed, Scielo and Lilacs databases to identify studies and literature reviews on the pharmacology and therapeutic use of cannabinoids for pain. The following keywords were used: Cannabis sativa, tetra-hydrocannabinol, cannabidiol, sativex®, cannador®, cannabinoids, endocannabinoid, pain and neuropathic pain. Synthetic cannabinoids and Cannabis sativa extracts have shown analgesic effects in several clinical trials, suggesting their potential role for pain management, especially neuropathic pain. Synthetic cannabinoids and CS extracts have also induced anxiolytic effects when used as adjuvants to treat cancer pain, rheumatoid arthritis and multiple sclerosis. However, significant adverse effects, such as euphoria, depression and sedation limit the clinical use of such cannabinoids. CONCLUSION: Further understanding of endocannabinoid system pharmacology, together with study results involving pain management with cannabinoid substances may be very useful for the development of drugs allowing a significant advance in the treatment of patients with painful syndromes, especially difficult to control. However, further studies are needed to confirm such findings and to determine the safety of such compounds.

Mechanisms Involved in Exercise-Induced Cardioprotection: A Systematic Review / Mecanismos Envolvidos na Cardioproteção Induzida pelo Exercício Físico: Uma Revisão Sistemática

Acute myocardial infarction is the leading cause of morbidity and mortality worldwide. Furthermore, research has shown that exercise, in addition to reducing cardiovascular risk factors, can also protect the heart against injury due to ischemia and reperfusion through a direct effect on the myocardium. However, the specific mechanism involved in exerciseinduced cardiac preconditioning is still under debate.

O infarto agudo do miocárdio é a principal causa de mortalidade e de morbidade na população mundial. Por outro lado, pesquisas já demonstraram que o exercício físico, além de reduzir os fatores de risco cardiovascular, também é capaz de promover cardioproteção contra lesões por isquemia e reperfusão, por meio de um efeito direto no miocárdio. No entanto, o mecanismo específico envolvido no pré-condicionamento cardíaco induzido pelo exercício ainda é alvo de discussão.

Mechanisms Involved in Exercise-Induced Cardioprotection: A Systematic Review.

BACKGROUND: Acute myocardial infarction is the leading cause of morbidity and mortality worldwide. Furthermore, research has shown that exercise, in addition to reducing cardiovascular risk factors, can also protect the heart against injury due to ischemia and reperfusion through a direct effect on the myocardium. However, the specific mechanism involved in exerciseinduced cardiac preconditioning is still under debate. OBJECTIVE: To perform a systematic review of the studies that have addressed the mechanisms by which aerobic exercise promotes direct cardioprotection against ischemia and reperfusion injury. METHODS: A search was conducted using MEDLINE, Literatura Latino-Americana e do Caribe de Informação em Ciências da Saúde, and Scientific Electronic Library Online databases. Data were extracted in a standardized manner by two independent researchers, who were responsible for assessing the methodological quality of the studies. RESULTS: The search retrieved 78 studies; after evaluating the abstracts, 30 studies were excluded. The manuscripts of the remaining 48 studies were completely read and, of these, 20 were excluded. Finally, 28 studies were included in this systematic review. CONCLUSION: On the basis of the selected studies, the following are potentially involved in the cardioprotective response to exercise: increased heat shock protein production, nitric oxide pathway involvement, increased cardiac antioxidant capacity, improvement in ATP-dependent potassium channel function, and opioid system activation. Despite all the previous investigations, further research is still necessary to obtain more consistent conclusions.

Delta opioid receptors: the link between exercise and cardioprotection.

