Pharmacological profiling of stretch activated channels in proprioceptive neurons.

Proprioception in mammals and invertebrates occurs through stretch activated ion channels (SACs) localized in sensory endings. In mammals, the primary organs for proprioception are the intrafusal muscle spindles embedded within extrafusal muscle. In invertebrates there are varied types of sensory organs, from chordotonal organs spanning joints to muscle receptor organs (MRO) which are analogous to the mammalian muscle spindles that monitor stretch of muscle fibers. A subset of SACs are the PIEZO channels. They are comprised of a distinct type of protein sequence and are similar among species, from mammals to invertebrates. We screened several new agents (YODA 1, JEDI 2, OB 1 and DOOKU) which have been identified to act on SACs of the PIEZO 1 subtype. JEDI 2 increased activity in the crayfish MRO but not the crab chordotonal organs. The SACs of the crustacean proprioceptors have not been satisfactorily pharmacologically classified, nor has their molecular makeup been identified. We screened these pharmacological agents on model sensory organs in crustaceans to learn more about their subtype classification and compare genomic profiles of related species.

ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex in rats.

The role of the acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex is unknown, despite the fact that ASIC1a is opened by decreases in pH in the physiological range. This fact prompted us to test the hypothesis that ASIC1a plays an important role in evoking the exercise pressor reflex in decerebrated rats with freely perfused hindlimb muscles. To test this hypothesis, we measured the effect of injecting two ASIC1a blockers into the arterial supply of the triceps surae muscles on the reflex pressor responses to four maneuvers, namely 1) static contraction of the triceps surae muscles (i.e., the exercise pressor reflex), 2) calcaneal tendon stretch, 3) intra-arterial injection of lactic acid, and 4) intra-arterial injection of diprotonated phosphate. We found that the 2 ASIC1a blockers, psalmotoxin-1 (200 ng/kg) and mambalgin-1 (6.5 µg/kg), decreased the pressor responses to static contraction as well as the peak pressor responses to injection of lactic acid and diprotonated phosphate. In contrast, neither ASIC1a blocker had any effect on the pressor responses to tendon stretch. Importantly, we found that ASIC1a blockade significantly decreased the pressor response to static contraction after a latency of at least 8 s. Our results support the hypothesis that ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex.NEW & NOTEWORTHY The role played by acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex remains unknown. In decerebrated rats with freely perfused femoral arteries, blocking ASIC1a with psalmotoxin-1 or mambalgin-1 significantly attenuated the pressor response to static contraction, lactic acid, and diprotonated phosphate injection but had no effect on the pressor response to stretch. We conclude that ASIC1a plays a key role in evoking the exercise pressor reflex by responding to contraction-induced metabolites, such as protons.

Modulating mechanosensory afferent excitability by an atypical mGluR.

Mechanotransduction by proprioceptive sensory organs is poorly understood. Evidence was recently shown that muscle spindle and hair follicle primary afferents (lanceolates) constantly release glutamate from synaptic-like vesicles (SLVs) within the terminals. The secreted glutamate activates a highly unusual metabotropic glutamate receptor (mGluR) to modulate the firing rate (spindles) and SLV recycling (lanceolates). This receptor has yet to be isolated and sequenced. To further investigate this receptor's pharmacology, ligands selective for classical mGluRs have been recently characterised for their ability to alter stretch-evoked spindle firing and SLV endocytosis in these different endings. Here, it is described how the results of these screens facilitated the development of novel compounds to be used in the process of isolating and sequencing of this non-canonical mGluR. This study shows how the compounds were tested for their ability to alter stretch-evoked afferent firing in muscle spindles and SLV endocytosis in the lanceolate endings of hair follicles to ensure they maintained their ability to bind to the receptor. For the development of novel compounds, kainate was chosen as the parent ligand due to its potency and ease of chemical modification. Novel kainate derivatives were then synthesised and tested to find potent analogues suitable for 'click-chemistry', an established technique for relatively quick, cheap, stereospecific and high-yield chemical modifications (Angewandte Chemie (International ed. in English), 40, 2001, pp2004). Of the novel kainate analogues developed, unfortunately ZCZ49 and ZCZ50 lost the ability to produce a significant change in spindle stretch-evoked firing. However, ZCZ90 was as potent as kainate, increasing firing by a similar margin at 1 µm (n = 8; P < 0.001). The addition of either a biotin or a fluorescein side group to ZCZ90, using the click-chemistry technique, did not affect the potency and hence these compounds will be used in further studies of the receptor. As well as the development of these compounds, the study found not only many similarities, but also some key differences between the two types of primary mechanosensory endings investigated. These differences must be taken into account in further study. However, they also present an intriguing opportunity for these receptors to be targeted selectively to modulate ending sensitivity as treatments for muscle spasm in multiple sclerosis and spinal cord injury, and possibly even baroreceptor firing to treat hypertension.

