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PubMed2003

New achievements and pharmacotherapeutic approaches to impotence in the elderly.

Erectile dysfunction (ED) has a negative impact on the quality of life of elderly men, but impotence is not an absolute concomitant of aging. Aging changes influencing sexual function in men consist of a decreased capacity to reach arousal by imagination or view, fragility of erection, and an increase in the refractory period. These events may be part of the andropause syndrome, which includes a decrease in intellectual activity, fatigue, depression, decreases in body hair, lean body mass and bone mineral density, accompanied by an increase in weight. As a consequence, the overlap of aging processes, concurrent diseases and social situations to which elderly men are subject, results in the great variability reported in epidemiological studies. In the same way, the complex physiology of erection depends on the social, environmental, or physical context in which it occurs. New achievements in research on intracellular mechanisms of erection and on the neuroendocrinology of aging contribute to better understanding the pathophysiology of ED in the elderly. For example, testosterone declines with age with great interindividual variability, since other hormonal changes are also involved. What currently can be easily identified is the alteration of LH-testosterone feedback alterations, although hormone levels fall in the normal range. Nevertheless, the extent to which age-dependent decline in hormones leads to health problems that may affect the quality of life remains to be clarified. Several concepts on aging-related processes have been challenged, and conditions that were once accepted as physiologically age-related are now thought to lead to medical problems, but until now erectile dysfunction remains underreported, underdiagnosed, and undertreated, especially in the elderly. Nowadays, we are witnessing a rapid growth in available pharmacotherapies, from intracavernous injections of vasoactive drugs, to powerful new oral agents, with differing pharmacological dynamic and kinetic properties. New options for treatment are therefore possible, taking into account both the possibility of changing ineffective drugs and augmenting efficacy by means of synergistic associations. This rich generation of progress is certainly contributing to a better medical approach to sexuality in aging people.

Age Distribution↗

PubMed2001

Acute stress-induced facilitation of the hypothalamic-pituitary-adrenal axis: evidence for the roles of stressor duration and serotonin.

Stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis stimulates the release of both facilitatory and inhibitory components. We proposed that the transient removal of the inhibitory component, corticosterone, during a stressor would leave the HPA axis in a state of hyper-responsiveness (facilitated state). Consistent with this expectation, we have previously observed that aminoglutethimide (AG)-induced removal of corticosterone during an immobilization stressor resulted in the hypersecretion of both ACTH and corticosterone to a subsequent stressor. In the present study we determined the effect of stressor duration on the magnitude of facilitation. AG plus a 10-min immobilization (IMM(10)) stress on day 1 resulted in facilitation of the HPA axis. This was reflected in higher ACTH and corticosterone responses to an injection stress on day 2 as compared to appropriate control rats. AG plus a 60-min immobilization (IMM(60)) stress on day 1 resulted in significantly greater facilitation as compared to the AG+IMM(10) pretreatment. It is apparent that facilitation of the HPA axis is dependent on the duration of stress. Stress can alter plasma corticosterone-binding globulin levels and AG administration can cause accumulation of the corticosterone biosynthetic precursor, adrenal cholesterol. In order to rule out these peripheral reasons for the hypersecretion of ACTH and corticosterone in our paradigm, we measured the plasma free fraction of corticosterone and adrenal mitochondrial cholesterol levels on day 2 after different pretreatments on day 1. AG+IMM(60) pretreatment caused a significant increase in the plasma free fraction of corticosterone. Hypersecretion of ACTH and corticosterone in this group, despite an enhanced feedback signal, suggests central loci for the origin of facilitation. Also, AG treatment on day 1 did not result in accumulation of free or esterified adrenal cholesterol levels on day 2, and therefore cannot account for the hypersecretion of corticosterone. In our final study we attempted to determine if serotonin released during the first stressor is partially responsible for stress-induced facilitation of the HPA axis. We administered 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT), a 5HT(1A) agonist, either alone or in conjunction with stress and examined the effects of these pretreatments on the magnitude of facilitation. Interestingly, DPAT administered in lieu of stress produced facilitation similar in magnitude to that produced by IMM(10). DPAT administered in conjunction with IMM(10) augmented stress-induced facilitation. Our results suggest that stress-induced facilitation of the HPA axis is associated with the release of serotonin during stress.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1980

Stimulus-induced corticotropin-releasing factor content and adrenocorticotropin release are augmented after unilateral adrenalectomy, independently of circulating corticosteroid levels.

