Commonalities and Differences in Carotid Body Dysfunction in Hypertension and Heart Failure

Carotid body pathophysiology is associated with many cardiovascular-respiratory-metabolic diseases. This pathophysiology reflects both hyper-sensitivity and hyper-tonicity. From both animal models and human patients, evidence indicates that amelioration of this pathophysiological signalling improves disease states such as a lowering of blood pressure in hypertension, a reduction of breathing disturbances with improved cardiac function in heart failure (HF) and a re-balancing of autonomic activity with lowered sympathetic discharge. Given this, we have reviewed the mechanisms of carotid body hyper-sensitivity and hyper-tonicity across disease models asking whether there is uniqueness related to specific disease states. Our analysis indicates some commonalities and some potential differences, although not all mechanisms have been fully explored across all disease models. One potential commonality is that of hypoperfusion of the carotid body across hypertension and HF, where the excessive sympathetic drive may reduce blood flow in both models and, in addition, lowered cardiac output in HF may potentiate the hypoperfusion state of the carotid body. Other mechanisms are explored that focus on neurotransmitter and signalling pathways intrinsic to the carotid body (e.g. ATP, carbon monoxide) as well as extrinsic molecules carried in the blood (e.g. leptin); there are also transcription factors found in the carotid body endothelium that modulate its activity (Krüppel-like factor 2). The evidence to date fully supports that a better understanding of the mechanisms of carotid body pathophysiology is a fruitful strategy for informing potential new treatment strategies for many cardiovascular, respiratory and metabolic diseases, and this is highly relevant clinically

Chronic Intermittent Hypoxia Depresses Afferent Neurotransmission in NTS Neurons by a Reduction in the Number of Active Synapses

Long-term synaptic plasticity has been recently described in brainstem areas associated to visceral afferent sensory integration. Chronic intermittent hypoxia (CIH), an animal model for studying obstructive sleep apnea in humans, depresses the afferent neurotransmission in nucleus tractus solitarii (NTS) neurons, which affect respiratory and autonomic regulation. Here we identified the synaptic mechanisms of CIH-induced depression of the afferent neurotransmission in NTS neurons in juvenile rats. We verified that CIH reduced the amplitude of both NMDA and non-NMDA glutamatergic excitatory currents (eEPSCs) evoked by tractus solitarii stimulation (TS-eEPSC) of second-order neurons in the NTS. No changes were observed in release probability, evidenced by absence of any CIH-elicited effects on short-term depression and failures in EPSCs evoked in low calcium. CIH also produced no changes in TS-eEPSC quantal size, since the amplitudes of both low calcium-evoked EPSCs and asynchronous TS-eEPSCs (evoked in the presence of Sr2+) were unchanged. Using single TS afferent fiber stimulation in slices from control and CIH rats we clearly show that CIH reduced the quantal content of the TS-eEPSCs without affecting the quantal size or release probability, suggesting a reduction in the number of active synapses as the mechanism of CIH induced TS-eEPSC depression. In accordance with this concept, the input-output relationship of stimulus intensity and TS-eEPSC amplitude shows an early saturation in CIH animals. These findings open new perspectives for a better understanding of the mechanisms underlying the synaptic plasticity in the brainstem sensory neurons under challenges such as those produced by CIH in experimental and pathological conditions.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2008/54953-0, 2008/04618-0, 2009/50113-0]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP

Role of ventral medullary catecholaminergic neurons for respiratory modulation of sympathetic outflow in rats

Abstract Sympathetic activity displays rhythmic oscillations generated by brainstem inspiratory and expiratory neurons. Amplification of these rhythmic respiratory-related oscillations is observed in rats under enhanced central respiratory drive or during development of neurogenic hypertension. Herein, we evaluated the involvement of ventral medullary sympatho-excitatory catecholaminergic C1 neurons, using inhibitory Drosophila allatostatin receptors, for the enhanced expiratory-related oscillations in sympathetic activity in rats submitted to chronic intermittent hypoxia (CIH) and following activation of both peripheral (hypoxia) and central chemoreceptors (hypercapnia). Pharmacogenetic inhibition of C1 neurons bilaterally resulted in reductions of their firing frequency and amplitude of inspiratory-related sympathetic activity in rats in normocapnia, hypercapnia or after CIH. In contrast, hypercapnia or hypoxia-induced enhanced expiratory-related sympathetic oscillations were unaffected by C1 neuronal inhibition. Inhibition of C1 neurons also resulted in a significant fall in arterial pressure and heart rate that was similar in magnitude between normotensive and CIH hypertensive rats, but basal arterial pressure in CIH rats remained higher compared to controls. C1 neurons play a key role in regulating inspiratory modulation of sympathetic activity and arterial pressure in both normotensive and CIH hypertensive rats, but they are not involved in the enhanced late-expiratory-related sympathetic activity triggered by activation of peripheral or central chemoreceptors

Sistemas Hipertexto & Hipermédia - Reflexão, Ensino e Arte

Neste artigo começa por caracterizar-se o desenvolvimento dos sistemas hiper-texto/hipermédia associado ao paradigma da representação mental. Procura-se analisar o fundamento da atitude de mimésis entre os referidos sistemas e as representações internas do indivíduo no processamento de informação. Seguidamente, destaca-se o papel das tecnologias hipertexto/hipermédia no sistema educativo e o impacto inerente à sua implementação. Inclui, no final, uma reflexão sobre a cultura hipertexto/hipermédia e as suas repercussões no mundo da arte