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Hemorrhage secondary to rupture of a brain arteriovenous malformations (AVM) is one of the initial manifestations, and the main cause of, morbidity and mortality in patients with this condition. Current treatment strategies include endovascular embolization with the goal of AVM obliteration and neurological preservation. In the transvenous endovascular embolization procedure, adenosine is the preferred agent to induce temporary hypotension and allow adequate AVM embolization. We describe the intraoperative management of an adenosine-resistant 38 year-old male who underwent a successful intracranial AVM embolization after concomitant administration of gradually increasing doses of nitroglycerin. This report suggests that nitroglycerin infusion can be combined with adenosine boluses to create a pronounced and dose-dependent hypotension in patients partially unresponsive to adenosine alone.
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INTRODUCTION: A cerebral vasospasm (CVSP) is a potent vasoconstriction of the cerebral vasculature and the primary cause of morbidity and mortality following a subarachnoid hemorrhage. The middle cerebral artery (MCA) is commonly affected by CVSPs. Concomitant administration of dantrolene and nimodipine synergistically reduces vasospasms in aortic rings from Sprague Dawley rats. To determine if the effects observed in the systemic vasculature extend to the cerebral circulation, we investigated the effect of intravenous administration of dantrolene (2.5 mg/kg) and nimodipine (1 mg/kg and 2 mg/kg) on MCA blood flow velocity (BFV) 7 days after the induction of CVSPs. METHODS: Vasospasms were induced by bathing the left common carotid artery with autologous whole blood. Age-matched sham rats were used as controls. BFV, mean arterial pressure (MAP), and heart rate (HR) were measured with a PeriFlux 5000 Laser Doppler System, and a CODA non-invasive blood pressure system, before and after administering the drugs. Morphometric evaluations were also performed to assess vascular alterations. RESULTS: BFV was reduced by 37% with dantrolene alone (n = 6, p ≤ 0.05) and by 27% with 2 mg/kg nimodipine (n = 6, p < 0.05), while it was not affected by 1 mg/kg nimodipine. The combination of 1 mg/kg nimodipine with dantrolene, however, decreased BFV by 35% (from 435.70 ± 21.53 to 284.30 ± 23.13 perfusion units, n = 7, p ≤ 0.05). A similar reduction (31%) was obtained with dantrolene and 2 mg/kg nimodipine (from 536.00 ± 32.61 to 367.80 ± 40.93 perfusion units, n = 6, p ≤ 0.05). Neither MAP nor HR was affected by dantrolene or nimodipine alone. The combination of dantrolene with 2 mg/kg nimodipine, however, decreased MAP and increased HR. Furthermore, 7 days after the induction of vasospasms, lumen area of the left common carotid artery decreased, whereas media thickness and the wall-to-lumen ratio increased when compared to contralateral controls. The latter finding suggests that vascular remodeling was present at this stage. CONCLUSION: Altogether, our results indicate that 2.5 mg/kg dantrolene significantly reduces BFV in the MCA without altering systemic hemodynamic parameters to a similar extent than the highest dose of nimodipine or the combination of dantrolene and the lowest dose of nimodipine. Therefore, dantrolene may provide a promising alternative to lower the risk, or partially revert, CVSP.
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Nimodipina , Hemorragia Subaracnóidea , Ratos , Animais , Nimodipina/farmacologia , Nimodipina/uso terapêutico , Dantroleno/farmacologia , Dantroleno/uso terapêutico , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Circulação CerebrovascularRESUMO
BACKGROUND: Diabetics have a higher risk of developing cerebral vasospasms (CVSPs) than non-diabetics. Current therapies are ineffective in reducing CVSPs, but a a combination of dantrolene and nimodipine may be a viable treatment. Considering the potentially harmful secondary effects of dantrolene, however, we evaluated the efficacy of 10 µM dantrolene compared to 50 µM dantrolene alone or in combination with 50 nM nimodipine. METHODS: Dose-response curves for the phenylephrine (PHE)-induced contraction and acetylcholine (ACh)-induced relaxation were performed on aortic rings from diabetic and non-diabetic rats, before and after a 30-min incubation period with dantrolene (50 µM and 10 µM), alone or in combination with 50 nM nimodipine. RESULTS: Whereas 50 µM dantrolene reduced PHE-induced contraction by 47% in diabetic rats and 29% in controls, 10 µM dantrolene failed to reduce this parameter in either group. Furthermore, 50 µM dantrolene reduced PHE-induced contraction by about 80% in both diabetic and controls when combined with nimodipine (N = 9, P < 0.05). The combination of 10 µM dantrolene and 50 nM nimodipine, however, was ineffective. Only 50 µM dantrolene improved endothelial dysfunction. CONCLUSIONS: Improved endothelial-dependent relaxation and reduced vascular contractility with dantrolene are dose dependent. Thus, although dantrolene appears to be a promising alternative for the treatment of CVSPs when added to conventional therapies, careful titration should be performed to achieve a significant reduction in vascular hyperreactivity. Moreover, if our findings with rats are applicable to humans, the combined use of dantrolene and nimodipine at optimal doses may reduce CVSPs, especially in the diabetic population.
