Effects of substance P (SP) and selective tachykinin agonists on neurotransmission at guinea-pig intracardiac ganglia were studied in vitro. Voltage responses of neurons to superfused tachykinins and nerve stimulation were measured using intracellular microelectrodes. Predominant effects of SP (1 μM) were to cause slow depolarization and enable synaptic transmission at low intensities of nerve stimulation. Augmented response to nerve stimulation occurred with 29 of 40 intracardiac neurons (approx. 73%). SP inhibited synaptic transmission at 23% of intracardiac neurons but also caused slow depolarization. Activation of NK3 receptors with 100 nM [MePhe 7]neurokinin B caused slow depolarization, enhanced the response of many intracardiac neurons to low intensity nerve stimulation or local application of acetylcholine, and triggered action potentials independent of other stimuli in 6 of 42 neurons. The NK1 agonist [Sar 9,Met(O2)11]SP had similar actions but was less effective and did not trigger action potentials independently. Neither selective agonist inhibited cholinergic neurotransmission. We conclude that SP can function as a positive or negative neuromodulator at intracardiac ganglion cells, which could be either efferent neurons or interneurons. Potentiation occurs primarily through NK3 receptors and may enable neuronal responses with less preganglionic nerve activity. Inhibition of neurotransmission by SP is most likely explained by the known blocking action of this peptide at ganglionic nicotine receptors.

Substance P and neurokinin A are tachykinins that are co-localized with calcitonin gene-related peptide (CGRP) in a unique subpopulation of cardiac afferent nerve fibers. These neurons are activated by nociceptive stimuli and exhibit both sensory and motor functions that are mediated by the tachykinins and/or CGRP. Sensory signals (e.g., cardiac pain) are transmitted by peptides released at central processes of these neurons, whereas motor functions are produced by the same peptides released from peripheral nerve processes. This review summarizes our current understanding of intracardiac actions of the tachykinins. The major targets for the tachykinins within the heart are the intrinsic cardiac ganglia and coronary arteries. Intrinsic cardiac ganglia contain cholinergic neurons that innervate the heart and coronary vasculature. Tachykinins can stimulate NK3 receptors on these neurons to increase their excitability and evoke spontaneous firing of action potentials. This action provides a mechanism whereby tachykinins can indirectly influence cardiac function and coronary tone. Tachykinins also have direct effects on coronary arteries to decrease or increase tone. Stimulation of NK1 receptors on the endothelium causes vasodilation mediated by nitric oxide. This effect is normally dominant, but NK2 receptor-mediated vasoconstriction can also occur and is augmented when NK1 receptors are blocked. It is proposed that these ganglion stimulant and vascular actions are manifest by endogenous tachykinins during myocardial ischemia.

A diabetes mellitus (DM) pode levar a distúrbios da motilidade gastrointestinal que podem se tornar clinicamente relevantes em alguns pacientes. Modelos de Dm em roedores indicam anormalidades morfofuncionais do sistema nervoso entérico nessa doença. Neste trabalho, avaliamos se o DM experimental pode levar a alterações na eferência colinérgica excitatória, densidade neuronal e expressão dos canais de sódio voltagemdependente (Nav) no plexo mioentérico do íleo. Hiperglicemia induzida por estreptozotocina em ratas foi desenvolvida durante oito semanas. Experimentos de imunofluorescência de tripla marcação revelaram que a densidade de neurônios por área do íleo no DM foi significativamente reduzida quando comparada ao controle. Foram observadas reduções médias de 52,2% do total de neurônios (p=0,0001); 50,0% dos neurônios colinérgicos (p=0,0068) e 54,8% dos neurônios nitrérgicos (p=0,0042). Também foram observadas reduções significativas de neurônios por área de gânglio (28,2% do total, p=0,0002; 27,7% de colinérgicos, p= 0,0002 e 32,1% de neurônios nitrérgicos, p=0,0016). A densidade de fibras colinérgicas na superfície do músculo longitudinal também foi significativamente reduzida (controle: 41 ± 2, DM: 24 ± 3%; p=0,003), embora a análise western-blot não indicasse redução na expressão de ChAT no DM. grupo. A isoforma Nav1.6 foi detectada em diferentes neurônios mioentéricos e a DM tendeu a mudar o padrão de imunomarcação para neurônios de tamanho maior (297,4 ± 10 vs. 372,5 ± 8,4 µm2), mas esse efeito não foi significativo (p=0,3). Os dados de RT-qPCR não sugeriram uma alteração dos transcritos para ChAT, nNOS, Nav1.3, Nav1.6 ou Nav1.7. Nossos dados confirmam a visão de que o DM crônico leva à redução das fibras colinérgicas excitatórias e da densidade neuronal. No entanto, mudanças no perfil de expressão do canal de sódio, que poderiam levar à disfunção neuronal, não foram detectadas. / Diabetes mellitus (DM) may lead to gastrointestinal motility disorders that may become clinically relevant in some patients. Rodent models of DM indicate morpho-functional abnormalities of the enteric nervous system in this disease. In this work, we have evaluated whether experimental DM can lead to changes in excitatory cholinergic efference, neuronal density and voltage-gate sodium channels (Nav) expression in the myenteric plexus of ileum. Streptozotocin-induced hiperglycemia in female rats was allowed to develop during eight weeks. Triple immunofluorescence labeling experiments revealed that the density of neurons per area of ileum in DM was significantly reduced when compared to the control. It were observed average reductions of 52.2% of total neurons (p=0.0001); 50.0% of cholinergic (p=0.0068) and 54.8% of nitrergic neurons (p=0.0042). Significant reductions of neurons per area of ganglion were also observed (28.2% of total, p=0.0002; 27.7% of cholinergic, p=0,0002 and 32.1% of nitrergic neurons, p=0.0016). The cholinergic fibers density at the surface of longitudinal muscle was also significantly reduced (control: 41 ± 2, DM: 24 ± 3%; p=0.003), although western-blot analysis did not indicate a reduction in the expression of ChAT in DM group. The Nav1.6 isoform was detected in different myenteric neurons and DM tended to shift the immunolabeling pattern towards neurons of bigger size (297.4 ± 10 vs. 372.5 ± 8.4 m2), but this effect was not significant (p=0.3). RT-qPCR data did not suggest an alteration of transcripts for ChAT, nNOS, Nav1.3, Nav1.6 or Nav1.7. Our data support the view that chronic DM leads to reduction in excitatory cholinergic fibers and neuronal density. However, changes in sodium channel expression profiling, which could lead to neuronal dysfunction, were not detected. / Fundação de Amparo à Pesquisa do Estado de Minas Gerais