Myocardial performance in conscious streptozotocin diabetic rats

BACKGROUND: In spite of a large amount of studies in anesthetized animals, isolated hearts, and in vitro cardiomyocytes, to our knowledge, myocardial function was never studied in conscious diabetic rats. Myocardial performance and the response to stress caused by dobutamine were examined in conscious rats, fifteen days after the onset of diabetes caused by streptozotocin (STZ). The protective effect of insulin was also investigated in STZ-diabetic rats. METHODS: Cardiac contractility and relaxation were evaluated by means of maximum positive (+dP/dt(max)) and negative (-dP/dt(max)) values of first derivative of left ventricular pressure over time. In addition, it was examined the myocardial response to stress caused by two dosages (1 and 15 μg/kg) of dobutamine. One-way analysis of variance (ANOVA) was used to compare differences among groups, and two-way ANOVA for repeated measure, followed by Tukey post hoc test, to compare the responses to dobutamine. Differences were considered significant if P < 0.05. RESULTS: Basal mean arterial pressure, heart rate, +dP/dt(max )and -dP/dt(max )were found decreased in STZ-diabetic rats, but unaltered in control rats treated with vehicle and STZ-diabetic rats treated with insulin. Therefore, insulin prevented the hemodynamic and myocardial function alterations observed in STZ-diabetic rats. Lower dosage of dobutamine increased heart rate, +dP/dt(max )and -dP/dt(max )only in STZ-diabetic rats, while the higher dosage promoted greater, but similar, responses in the three groups. In conclusion, the results indicate that myocardial function was remarkably attenuated in conscious STZ-diabetic rats. In addition, the lower dosage of dobutamine uncovered a greater responsiveness of the myocardium of STZ-diabetic rats. Insulin preserved myocardial function and the integrity of the response to dobutamine of STZ-diabetic rats. CONCLUSION: The present study provides new data from conscious rats showing that the cardiomyopathy of this pathophysiological condition was expressed by low indices of contractility and relaxation. In addition, it was also demonstrated that these pathophysiological features were prevented by the treatment with insulin

Role of cGMP and cAMP in the hemodynamic response to intrathecal sildenafil administration

INTRODUCTION: Results from our laboratory have demonstrated that intracerebroventricular administration of sildenafil to conscious rats promoted a noticeable increase in both lumbar sympathetic activity and heart rate, with no change in the mean arterial pressure. The intracerebroventricular administration of sildenafil may have produced the hemodynamic effects by activating sympathetic preganglionic neurons in the supraspinal regions and spinal cord. It is well documented that sildenafil increases intracellular cGMP levels by inhibiting phosphodiesterase type 5 and increases cAMP levels by inhibiting other phosphodiesterases. OBJECTIVE: To examine and compare, in conscious rats, the hemodynamic response following the intrathecal administration of sildenafil, 8-bromo-cGMP (an analog of cGMP), forskolin (an activator of adenylate cyclase), or dibutyryl-cAMP (an analog of cAMP) in order to elucidate the possible role of the sympathetic preganglionic neurons in the observed hemodynamic response. RESULTS: The hemodynamic responses observed following intrathecal administration of the studied drugs demonstrated the following: 1) sildenafil increased the mean arterial pressure and heart rate in a dose-dependent manner, 2) increasing doses of 8-bromo-cGMP did not alter the mean arterial pressure and heart rate, 3) forskolin did not affect the mean arterial pressure but did increase the heart rate and 4) dibutyryl-cAMP increased the mean arterial pressure and heart rate, similar to the effect observed following the intrathecal injection of the highest dose of sildenafil. CONCLUSION: Overall, the findings of the current study suggest that the cardiovascular response following the intrathecal administration of sildenafil to conscious rats involves the inhibition of phosphodiesterases other than phosphodiesterase type 5 that increase the cAMP level and the activation of sympathetic preganglionic neurons

Utility of a novel biofeedback device for within-breath modulation of heart rate in rats:a quantitative comparison of vagus nerve versus right atrial pacing