Synthesis and biological evaluation of (-)-kainic acid analogues as phospholipase D-coupled metabotropic glutamate receptor ligands.

(-)-Kainic acid potently increases stretch-induced afferent firing in muscle spindles, probably acting through a hitherto uncloned phospholipase D (PLD)-coupled mGlu receptor. Structural modification of (-)-kainic acid was undertaken to explore the C-4 substituent effect on the pharmacology related to muscle spindle firing. Three analogues 1a-c were synthesised by highly stereoselective additions of a CF3, a hydride and an alkynyl group to the Re face of the key pyrrolidin-4-one intermediate 5a followed by further structural modifications. Only the 4-(1,2,3-triazolyl)-kainate derivative 1c retained the kainate-like agonism, increasing firing in a dose-dependent manner. Further modification of 1c by introduction of a PEG-biotin chain on the 1,2,3-triazole fragment afforded compound 14 which retained robust agonism at 1 µM and appears to be suitable for future use in pull-down assays and far western blotting for PLD-mGluR isolation.

The role of gap junctions in stretch-induced atrial fibrillation.

AIMS: The aim of this study was to investigate the role of gap junctions in atrial fibrillation (AF) by analysing the effects of a gap junction enhancer and blocker on AF vulnerability and electrophysiological properties of isolated hearts. METHODS AND RESULTS: The acute atrial stretch model of AF in the isolated rabbit heart was used. Sustained AF (SAF) was induced by a burst of high-frequency stimulation of the Bachmann's bundle. The effective refractory period (ERP) was measured, and the total conduction time (TCT) and the pattern of conduction of the anterior surface of the left atrium were monitored by using an optical mapping system. The effect of enhancing gap junction function by 100-1000 nM rotigaptide (ZP123) and block by 30 µM carbenoxolone on these parameters was measured. SAF inducibility was increased with an elevation of intra-atrial pressure. Enhanced gap junction conductance induced by treatment with 100-1000 nM rotigaptide reduced SAF inducibility, and the gap junction blocker carbenoxolone increased SAF inducibility. In the absence of gap junction enhancer or blocker, normal conduction was observed at 0 cmH2O. When intra-atrial pressure was raised to 12 cmH2O, the conduction pattern was changed to a heterogeneous zig-zag pattern and TCT was prolonged. Conduction pattern was not affected by either agent. Rotigaptide shortened TCT, whereas carbenoxolone prolonged TCT. ERP was significantly shortened with an increase in intra-atrial pressure, but ERP was unaffected by either agent. CONCLUSION: Gap junction modulators changed AF inducibility through their effects on atrial conduction, not by altering ERP.

Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles.

The protease ß-secretase 1 (Bace1) was identified through its critical role in production of amyloid-ß peptides (Aß), the major component of amyloid plaques in Alzheimer's disease. Bace1 is considered a promising target for the treatment of this pathology, but processes additional substrates, among them Neuregulin-1 (Nrg1). Our biochemical analysis indicates that Bace1 processes the Ig-containing ß1 Nrg1 (IgNrg1ß1) isoform. We find that a graded reduction in IgNrg1 signal strength in vivo results in increasingly severe deficits in formation and maturation of muscle spindles, a proprioceptive organ critical for muscle coordination. Further, we show that Bace1 is required for formation and maturation of the muscle spindle. Finally, pharmacological inhibition and conditional mutagenesis in adult animals demonstrate that Bace1 and Nrg1 are essential to sustain muscle spindles and to maintain motor coordination. Our results assign to Bace1 a role in the control of coordinated movement through its regulation of muscle spindle physiology, and implicate IgNrg1-dependent processing as a molecular mechanism.

