Pulsatile Discharge Research Articles

PULSATILE DRUG DELIVERY SYSTEM-A TECHNIQUE OF DELIVERING DRUG IN ACCORDANCE WITH BIOLOGICAL CLOCK - A REVIEW

Over last 30 years pulsatile drug delivery system has achieved a lot of importance in drug delivery technology. And the reason why this pulsatile drug delivery is gaining importance is because of its strategy of delivering drug molecule at right place, right time. There are certain diseases which are controlled by biological clock of our body and follow circadian rhythms like congestive heart failure, asthma, rheumatoid arthritis ,osteoarthritis, inflammatory disorders and other hormonal disorders, for this type of diseases conventional solid dosage forms like immediate release tablets or modified dosage forms like sustained, controlled release tablets cant give the required therapeutic response and also for such diseases delivering the drug at right time in right amount is very important. And that task is accomplished by this pulsatile drug delivery system. These pulsatile drug delivery framework is planned by the organic mood i.e., biological rhythms of the body, and medication conveyance is worked with by as per disease cadence. The rule for the utilization of pulsatile drug delivery of the medications is the place where a consistent drug discharge isnt wanted. The principle for the utilization of pulsatile release of the medications is the place where a steady drug discharge isnt wanted, yet drug release must be planned in such a way that, quick medication discharge is accomplished after the lag time. Current review examined the clarifications for improvement of pulsatile drug delivery framework in accordane with body circadian rhythm, kinds of the illness during which pulsatile discharge is required, order, assessments, benefits, impediments.

Pulsatile Discharge from Polymeric Scaffolds: A Novel Method for Modulated Drug Release

Abstract Controlled drug release holds promise to revolutionize medicine, particularly if short-term and long-term release can be combined in a single system. We present here a new pulsatile release system, in which the pulses were achieved using 3D scaffolds of poly(l-lactic acid), PLLA. From a morphological characterization of the scaffold’s surfaces, before and after releasing experiments at distinct pHs, we infer that release is governed by electrostatic interactions and the fractal geometry of the scaffolds. Furthermore, the scaffold can present short-term (within hours) or long-term (several days long) releasing profiles by varying the pH, which opens the way for unprecedented drug release control.

Stokes-layer formation under absence of moving parts—A novel oscillatory plasma actuator design for turbulent drag reduction

A novel plasma actuator concept is proposed to mimic the effect of spanwise wall oscillations without mechanically moving parts, where four groups of electrodes and three independently operated high-voltage power supplies maintain a pulsatile dielectric barrier discharge (DBD) array. Time-resolved planar velocity fields are obtained with high-speed particle image velocimetry (PIV) in proximity of the discharge zones for quiescent ambient conditions. Resulting flow topologies and wall-normal velocity profiles indicate the Stokes-layer-like flow formation, which is elevated above the wall due to the no-slip condition. The underlying body forces are derived from the PIV data to provide further insight into cause-effect relations between pulsatile discharge and oscillatory flow. The momentum transfer domain is found to be only interrupted with the width of the exposed electrode, which is an important step toward homogeneous virtual wall oscillations. A comparison with earlier studies by Gatti et al. [“Experimental assessment of spanwise-oscillating dielectric electroactive surfaces for turbulent drag reduction in an air channel flow,” Exp. Fluids 56, 110 (2015)] leads to the hypothesis that DBD-based turbulent drag reduction might be a competing alternative to conventional active and passive shear-layer formation strategies, where the adjustability of both oscillation frequency and velocity amplitude might cover a wide range of Reynolds numbers.