In an emerging bioelectronics era, there is a clinical need for physiological devices incorporating biofeedback that permits natural and demand-dependent control in real time. Here, we describe a novel device termed a central pattern generator (CPG) that uses cutting edge analogue circuitry producing temporally controlled, electrical stimulus outputs based on the real time integration of physiological feedback. Motivated by the fact that respiratory sinus arrhythmia (RSA), which is the cyclical changes in heart rate every breath, is an essential component of heart rate variability (an indicator of cardiac health), we have explored the versatility and efficiency of the CPG for producing respiratory modulation of heart rate in anaesthetised, spontaneously breathing rats. Diaphragmatic electromyographic activity was used as the input to the device and its output connected to either the right cervical vagus nerve or the right atrium for pacing heart rate. We found that the CPG could induce respiratory related heart rate modulation that closely mimicked RSA. Whether connected to the vagus nerve or right atrium, the versatility of the device was demonstrated by permitting: (i) heart rate modulation in any phase of the respiratory cycle, (ii) control of the magnitude of heart rate modulation and (iii) instant adaptation to changes in respiratory frequency. Vagal nerve pacing was only possible following transection of the nerve limiting its effective use chronically. Pacing via the right atrium permitted better flexibility and control of heart rate above its intrinsic level. This investigation now lays the foundation for future studies using this biofeedback technology permitting closer analysis of both the function and dysfunction of RSA

Cardiovascular autonomic control in mice lacking angiotensin AT1a receptors

Studies examined the role of angiotensin (ANG) AT1a receptors in cardiovascular autonomic control by measuring arterial pressure (AP) and heart rate (HR) variability and the effect of autonomic blockade in mice lacking AT1a receptors (AT1a-/-). Using radiotelemetry in conscious AT1a-/- and AT1a-/- mice, we determined 1) AP and pulse interval (PI) variability in time and frequency (spectral analysis) domains, 2) AP response to alpha(1)-adrenergic and ganglionic blockade, and 3) intrinsic HR after ganglionic blockade. Pulsatile AP was recorded (5 kHz) for measurement of AP and PI and respective variability. Steady-state AP responses to prazosin (1 mu g/g ip) and hexamethonium (30 mu g/g ip) were also measured. AP was lower in AT1a-/- vs. AT1a-/-, whereas HR was not changed. Prazosin and hexamethonium produced greater decreases in mean AP in AT1a-/- than in AT1a -/-. the blood pressure difference was marked after ganglionic blockade (change in mean AP of -44 +/- 10 vs. -18 +/- 2 mmHg, AT1a-/- vs. AT1a-/- mice). Intrinsic HR was also lower in AT1a-/- mice (431 +/- 32 vs. 524 +/- 22 beats/min, AT1a-/- vs. AT1a-/-). Beat-by-beat series of systolic AP and PI were submitted to autoregressive spectral estimation with variability quantified in low-frequency (LF: 0.1-1 Hz) and high-frequency (HF: 1-5 Hz) ranges. AT1a-/- mice showed a reduction in systolic AP LF variability (4.3 +/- 0.8 vs. 9.8 +/- 1.3 mmHg(2)), with no change in HF (2.7 +/- 0.3 vs. 3.3 +/- 0.6 mmHg2). There was a reduction in PI variability of AT1a-/- in both LF (18.7 +/- 3.7 vs. 32.1 +/- 4.2 ms(2)) and HF (17.7 +/- 1.9 vs. 40.3 +/- 7.3 ms(2)) ranges. the association of lower AP and PI variability in AT1a-/- mice with enhanced AP response to alpha(1)-adrenergic and ganglionic blockade suggests that removal of the ANG AT1a receptor produces autonomic imbalance. This is seen as enhanced sympathetic drive to compensate for the lack of ANG signaling.Wright State Univ, Sch Med, Dept Pharmacol & Toxicol, Dayton, OH 45435 USAUniversidade Federal de São Paulo, Sch Med, São Paulo, BrazilUniv São Paulo, Sch Med, BR-14049 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, Sch Med, São Paulo, BrazilWeb of Scienc

Cardiac acetylcholine inhibits ventricular remodeling and dysfunction under pathologic conditions

Autonomic dysfunction is a characteristic of cardiac disease and decreased vagal activity is observed in heart failure. Rodent cardiomyocytes produce de novo ACh, which is critical in maintaining cardiac homeostasis. We report that this nonneuronal cholinergic system is also found in human cardiomyocytes, which expressed choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT). Furthermore, VAChT expression was increased 3- and 1.5-fold at the mRNA and protein level, respectively, in ventricular tissue from patients with heart failure, suggesting increased ACh secretion in disease. Weusedmicewith geneticdeletionof cardiomyocytespecificVAChTor ChATandmice overexpressingVAChT to test the functional significance of cholinergic signaling. Mice deficient for VAChT displayed an 8% decrease in fractional shortening and 13% decrease in ejection fraction comparedwith angiotensin II (Ang II)-treated control animals, suggesting enhanced ventricular dysfunction and pathologic remodeling in response to Ang II. Similar results were observed in ChAT-deficient mice. Conversely, no decline in ventricular function was observed in Ang II-treated VAChT overexpressors. Furthermore, the fibrotic area was significantly greater (P \u3c 0.05) in Ang II- treated VAChT-deficient mice (3.61 ± 0.64%) compared with wild-type animals (2.24±0.11%). In contrast, VAChT overexpressing mice didnot display an increase in collagen deposition. Our results provide new insight into cholinergic regulation of cardiac function, suggesting that a compensatory increase in cardiomyocyte VAChT levels may help offset cardiac remodeling in heart failure