Bradykinin B2 receptor contributes to the exaggerated muscle mechanoreflex in rats with femoral artery occlusion.

Static muscle contraction activates the exercise pressor reflex, which in turn increases sympathetic nerve activity (SNA) and blood pressure (BP). Bradykinin (BK) is considered as a muscle metabolite responsible for modulation of the sympathetic and cardiovascular responses to muscle contraction. Prior studies have suggested that kinin B2 receptor mediates the effects of BK on the reflex SNA and BP responses during stimulation of skeletal muscle afferents. In patients with peripheral artery disease and a rat model with femoral artery ligation, amplified SNA and BP responses to static exercise were observed. This dysfunction of the exercise pressor reflex has previously been shown to be mediated, in part, by muscle mechanoreflex overactivity. Thus, in this report, we determined whether kinin B2 receptor contributes to the augmented mechanoreflex activity in rats with 24 h of femoral artery occlusion. First, Western blot analysis was used to examine protein expression of B2 receptors in dorsal root ganglion tissues of control limbs and ligated limbs. Our data show that B2 receptor displays significant overexpression in ligated limbs as compared with control limbs (optical density: 0.94 ± 0.02 in control and 1.87 ± 0.08 after ligation, P < 0.05 vs. control; n = 6 in each group). Second, mechanoreflex was evoked by muscle stretch and the reflex renal SNA (RSNA) and mean arterial pressure (MAP) responses to muscle stretch were examined after HOE-140, a B2 receptors blocker, was injected into the arterial blood supply of the hindlimb muscles. The results demonstrate that the stretch-evoked reflex responses were attenuated by administration of HOE-140 in control rats and ligated rats; however, the attenuating effects of HOE-140 were significantly greater in ligated rats, i.e., after 5 µg/kg of HOE-140 RSNA and MAP responses evoked by 0.5 kg of muscle tension were attenuated by 43% and 25% in control vs. 54% and 34% in ligation (P < 0.05 vs. control group; n = 11 in each group). In contrast, there was no significant difference in B1 receptor expression in both experimental groups, and arterial injection of R-715, a B1 receptors blocker, had no significant effects on RSNA and MAP responses evoked by muscle stretch. Accordingly, results obtained from this study support our hypothesis that heightened kinin B2 receptor expression in the sensory nerves contributes to the exaggerated muscle mechanoreflex in rats with femoral artery occlusion.

Using vertebral movement and intact paraspinal muscles to determine the distribution of intrafusal fiber innervation of muscle spindle afferents in the anesthetized cat.

Increasing our knowledge regarding intrafusal fiber distribution and physiology of paraspinal proprioceptors may provide key insights regarding proprioceptive deficits in trunk control associated with low back pain and lead to more effective clinical intervention. The use of vertebral movement as a means to reliably stretch paraspinal muscles would greatly facilitate physiological study of paraspinal muscle proprioceptors where muscle tendon isolation is either very difficult or impossible. The effects of succinylcholine (SCh) on 194 muscle spindle afferents from lumbar longissimus or multifidus muscles in response to computer-controlled, ramp-and-hold movements of the L(6) vertebra were investigated in anesthetized cats. Paraspinal muscles were stretched by moving the L(6) vertebra 1.5-1.7 mm in the dorsal-ventral direction. Initial frequency (IF), dynamic difference (DD), their changes (∆) following SCh injection (100-400 µg kg(-1)), and post-SCh dynamic difference (SChDD) were measured. Muscle spindle intrafusal fiber terminations were classified as primary or secondary fibers as well as bag(1) (b(1)c), bag(2) (b(2)c), b(1)b(2)c, or chain (c) fibers. Intrafusal fiber subpopulations were distinguished using logarithmic transformation of SChDD and ∆IF distributions as established by previous investigators. Increases in DD indicate strength of b(1)c influence while increases in IF indicate strength of b(2)c influence. Out of 194 afferents, 46.9 % of afferents terminated on b(2)c fibers, 46.4 % on b(1)b(2)c fibers, 1 % on b(1)c fibers, and 5.7 % terminated on c fibers. Based on these intrafusal fiber subpopulation distributions, controlled vertebral movement can effectively substitute for direct tendon stretch and allow further investigation of paraspinal proprioceptors in this anatomically complex body region.