This study investigated the role of opioid receptor (OR) subtypes as a mechanism by which endurance exercise promotes cardioprotection against myocardial ischemia-reperfusion (IR) injury. Wistar rats were randomly divided into one of seven experimental groups: 1) control; 2) exercise-trained; 3) exercise-trained plus a non-selective OR antagonist; 4) control sham; 5) exercise-trained plus a kappa OR antagonist; 6) exercise-trained plus a delta OR antagonist; and 7) exercise-trained plus a mu OR antagonist. The exercised animals underwent 4 consecutive days of treadmill training (60 min/day at ∼70% of maximal oxygen consumption). All groups except the sham group were exposed to an in vivo myocardial IR insult, and the myocardial infarct size (IS) was determined histologically. Myocardial capillary density, OR subtype expression, heat shock protein 72 (HSP72) expression, and antioxidant enzyme activity were measured in the hearts of both the exercised and control groups. Exercise training significantly reduced the myocardial IS by approximately 34%. Pharmacological blockade of the kappa or mu OR subtypes did not blunt exercise-induced cardioprotection against IR-mediated infarction, whereas treatment of animals with a non-selective OR antagonist or a delta OR antagonist abolished exercise-induced cardioprotection. Exercise training enhanced the activities of myocardial superoxide dismutase (SOD) and catalase but did not increase the left ventricular capillary density or the mRNA levels of HSP72, SOD, and catalase. In addition, exercise significantly reduced the protein expression of kappa and delta ORs in the heart by 44% and 37%, respectively. Together, these results indicate that ORs contribute to the cardioprotection conferred by endurance exercise, with the delta OR subtype playing a key role in this response.

Physical exercise restores microvascular function in obese rats with metabolic syndrome.

BACKGROUND: Obesity and metabolic syndrome are related to systemic functional microvascular alterations, including a significant reduction in microvessel density. The aim of this study was to investigate the effects of exercise training on functional capillary density in the skeletal muscle and skin of obese rats with metabolic syndrome. METHODS: We used male Wistar-Kyoto rats that had been fed a standard commercial diet (CON) or high-fat diet (HFD) for 32 weeks. Animals receiving the HFD were randomly divided into sedentary (HFD+SED) and training groups (HFD+TR) at the 20(th) week. After 12 weeks of aerobic treadmill training, the maximal oxygen uptake (VO2max); hemodynamic, biochemical, and anthropometric parameters; and functional capillary density were assessed. In addition, a maximal exercise test was performed. RESULTS: Exercise training increased the VO2max (69 ± 3 mL/kg per min) and exercise tolerance (30 ± 1 min) compared with the HFD+SED (41 ± 6 mL/kg per min, P < 0.05 and 16 ± 1 min, P < 0.001) and with the CON (52 ± 7 mL/kg per min and 18 ± 1 min, P < 0.05) groups. The HFD+TR group also showed reduced retroperitoneal fat (0.03 ± 0.00 vs. 0.05 ± 0.00 gram/gram, P < 0.001), epididymal fat (0.01 ± 0.00 vs. 0.02 ± 0.00 gram/gram, P < 0.001), and systolic blood pressure (127 ± 2 vs. 150 ± 2 mmHg, P<0.001). The HFD+TR group also demonstrated improved glucose tolerance, as evaluated by an intraperitoneal glucose tolerance test, fasting plasma glucose levels (5.0 ± 0.1 vs. 6.4 ± 0.2 mmol/L, P<0.001) and fasting plasma insulin levels (26.5 ± 2.3 vs. 38.9 ± 3.7 µIU/mL, P < 0.05). Glucose tolerance did not differ between HFD+TR and CON groups. Exercise training also increased the number of spontaneously perfused capillaries in the skeletal muscle (252 ± 9 vs. 207 ± 9 capillaries/mm(2)) of the training group compared with that in the sedentary animals (260 ± 15 capillaries/mm(2)). CONCLUSIONS: These results demonstrate that exercise training reverses capillary rarefaction in our experimental model of metabolic syndrome and obesity.

Acute Chagas disease induces cerebral microvasculopathy in mice.