RATOS ESPONTANEAMENTE HIPERTENSOS E NEUROPATIAS PERIFÉRICAS

Modelo do Estudo: O presente estudo é uma revisão de literatura sobre o modelo de hipertensão espontânea e as conseqüências da hipertensão para o sistema nervoso periférico, somático e autonômico. Importância do problema: Hipertensão é o principal fator de risco para acidente vascular cerebral e demência vascular, por causar importantes mudanças cerebrovasculares, tornando o cérebro propenso a infartos, microaneurismas e isquemias. As principais mudanças causadas no sistema nervoso central (SNC) pela hipertensão, incluem: diminuição do volume cerebral, aumento no volume dos ventrículos e perda neuronal. Além das alterações no cérebro, a hipertens ão causa outros danos que culminam em uma série de alterações patológicas renais e outras doenças, as quais sustentam a elevação da pressão arterial, aumento da freqüência cardíaca, e aumento da resistência vascular periférica. O rato espontaneamente hipertenso (SHR) é reconhecido como um excelente modelo de hipertensão experimental e pode servir como modelo de estudos clínicos da hipertensão essencial humana. Embora esse modelo tenha sido bastante explorado em termos fisiológicos, estudos morfológicos, quando presentes, se limitam aos vasos. Mesmo quando nervos periféricos foram estudados morfologicamente nesses animais, os vasos epineurais, perineurais e endoneurais foram o alvo do estudo. Raros são os estudos que envolvem as fibras nervosas nesse modelo de hipertensão. Comentários: Recentemente, estudamos as alterações do nervo depressor aórtico (NDA) em SHR. Nossos resultados mostraram redução do tamanho das fibras mielínicas e redução do tamanho e número das fibras amielínicas, comparados aos controles normotensos da linhagem Wistar-Kyoto. Outro estudo recente do nosso laboratório mostrou que, embora os níveis pressóricos dos SHR machos, bem como a freqüência cardíaca, sejam muito superiores aos das fêmeas, não há diferença morfológica nos nervos vagos cervicais entre SHR machos e fêmeas. Ainda, fazemos uma descrição morfológica e morfométrica do nervo sural de SHR, fornecendo parâmetros morfológicos para posteriores estudos funcionais.    Type of the study: The present study is a literature review about the spontaneous hypertension animal model, and the consequences of the hypertension to the peripheral nervous system, somatic and autonomic. Importance of the topic: Hypertension is the main risk factor to stroke and vascular dementia, due to important cerebrovascular changes that may lead to cerebral microaneurysms, infarction and acute ischemia. The main central nervous system changes due to hypertension are the reduction of the cerebral volume, increase of the ventricles volume and loss of neurons. Moreover, hypertension causes renal alterations and other pathologies that might sustain the high blood pressure, the tachycardia and the elevation of the peripheral vascular resistance. The spontaneously hypertensive rat (SHR) is recognized as an excellent model of the human essential hypertension. Nevertheless, despite that this animal model has been widely explored in terms ofphysiological studies, morphological studies, when available, are limited to the vessels. Even when periphera  nerves are being explored, the epineural, perineural and endoneural vessels are the subject of the studies. Information on the alterations of the myelinated and unmyelinated fibers in this model of hypertension is scanty. Comments: Recently, we studied the morphology and morphometry of the aortic depressor nerve (ADN) in SHR and our results have demonstrated a reduction of the myelinated fibers size and a reduction of the number and size of the unmyelinated fibers, compared to the normotensive controls Wistar-Kyoto. Another recent study from our laboratory showed that, despite the significantly higher blood pressure and heart rate on male SHR, compared to female SHR, there are no morphological differences on the vagus nerves between males and females. Also, we have described the morphological and morphometric characteristics of the sural nerve in SHR, thus providing morphological background for further functional studies.