Tomographic 3D Analysis of Reduction Displacement Reaction with Associated Formation of a Conductive Network in High Energy Primary Batteries

Hybrid Ag2VO2PO4-CFx battery electrodes with high energy and pulse performance were investigated in regards to their structural and morphological changes during electrochemical discharge. Reduction products of CFx and Ag2VO2PO4, carbon and Ag0, respectively, were identified via bulk laboratory X-ray diffraction and were characterized further by SEM-EDS to identify variations in Ag2VO2PO4-Ag0 agglomerate distributions in the electrode. X-ray tomography was used to characterize the statistical formation and redistribution of these agglomerates at a higher discharge state. Using this technique, we observed the agglomerates within the electrode to increase from 20–40 μm3 to larger sizes (>500 μm3) upon discharge. These data were used to rationalize the changes in conductivity of the composite material upon galvanostatic discharge, as determined under high rate pulsatile discharge and impedance spectroscopy. Both volumetric and spatial redistribution of the materials identified in this study provides insight toward the development and understanding of future high energy and high power primary batteries.

Operando Synchrotron XRD Investigation of Silver Metal Formation upon Electrochemical Reduction of Silver Iron Pyrophosphate (Ag7Fe3(P2O7)4)

The formation of conductive metallic silver upon electrochemical reduction and lithiation of Ag7Fe3(P2O7)4 is investigated. Alternating current impedance spectroscopy measurements show a 34% decrease in charge transfer resistance upon one electron equivalent (ee) of reduction, which is coincident with the formation of a Ag metal conductive network evidenced by both ex situ and operando X-ray diffraction. Quantitative assessment of Ag metal formation derived from operando XRD shows that only Ag+ ions are reduced during the first 3ee, followed by simultaneous reduction of Ag+ and Fe3+ reduction for the next 5ee (3ee to 8ee), culminating in reduction of the remaining Ag+. Scanning electron microscopy images show smaller Ag metal crystallite size and shorter nearest neighbor distance between and among Ag particles with higher depth of discharge. A high rate intermittent pulsatile discharge test is conducted where the cell delivers 12 total pulses during full discharge to probe the effect of Ag metal formation on the Li/Ag7Fe3(P2O7)4 cell electrochemistry. The Ohmic resistance is derived from the voltage drop of each pulse. The resistance is 65 Ω initially, reaches its minimum of 26 Ω at 4.5 ee discharge, and levels off at 35 Ω after 7.0 ee reduction. The initial Ag reduction is more significant for the conductive network formation indicated by the decrease of both Rct and Ohmic resistance, which facilitates the high power output of the cell.

Optimum selection of an implantable secondary battery for an artificial heart by examination of the cycle life test.

An implantable secondary battery is one of the key components in a total artificial heart system. Because a 2 year cycle life is required, the cycle life of the secondary battery as well as its charge and discharge properties are important parameters for selection of an appropriate battery. We carried out cycle life tests on four kinds of rechargeable batteries (a Ni-MH secondary battery, a Ni-Cd secondary battery, a Li-ion battery with a graphite anode, and a Li-ion battery with a nongraphitizable carbon electrode) to determine their suitability as implanted back-up batteries. Each of the batteries was charge/discharge cycled at 37 degrees C to 39 degrees C using a charge current of 1 C ampere, and they were each fully discharged under either pulsatile discharge loads, which mimicked pulsatile operation, or a nonpulsatile load equivalent to the average of the pulsatile loads. The two Li-ion batteries made by different manufacturers both met the minimum requirement of cycle life of more than 1,500 cycles, considering safety coefficient regardless of the discharge pattern. In addition, the temperature increase of these Li-ion batteries (3 degrees C) was lower than that of Ni-Cd and Ni-MH batteries (15-25 degrees C). Out of these four batteries, the two Li-ion batteries are the most suitable for use in a totally implantable artificial heart system.