There is evidence for a neural link between the adrenal and hypothalamus that may mediate increased corticotropin-releasing factor and ACTH secretion within seconds after bilateral adrenalectomy. These studies on young male rats tested the possibility that functional evidence for adrenal afferent nerves might be revealed by the application of ACTH-releasing stimuli after the acute ACTH and corticosteroid responses to unilateral or sham adrenalectomy had subsided. Resting ACTH and corticosterone levels were not different in the two groups 1, 3, or 7-10 days after adrenal surgery. Despite similar initial conditions, the ACTH response to ether or to laparotomy with intestinal traction (but not to ip saline injections) was greater after unilateral adrenalectomy (P less than 0.01) at times when plasma corticosterone levels were not different. Hypothalamic corticotropin-releasing factor-like activity was higher in unilaterally adrenalectomized than in sham-operated rats 2 min after exposure to ether (P less than 0.05). We conclude that these results may represent a functional demonstration of decreased inhibitory neural feedback from the adrenal to the hypothalamus after unilateral adrenalectomy, and discuss the possibility that the absence of neural feedback may contribute to the well known hyperresponsiveness of bilaterally adrenalectomized rats to ACTH-releasing stimuli.

Adrenalectomy↗

PubMed2000

Granulocytopoiesis versus cytokine activities in peritoneal diffusion chamber cultures in the mouse.

Regulation of granulocyte formation was studied by correlating granulocytopoiesis in diffusion chambers with activities of putative regulatory cytokines in such chambers. The implantation procedure increased the levels in 1- and 2-d chambers of interleukin 6 (IL-6), G-CSF, TNF-alpha, and non-specific granulocyte/macrophage (G/M) colony-stimulating activities (CSA), assessed with bioassays and immunoassays. The activities subsided rapidly thereafter. They could be increased by vinblastine, cyclophosphamide, and a sterile inflammatory reaction (s.c. implanted copper rods; Cu-r). Anti-inflammatory indomethacin curtailed the IL-6, but raised the TNF-alpha, G-CSF, and CSA levels in Cu-r mice. Interferon inducer poly-I:C augmented G-CSF, but decreased TNF-alpha levels. Mouse blood cells cultured in chambers expanded their granulocyte/macrophage progenitor population rapidly during the first week of culture; this population being significantly larger on day 3 in perturbed than in unperturbed mice. A marked decline followed in the second week, significantly larger in mice given cytotoxic treatment than in controls. Peritoneal G-CSF and TNF-alpha may explain progenitor and granulocyte growth and development in diffusion chambers during the first week of culture. GM-CSF and IL-3 were apparently without any influence. None of the peritoneal cytokines assayed could explain the population decline during the second week, which was possibly caused by exhaustion of earlier progenitor cells, rather than by intra-chamber feedback mechanisms.

Animals↗

PubMed1992

Vagal modulation of respiratory muscle activity in awake dogs during exercise and hypercapnia.