Muscle spindle responses to horizontal support surface perturbation in the anesthetized cat: insights into the role of autogenic feedback in whole body postural control.

Intact cats and humans respond to support surface perturbations with broadly tuned, directionally sensitive muscle activation. These muscle responses are further sensitive to initial stance widths (distance between feet) and perturbation velocity. The sensory origins driving these responses are not known, and conflicting hypotheses are prevalent in the literature. We hypothesize that the direction-, stance-width-, and velocity-sensitive muscle response during support surface perturbations is driven largely by rapid autogenic proprioceptive pathways. The primary objective of this study was to obtain direct evidence for our hypothesis by establishing that muscle spindle receptors in the intact limb can provide appropriate information to drive the muscle response to whole body postural perturbations. Our second objective was to determine if spindle recordings from the intact limb generate the heightened sensitivity to small perturbations that has been reported in isolated muscle experiments. Maintenance of this heightened sensitivity would indicate that muscle spindles are highly proficient at detecting even small disturbances, suggesting they can provide efficient feedback about changing postural conditions. We performed intraaxonal recordings from muscle spindles in anesthetized cats during horizontal, hindlimb perturbations. We indeed found that muscle spindle afferents in the intact limb generate broadly tuned but directionally sensitive activation patterns. These afferents were also sensitive to initial stance widths and perturbation velocities. Finally, we found that afferents in the intact limb have heightened sensitivity to small perturbations. We conclude that muscle spindle afferents provide an array of important information about biomechanics and perturbation characteristics highlighting their potential importance in generating appropriate muscular response during a postural disturbance.

Somatosensory evoked potentials of hand muscles in stroke and their modification by botulinum toxin: a preliminary study.

OBJECTIVE: To determine the effect of botulinum toxin A on spasticity and somatosensory evoked potentials of hand muscles in patients who have undergone cerebrovascular accident. DESIGN: Preliminary, prospective, before-after study design. PATIENTS: Six subjects prospectively followed after application of botulinum toxin A in the rehabilitation department of a university hospital. METHODS: All patients underwent botulinum toxin A injection to the upper extremity muscles in varying combinations and carried out a home-based exercise programme. Primary outcome measure was median somatosensory evoked potential of hand muscles (N20). Secondary outcome measures were: spasticity assessed clinically by Modified Ashworth Scales (MAS); functional ability analysis assessed by Physician's Rating Scale (PRS); and functional difficulties reported by patients or their care-givers by patient disability and care-giver burden rating scale (PD & CBRS). RESULTS: MAS, PRS and PD & CBRS improved with botulinum toxin A treatment. In the affected limb, N20 potentials were impaired compared with those in the unaffected side. With botulinum toxin A treatment, although improvement in overall N20-P25 amplitudes was significant, as a result of limited sample size, post hoc pair-wise comparisons with Bonferroni correction failed to yield any significant pairs. CONCLUSION: The improvement in the median somatosensory evoked potentials following botulinum toxin A treatment suggests that central somatosensory patterns in hemiplegia can be modified by peripheral inputs.

The role of muscle spindles in the development of the monosynaptic stretch reflex.

