Neurally-mediated increase in calcineurin activity regulates cardiac contractile function in absence of hypertrophy.
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OBJECTIVE: The calcineurin pathway has been involved in the development of cardiac hypertrophy, yet it remains unknown whether calcineurin activity can be regulated in myocardium independently from hypertrophy and cardiac load. METHODS: To test that hypothesis, we measured calcineurin activity in a rat model of infrarenal aortic constriction (IR), which affects neurohormonal pathways without increasing cardiac afterload. RESULTS: In this model, there was no change in arterial pressure over the 4-week experimental period, and the left ventricle/body weight ratio did not increase. At 2 weeks after IR, calcineurin activity was increased 1.8-fold (P<0.05) and remained elevated at 4 weeks (1.7-fold, P<0.05). Similarly, the cardiac activity of calcium calmodulin kinase II (CaMKII) was increased significantly after IR, which confirms a regulation of Ca(2+)-dependent enzymes in this model. In cardiac myocytes, the increased activity of calcineurin was accompanied by a significant decrease in L-type Ca(2+) channel activity (I(Ca)) and contraction velocity (-dL/dt). Cardiac denervation prevented the activation of calcineurin after IR, which demonstrates that a neurohormonal mechanism is responsible for the changes in enzymatic activity. In addition, cardiac denervation suppressed the effects of IR on I(Ca) and -dL/dt, which shows that calcineurin activation is related to altered contractility. However, action potential duration, the densities of inward rectifier K(+) currents (I(K1)), and outward K(+) currents (I(to) and I(K)) were not altered in IR myocytes. CONCLUSIONS: Calcineurin can be activated in the heart through a neural stimulus, which induces alterations in Ca(2+) currents and contractility. These effects occur in the absence of myocyte hypertrophy, electrophysiological changes in action potential, and K(+) channel currents. (+info)
Long-lasting activation of rhythmic neuronal activity by a novel mechanosensory system in the crustacean stomatogastric nervous system.
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Sensory neurons enable neural circuits to generate behaviors appropriate for the current environmental situation. Here, we characterize the actions of a population (about 60) of bilaterally symmetric bipolar neurons identified within the inner wall of the cardiac gutter, a foregut structure in the crab Cancer borealis. These neurons, called the ventral cardiac neurons (VCNs), project their axons through the crab stomatogastric nervous system to influence neural circuits associated with feeding. Brief pressure application to the cardiac gutter transiently modulated the filtering motor pattern (pyloric rhythm) generated by the pyloric circuit within the stomatogastric ganglion (STG). This modulation included an increased speed of the pyloric rhythm and a concomitant decrease in the activity of the lateral pyloric neuron. Furthermore, 2 min of rhythmic pressure application to the cardiac gutter elicited a chewing motor pattern (gastric mill rhythm) generated by the gastric mill circuit in the STG that persisted for < or =30 min. These sensory actions on the pyloric and gastric mill circuits were mimicked by either ventral cardiac nerve or dorsal posterior esophageal nerve stimulation. VCN actions on the STG circuits required the activation of projection neurons in the commissural ganglia. A subset of the VCN actions on these projection neurons appeared to be direct and cholinergic. We propose that the VCN neurons are mechanoreceptors that are activated when food stored in the foregut applies an outward force, leading to the long-lasting activation of projection neurons required to initiate chewing and modify the filtering of chewed food. (+info)
Nitric oxide and thyroid gland: modulation of cardiovascular function in autonomic-blocked anaesthetized rats.