Cardiomyopathy is the main clinical form of Chagas disease (CD); however, cerebral manifestations, such as meningoencephalitis, ischemic stroke and cognitive impairment, can also occur. The aim of the present study was to investigate functional microvascular alterations and oxidative stress in the brain of mice in acute CD. Acute CD was induced in Swiss Webster mice (SWM) with the Y strain of Trypanosoma cruzi (T. cruzi). Cerebral functional capillary density (the number of spontaneously perfused capillaries), leukocyte rolling and adhesion and the microvascular endothelial-dependent response were analyzed over a period of fifteen days using intravital video-microscopy. We also evaluated cerebral oxidative stress with the thiobarbituric acid reactive species TBARS method. Compared with the non-infected group, acute CD significantly induced cerebral functional microvascular alterations, including (i) functional capillary rarefaction, (ii) increased leukocyte rolling and adhesion, (iii) the formation of microvascular platelet-leukocyte aggregates, and (iv) alteration of the endothelial response to acetylcholine. Moreover, cerebral oxidative stress increased in infected animals. We concluded that acute CD in mice induced cerebral microvasculopathy, characterized by a reduced incidence of perfused capillaries, a high number of microvascular platelet-leukocyte aggregates, a marked increase in leukocyte-endothelium interactions and brain arteriolar endothelial dysfunction associated with oxidative stress. These results suggest the involvement of cerebral microcirculation alterations in the neurological manifestations of CD.

Exercicio Aerobio Intervalado Induz Maior Reducao na Sobrecarga Cardiaca na Recuperacao em Ratos / Aerobic Interval Exercise Training Induces Greater Reduction in Cardiac Workload in the Recovery Period in Rats

Fundamento: O treinamento aeróbio intervalado produz maior benefício na função cardiovascular comparado ao treinamento aeróbio contínuo. Objetivo: O presente estudo teve como objetivo analisar os efeitos de ambas as modalidades nas respostas hemodinâmicas de ratos sadios. Métodos: Ratos machos foram distribuídos aleatoriamente em três grupos: exercício contínuo (EC, n = 10); exercício intervalado (EI, n = 10); e controle (C, n = 10). A sessão do grupo EC consistiu em 30 min à intensidade de 50% da velocidade máxima (Vel Máx). O grupo EI realizou 30 min, incluindo três períodos de 4 min a 60% da Vel Máx intercalados com 4 min de recuperação a 40% da Vel Máx. Frequência Cardíaca (FC), Pressão Arterial (PA) e Duplo Produto (DP) foram medidos antes, durante e após o exercício. Resultados: Os grupos EC e EI apresentaram aumento da PA sistólica e DP durante o exercício em comparação ao repouso. Após o término do exercício, o grupo EC mostrou menor resposta da PA sistólica e do DP em relação ao repouso, enquanto o grupo EI apresentou menor PA sistólica e PA média. No entanto, somente no grupo EI a FC e o DP apresentaram menor resposta na recuperação. Conclusão: Uma sessão de exercício intervalado em ratos sadios induziu respostas hemodinâmicas similares durante o exercício às obtidas em exercício contínuo. Na recuperação, o exercício intervalado promoveu maiores reduções no esforço cardíaco do que em sessões contínuas de exercício. .

Background: Aerobic interval exercise training has greater benefits on cardiovascular function as compared with aerobic continuous exercise training. Objective: The present study aimed at analyzing the effects of both exercise modalities on acute and subacute hemodynamic responses of healthy rats. Methods: Thirty male rats were randomly assigned into three groups as follows: continuous exercise (CE, n = 10); interval exercise (IE, n = 10); and control (C, n = 10). Both IE and CE groups performed a 30-minute exercise session. The IE group session consisted of three successive 4-minute periods at 60% of maximal velocity (Max Vel), with 4-minute recovery intervals at 40% of Max Vel. The CE group ran continuously at 50% of Max Vel. Heart rate (HR), blood pressure(BP), and rate pressure product (RPP) were measured before, during and after the exercise session. Results: The CE and IE groups showed an increase in systolic BP and RPP during exercise as compared with the baseline values. After the end of exercise, the CE group showed a lower response of systolic BP and RPP as compared with the baseline values, while the IE group showed lower systolic BP and mean BP values. However, only the IE group had a lower response of HR and RPP during recovery. Conclusion: In healthy rats, one interval exercise session, as compared with continuous exercise, induced similar hemodynamic responses during exercise. However, during recovery, the interval exercise caused greater reductions in cardiac workload than the continuous exercise. .