OPTIMUM SELECTION OF IMPLANTABLE SECONDARY BATTERY FOR ARTIFICIAL HEART BY EXAMINATION OF LIFE CYCLE TEST

An implantable secondary battery is one of key components in at total artificial heart system. Life cycle of the secondary battery is and important parameter on selection of the secondary battery as well as charge and discharge characters because the secondary battery has to provide enough life cycles for two years' use. We evaluated four kinds of rechargeable batteries (a Ni-MH battery, a Ni-Cd battery, a Li-ion battery using a graphite electrode, and a Li-ion battery using at non-graphitizable carbon electrode) by a life-cycle experiment using them as implanted back-up batteries. Each of the batteries was charge/discharge cycled at 37 39 using a charge current of 1C ampere, and fully discharged under either pulsatile discharge loads, which mimicked a pulsatile operation, or a nonpulsatile load equivalent to the average of the pulsatile loads. The results showed that the Li-ion battery with a non-graphite carbon electrode provided a longer operating period (up to 5000 cycles) and a lower temperature rise by 3 than those of other batteries regardless of the discharge pattern. While each of the batteries had operating cycles of 1000 2000, which is an enough cycle for artificial hearts, Ni-MH and Ni-Cd batteries had more temperature rise by 15 25. From the above results, Li-ion batteries have enough performances to be applied to the totally implantable artificial heart system.

Coming to term with GABA

Oxytocin, the most powerful uterotonic agent known, is released from the pituitary gland in large amounts during parturition in all placental mammals studied so far, including humans. Although parturition can proceed in its absence, oxytocin is thought to play an important role (see Russell & Leng, 1998). In the rat, pregnancy normally lasts for 21 days. About 24 h before the pups are born, increased production of prostaglandins by the uterus induces luteolysis, and ovarian progesterone production falls dramatically. This fall is an essential prelude to parturition; if prevented, then the rat pups will remain unborn. The fall leads to a further increase in prostaglandin production, and, directly or indirectly, to a host of changes that prepare the uterus and birth canal for parturition. In the last few hours of pregnancy, oxytocin receptors appear in high concentrations in the uterus, and establish a positive-feedback loop between the uterus and the hypothalamic oxytocin system. Uterine contractions, triggered by prostaglandins, excite the oxytocin cells, and oxytocin release triggers further prostaglandin production and further uterine contraction. Thus progesterone plays a critical role in the timing of parturition through its peripheral actions (see Leng & Brown, 1997). A paper in this issue of The Journal of Physiology (Brussaard et al. 1999) suggests that actions of progesterone at the oxytocin cells in the hypothalamus may also be important for parturition. Classically, progesterone acts through specific intracellular receptors to regulate gene expression. However, metabolites of progesterone can also have membrane actions, and in particular, allopregnanolone can act at GABAA receptors to potentiate the actions of GABA, depending upon the particular subunit composition of the receptor. GABA is an important neurotransmitter for oxytocin cells about 45 % of all synapses onto them contain GABA, and the total number of GABA synapses in the supraoptic nucleus is substantially higher in lactating animals than in virgins (El Majdoubi et al. 1997). The GABA innervation appears to play a role in patterning the pulsatile discharge of oxytocin cells that is observed both during parturition and during suckling-induced reflex milk ejection (Moos, 1995; Voisin et al. 1995). Brussaard et al. (1999) recorded GABAA receptor-mediated spontaneous monoquantal inhibitory postsynaptic currents (sIPSCs) from rat supraoptic neurones in hypothalamic slices in vitro. They found a higher incidence of sIPSCs in pregnant rats than in virgin rats, consistent with the observations of an increase in the density of GABA-containing synaptic boutons. Importantly, the sIPSCs were markedly prolonged in the presence of allopregnanolone. Taking into account the frequency and amplitude of sIPSCs, the action of allopregnanolone and the hypertrophy of oxytocin neurones in lactation (reflected in increased capacitance), Brussaard et al. (1999) inferred that the effective GABAA receptor-mediated synaptic current density was much greater in pregnant rats than in virgin or lactating rats. Thus the collapse of progesterone production at term may abruptly reduce the effectiveness of GABA inhibition, and thereby enhance the excitability of oxytocin cells. Clearly this may be important during parturition, but the effect may not persist for long. Indeed, within a day the duration of sIPSCs is significantly longer in the absence of allopregnanolone, which now has no significant effect. This seems to be due to a rapid switch in the types of a subunits inserted into the GABAA receptors. By mid-lactation, a massive change in expression of GABAA receptor subunit mRNAs is apparent. With competitive polymerase chain reaction Brussaard and colleagues found that, while the expression of both a1 and a2 subunit mRNAs was increased, the ratio of a1 : a2 subunit mRNA expression was changed 8-fold in favour of a2 subunit mRNA. (ABSTRACT TRUNCATED)