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Dantroleno/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Nimodipina/administração & dosagem , Vasoespasmo Intracraniano/prevenção & controle , Acetilcolina/farmacologia , Animais , Dantroleno/farmacologia , Diabetes Mellitus Experimental/complicações , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Masculino , Nimodipina/farmacologia , Fenilefrina/administração & dosagem , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacologia , Vasoespasmo Intracraniano/etiologiaRESUMO
Increased vascular angiotensin-converting enzyme (ACE) activity and oxidative stress are present in young Syrian cardiomyopathic hamsters (SCH) before the clinical manifestation of heart failure (HF). The developmental time-course of these alterations and their potential interactions, however, are still unknown. We evaluated mRNA and protein levels of ACE, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) in the vasculature of SCH from one to four months of age. Total RNA and proteins were quantified with real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, respectively. The role of nitric oxide (NO) on vascular ACE activity was also assessed. ACE mRNA and protein levels were up-regulated in SCH at two months of age compared with controls (CT) (p < 0.05). At this two-month stage, eNOS protein levels were lower in SCH (87%) than in CT (100%) (p < 0.05), although iNOS protein levels increased significantly (482%) compared to CT (100%; p < 0.05). In addition, ACE mRNA expression and activity were modulated by NO at two months of age. Thus, the combination of low eNOS and high iNOS protein levels may underlie vascular renin-angiotensin system (RAS) over-activation. Altogether, these factors may contribute to the development of endothelial dysfunction and vascular hyper-reactivity in the early stages of heart failure, and eventually trigger cardiac deterioration in this animal model of HF.
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BACKGROUND: Therapy with HMG-CoA reductase inhibitors (statins) has been associated with a significant reduction in the number of major cardiovascular (CV) events in diabetic patients. The mechanisms by which these drugs improve cardiac status remain unclear. We assessed the effects of atorvastatin (10 mg/kg/day) on CV function in streptozotocin (STZ)-induced diabetic rats. METHODS: Age-matched, nondiabetic rats were used as controls. Echocardiographic parameters, systolic blood pressure (SBP), endothelial-dependent relaxation, cardiac and vascular oxidative stress, perivascular fibrosis, and cholesterol levels were evaluated after a 4-week atorvastatin treatment period. RESULTS: In diabetic rats, SBP was higher than in controls. Atorvastatin decreased SBP in diabetic rats by 14% (n = 10, p < 0.05), and significantly increased stroke volume, ejection fraction, and cardiac output index. Whereas atorvastatin reduced left ventricular end systolic volume (LVESV) by 50% (p < 0.05), it failed to reduce left ventricular end diastolic volume (LVEDV). Total cholesterol was higher in diabetic rats than in controls and atorvastatin was ineffective in reducing cholesterol levels. The statin, however, decreased perivascular fibrosis and media thickness, and the markers of oxidative stress malondialdehyde (MDA) and 4-hidroxyalkenals (4-HAE) in aortic homogenates from diabetic rats. In addition, atorvastatin improved endothelial function by increasing the E MAX value of the acetylcholine-induced relaxation from 53.7 ± 4.1% in untreated diabetic to 82.1 ± 7.0% in treated diabetic rats (n = 10, p < 0.05). L-NAME fully abolished this improvement, suggesting that the increased vascular relaxation with atorvastatin is NO-dependent. CONCLUSIONS: Whereas atorvastatin does not reverse ventricular dilatation, it does have a positive hemodynamic effect on the CV system of diabetic rats. This hemodynamic benefit is independent of cholesterol levels, and is observed concomitantly with reduced oxidative stress, vascular remodeling, and improved endothelial function. Together, these results suggest that atorvastatin decreases the workload on the heart and improves systolic performance in type 1 diabetic rats by reducing oxidative stress, vascular tone, and systemic vascular resistance.