Aerobic interval exercise training induces greater reduction in cardiac workload in the recovery period in rats.

BACKGROUND: Aerobic interval exercise training has greater benefits on cardiovascular function as compared with aerobic continuous exercise training. OBJECTIVE: The present study aimed at analyzing the effects of both exercise modalities on acute and subacute hemodynamic responses of healthy rats. METHODS: Thirty male rats were randomly assigned into three groups as follows: continuous exercise (CE, n = 10); interval exercise (IE, n = 10); and control (C, n = 10). Both IE and CE groups performed a 30-minute exercise session. The IE group session consisted of three successive 4-minute periods at 60% of maximal velocity (Max Vel), with 4-minute recovery intervals at 40% of Max Vel. The CE group ran continuously at 50% of Max Vel. Heart rate (HR), blood pressure(BP), and rate pressure product (RPP) were measured before, during and after the exercise session. RESULTS: The CE and IE groups showed an increase in systolic BP and RPP during exercise as compared with the baseline values. After the end of exercise, the CE group showed a lower response of systolic BP and RPP as compared with the baseline values, while the IE group showed lower systolic BP and mean BP values. However, only the IE group had a lower response of HR and RPP during recovery. CONCLUSION: In healthy rats, one interval exercise session, as compared with continuous exercise, induced similar hemodynamic responses during exercise. However, during recovery, the interval exercise caused greater reductions in cardiac workload than the continuous exercise.

Cardiac microvascular rarefaction in hyperthyroidism-induced left ventricle dysfunction.

OBJECTIVE: The pathophysiology underlying hyperthyroidism-induced left ventricle (LV) dysfunction and hypertrophy directly involves the heart and indirectly involves the neuroendocrine systems. The effects of hyperthyroidism on the microcirculation are still controversial in experimental models. We investigated the effects of hyperthyroidism on the cardiac function and microcirculation of an experimental rat model. METHODS: Male Wistar rats (170-250 g) were divided into two groups: the euthyroid group (n = 10), which was treated with 0.9% saline solution, and the hyperthyroid group (n = 10), which was treated with l-thyroxine (600 µg/kg/day, i.p.) during 14 days. An echocardiographic study was performed to evaluate the alterations in cardiac function, structure and geometry. The structural capillary density and the expression of angiotensin II AT1 receptor in the LV were analyzed using histochemistry and immunohistochemistry, respectively. RESULTS: Hyperthyroidism was found to induce profound cardiovascular alterations, such as systolic hypertension, tachycardia, LV dysfunction, cardiac hypertrophy, and myocardial fibrosis. This study demonstrates the existence of structural capillary rarefaction and the down-regulation of the cardiac angiotensin II AT1 receptor in the myocardium of hyperthyroid rats in comparison with euthyroid rats. CONCLUSIONS: Microvascular rarefaction may be involved in the pathophysiology of hyperthyroidism-induced cardiovascular alterations.

Microvascular effects of centrally acting antihypertensive drugs in spontaneously hypertensive rats.

We investigated the effects of oral long-term antihypertensive treatment using centrally acting sympathoinhibitory drugs on capillary density in the skin, skeletal muscle, and heart in the spontaneously hypertensive rat (SHR). Wistar Kyoto rats (WKY) were used as normotensive control groups. Functional capillary density was assessed using intravital fluorescence videomicroscopy and structural capillary density with histochemical analysis. Groups of 10 SHRs were orally treated over 28 days with clonidine (0.1 mg x kg x d), rilmenidine (1 mg x kg x d), or moxonidine (10 mg x kg x d). A group of WKY was also treated with clonidine (0.1 mg x kg x d). Treatment with all antihypertensive drugs induced a normalization of arterial pressure accompanied by a reversion of functional capillary rarefaction in the skeletal muscle and skin of SHR. Clonidine treatment also reduced arterial pressure and increased functional capillary density in the skin and skeletal muscle of WKY. Histochemical analysis showed that SHR had a lower capillary to fiber ratio in the skeletal muscle (P < 0.0001), which was normalized by all treatments. The capillary volume density to fiber volume density ratio in the left ventricle of SHR was also significantly reduced (P < 0.0001). However, myocardial capillary rarefaction was not altered by the different treatments. In conclusion, the results showed that long-term antihypertensive treatment with centrally acting drugs enhanced tissue perfusion and reversed capillary rarefaction in the skeletal muscle of SHRs.