Feasibility of a nickel-metal hydride battery for totally implantable artificial hearts.

An implantable rechargeable battery is one of the key technologies for totally implantable artificial hearts. The nickel-metal hydride (Ni-MH) battery is promising for its high energy density of 1.5-2.0 times that of a nickel-cadmium battery. In this study, the effects of pulsatile discharge loads on the operating time and cycle life of Ni-MH batteries at 39 degrees C were studied. Two battery cells (TH-3M, 1,200 mAh, phi 14.5 x 49 mm; Toshiba, Tokyo, Japan) in series were charge/discharge cycled at 39 degrees C using a charge current of 1CA (1,200 mA) and then were fully discharged to 1.0 V/cell under either pulsatile discharge loads, which mimicked a systole (1 A for 0.3 sec) and a diastole (0.4 A for 0.3 sec), or a non pulsatile discharge load equivalent to the average of the pulsatile loads (0.7 A). Each cycle life test was interrupted on the 482nd cycle under pulsatile load, and on the 423rd cycle under non pulsatile load, because of malfunction of each battery charger. The tests showed that the pulsatile discharge cells had significantly (p < 0.001) less operating time (74.0 +/- 7.15 min) throughout the test period (up to 482 days) compared to the cells under equivalent non pulsatile discharge loads (93.7 +/- 7.74 min). The pulsatile-discharged Ni-MH cells provide significantly less operating time than the constantly discharged cells; the Ni-MH battery has an operating time of over 78 min and a cycle life of almost 500 cycles at 39 degrees C. In conclusion, the Ni-MH battery is feasible as an implantable back-up battery for a totally implantable artificial heart system.

The Effect of Pulsatile Power Loads on Nickel/Cadmium Battery Cells for Mechanical Circulatory Support Devices

A number of portable medical devices, including the implantable ventricular assist device, demand fluctuating or pulsatile power from their batteries. Therefore, a study was undertaken to determine the effects of these pulsatile discharge loads on the cycle life and operating time of rectangular prismatic nickel/cadmium battery cells. The battery cells were charge/discharge cycled at 37 degrees C using either a pulsatile discharge load of 10.0 or 11.25 W (average) or a nonpulsatile discharge load equivalent to the average of the pulsatile loads. The tests showed that the pulsatile discharged cells gave significantly less operating time throughout their cycle life, by a mean of 3 +/- 3-8 +/- 2 min on each cycle (ie, 8 +/- 8-18 +/- 5%), compared to the cells under equivalent nonpulsatile discharge loads. The tests also showed that the pulsatile discharged cells had significantly shorter cycle lives, by 61-97 cycles (11-17%), than the nonpulsatile discharged cells. The results show that, under the test conditions of this study, pulsatile discharge loads reduce the cycle lives and operating times of rectangular prismatic nickel/cadmium battery cells, compared to cells discharged under nonpulsatile loads of equivalent average power.