Using chronically instrumented awake tracheotomized dogs, we examined the contributions of vagal feedback to respiratory muscle activities, both electrical and mechanical, during normoxic hypercapnia (inspired CO2 fraction = 0.03, 0.04, 0.05, and 0.06) and during mild treadmill exercise (3, 4.3, and 6.4 km/h). Cooling exteriorized vagal loops eliminated both phasic and tonic mechanoreceptor input during either of these hyperpneas. At a given chemical or locomotor stimulus, vagal cooling caused a further increase in costal, crural, parasternal, and rib cage expiratory (triangularis sterni) muscles. No further change in abdominal expiratory muscle activity occurred secondary to vagal cooling during these hyperpneas. However, removal of mechanoreceptor input during hypercapnia was not associated with consistent changes in end-expiratory lung volume, as measured by the He-N2 rebreathe technique. We conclude that during these hyperpneas 1) vagal input is not essential for augmentation of expiratory muscle activity and 2) decrements in abdominal expiratory muscle activity may be offset by increments in rib cage expiratory muscle activity and contribute to the regulation of end-expiratory lung volume.

Afferent Pathways↗

PubMed1988

Centrifugal regulation of neuronal activity in the olfactory bulb of the waking rabbit as revealed by reversible cryogenic blockade.

The influences of centrifugal projections to the olfactory bulb were examined on the bulbar EEG and mitral-tufted cell activity in waking rabbits. Each of 6 rabbits was implanted, under surgical anesthesia, with fine wire electrodes for recording of the EEG and mitral-tufted cell unit activity and for stimulating the lateral olfactory tract. Two cooling probes, for reversible cryogenic blockade, were implanted on either side of the left olfactory peduncle. Records of EEG and unit activity were taken for 200 s before, during and after cooling of the probes to 3 degrees centigrade. Antidromic evoked potentials were used to assess the efficacy of the blockade. During the cryogenic blockade bursts of EEG activity, evoked in the bulb by inspiration through the nose, were augmented in amplitude and reduced in frequency. Mitral-tufted cell unit activity was reduced in rate but was more highly correlated with the phase and amplitude of the EEG bursts. Analysis of individual EEG bursts revealed that the variance in frequency of bulbar activity was significantly reduced in the isolated state. The data demonstrate that oscillatory bursting activity in the olfactory bulb is intrinsically maintained within a relatively fixed frequency range during receptor input and does not depend on centrifugal projections for its electrogenesis. Changes in EEG frequency, amplitude and correlation with unit activity support the hypothesis that centrifugal projections act in part to inhibit mitral-tufted cell output by direct excitation of granule cells. These findings are supported by a theoretical model in which distributed feedback to the granule cells from more central olfactory structures acts to regulate the coherency of bulbar activity.

Action Potentials↗

PubMed2002

Regulation of IGF-I mRNA by GH: putative functions for class 1 and 2 message.

This study investigated mechanisms regulating hepatic insulin-like growth factor (IGF)-I class 1 and 2 mRNA levels. Lambs were treated with growth hormone (GH) either as an acute, single dose or over a longer term. Total hepatic unspliced, pre-mRNA levels increased after the single dose of GH but were attenuated after 8 days of GH, with exon 1- and 2-derived pre-mRNA levels displaying coordinate responses. Surprisingly, changes in total spliced, mature mRNA levels did not reflect those for pre-mRNA, instead being augmented after 8 days of GH. GH also induced a differential increase in the ratio of mature class 2-to-class 1 IGF-I mRNA; therefore, this must be predominantly via posttranscriptional mechanisms. Increases in the ratio of class 2-to-class 1 mRNA were observed in polysomal vs. total RNA preparations derived from GH-treated but not control lambs, indicating an increased proportion of class 2 transcripts engaged in translation. Our findings indicate that GH may stabilize mature class 2 transcripts or destabilize mature class 1 transcripts and that class 2 mRNA may have a greater translational potential. The following two main functions of hepatic class 2 IGF-I mRNA are suggested: an efficient "monitor" of GH status via providing a rapid negative feedback mechanism and a coordinator of endocrine-regulated tissue growth.

Animals↗

PubMed1999

Effect of estradiol and selected antiestrogens on pro- and antioxidant pathways in mammalian uterus.

