DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model. (1/527)

Myotonic dystrophy (DM) is the most common form of muscular dystrophy and is caused by expansion of a CTG trinucleotide repeat on human chromosome 19. Patients with DM develop atrioventricular conduction disturbances, the principal cardiac manifestation of this disease. The etiology of the pathophysiological changes observed in DM has yet to be resolved. Haploinsufficiency of myotonic dystrophy protein kinase (DMPK), DM locus-associated homeodomain protein (DMAHP) and/or titration of RNA-binding proteins by expanded CUG sequences have been hypothesized to underlie the multi-system defects observed in DM. Using an in vivo murine electrophysiology study, we show that cardiac conduction is exquisitely sensitive to DMPK gene dosage. DMPK-/- mice develop cardiac conduction defects which include first-, second-, and third-degree atrioventricular (A-V) block. Our results demonstrate that the A-V node and the His-Purkinje regions of the conduction system are specifically compromised by DMPK loss. Importantly, DMPK+/- mice develop first-degree heart block, a conduction defect strikingly similar to that observed in DM patients. These results demonstrate that DMPK dosage is a critical element modulating cardiac conduction integrity and conclusively link haploinsufficiency of DMPK with cardiac disease in myotonic dystrophy.  (+info)

Sympathetic neuroeffector transmission in the rat anococcygeus muscle. (2/527)

1. When intracellular recordings were made from preparations of rat anococcygeus muscle, transmural nerve stimulation evoked noradrenergic excitatory junction potentials (EJPs) made up of two distinct components. Both components were abolished by either guanethidine or alpha-adrenoceptor antagonists, indicating that they resulted from the release of transmitter from sympathetic nerves and the subsequent activation of alpha-adrenoceptors. 2. The first component was associated with a transient increase in the intracellular concentration of calcium ions ([Ca2+]i) and a contraction. Although the second component was often associated with a long lasting increase in [Ca2+]i it was not associated with a contraction unless the second component initiated an action potential. 3. The increase in [Ca2+]i associated with the first component resulted from Ca2+ release from an intracellular store and from entry of Ca2+ through voltage-dependent Ca2+ channels. The increase in [Ca2+]i associated with the second component resulted only from the entry of Ca2+ through L-type Ca2+ channels (CaL channels). The depolarization associated with the initial increase in [Ca2+]i was abolished by reducing the external concentration of chloride ions ([Cl-]o), suggesting that it involved the activation of a Cl- conductance. 4. When the relationships between changes in [Ca2+]i, membrane depolarization and contraction produced by an increasing number of sympathetic nerve stimuli were determined in control, and caffeine- and nifedipine-containing solutions, it was found that an increase in [Ca2+]i recorded in nifedipine produced a larger contraction and larger membrane depolarization than did a similar increase in [Ca2+]i recorded in either control or caffeine-containing solutions. These observations indicate that Ca2+ released from stores more readily triggers contraction and membrane depolarization than does Ca2+ entry via CaL channels.  (+info)

Spread of vasodilatation and vasoconstriction along feed arteries and arterioles of hamster skeletal muscle. (3/527)

1. In arterioles of the hamster cheek pouch, vasodilatation and vasoconstriction can spread via the conduction of electrical signals through gap junctions between cells that comprise the vessel wall. However, conduction in resistance networks supplying other tissues has received relatively little attention. In anaesthetized hamsters, we have investigated the spread of dilatation and constriction along feed arteries and arterioles of the retractor muscle, which is contiguous with the cheek pouch. 2. When released from a micropipette, acetylcholine (ACh) triggered vasodilatation that spread rapidly along feed arteries external to the muscle and arterioles within the muscle. Responses were independent of changes in wall shear rate, perivascular nerve activity, or release of nitric oxide, indicating cell-to-cell conduction. 3. Vasodilatation conducted without decrement along unbranched feed arteries, yet decayed markedly in arteriolar networks. Thus, branching of the conduction pathway dissipated the vasodilatation. 4. Noradrenaline (NA) or a depolarizing KCl stimulus evoked constriction of arterioles and feed arteries of the retractor muscle that was constrained to the vicinity of the micropipette. This behaviour contrasts sharply with the conduction of vasodilatation in these microvessels and with the conduction of vasoconstriction elicited by NA and KCl in cheek pouch arterioles. 5. Focal electrical stimulation produced constriction that spread rapidly along feed arteries and arterioles. These responses were inhibited by tetrodotoxin or prazosin, confirming the release of NA along perivascular sympathetic nerves, which are absent from arterioles studied in the cheek pouch. Thus, sympathetic nerve activity co-ordinated the contraction of smooth muscle cells as effectively as the conduction of vasodilatation co-ordinated their relaxation. 6. In the light of previous findings in the cheek pouch, the properties of vasoconstriction and vasodilatation in feed arteries and arterioles of the retractor muscle indicate that substantive differences can exist in the nature of signal transmission along microvessels of tissues that differ in structure and function.  (+info)

Trigeminal nerve ganglion stimulation-induced neurovascular reflexes in the anaesthetized cat: role of endothelin(B) receptors in carotid vasodilatation. (4/527)