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OBJECTIVE: Chronic activation of the renin-angiotensin-aldosterone system is a major contributing factor to the pathogenesis and progression of cardiovascular and renal diseases. METHODS: To evaluate the role of renin-angiotensin-aldosterone system blockade with aliskiren, a direct renin inhibitor, in the development and progression of dilated cardiomyopathy in the Syrian cardiomyopathic hamster (SCH) model, we treated 1-month-old SCH with aliskiren (10 mg·kg·d) over a 4-month period. For comparative purposes, we also evaluated the effects of the angiotensin receptor blocker valsartan (10 mg·kg·d) and the combination of both drugs. Age-matched golden hamsters were used as controls. Left ventricular end-diastolic volume and end-systolic volume, ejection fraction, and diastolic function were determined by echocardiography. Systolic blood pressure (SBP) was also measured in the left femoral artery by sphygmomanometry. RESULTS: Results indicate that at 2 months of age, SBP is higher in SCH than in controls, and administration for 1 month of aliskiren, valsartan, or the combination of these drugs normalized SBP in SCH to a similar extent. In 5-month-old SCH, aliskiren improved ejection fraction (from 48.6% ± 5.8% to 69.4% ± 3.2%, n = 5, P < 0.05), left ventricular end-systolic volume (from 0.28 ± 0.06 to 0.10 ± 0.01 mL/100 g body weight), left ventricular end-diastolic volume (from 0.61 ± 0.05 to 0.34 ± 0.02 mL/100 g body weight), and normalized diastolic function (E:A ratio increases from 0.93 ± 0.13 to 1.70 ± 0.03, n = 5, P < 0.05). Similar results were observed with valsartan or the combination of aliskiren and valsartan. CONCLUSIONS: Our results indicate that in this animal model, aliskiren is as effective as valsartan, or the combination of both drugs, in improving diastolic function and in preventing the development of dilated cardiomyopathy. These findings suggest that aliskiren may be used as a monotherapy in heart failure management. Clinical studies, however, are needed to assess the effectiveness of this drug in patients with heart failure.
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Amidas/farmacologia , Cardiomiopatia Dilatada/tratamento farmacológico , Fumaratos/farmacologia , Renina/antagonistas & inibidores , Disfunção Ventricular Esquerda/tratamento farmacológico , Amidas/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/prevenção & controle , Cricetinae , Modelos Animais de Doenças , Progressão da Doença , Quimioterapia Combinada , Fumaratos/administração & dosagem , Masculino , Sistema Renina-Angiotensina/efeitos dos fármacos , Tetrazóis/administração & dosagem , Tetrazóis/farmacologia , Valina/administração & dosagem , Valina/análogos & derivados , Valina/farmacologia , ValsartanaRESUMO
BACKGROUND: People with diabetes are at increased risk of cardiovascular (CV) morbidity and mortality during surgery. The most appropriate anaesthetic induction agent for these patients is unknown. METHODS AND RESULTS: We assessed the CV effects of propofol, etomidate and ketamine in streptozotocin (65 mg/kg, IP) diabetic rats. In non-diabetic rats, none of these anaesthetics significantly modified cardiac output, heart rate or stroke volume, but ketamine increased systolic blood pressure (SBP) compared to etomidate and propofol (89.6 ± 2.4 mmHg, vs. 72.7 ± 3.0 and 75.4 ± 1.9; p < 0.05). In diabetic rats, by contrast, cardiac output was lower with ketamine (82.6 ± 14 ml/min) and etomidate (78.2 ± 15.8 ml/min) than with propofol (146 ± 21 ml/min, N = 8, p < 0.01). SBP, however, was higher in the propofol-treated group (93.3 ± 3.4 mmHg, p < 0.05). CONCLUSION: These results suggest that hyperglycaemia modifies CV responses to induction anaesthetics.