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We have previously reported that acute administration of N(G)-nitro-l-arginine methyl ester (L-NAME) increases the mean arterial pressure (MAP) and heart rate (HR) in autonomic-blocked (CAB) anaesthetized rats. In the present study we examined whether thyroid and adrenal glands are involved in these pressor and chronotropic responses. Sprague-Dawley rats were studied after bilateral vagotomy and ganglionic blockade with hexamethonium (10 mg kg(-1)), and stabilization of MAP with infusion of phenylephrine (PE) (6 microg kg(-1) min(-1)). The rats were divided into groups: L, CAB; PE, CAB + PE bolus (6 microg kg(-1)); L-TX, thyroidectomy + CAB; L-AX, adrenalectomy + CAB; TX, only thyroidectomy; C, CAB. L, L-AX and L-TX groups received a bolus of l-NAME (7.5 mg kg(-1)). Triiodothyronine (T3), thyroxin (T4) and thyrotropin (TSH) levels were measured in L and L-TX rats before and after l-NAME administration. Reduced nicotamide adenine dinucleotide (NADPH) diaphorase activity was determined in heart and aorta of the TX group. The pressor response induced by l-NAME was similar in all groups. l-NAME-induced-tachycardia was associated with this rise in MAP. Adrenalectomy did not modify this chronotropic response, but it was attenuated by thyroidectomy. Thyroidectomy by itself decreased the circulating levels of T3 but it had no effect on the plasma levels of T4 and TSH. L and L-TX groups showed similar levels of circulating T4 and TSH, meanwhile the plasma level of T3 decreased in the L group. Nitric oxide synthase (NOS) activity in atria as well as in aorta was greater in the TX group compared with C. When autonomic influences are removed, the thyroid gland modulates intrinsic heart rate via a mechanism that involves, at least in part, the nitric oxide pathway. (+info)
Systemic inhibition of nitric oxide synthase unmasks neural constraint of maximal myocardial blood flow in humans.
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BACKGROUND: Nitric oxide (NO) is an endothelial mediator that regulates vascular smooth muscle tone, but it may exert its cardiovascular action also by modulating the autonomic control of vasomotor tone. We assessed the effect of simultaneous inhibition of both endothelial (eNOS) and neuronal (nNOS) NO synthase isoforms on myocardial blood flow (MBF) and coronary flow reserve (CFR) in volunteers and in (denervated) transplant recipients. METHODS AND RESULTS: MBF (mL x min(-1) x g(-1)) was measured at rest and during adenosine-induced hyperemia with positron emission tomography and 15O-labeled water. CFR was calculated as adenosine/resting MBF. Measurements were repeated during one of the following intravenous infusions: group 1 (n=12), saline; group 2 (n=9), 3 mg/kg N(G)-monomethyl-L-arginine (L-NMMA), which crosses the blood-brain barrier and inhibits both eNOS and nNOS; group 3 (n=13), 10 mg/kg L-NMMA; group 4 (n=8), phenylephrine titrated to simulate the hemodynamic changes in group 3; and group 5 (n=6), 10 mg/kg L-NMMA infused into the heart transplant recipients. After intervention, hyperemic MBF and CFR were unchanged in groups 1, 2, and 4. By contrast, both hyperemic MBF (+53%, P<0.0001 versus baseline) and CFR (+52%, P<0.0001 versus baseline) increased in group 3, whereas they remained unchanged in group 5, which suggests that an intact cardiac innervation was required for the increase in MBF and CFR observed in group 3. CONCLUSIONS: The results of the present study suggest that maximal adenosine-induced hyperemia and CFR in humans are constrained by neurally mediated vasoconstriction, which can be relieved by systemic NOS inhibition with L-NMMA. (+info)
Central adenosine signaling plays a key role in centrally mediated hypotension in conscious aortic barodenervated rats.
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We tested the hypothesis that clonidine-evoked hypotension is dependent on central adenosinergic pathways. Five groups of male, conscious, aortic baroreceptor-denervated (ABD) rats received clonidine (10 microg/kg i.v.) 30 min after i.v. 1) saline, 2) theophylline (10 mg/kg), or 3) 8-(p-sulfophenyl)theophylline (8-SPT) (2.5 mg/kg) or 1 h after i.p. 4) dipyridamole (5 mg/kg) or 5) an equal volume of sesame oil. Blockade of central (theophylline) but not peripheral (8-SPT) adenosine receptors abolished clonidine hypotension. In contrast, dipyridamole substantially enhanced the bradycardic response to clonidine. In additional groups, intracisternal (i.c.) dipyridamole (150 microg) and 8-SPT (10 microg) enhanced and abolished, respectively, clonidine (0.6 microg i.c.)-evoked hypotension. Because clonidine is a mixed I1/alpha2 agonist, we also investigated whether adenosine signaling is linked to the I1 or the alpha2A receptor by administering the selective I1 (rilmenidine, 25 microg) or alpha2A [alpha-methylnorepinephrine (alpha-MNE), 4 microg] agonist 30 min after central adenosine receptor blockade (8-SPT; 10 microg i.c.) or artificial cerebrospinal fluid. The hypotensive response elicited by rilmenidine or alpha-MNE was abolished in 8-SPT-pretreated rats. To delineate the role of the adenosine A2A receptor in clonidine-evoked hypotension, i.c. clonidine (0.6 microg) was administered 30 min after central adenosine receptor A2A blockade [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-epsilon]-1,2,4-triazolo[1,5-c ]-pyrimidine (SCH58261); 150 microg i.c.]. The latter virtually abolished the hypotensive and bradycardic responses elicited by clonidine. In conclusion, central adenosine A2A signaling plays a key role in clonidine-evoked hypotension in conscious aortic barodenervated rats. (+info)
Mucosal stimulation activates secretomotor neurons via long myenteric pathways in guinea pig ileum.