Antihypertensive effects of crude extracts from leaves of Echinodorus grandiflorus.

The antihypertensive action of a crude ethanolic extract (EEEG) from leaves of Echinodorus grandiflorus (Alismataceae) was investigated in spontaneously hypertensive rats. The intraperitoneal injection of increasing doses of EEEG (300-1000 mg/kg) elicited dose-dependent reductions in mean arterial pressure (MAP) that were paralleled by reductions of cardiac output and systemic vascular resistance, reaching the maximum of 23 +/- 5%, 13 +/- 3% and 18 +/- 4%, respectively (n = 5, P < 0.05). Comparable reductions of MAP were obtained upon i.v. administration of EEEG (3-100 mg/kg), reaching the maximum decrease of 51 +/- 6% (n = 7; P < 0.001). The blockade of nitric oxide synthesis significantly reduced the hypotension induced by i.v. administration of EEEG. Moreover, the pre-treatment of the animals with a selective antagonist of cholinergic muscarinic receptors or of platelet-activating factor (PAF) receptors partially blunted the cardiovascular effects of EEEG. The i.v. pre-treatment with the selective B(2) bradykinin receptor antagonist HOE 140 or with indomethacin, an inhibitor of the enzyme cyclooxygenase, did not prevent the hypotensive effects induced by EEEG. Finally, the chronic oral treatment with EEEG presented a significant antihypertensive effect that was comparable to that of reference antihypertensive drugs currently used to treat arterial hypertension. It is concluded that EEEG elicits significant acute antihypertensive effects through the release of nitric oxide and the stimulation of cholinergic muscarinic and PAF receptors. Moreover, our results suggest that EEEG may be appropriate to chronic oral treatment of arterial hypertension.

Pharmacological mechanisms involved in the vasodilator effects of extracts from Echinodorus grandiflorus.

We investigated the vascular effects of a crude aqueous extract (AEEG) of Echinodorus grandiflorus (Alismataceae) using the in vitro experimental models of the rabbit isolated aorta and perfused kidney. Echinodorus grandiflorus, a native semi-aquatic plant widely distributed in Brazil, has been extensively used in Brazilian folk medicine for the treatment of high blood pressure and inflammatory diseases. The bolus injection of AEEG (0.1-10 mg) into the rabbit renal circulation pre-contracted with norepinephrine induced marked and dose-dependent vasodilator responses (maximum of 37+/-4%; n=6; P<0.001), which was similar to that induced by injection of 10 mmol acetylcholine (41+/-3%). Moreover, AEEG elicited a significant and concentration-dependent relaxation in the endothelium-intact, but not endothelium-denuded aortic rings, reaching the maximum of 81+/-5% (n=7, P<0.001). Inhibition of the nitric oxide-cGMP pathway with L-NAME (100 microM) or Methylene Blue (20 microM) reduced maximum relaxation induced by AEEG from 81+/-5% to 46+/-3 and 45+/-3%, respectively (n=7, P<0.001). A similar reduction was obtained with the incubation of the aortic rings with the selective PAF receptor antagonist WEB 2086 (10 microM) (from 81+/-5% to 55+/-3%; n=7; P<0.01). Conversely, blockade of muscarinic receptors with atropine (10 microM) did not affect the vasodilator effects of AEEG, while inhibition of the enzyme cyclooxigenase not only did not block, but rather potentiated vasodilation induced by AEEG (n=7, P<0.001). Finally, blockade of Ca(2+)- and ATP-activated K(+) channels using the specific blockers charydbotoxin (100 nM) and glibenclamide (3 microM), respectively, did not modify aortic relaxation induced by AEEG. We conclude that water-soluble extracts from leaves of Echinodorus grandiflorus elicit an endothelium-dependent, nitric oxide and PAF receptor-mediated vasodilation in rabbit aortic rings, which does not appear to involve the generation of vasodilating prostaglandins or the activation of K(+) channels. This potent vasodilator effect of the extracts was confirmed in the isolated rabbit renal circulation.