Evaluation of Nickel-Cadmium Battery Packs for Mechanical Circulatory Support Devices

The mismatching of battery cell capacities within a rechargeable battery pack can result in reduced cycle life and operating time, as well as an increased safety risk due to gas release, which is a concern when used in implantable medical devices, such as a ventricular assist device (VAD). Two groups of four nickel/cadmium (Ni/Cd) battery packs containing 10 cells each (i.e., 12 volt packs) were evaluated for their cycle life, safe operating time, and the impact of mismatched cell capacities within the pack. Four control battery packs containing capacity matched cells (within +/- 0.4% of mean) and four battery packs each containing one low capacity cell (4.7-10.7% below mean) together with nine high capacity matched cells (within +/- 0.6% of mean) were charge/discharge cycled at 37 degrees C using a 9.7 W average pulsatile discharge load and a 30 minute discharge time on each cycle. Periodically, the battery packs were fully discharged down to 10 volts and each cell was monitored for negative voltages. The capacity matched and mismatched packs yielded similar performance curves, with an initial decline in mean total operating time until a plateau was reached of 41.1 +/- 1.5 and 41.8 +/- 1.8 minutes of discharge time, respectively. The mean total operating times of the matched and mismatched packs began to decline again after approximately 670 and 635 cycles, respectively. Cell voltage monitoring showed no negative voltages, indicating that no gases were released from the cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Circadian rhythm of plasma testosterone in men with idiopathic hypogonadotrophic hypogonadism before and during pulsatile administration of gonadotrophin-releasing hormone.

The aim was to investigate whether a pulsatile discharge of LH from the pituitary is necessary to achieve the circadian secretion of testosterone. The daily rhythm of the androgen has been studied in patients with idiopathic hypogonadotrophic hypogonadism (IHH) both in the absence of therapy and during pulsatile administration of gonadotrophin releasing hormone (GnRH). Six patients with IHH and ten normal subjects were analysed. Blood sampling was performed at 2-hourly intervals, for 24 hours. The IHH patients then received synthetic GnRH i.v. at the rate of one pulse every 2 hours (10 micrograms/pulse). On day 11 of treatment, blood samples were taken for the rhythm analysis every 2 hours, for 24 hours. Plasma testosterone and LH were measured in the individual samples by radioimmunoassay. Evaluation of the rhythm was performed by cosinor analysis. A significant circadian rhythm of plasma testosterone was statistically validated in the normal subjects, whereas no rhythm was detected in the IHH patients in the absence of therapy. On day 11 of GnRH pulsatile administration the IHH patients showed normal testosterone levels and a statistically significant circadian rhythm of the androgen was evident, with acrophase between 0700 and 0800 h. Moreover, the amplitude, acrophase and mesor of testosterone rhythm in IHH patients in the course of treatment were statistically indistinguishable from the corresponding values in the normal subjects. Plasma LH did not show statistically significant circadian variations, either in the control group or in the IHH patients before or during therapy. We conclude that a physiological circadian rhythm of plasma testosterone can be obtained, in IHH men, by treatment with GnRH. Since the pulsatile administration of exogenous GnRH at constant doses induced a circadian rhythm in testosterone and no daily variations in LH were evident, we suggest that, although a pulsatile secretion of LH is probably necessary for the synchronization of the circadian rhythm with acrophase in the morning, the testosterone variations might be the results of a local testicular modulation of LH action.

Neuromodulatory regulation of gonadotropin-releasing hormone pulsatile discharge in women

International Journal of Gynecology & ObstetricsVolume 36, Issue 1 p. 86-86 Citation from the literature Gynecological endocrinology Neuromodulatory regulation of gonadotropin-releasing hormone pulsatile discharge in women RB Jaffe, RB JaffeSearch for more papers by this authorS Plosker, S PloskerSearch for more papers by this authorL Marshall, L MarshallSearch for more papers by this authorMC Martin, MC MartinSearch for more papers by this author RB Jaffe, RB JaffeSearch for more papers by this authorS Plosker, S PloskerSearch for more papers by this authorL Marshall, L MarshallSearch for more papers by this authorMC Martin, MC MartinSearch for more papers by this author First published: September 1991 https://doi.org/10.1016/0020-7292(91)90216-RAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume36, Issue1September 1991Pages 86-86 RelatedInformation

Contrasting effects of vasopressin and angiotensin II on rabbit aortic baroreceptors