1. The effects of intravenous administration of endothelin (ET) receptor antagonists SB-209670 (0.001-10.0 mg kg(-1)), SB-217242, SB-234551 (0.01-10.0 mg kg(-1)) and BQ-788 (0.001-1.0 mg kg(-1)) were investigated on trigeminal nerve ganglion stimulation-induced neurovascular reflexes in the carotid vasculature of the anaesthetized cat. Comparisons were made with sumatriptan (0.003-3.0 mg kg(-1)) and alpha-CGRP8-37 (0.001-0.1 mg kg(-1)). 2. Trigeminal nerve ganglion stimulation produced frequency related increases in carotid blood flow, reductions in carotid vascular resistance and non-frequency related increases in blood pressure. Guanethidine (3 mg kg(-1), i.v.) blocked trigeminal nerve ganglion-induced increases in blood pressure but had no effect on changes in carotid flow or resistance. Maximal reductions in carotid vascular resistance was observed at 10 Hz, and this frequency was selected to investigate the effects of drugs on trigeminal nerve ganglion stimulation-induced responses in guanethidine treated cats. 3. Saline, alpha-CGRP8-37 SB-209670 and BQ-788 had little or no effect on resting haemodynamic parameters. SB-217242 (10 mg kg(-1), n=3) produced a 56% reduction in arterial blood pressure whereas SB-233451 (10 mg kg(-1), n=3) produced a 30% reduction in carotid vascular resistance. Sumatriptan produced dose-related reductions in resting carotid flow and increases (max. 104% at 0.3 mg kg(-1), n = 5) in vascular resistance. 4. SB-209670 (n=6-7), SB-217242 (n=3) and BQ-788 (n=3) produced inhibition of trigeminal nerve ganglion stimulation-induced reductions in carotid vascular resistance. Saline, SB-234551, alpha-CGRP8-37 and sumatriptan had no effect. 5. These data demonstrate ET(B) receptor blockade attenuates the vasodilator effects of trigeminal nerve ganglion stimulation in the carotid vascular bed of guanethidine pretreated anaesthetized cats.  (+info)

Investigating feed-forward neural regulation of circulation from analysis of spontaneous arterial pressure and heart rate fluctuations. (5/527)

BACKGROUND: Analysis of spontaneous fluctuations in systolic arterial pressure (SAP) and pulse interval (PI) reveals the occurrence of sequences of consecutive beats characterized by SAP and PI changing in the same (+PI/+SAP and -PI/-SAP) or opposite (-PI/+SAP and +PI/-SAP) direction. Although the former reflects baroreflex regulatory mechanisms, the physiological meaning of -PI/+SAP and +PI/-SAP is unclear. We tested the hypothesis that -PI/+SAP and +PI/-SAP "nonbaroreflex" sequences represent a phenomenon modulated by the autonomic nervous system reflecting a feed-forward mechanism of cardiovascular regulation. METHODS AND RESULTS: We studied anesthetized rabbits before and after (1) complete autonomic blockade (guanethidine+propranolol+atropine, n=13; CAB), (2) sympathetic blockade (guanethidine+propranolol, n=15; SB), (3) parasympathetic blockade (atropine, n=16), (4) sinoaortic denervation (n=10; SAD), and (5) controlled respiration (n=10; CR). Nonbaroreflex sequences were defined as >/=3 beats in which SAP and PI of the following beat changed in the opposite direction. CAB reduced the number of nonbaroreflex sequences (19. 1+/-12.3 versus 88.7+/-36.6, P<0.05), as did SB (25.3+/-11.7 versus 84.6+/-23.9, P<0.001) and atropine (11.2+/-6.8 versus 94.1+/-32.4, P<0.05). SB concomitantly increased baroreflex sensitivity (1.18+/-0. 11 versus 0.47+/-0.09 ms/mm Hg, P<0.01). SAD and CR did not significantly affect their occurrence. CONCLUSIONS: These results suggest that nonbaroreflex sequences represent the expression of an integrated, neurally mediated, feed-forward type of short-term cardiovascular regulation able to interact dynamically with the feedback mechanisms of baroreflex origin in the control of heart period.  (+info)

Recovery of locomotion after ventral and ventrolateral spinal lesions in the cat. II. Effects of noradrenergic and serotoninergic drugs. (6/527)