In this study, we examined the effect of 17 beta-estradiol and selected antiestrogens on uterine NADPH-oxidase activity, superoxide dismutase (SOD) activity, hydride (H.-), dienyl radical and O2 -radical generation, and membrane fluidity. NADPH oxidase activity was positively modulated in estradiol-treated animals and negatively regulated in animals that received injections of AF-45, RU-39411, tamoxifen, or ICI-182780. The SOD activity was markedly reduced in estradiol-treated animals when compared with the control animals. A positive modulation of SOD activity was observed upon treatment with AF45, RU39411, tamoxifen, and ICI 182780, though the potency varied among the individual test compounds. We observed detectable H(.-)-radical generation as evidenced from MNP H.- adduct formation in the uterine cell preparations from untreated control animals. Estradiol produced a tremendous augmentation in the superoxide radical profiles in uterine cell preparations compared to the control levels. All the other compounds that were tested significantly lowered the superoxide levels in the test set-up. AF-45, RU-39411, tamoxifen, and ICI-182780 induced varying orders of suppression of H(.-)-radical generation in the test subjects. There was a significant enhancement in membrane fluidity, hydride radical levels, and dienyl radical generation in the estradiol-treated group. All the antiestrogens did not exhibit a similar action on these parameters. RU-39411 exhibited antiestrogen-like activity in modulating hydride levels and membrane fluidity, whereas it stimulated dienyl radical generation. Thus our tests showed that the selected antiestrogens failed to show estrogen-like activity in these assays. It appears that estradiol exerts feedback control over pro- and antioxidant pathways and that markers of oxidative status could be used as a measure to evaluate the antiestrogenic activity of estradiol agonists/antagonists.

Animals↗

PubMed1983

Hageman factor-dependent pathways: mechanism of initiation and bradykinin formation.

The concentration of bradykinin in human plasma depends on its relative rates of formation and destruction. Bradykinin is destroyed by two enzymes: a plasma carboxypeptidase (anaphylatoxin inactivator) removes the COOH-terminal arginine to yield an inactive octapeptide, and a dipeptidase (identical to the angiotensin-converting enzyme) removes the COOH-terminal Phe-Arg to yield a fragment of seven amino acids that is further fragmented to an end product of five amino acids. Formation of bradykinin is initiated on binding of Hageman factor (HF) to certain negatively charged surfaces on which it autoactivates by an autodigestion mechanism. Initiation appears to depend on a trace of intrinsic activity present in HF that is at most 1/4000 that of activated HF (HFa); alternatively traces of circulating HFa could subserve the same function. HFa then converts coagulation factor XI to activated factor XI (XIa) and prekallikrein to kallikrein. Kallikrein then digests high-molecular-weight kininogen (HMW-kininogen) to form bradykinin. Prekallikrein and factor XI circulate bound to HMW-kininogen and surface binding of these complexes is mediated via this kininogen. In the absence of HMW-kininogen, activation of prekallikrein and factor XI is much diminished; thus HMW-kininogen has a cofactor function in kinin formation and coagulation. Once a trace of kallikrein is generated, a positive feedback reaction occurs in which kallikrein rapidly activates HF. This is much faster than the HF autoactivation rate; thus most HFa is formed by a kallikrein-dependent mechanism. HMW-kininogen is also therefore a cofactor for HF activation, but its effect on HF activation is indirect because it occurs via kallikrein formation. HFa can be further digested by kallikrein to form an active fragment (HFf), which is not surface bound and acts in the fluid phase. The activity of HFf on factor XI is minimal, but it is a potent prekallikrein activator and can therefore perpetuate fluid phase bradykinin formation until it is inactivated by the C1 inhibitor. In the absence of C1 inhibitor (hereditary angioedema) HFf may also interact with C1 and activate it enzymatically. The resultant augmented bradykinin formation and complement activation may account for the pathogenesis of the swelling characteristic of hereditary angioedema and the serologic changes observed during acute attacks.

Blood Coagulation↗

PubMed1980

A possible participation of endogenous opiates in respiratory reflexes induced by thin-fiber muscular afferents.