Arginine vasopressin (AVP) reportedly enhances, whereas angiotensin II (ANG II) attenuates, baroreflex control of the circulation. Here we examine whether these responses can be attributed, in part, to local actions on myelinated baroreceptor (BR) afferents, either directly or via changes in vascular tone. An in vitro rabbit aortic arch/aortic nerve preparation was used to study regularly discharging presumably myelinated BRs under controlled static and pulsatile pressures. At constant suprathreshold pressures, AVP (10(-13) M to 10(-6) M) had no effect on arch diameter or BR frequency, whereas equimolar concentrations of ANG II evoked dose-dependent vasoconstriction and associated BR inhibition. Differences were not caused by limited diffusion to BR endings lying outside the media, since similar results were obtained with either luminal or adventitial applications. AVP also had no effect on diameter or discharge in arches preconstricted with norepinephrine, whereas acetylcholine (ACh) relaxed the arch and thereby increased BR activity. These results eliminate possible AVP-induced endothelium-dependent vasodilation or potentiation of adrenergic vasoconstriction that would not be evident in isolated arches lacking tone. Finally, AVP did not sensitize BRs to changes in pressure, since ramp-evoked pressure-discharge curves remained constant and pulsatile discharge in response to sine-wave pressure inputs was unaltered. ANG II, however, shifted pressure-discharge curves to higher pressures and, with pulsatile inputs at constant mean pressure, reduced peak and average discharge firing rates. In conclusion, AVP has no apparent peripheral effect on aortic myelinated BRs in rabbits that could contribute to amplification of the baroreflex when AVP levels are elevated. In contrast, ANG II can inhibit BR firing as a consequence of local vasoconstriction, which may contribute to attenuation of the reflex when ANG II levels are elevated.

Neuromodulatory regulation of gonadotropin-releasing hormone pulsatile discharge in women

The pulsatile release of gonadotropin-releasing hormone and the consequent secretion of gonadotropins are regulated by a complex interplay of steroids, neuropeptides, catecholamines, and environmental factors. Estrogen and progesterone influence the amplitude and frequency of luteinizing hormone pulsatile secretion. These effects lead to both a diurnal variation in pulse frequency, with a lower frequency at night, and variation during the menstrual cycle, with a lower frequency and increased amplitude during the luteal phase. Opioid peptides inhibit the pulsatile discharge of gonadotropin-releasing hormone and luteinizing hormone. The opioid antagonist, naloxone, causes an increase in luteinizing hormone secretion, particularly during the luteal phase. The administration of opioid receptor agonists, such as beta-endorphin, results in a decline in serum luteinizing hormone during the early follicular phase. Corticotropin-releasing factor, which is increased during stress, inhibits pulsatile luteinizing hormone secretion, and this effect can be blocked by the simultaneous administration of naloxone. These observations suggest that corticotropin-releasing factor exerts its effects on luteinizing hormone through an opioidergic intermediary. Endogenous catecholamines such as dopamine inhibit pulsatile luteinizing hormone release; however, the mechanism involved is not clear.

Characteristics of C fibre baroreceptors in the carotid sinus of dogs.