The effects of serotoninergic and noradrenergic drugs (applied intrathecally) on treadmill locomotion were evaluated in two adult cats subjected to a ventral and ventrolateral spinal lesion (T13). Despite the extensive spinal lesion, severely damaging important descending pathways such as the reticulo- and vestibulospinal tracts, both cats recovered quadrupedal voluntary locomotion. As detailed in a previous paper, the locomotor recovery occurred in three stages defined as early period, when the animal could not walk with its hindlimbs, recovery period, when progressive improvement occurred, and plateau period, when a more stable locomotor performance was observed. At this latter stage, the cats suffered from postural and locomotor deficits, such as poor lateral stability, irregular stepping of the hindlimbs, and inconsistent homolateral fore- and hindlimb coupling. The present study aimed at evaluating the potential of serotoninergic and/or noradrenergic drugs to improve the locomotor abilities in the early and late stages. Both cats were implanted chronically with an intrathecal cannula and electromyographic (EMG) electrodes, which allowed determination, under similar recording conditions, of the locomotor performance pre- and postlesion and comparisons of the effects of different drugs. EMG and kinematic analyses showed that norepinephrine (NE) injected in early and plateau periods improved the regularity of the hindlimb stepping and stabilized the interlimb coupling, permitting to maintain constant locomotion for longer periods of time. Methoxamine, the alpha1-agonist (tested only at the plateau period), had similar effects. In contrast, the alpha2-agonist, clonidine, deteriorated walking. Serotoninergic drugs, such as the neurotransmitter itself, serotonin (5HT), the precursor 5-hydroxytryptophan (5HTP), and the agonist quipazine improved the locomotion by increasing regularity of the hindlimb stepping and by increasing the step cycle duration. In contrast, the 5HT1A agonist 8-hydroxy-dipropylaminotetralin (DPAT) caused foot drag in one of the cats, resulting in frequent stumbling. Injection of combination of methoxamine and quipazine resulted in maintained, regular stepping with smooth movements and good lateral stability. Our results show that the effects of drugs can be integrated to the residual voluntary locomotion and improve some of its postural aspects. However, this work shows clearly that the effects of drugs (such as clonidine) may depend on whether or not the spinal lesion is complete. In a clinical context, this may suggest that different classes of drugs could be used in patients with different types of spinal cord injuries. Possible mechanisms underlying the effect of noradrenergic and serotoninergic drugs on the locomotion after partial spinal lesions are discussed.  (+info)

Aerobic training and cutaneous vasodilation in young and older men. (7/527)

To determine the effect and underlying mechanisms of exercise training and the influence of age on the skin blood flow (SkBF) response to exercise in a hot environment, 22 young (Y; 18-30 yr) and 21 older (O; 61-78 yr) men were assigned to 16 wk of aerobic (A; YA, n = 8; OA, n = 11), resistance (R; YR, n = 7; OR, n = 3), or no training (C; YC, n = 7; OC, n = 7). Before and after treatment, subjects exercised at 60% of maximum oxygen consumption (VO2 max) on a cycle ergometer for 60 min at 36 degrees C. Cutaneous vascular conductance, defined as SkBF divided by mean arterial pressure, was monitored at control (vasoconstriction intact) and bretylium-treated (vasoconstriction blocked) sites on the forearm using laser-Doppler flowmetry. Forearm vascular conductance was calculated as forearm blood flow (venous occlusion plethysmography) divided by mean arterial pressure. Esophageal and skin temperatures were recorded. Only aerobic training (functionally defined a priori as a 5% or greater increase in VO2 max) produced a decrease in the mean body temperature threshold for increasing forearm vascular conductance (36.89 +/- 0.08 to 36.63 +/- 0.08 degrees C, P < 0.003) and cutaneous vascular conductance (36.91 +/- 0.08 to 36.65 +/- 0.08 degrees C, P < 0.004). Similar thresholds between control and bretylium-treated sites indicated that the decrease was mediated through the active vasodilator system. This shift was more pronounced in the older men who presented greater training-induced increases in VO2 max than did the young men (22 and 9%, respectively). In summary, older men improved their SkBF response to exercise-heat stress through the effect of aerobic training on the cutaneous vasodilator system.  (+info)

A soluble neuronal factor alters contractile function of ventricular myocytes without effect on troponin T isoform expression. (8/527)

OBJECTIVE: The purpose of this investigation was to establish a model system to facilitate identification of the sympathetic neuronal factor(s) that promotes improved contractility in neonatal cardiac myocytes. Conditioned medium from PC12 cells with sympathetic phenotype served as the source of the neuronal factor. METHODS: Contraction frequency, amplitude and velocity of cultured neonatal rat cardiac myocytes were measured by online video analysis. Interventions included in vitro sympathetic innervation, exposure to PC12 conditioned medium, neurotransmitters and antagonists. Metabolic activity was assayed by 2-deoxyglucose uptake. Troponin T isoform expression was analyzed by SDS-polyacrylamide gel electrophoresis. RESULTS: Medium conditioned by neuronal PC12 cells induced contractility changes similar to those induced by in vitro sympathetic innervation. These effects of PC12 conditioned medium and innervation were not suppressed by adrenergic or muscarinic antagonists nor reproduced by neuropeptide Y or somatostatin. Neuronal PC12 conditioned medium but not chromaffin PC12 conditioned medium, increased metabolic activity of the myocytes as detected by [3H]-2-deoxyglucose, indicating that the effect was specific to the neuronal PC12 cells. The in vitro switch of troponin T isoform expression was not altered by exposure to PC12 conditioned medium. CONCLUSIONS: Increased contractile function induced by sympathetic innervation is reproduced by PC12 conditioned medium, but neither is mediated by sympathetic or muscarinic neurotransmitters. Troponin T isoform expression is not related to the contractility changes. This model system will allow identification of the factor(s).  (+info)

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