Muscle sensory axons induce the development of specialized intrafusal muscle fibers in muscle spindles during development, but the role that the intrafusal fibers may play in the development of the central projections of these Ia sensory axons is unclear. In the present study, we assessed the influence of intrafusal fibers in muscle spindles on the formation of monosynaptic connections between Ia (muscle spindle) sensory axons and motoneurons (MNs) using two transgenic strains of mice. Deletion of the ErbB2 receptor from developing myotubes disrupts the formation of intrafusal muscle fibers and causes a nearly complete absence of functional synaptic connections between Ia axons and MNs. Monosynaptic connectivity can be fully restored by postnatal administration of neurotrophin-3 (NT-3), and the synaptic connections in NT-3-treated mice are as specific as in wild-type mice. Deletion of the Egr3 transcription factor also impairs the development of intrafusal muscle fibers and disrupts synaptic connectivity between Ia axons and MNs. Postnatal injections of NT-3 restore the normal strengths and specificity of Ia-motoneuronal connections in these mice as well. Severe deficits in intrafusal fiber development, therefore, do not disrupt the establishment of normal, selective patterns of connections between Ia axons and MNs, although these connections require the presence of NT-3, normally supplied by intrafusal fibers, to be functional.

Debunking the pathophysiological puzzle of dystonia--with special reference to botulinum toxin therapy.

New neurophysiological insights into the natural behaviour of dystonia, obtained during the successful botulinum toxin A (BoNT) treatment of the disorder, have urged the inclusion of sensory (and particularly somatosensory) mechanisms into the pathophysiological background of dystonia. Muscle spindles play a pivotal role in the generation of dystonic movements. Abnormal behaviour in the muscle spindles that generates an irregular proprioceptive input via the group-IA afferents may result in abnormal cortical excitability and intracortical inhibition in dystonia. The aim of this article is to support our hypothesis that dystonic movement is at the end of an impaired function of somatosensory pathways and analysers, which, in turn, may be hinged on the abnormality of sensorimotor integration, that is, brain plasticity. BoNT treatment can potentially modulate this plasticity mechanism and is probably the seminal cause of the sustained effect of the subsequent BoNT-treatment sessions and the long-term alleviation of symptoms of dystonia.

Thromboxane prostanoid receptor activation amplifies airway stretch-activated contractions assessed in perfused intact bovine bronchial segments.

A deep inspiration (DI) produces bronchodilation in healthy individuals. Conversely, in asthmatics, DIs are less effective in producing bronchodilation and can cause more rapid airway renarrowing and even bronchoconstriction in moderate to severe asthmatics. It is noteworthy that the manner by which a DI is able to cause bronchoconstriction via a stretch-activated contraction (R(stretch)) is thought to correlate positively with airway inflammation. Asthmatic airway inflammation is associated with increased production of thromboxane A(2) (TxA(2)) and subsequent thromboxane prostanoid (TP) receptor activation, causing the heightened contractility of airway smooth muscle. In this study, we sought to investigate the effect of TxA(2) on airway R(stretch) by using bovine bronchial segments. In brief, these intact bronchial segments (2 mm in diameter) were dissected, side branches were ligated, and the tissues were mounted horizontally in an organ bath. R(stretch) was elicited by varying the transmural pressure under isovolumic conditions. Using a pharmacological approach, we showed a reduced R(stretch) response in tissues pretreated with indomethacin, a cyclooxygenase inhibitor, a result mimicked by pretreatment with the TP-selective receptor antagonist 4-(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl)hexenoic acid (ICI 192605) and the selective p42/p44 mitogen-activated protein kinase inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD 95089) and by airway epithelial denudation. 9,11-Dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U46619), a TP receptor agonist, elicited enhanced R(stretch) responses in a dose-dependent manner. Pretreatment with 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH 6809), a prostaglandin E (EP) receptor 1/prostaglandin D2 (DP)-selective receptor antagonist, and 9α,15R-dihydroxy-11.ß-fluoro-15-(2,3-dihydro-1H-inden-2-yl)-16,17,18,19,20-pentanor-prosta-5Z,13E-dien-1-oic acid (AL 8810), a prostaglandin F (FP)-selective receptor antagonist, had no effect, suggesting EP, DP, and FP receptor activation is not involved in amplifying airway smooth muscle R(stretch). These data suggest a role for TP receptor activation and epithelial release of TxA(2) in amplifying airway R(stretch), thus providing novel insights into mechanisms regulating the DI-induced bronchoconstriction seen in asthmatics.

Sevoflurane reduces spinal reciprocal Ia-inhibition in humans.