In anesthetized, vagotomized, paralyzed, and artificially ventilated dogs, naloxone effects on respiratory responses induced by thin-fiber muscular afferents were studied by recording phrenic nerve discharges. Naloxone augmented respiratory outputs, before, during, and after the stimulation. Two different types were found in the returning phase of the respiratory response by thin-fiber muscular afferent stimulation: respiratory outputs were supressed below the pre-stimulus level within several minutes after the cessation of the stimulus in some cases, while in the other cases they remained above the pre-stimulus level. In the latter cases, naloxone did not change the pattern of returning phase of the response, on the other hand, in the former cases, the after-suppression was significantly reduced by naloxone. The present results suggest that endogenous opiates play a role in setting the level of respiratory outputs and that in addition to facilitatory effects on respiration, thin-fiber muscular afferents drive a negative feedback system via neurohumoral mechanisms.

Afferent Pathways↗

PubMed2004

[Endurance training and cardial adaptation (athlete's heart)].

One essential function of the cardiovascular system is to provide an adequate blood supply to all organs, including the skeletal muscles at rest and during exercise. Adaptation to chronic exercise proceeds mainly via the autonomic nervous system. On the one hand, peripheral muscles influence the autonomic reactions through "feedback" control via ergoreceptors, in particular, mechano- and chemoreceptors. On the other hand, there is central control in the sense of a "feed forward" regulation, e. g., the reaction of an athlete before competition. Along with other influential factors, such as circulatory presso-, chemo-, and volume receptors, the incoming impulses are processed in vegetative centers.A cardiovascular reaction, then, is the result of nerval and humoral sympathetic and parasympathetic activity. At rest, the parasympathetic tone dominates. It reduces heart frequency and conduction velocity. The high vagal tone is initially reduced with increasing physical exertion and switches at higher intensity to increasingly sympathetic activation. This mechanism of reaction to exercise is supported by inverse central and peripheral transmissions.Chronic endurance training leads to an improved local aerobic capacity of the exercised musculature. At rest, it augments parasympathetic activity when the muscle mass is sufficiently large, i. e., 20-30% of the skeletal musculature. The extent of the adaptation depends on individual factors, such as scope, intensity of training, and type of muscle fiber. A higher vagal tone delays the increase in the sympathetic tone during physical exertion. The regulatory range of heart rate, contractility, diastolic function, and blood pressure is increased. In addition, adaptation results in functional and structural changes in the vascular system. Cardiocirculatory work is economized, and maximum performance and oxygen uptake are improved. Endurance training exceeding an individual limit causes harmonic enlargement and hypertrophy of the heart. The thickness of both, the septum and posterior wall increases to the same extent as the interior volume. The mass/volume ratio, and therefore the maximum systolic wall stress, remains constant in contrast to pathologic forms of hypertrophy. Adaptations, including function and size of the heart, show a regression in healthy inactive persons without any structural heart disease.

Adaptation, Physiological↗

PubMed1996

The effect of hypophysectomy and growth hormone replacement on sst1 and sst2 somatostatin receptor subtype messenger ribonucleic acids in the arcuate nucleus.