1. We compared the pressure-response characteristics of C fibre and A fibre baroreceptors in the carotid sinus of anaesthetized dogs, recording impulses from the sinus nerve and varying mean pressure in the vascularly isolated sinus, which was distended with a pulsatile pressure. Functional stimulus-response curves were obtained by gradually increasing sinus pressure above and decreasing it below a set-point of 100 mmHg. Baroreceptors were identified by a pulsatile discharge synchronous with the pulsations in sinus pressure. A and C fibre baroreceptors were identified by the conduction velocities and blocking temperatures of their axons. 2. The pressure-response characteristics of C and A fibre baroreceptors differed in several respects. C fibres had a pulsatile firing threshold 50 mmHg higher than that of A fibres (105.8 +/- 1.8 and 54.6 +/- 2.9 mmHg, respectively), an average maximal sensitivity 35% of that of A fibres (0.39 and 1.12 impulses s-1 mmHg-1, respectively), and a maximal frequency (at 220 mmHg) 29% of that of A fibres (24.5 and 84.3 impulses/s, respectively). Although invariably pulsatile at pressures above threshold, the firing pattern of C fibre baroreceptors tended to be more irregular than that of their A fibre counterparts. 3. Impulses were also recorded from C fibres that were stimulated by increasing sinus pressure but had an irregular, non-pulsatile discharge, a high pressure threshold (averaging 154.1 +/- 7.2 mmHg), and a low maximum frequency (10.8 +/- 2.4 impulses/s). 4. Cooling the sinus nerve progressively attenuated conduction in both A and C fibres, A fibres being blocked between 12 and 4 degrees C (mean 6.8 degrees C) and C fibres between 4 and -1.5 degrees C (mean 1.0 degree C). Although cooling the sinus nerve to 7 degrees C did not block conduction in all A fibres, impulse activity in baroreceptor A fibres at a carotid sinus pressure of 200 mmHg was no greater than that at a pressure of 75 mmHg. By contrast, at 7 degrees C baroreceptor C fibres still provided a signal proportional to sinus pressure. 5. Our results suggest that A and C fibre baroreceptors subserve different reflex functions, the former signalling changes in arterial pressure both above and below the normal set-point, the latter only changes above. They also suggest that differential cold blockade may be a useful tool to determine the contribution of C fibre baroreceptors to cardiovascular reflexes.

Control of gonadotropin secretion in the ovine fetus: the effects of a specific gonadotropin-releasing hormone antagonist on pulsatile luteinizing hormone secretion.

To demonstrate the dependence of fetal pituitary LH secretion endogenous GnRH, we studied the effects of bolus iv administration of a specific GnRH antagonist analog [GnRH-Ant; (N-acetyl-D-p-chloro-Phe1,2,D-Trp3,D-Arg6,D-Ala10)GnRH] on pulsatile LH release in 10 chronically cannulated ovine fetuses of 104-129 days gestation (term, 147 days). Vehicle alone was given to 13 control fetuses of 107-125 days gestation. Blood samples for LH determination by RIA (NIH LH S16 standard) were taken after injection of either GnRH-Ant (175-300 micrograms dissolved in 1 ml 5% dextrose in water) or vehicle alone for 1.75-5 h. The efficacy of GnRH receptor blockade was then assessed by a bolus iv challenge with 50 micrograms synthetic GnRH. The mean (+/- SEM) observation period per animal was similar for the two groups (3.8 +/- 0.2 h for GnRH-Ant; 3.6 +/- 0.2 h for controls). The frequency of spontaneous pulsatile LH secretion was significantly decreased in the fetuses given GhRH-Ant (2 pulses over 38 h total observation vs. 13 pulses over 47.3 h in control fetuses; P = 0.006). The average interpulse interval was 19.0 h in the GnRH-Ant group compared to 3.6 h in controls. Although the mean pulse amplitude was lower in the GnRH-Ant group (2.8 +/- 1.2 vs. 7.6 +/- 1.1 ng/ml for controls), this difference was not statistically significant (P = 0.065, by one-tailed t test). The mean peak serum LH concentration in response to the GnRH challenge was significantly blunted in the GnRH-Ant group (4.6 +/- 0.8 vs. 20.6 +/- 1.8 ng/ml for controls; P less than 0.001). These results indicate that GnRH-Ant administration causes a virtual cessation of pulsatile LH discharge. As this GnRH-Ant blocks GnRH action at the receptor level, these data demonstrate that pulsatile LH secretion in the ovine fetus is dependent on endogenous GnRH release as early as 104 days gestation.

Norepinephrine inhibition of pulsatile LH release: receptor specificity.