BACKGROUND: Potentiation of inhibitory transmissions in the spinal cord is considered to be an important mechanism for the mediation of the immobilizing effects of anesthetics. However, the depressant effects on motoneurons could be counterbalanced by presynaptic effects that inhibit the depressant pathways. Here we investigated the effect of sevoflurane on a disynaptic inhibitory pathway onto motoneurons in a human reflex model. METHODS: The study was performed with 9 volunteers receiving sevoflurane anesthesia (end tidal: 0.8% sevoflurane). Reciprocal inhibition was estimated from the depression of the H-reflex following a conditioning stimulation of the muscle spindle afferents from the tibialis anterior muscle. Measurements were performed before, during and after drug administration. RESULTS: The inhibition (mean ± SE) amounted to 15.4% ± 6.8%, 1.9% ± 4.2% and 15.7% ± 8.8% for measurements before, during and after sevoflurane administration, respectively. Differences between the anesthetic state and the two controls were statistically significant (mixed-effect ANOVA, p<0.01). CONCLUSION: Sevoflurane reduces reciprocal Ia-inhibition on motoneurons in humans. These findings seem to contradict the accepted view that sevoflurane enhances inhibitory synaptic transmission. This contradiction might be explained by the inhibitory actions of sevoflurane within the disynaptic pathway prior to the final glycinergic transmission onto the motoneuron. Our results suggest that even in presumably simple pathways, postsynaptic effects of anesthetics could be superimposed by their presynaptic effects.

On muscle spindles, dystonia and botulinum toxin.

Dystonia may produce co-contractions and constant strain in numerous muscle fibers, including those of the muscle spindles. As proprioceptors, muscle spindles detect dynamic or static changes in muscle length and their afferent projections to the spinal cord play a central role in control of antagonistic muscles. Their parallel arrangement with extrafusal muscle fibers and association with the earlier recruited oxidative motor units allow them to conveniently sample the activity of all motor units and effectively modulate movement. At the same time, fusimotor muscle spindle innervation contracts the striated polar portions of the intrafusal muscle fibers and prevents their slackening during extrafusal muscle contractions. Botulinum toxin remains the most efficient therapy of dystonia. Its muscular mechanism of action is hinged on cholinergic blockade not only of extrafusal, but also of intrafusal muscle fibers. Besides being a targeted muscular therapy, the alteration of the corresponding sensory input following an effect of botulinum toxin on the intrafusal muscle fibers is pivotal in modulating loss of pre-synaptic inhibition in dystonia, including suppression of the tonic vibration reflex. Whether or not trans-synaptic botulinum toxin migration occurs, a modification of the central motor programming is bound to happen in dystonia, with botulinum toxin acting either as another 'sensory trick' or as a form of 'short-term plasticity'. Knowledge of the muscle spindle anatomy and function is key to unify our understanding of abnormal movements and of effects of botulinum toxin therapy. Thus, in dystonia, overactivity of muscles and increased spindle sensitivity are germane to botulinum toxin targets of action.

Pharmacological modifications of the stretch-induced effects on ventricular fibrillation in perfused rabbit hearts.

Stretch induces modifications in myocardial electrical and mechanical activity. Besides the effects of substances that block the stretch-activated channels, other substances could modulate the effects of stretch through different mechanisms that affect Ca(2+) handling by myocytes. Thirty-six Langendorff-perfused rabbit hearts were used to analyze the effects of the Na(+)/Ca(2+) exchanger blocker KB-R7943, propranolol, and the adenosine A(2) receptor antagonist SCH-58261 on the acceleration of ventricular fibrillation (VF) produced by acute myocardial stretching. VF recordings were obtained with two epicardial multiple electrodes before, during, and after local stretching in four experimental series: control (n = 9), KB-R7943 (1 microM, n = 9), propranolol (1 microM, n = 9), and SCH-58261 (1 microM, n = 9). Both the Na(+)/Ca(2+) exchanger blocker KB-R7943 and propranolol induced a significant reduction (P < 0.001 and P < 0.05, respectively) in the dominant frequency increments produced by stretching with respect to the control and SCH-58261 series (control = 49.9%, SCH-58261 = 52.1%, KB-R7943 = 9.5%, and propranolol = 12.5%). The median of the activation intervals, the functional refractory period, and the wavelength of the activation process during VF decreased significantly under stretch in the control and SCH-58261 series, whereas no significant variations were observed in the propranolol and KB-R7943 series, with the exception of a slight but significant decrease in the median of the fibrillation intervals in the KB-R7943 series. KB-R7943 and propranolol induced a significant reduction in the activation maps complexity increment produced by stretch with respect to the control and SCH-58261 series. In conclusion, the electrophysiological effects responsible for stretch-induced VF acceleration in the rabbit heart are reduced by the Na(+)/Ca(2+) exchanger blocker KB-R7943 and by propranolol but not by the adenosine A(2) receptor antagonist SCH-58261.