Although considerable evidence indicates that somatostatin (SRIF) exerts direct actions on GH-releasing hormone-containing arcuate neurons within the hypothalamus to modulate hypophyseal GH secretion, the underlying mechanism(s) remains to be elucidated. We recently demonstrated high levels of expression of the messenger RNAs (mRNAs) coding for two prototypic receptors of the recently cloned SRIF receptor (sst) family, sst1 and sst2, in the arcuate nucleus of the rat hypothalamus. However, information on the biological roles of these receptor subtypes and the factors regulating their expression is lacking. In the present study, we hypothesized that perturbations in GH would influence sst mRNA levels in cells of the arcuate nucleus in vivo. To test this hypothesis, we examined the effects of hypophysectomy (HPX) and HPX with GH replacement, on sst1 and sst2 mRNA levels in the brains of adult male rats by in situ hybridization using 35S-labeled antisense riboprobes. The number of labeled cells and the density of silver grains per cell were quantified using a computer-assisted image analysis system. Two weeks after HPX, there was a 50-60% reduction in both the number and labeling density of sst1 and sst2 mRNA-expressing cells in the arcuate nucleus compared to those in sham-operated control rats. Administration of recombinant human GH (200 micrograms/day for 7 days by continuous sc infusion using osmotic minipumps) to HPX rats augmented both the cell number (P < 0.05) and labeling density (P < 0.01) of sst1 mRNA in the arcuate nucleus, but did not significantly alter sst2 mRNA levels compared to those in HPX rats infused with H2O. There were no significant changes in sst1 and sst2 mRNA levels in extra-arcuate areas, including the cerebral cortex and medial habenula, or in suprachiasmatic, medial preoptic, and magnocellular preoptic nuclei after either HPX or GH replacement. These results indicate that the expression of both sst1 and sst2 SRIF receptor subtypes in brain is under the regulatory influence of pituitary hormones. They further suggest that GH may participate in the regulation of its own secretion by influencing the expression of the sst1 receptor gene on arcuate neurons. Such a mechanism may be important in the feedback regulation of GH secretion by the arcuate nucleus.

Animals↗

PubMed2006

Basic mechanisms of augmentation of antidepressant effects with thyroid hormone.

The thyroid hormone triiodothyronine (T3) has been used both to augment and accelerate the clinical effects of antidepressants, particularly the tricyclics. More recent work indicates that it may have similar actions with regard to the SSRIs. Two main mechanisms have been put forward to explain its antidepressant actions, (a) an action at the nuclear level involving stimulation of gene transcription, (b) an action at the cell membrane level involving potentiation of neurotransmission. In particular, there is considerable evidence for potentiation by T3 of the actions of the neurotransmitter 5-HT or serotonin. This evidence, which is mainly based on in vivo microdialysis studies, is reviewed, and evidence based on human and animal neuroendocrine studies considered. The effects of T3, alone and together with the SSRI fluoxetine, on mRNA levels for the 5-HT1A and 5-HT1B autoreceptors, which mediate serotonergic neurotransmission by feedback actions at the levels of cell firing(somatodendritic 5-HT1A autoreceptors) and neurotransmitter release (nerve terminal 5-HT1B autoreceptors) were also determined. Administration of a combination of fluoxetine and T3 induced reductions in the transcription of these autoreceptors, which may explain the clinical potentiating effects of this combination, and thus link the nuclear and neurotransmitter hypotheses of T3 action.

Animals↗

PubMed1999

Alpha2-adrenoceptor-mediated restraint of norepinephrine synthesis, release, and turnover during immobilization in rats.

Stress-related release of norepinephrine (NE) in the brain and periphery probably underlies several neuroendocrine and neurocirculatory responses. NE might influence its own synthesis, release, and turnover, by negative feedback regulation via alpha2-adrenoceptors. We examined central and peripheral noradrenergic function by measuring concentrations of NE, dihydroxyphenylglycol (DHPG), and dihydroxyphenylacetic acid (DOPAC) in hypothalamic paraventricular nucleus (PVN) microdialysate and arterial plasma simultaneously during immobilization (IMMO) in conscious rats. The alpha2-adrenoceptor antagonist yohimbine (YOH) was injected i.p. or perfused locally into the PVN via the microdialysis probe. The i.p. YOH increased plasma NE, epinephrine (EPI), DHPG, dihydroxyphenylalanine, and DOPAC levels by 4.3, 7.3, 2.5, 0.6 and 1.8-fold and PVN microdialysate NE, DHPG, and DOPAC by 1. 2, 0.6 and 0.5-fold. The i.p. YOH also enhanced effects of IMMO on plasma and microdialysate NE, DHPG, and DOPAC. YOH delivered via the PVN microdialysis probe did not affect microdialysate or plasma levels of the analytes at baseline and only slightly augmented microdialysate NE responses to IMMO. The results indicate that alpha2-adrenoceptors tonically restrain NE synthesis, release, and turnover in sympathetic nerves and limit IMMO-induced peripheral noradrenergic activation. In the PVN, alpha2-adrenoceptors do not appear to contribute to these processes tonically and exert relatively little restraint on IMMO-induced local noradrenergic activation.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Short-term synaptic plasticity.

Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca(2+)]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases of synaptic enhancement, as well as the interpretation of statistical changes in transmitter release and roles played by other factors such as alterations in presynaptic Ca(2+) influx or postsynaptic levels of [Ca(2+)]i. Synaptic depression dominates enhancement at many synapses. Depression is usually attributed to depletion of some pool of readily releasable vesicles, and various forms of the depletion model are discussed. Depression can also arise from feedback activation of presynaptic receptors and from postsynaptic processes such as receptor desensitization. In addition, glial-neuronal interactions can contribute to short-term synaptic plasticity. Finally, we summarize the recent literature on putative molecular players in synaptic plasticity and the effects of genetic manipulations and other modulatory influences.

Animals↗

PubMed1996

Adaptive control for backward quadrupedal walking V. Mutable activation of bifunctional thigh muscles.

1. In this, the fifth article in a series to assess changes in posture, hindlimb dynamics, and muscle synergies associated with backward (BWD) quadrupedal walking, we compared the recruitment of three biarticular muscles of the cat's anterior thigh (anterior sartorius, SAa; medial sartorius, SAm; rectus femoris, RF) for forward (FWD) and BWD treadmill walking. Electromyography (EMG) records from these muscles, along with those of two muscles (semitendinosus, ST; anterior biceps femoris, ABF) studied previously in this series, were synchronized with kinematic data digitized from high-speed ciné film for unperturbed steps and steps in which a stumbling corrective reaction was elicited during swing. 2. During swing, the relative timing of EMG activity for the unifunctional SAm (hip and knee flexor) was similar for unperturbed steps of FWD and BWD walking. The SAm was active before paw lift off and remained active during most of swing (75%) for both forms of walking, but there was a marked decrease in EMG amplitude after paw off during BWD and not FWD swing. In contrast, the relative timing of EMG activity for the SAa and RF, two bifunctional muscles (hip flexors, knee extensors), was different for FWD and BWD swing. During FWD swing, the SAa and the RF (to a lesser extent) were coactive with the SAm; however, during BWD swing, the SAa and RF were active just before paw lift off and then inactive for the rest of swing until just before paw contact (see 3). Thus the swing-phase activity of the SAa and RF was markedly shorter for BWD than FWD swing. 3. Activity in SAa and RF was also different during FWD and BWD stance. The RF was consistently active from mid-to-late stance of FWD walking, and the SAa was also active during this period in some FWD steps. During the stance phase of BWD walking, however, the onset of activity in both muscles consistently shifted to early stance as both muscles became active just before paw contact (the E1 phase). Activity in RF consistently persisted through most of BWD stance. The duration of SAa recruitment during BWD stance was more variable across cats with offsets ranging from mid- to late stance. 4. The activation patterns of the biarticular anterior thigh muscles during stumbling corrective reactions were, in general, similar to their different activations during FWD and BWD swing. The initial response to a mechanical stimulus applied to the dorsum of the paw that obstructed FWD swing was an augmentation of knee flexion and increased activity in ST and SAm. A mechanical stimulus applied to the ventral surface of the paw to obstruct BWD swing resulted in an initial conversion of hip extension to flexion and a slowing of knee flexion. There was a corresponding recruitment of SAa and RF and an enhancement of background activity in SAm. 5. The two forms of walking are differentiated by posture and limb dynamics, yet muscles participating in the basic flexor and extensor synergies are unchanged. Although central pattern generating (CPG) circuits determine the basic timing of these synergies, changes in the duration and waveform of muscle activity may depend on unique interactions among the CPG, supraspinal inputs that set posture and the animal's goal (to walk BWD or FWD) and motion-related feedback from the hindlimb. Output mutability to each muscle may depend on the balance of this tripartite input; muscles with immutable patterns may rely heavily on input from CPG circuits, whereas muscles with mutable patterns may rely more on form-specific proprioceptive and supraspinal inputs.