Infusion of norepinephrine (NE) into the third ventricle of ovariectomized (OVX) adult rats inhibits pulsatile luteinizing hormone (LH) secretion. This study examines the effects of pretreatment with specific alpha- and beta-adrenergic blockers on the subsequent NE-induced suppression of LH release. Unanesthetized long-term OVX rats were injected ip or iv with phenoxybenzamine (alpha-adrenergic receptor blocker), propranolol (beta-adrenergic blocker), or an equal volume of saline (as controls). Approximately 1-1.5 h later, the animals were given an intraventricular (ivt) administration of NE. Infusion of acidified saline into the third ventricle of OVX rats failed to affect the pulsatile pattern of LH release characteristic of these animals. After ivt of NE, the control rats showed a significant decrease in mean blood LH level of ca. 30%. Pretreatment of OVX rat with propranolol either ivt or ip failed to affect pulsatile LH release. Subsequent ivt infusion of NE either at 1 h or 15 min after propranolol treatment also caused a 28-30% decrease in the mean LH levels and suppressed pulsatile discharge of LH, an effect that lasted for approximately 45-50 min. In sharp contrast to the saline and propranolol-treated groups, rats pretreated with phenoxybenzamine had sporadic or no LH pulses during the 70-min postphenoxybenzamine period and had significantly lower mean LH levels when compared with control animals (P less than 0.05). Moreover, a drop in mean blood LH levels after NE infusion was not observed in the rats pretreated with phenoxybenzamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathological mechanisms in polycystic ovary syndrome: modulation of LH pulsatility by progesterone.

The pulsatile discharge of luteinizing hormone (LH) in nine patients with polycystic ovary syndrome (PCO) and nine patients with amenorrhoea but without PCO, who exhibited LH discharge in response to oestrogen provocation, were studied by 4-h measurement of gonadotrophin pulsatility before and after a course of progesterone injections. No significant differences were found in the gonadotrophin pulsatility patterns of the two groups, although the LH/FSH ratio rose significantly in the patients without PCO after progesterone but not in the patients with PCO, suggesting an abnormality of FSH storage. The ability to discharge gonadotrophins in response to oestrogen provocation has been reported to be present in patients with greater than or equal to 3 LH pulses in a 4-h study period. This, however, was not demonstrated in five of the nine PCO patients despite the presence of 'normal' gonadotrophin pulsatility patterns.

Changes in the pituitary-gonadal axis associated with puberty in Holstein bulls.

The temporal pattern of the endocrine changes associated with puberty were studied using 52 bulls born in October or April. Blood samples were taken weekly and at 30-min intervals for 5 h every 4-wk. Bulls were castrated at one of six 4-wk intervals between 12 and 32 wk and blood samples were taken. Season of birth affected concentrations of testosterone (greater for spring-born) in intact bulls, but not luteinizing hormone (LH) or follicle stimulating hormone (FSH). The concentration of FSH increased about 30% between 4 and 32 wk, without evidence of pulsatile discharge. Basal concentration of LH was low and pulsatile discharges were infrequent at 4 or 8 wk. At 12, 16 and 20 wk, however, basal LH concentration was elevated and LH discharges were at less than 2-h intervals. Testosterone concentration did not rise until 18 to 20 wk, but then continued to rise; LH discharge was suppressed concomitantly. Bulls castrated at 16 or 20 wk had higher concentrations of LH in their blood both before and shortly after castration values for bulls, but by 21 d after castration values for bulls of all ages were similar. It was concluded that elimination of an unidentified suppressive factor allows frequent discharges of LH between 12 an 16 wk, but the testes do not respond by secreting more testosterone until 18 to 20 wk. By 24 wk, the testes are secreting more testosterone and pituitary production of LH is restored to a lower level; LH discharges decline in frequency and basal LH level declines. The high frequency discharges of LH between 12 and 20 wk are postulated to induce responsiveness of Leydig cells to LH and, thus, enable elevation of intratesticular testosterone to levels necessary for Sertoli cell differentiation and initiation of spermatogenesis.