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This study examined whether mucosal stimulation activates long secretomotor neural reflexes and, if so, how they are organized. The submucosa of in vitro full thickness guinea pig ileal preparations was exposed in the distal portion and intracellular recordings were obtained from electrophysiologically identified secretomotor neurons. Axons in the intact mucosa of the oral segment were stimulated by a large bipolar stimulating electrode. In control preparations, a single stimulus pulse evoked a fast excitatory postsynaptic potential (EPSP) in 86% of neurons located 0.7-1.0 cm anal to the stimulus site. A stimulus train evoked multiple fast EPSPs, but slow EPSPs were not observed. To examine whether mucosal stimulation specifically activated mucosal sensory nerve terminals, the mucosa/submucosa was severed from the underlying layers and repositioned. In these preparations, fast EPSPs could not be elicited in 89% of cells. Superfusion with phorbol dibutyrate enhanced excitability of sensory neurons and pressure-pulse application of serotonin to the mucosa increased the fast EPSPs evoked by mucosal stimulation, providing further evidence that sensory neurons were involved. To determine whether these reflexes projected through the myenteric plexus, this plexus was surgically lesioned between the stimulus site and the impaled neuron. No fast EPSPs were recorded in these preparations following mucosal stimulation whereas lesioning the submucosal plexus had no effect. These results demonstrate that mucosal stimulation triggers a long myenteric pathway that activates submucosal secretomotor neurons. This pathway projects in parallel with motor and vasodilator reflexes, and this common pathway may enable coordination of intestinal secretion, blood flow, and motility. (+info)
Arterial baroreflex function does not influence telomere length in kidney of rats.
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AIM: To investigate the relationship between arterial baroreflex (ABR) function and telomere length in kidney of rats. METHODS: Stroke-prone spontaneously hypertensive rats (SHR-SP) and sinoaortic denervated rats (SAD) were used as models with depressed arterial baroreflex. In the first experiments, SHR-SP rats were examined at the age of 24 weeks for both sexes and 40 weeks for female rats. In the second experiments, SAD rats were studied 4 and 35 weeks after SAD operation. Blood pressure was continuously recorded for 4 h in a conscious state. After the determination of baroreflex sensitivity (BRS), the terminal restriction fragment (TRF) of rat kidney was analyzed using Southern blot. RESULTS: The TRF length was found shorter in: a) male SHR-SP compared with age-matched female SHR-SP; b) female SHR-SP 40 weeks of age compared with 24 weeks of age; c) in rats 35 weeks after operation compared with rats 4 weeks post operation in both sham-operated and SAD rats. CONCLUSION: In SHR-SP, the TRF length did not correlate with BRS. In addition, SAD did not affect TRF length at either 4 or 35 weeks post-surgery. It may be concluded that baroreflex function does not influence the terminal restriction fragment (TRF) length in rats. (+info)
Autonomic nerves in pulmonary veins.
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Rapid repetitive activities arising from pulmonary veins may initiate atrial fibrillation. The basis of these rapid repetitive activities remains unclear, but recent evidence suggests that the autonomic nervous system plays an important role in their formation. Pulmonary veins and the adjoining left atrium are highly innervated structures. This review summarizes recent developments in the understanding of the anatomy of autonomic nerves in and around pulmonary veins and their implications for atrial fibrillation. (+info)