Adaptation, Physiological↗

PubMed1999

Neuroendocrine aspects of polycystic ovary syndrome.

A series of investigations have emphasized the heterogeneous nature of the clinical condition known as PCOS and have delineated several factors that may contribute to the hyperandrogenemia and anovulation in this condition. Currently, it remains unclear whether intrinsic abnormalities of ovarian steroidogenesis, the effects of hyperinsulinemia in augmenting LH stimulation of ovarian androgen production, and the persistent rapid frequency of LH/GnRH secretion are primary factors in all patients. Indeed, these factors may have variable roles in different patients, all of whom present with the clinical syndrome of PCOS. A consensus has emerged that abnormalities in the neuroendocrine control of GnRH secretion exist in a significant subset of patients and lead to persistent hypersecretion of LH, which seems to be an important component of the syndrome, particularly in nonobese patients. The relative frequency of primary abnormalities in the regulation of GnRH secretion versus secondary changes reflecting altered circulating concentrations of ovarian steroid remains uncertain. No clear evidence exists for an underlying neuroendocrine abnormality of GnRH regulation in all patients. The recent data showing insensitivity of the hypothalamic GnRH pulse generator to E2 progesterone feedback have suggested potential mechanisms that may explain the abnormalities of GnRH secretion seen in adolescent girls in whom the clinical syndrome of PCOS is destined to develop. Further studies are required in adolescents to establish whether GnRH regulation is impaired during puberty or whether data in adults simply reflect the long-term effects of elevated androgens, estrogens, or other hormones on the hypothalamus. Studies in carefully delineated subgroups of patients with PCOS are needed to establish these points, with a long-term goal of providing patients with improved methods of inducing ovulation and reducing hyperandrogenemia.

Adolescent↗

PubMed1995

Ca(2+)-dependent Cl- current in canine tracheal smooth muscle cells.

Our goal was to investigate the role of Ca2+ entry in regulating Cl- current (ICl) in smooth muscle cells from canine trachealis. When studies were done using the perforated patch configuration, depolarization elicited a dihydropyridine-sensitive Ca2+ current (ICa), followed in many cells by a sustained current. This sustained current reversed direction close to the Cl- equilibrium potential, consistent with its representing ICl. The ICl was also apparent as slowly deactivating tail currents seen upon repolarization to negative potentials. The Cl- channel blocker niflumic acid abolished both the sustained and tail currents, without affecting ICa. Several observations indicated that the ICl was dependent on Ca2+ entry. ICl was increased in magnitude when Ca2+ influx was augmented [by prolonging the depolarization or using BAY K 8644 or acetylcholine (ACh)] and decreased in magnitude when Ca2+ influx was reduced (using nifedipine). Based on these findings, we conclude that depolarization causes Ca2+ entry, with resultant elevation of cytosolic free Ca2+ concentration leading to activation of ICl (ICl(Ca)). We investigated whether Ca(2+)-induced Ca2+ release from the sarcoplasmic reticulum was involved in activation of ICl(Ca), by depleting intracellular stores of Ca2+ using cyclopiazonic acid to block the sarcoplasmic Ca(2+)-adenosinetriphosphatase and repeated stimulation with ACh. In such Ca(2+)-depleted cells, depolarization-mediated Ca2+ entry continued to activate ICl(Ca), suggesting that Ca(2+)-induced Ca2+ release was not required for its activation. We conclude that Ca2+ entry can activate Cl- channels in tracheal smooth muscle. This represents a positive-feedback system, which would promote excitation and contraction of airway muscle.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