Medicamentos anti-hipertensivos que atuam no sistema nervoso central / Centrally acting antihypertensive drugs

O aumento do tônus simpático central é um achado precoce e constante na fisiopatologia da hipertensão arterial primária. Por conseguinte, os medicamentos anti-hipertensivos de ação central caracterizam-se por inibir a atividade do sistema nervoso simpático central em grupos neuronais envolvidos no controle do sistema cardiovascular, com conseqüente redução da pressão arterial sistêmica.Apesar de serem medicamentos eficazes no controle da pressão arterial, os anti-hipertensivos de ação central ditos de primeira geração, tais como a clonidina e a metildopa, apresentam um perfil de efeitos adversos desfavoráveis com relação a outras classes de agentes anti-hipertensivos. Esses efeitos adversos caracterizam-se principalmente por sonolência e xerostomia. No entanto, na última década, os sítios de ligação bulbares específicos de imidazolinas (SU) foram reconhecidos como alvo terapêutico inovador para o desenvolvimento de novas drogas anti-hipertensivas de ação central. Neste contexto, foram sintetizadas novas moléculas consideradas como sendo de segunda geração, representadas atualmente pela rilmenidina e pela moxonidina, que apresentam seletividade maior pelos SLI do que a clonidina. Essas drogas são praticamente isentas dos efeitos colaterais de origem central característicos dos agentes de primeira geração, que resultam da ativação de receptores a2-adrenérgicos. Embora apresentem alguma atividade a2-adrenérgica, a rilmenidina e a moxonidina induzem hipotensão arterial, pelo menos em parte, por inibição da atividade simpática central, ativando os SLI

Acute cardiodepressant effects induced by bolus intravenous administration of amiodarone in rabbits.

Amiodarone is a potent anti-arrhythmic with a large pharmacological spectrum that shares the mechanisms of action of all classes of anti-arrhythmic drugs. Originally used in the treatment of supraventricular arrhythmias, it has also been used to treat ventricular tachyarrhythmias. The recent inclusion of amiodarone in the Advanced Cardiac Life Support protocols warrants the characterization of the hemodynamic profile resulting from the rapid venous administration of the drug. Thus, the main purpose of the present study was to investigate the acute hemodynamic profile resulting from the bolus i.v. injection of amiodarone, compared with bolus i.v. administration of lidocaine. We investigated the acute hemodynamic effects of amiodarone and lidocaine, in an experimental model of open-chest pentobarbital-anesthetized rabbits (n = 24). Amiodarone (5 mg/kg) induced immediate reductions in mean arterial pressure (MAP) of 32 +/- 5% (P < 0.001), accompanied by reductions in cardiac contractility and relaxation, as assessed by left ventricular (LV) +dP/dt(max) and -dP/dt(max) (40 +/- 4 and 36 +/- 4% respectively) (P < 0.001), heart rate (HR) 10 +/- 1% (P < 0.05), cardiac output (CO) 24 +/- 5% (P < 0.001) and systemic vascular resistance (SVR) 19 +/- 3.5% (P < 0.05). Lidocaine (3 mg/kg) induced reductions in: MAP of 18 +/- 7% (P < 0.001), LV +dP/dt(max) and -dP/dt(max) (40 +/- 5 and 22 +/- 7% respectively) (P < 0.001), HR 7 +/- 1% (P < 0.01) and CO of 23 +/- 6% (P < 0.001). SVR increased by 9 +/- 1.5% (P > 0.05). It is concluded that rapid i.v. administration of both amiodarone and lidocaine induces significant cardiovascular depression mainly characterized by immediate reductions in cardiac contractility.