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Anestésicos/farmacologia , Complicações do Diabetes/etiologia , Diabetes Mellitus Experimental/complicações , Etomidato/farmacologia , Hemodinâmica/efeitos dos fármacos , Ketamina/farmacologia , Propofol/farmacologia , Anestésicos/administração & dosagem , Animais , Glicemia/metabolismo , Débito Cardíaco/efeitos dos fármacos , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus Experimental/sangue , Etomidato/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Injeções Intraperitoneais , Ketamina/administração & dosagem , Propofol/administração & dosagem , Ratos , Ratos Sprague-Dawley , Volume Sistólico/efeitos dos fármacosRESUMO
BACKGROUND: Coronary vasospasms have been reported in the early stages of cardiomyopathy in the Syrian cardiomyopathic hamster (CM; BIO-TO2 strain). It has been proposed these alterations could lead to ischemic heart disease and heart failure. However, the cause of these coronary abnormalities has not been established. In this study, we evaluated coronary hemodynamic to assess the role of Ang-II, reactive oxygen species, and nitric oxide (NO) in the development of these alterations in CM of 1, 2, and 6 months of age. METHODS AND RESULTS: Excised hearts from control (CT) and CM were retroperfused with Krebs-Ringer bicarbonate solution (KRB), and coronary resistance (CR) was determined. The experimental protocol involved sequential infusions of the thromboxane analog U46619 (THX, 0.1micromol/L), bradykinin (BKN, 10micromol/L), and sodium nitroprusside (SNP, 10micromol/L). Similar experiments were conducted after treatment of hearts with N(omega)-nitro-L-arginine methyl ester (L-NAME, 10micromol/L). Basal CR increased with age, but no significant differences were observed between CT and CM. Reactivity to THX was increased (69%, P < .05) in 2-month-old CM when compared with CT. This effect was observed concomitantly with a significant reduction (53%, P < .05) in BKN-induced relaxation. The reduction in BKN-dependent relaxation was prevented by treatment for 1 month with the antioxidant N-acetylcysteine (1 g.kg.day), or losartan, an Ang II type 1 receptor blocker (10 mg.kg.day). Losartan also prevented the THX-induced increased reactivity in 2-month-old CM. The BKN-induced relaxation occurred through an L-NAME-sensitive pathway that was impaired with age. SNP dilation was preserved in all animal groups. CONCLUSIONS: Our results strongly implicate vascular renin-angiotensin-system (RAS) and oxidative stress in endothelial dysfunction and increased reactivity in the early stages of cardiomyopathy in CM. These findings could be relevant to understand the etiology of cardiovascular disorders, in particular, in patients with sarcoglycanopathies.
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Envelhecimento/fisiologia , Angiotensina II/fisiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Circulação Coronária/fisiologia , Hemodinâmica/fisiologia , Animais , Cricetinae , Frequência Cardíaca/fisiologia , Masculino , MesocricetusRESUMO
The Syrian cardiomyopathic hamster (SCH) is an established animal model for genetic cardiomyopathy. The disease in the hamster develops through similar stages to those observed in humans with this condition. The pathophysiological basis for this condition in the hamster resides in an inherited mutation in the gene encoding for delta-sarcoglycan, a component of the dystrophin complex. Two basic mechanisms contribute to cardiomyopathy in this model: ischemic heart disease by vasospasms of the coronary circulation and cardiomyocyte loss due to intrinsic cell defects. This review focuses on the etiology of vascular dysfunction and its role in the development of heart failure (HF) in this animal model. The data presented suggest that the vascular renin-angiotensin-system (RAS) plays a critical role in the generation of increased coronary reactivity and resistance in young SCH that have not yet developed the clinical manifestations of HF. The increased reactivity of the coronary vasculature results from endothelial dysfunction secondary to Ang II-dependent, oxidative stress. These alterations favor the development of ischemic heart disease and cardiomyopathy in adult animals. Indeed, RAS blockade during early stages of the disease significantly improves the clinical signs of dilated cardiomyopathy in this experimental model. These findings have significant implications for the prevention and treatment of cardiomyopathy in patients with ischemic heart disease, in particular, to those with familial sarcoglycanopathies.
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Cardiomiopatias/fisiopatologia , Animais , Cardiomiopatias/enzimologia , Cricetinae , Modelos Animais de Doenças , Peptidil Dipeptidase A/fisiologiaRESUMO
The association between nitric oxide synthase (eNOS and iNOS) status, oxidative stress, and cardiac function was evaluated in streptozotocin (STZ)-diabetic rats to understand the etiology of diabetic cardiomyopathy. Cardiac function was determined by echocardiography. eNOS and iNOS status and superoxide production were assessed by immunohistochemistry and chemiluminescence, respectively. In STZ-diabetic rats, stroke volume, cardiac output, and left ventricular ejection fraction were significantly lower than in controls (CT, P < .05), whereas left ventricular end-systolic volume was higher. Cardiac NOS activity increased from 161 +/- 18 cpm/mg tissue in CT rats to 286 +/- 20 cpm/mg tissue (P < .001) in STZ-diabetic rats. Furthermore, superoxide production and cardiac eNOS and iNOS levels were higher in STZ-diabetic rats than in CT rats (P < .05). An increased activation of cardiac eNOS and iNOS is observed concomitantly with decreased cardiac function. Thus, increased oxidative stress in the heart may be implicated in the development of dilated cardiomyopathy in STZ-diabetic rats.