Cyclooxygenase inhibition attenuates sympathetic responses to muscle stretch in humans.

Passive muscle stretch performed during a period of post-exercise muscle ischemia (PEMI) increases muscle sympathetic nerve activity (MSNA), and this suggests that the muscle metabolites may sensitize mechanoreceptors in healthy humans. However, the responsible substance(s) has not been studied thoroughly in humans. Human and animal studies suggest that cyclooxygenase products sensitize muscle mechanoreceptors. Thus we hypothesized that local cyclooxygenase inhibition in exercising muscles could attenuate MSNA responses to passive muscle stretch during PEMI. Blood pressure (Finapres), heart rate, and MSNA (microneurography) responses to passive muscle stretch were assessed in 13 young healthy subjects during PEMI before and after cyclooxygenase inhibition, which was accomplished by a local infusion of 6 mg ketorolac tromethamine in saline via Bier block. In the second experiment, the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased prostaglandin synthesis to approximately 34% of the baseline. Before ketorolac Bier block, passive muscle stretch evoked significant increases in MSNA (P < 0.005) and mean arterial blood pressure (P < 0.02). After ketorolac Bier block, passive muscle stretch did not evoke significant responses in MSNA (P = 0.11) or mean arterial blood pressure (P = 0.83). Saline Bier block had no effect on the MSNA or blood pressure response to ischemic stretch. These observations indicate that cyclooxygenase inhibition attenuates MSNA responses seen during PEMI and suggest that cyclooxygenase products sensitize the muscle mechanoreceptors.

Local prostaglandin blockade attenuates muscle mechanoreflex-mediated renal vasoconstriction during muscle stretch in humans.

During exercise, muscle mechanoreflex-mediated sympathoexcitation evokes renal vasoconstriction. Animal studies suggest that prostaglandins generated within the contracting muscle sensitize muscle mechanoreflexes. Thus we hypothesized that local prostaglandin blockade would attenuate renal vasoconstriction during ischemic muscle stretch. Eleven healthy subjects performed static handgrip before and after local prostaglandin blockade (6 mg ketorolac tromethamine infused into the exercising forearm) via Bier block. Renal blood flow velocity (RBV; Duplex Ultrasound), mean arterial pressure (MAP; Finapres), and heart rate (HR; ECG) were obtained during handgrip, post-handgrip muscle ischemia (PHGMI) followed by PHGMI with passive forearm muscle stretch (PHGMI + stretch). Renal vascular resistance (RVR, calculated as MAP/RBV) was increased from baseline during all paradigms except during PHGMI + stretch after the ketorolac Bier block trial where RVR did not change from baseline. Before Bier block, RVR rose more during PHGMI + stretch than during PHGMI alone (P < .01). Similar results were found after a saline Bier block trial (Delta53 +/- 13% vs. Delta35 +/- 10%; P < 0.01). However, after ketorolac Bier block, RVR was not greater during PHGMI + stretch than during PHGMI alone [Delta39 +/- 8% vs. Delta40 +/- 12%; P = not significant (NS)]. HR and MAP responses were similar during PHGMI and PHGMI + stretch (P = NS). Passive muscle stretch during ischemia augments renal vasoconstriction, suggesting that ischemia sensitizes mechanically sensitive afferents. Inhibition of prostaglandin synthesis eliminates this mechanoreceptor sensitization-mediated constrictor responses. Thus mechanoreceptor sensitization in humans is linked to the production of prostaglandins.