A limit cycle mathematical model of the rapid-eye-movement (REM) sleep oscillator system has been developed from a structural model of interaction of populations of REM-on and REM-off neurons. The marked differences in latency, amplitude, and duration of the first REM sleep period seen with circadian variation and depressive pathology are modeled by beginning the REM oscillation at different initial points relative to the final position in the limit cycle. Beginning from a point that is graphically interior to the limit cycle produces a long-latency, short-duration, and less intense first REM period. Beginning from a point graphically exterior to the limit cycle produces a short-latency, long-duration, and more intense first REM period. In the model the determinant of whether the oscillation begins exterior or interior to the limit cycle is the time course of decay of the REM-off population discharge activity at sleep onset. When this time course is made to depend on circadian phase, the model produces a very close match to the empirically observed large shifts between the first and second REM periods in duration (often a 50% change) and intensity and also closely mimics the empirically observed shifts in REM latency as human sleep begins at different circadian phases. Although this variation in limit cycle entry accounts for the major changes in REM sleep over the night, the model also postulates a continuous but small circadian variation (of the order of +/- 5% change in REM parameters) acting throughout the course of a night's sleep. Because the model is derived from actual physiological data, rather than being a purely ad hoc or phenomenological construct, it offers the possibility of direct tests of its postulates through neurobiological studies in animals, by circadian phase-related manipulations of the sleep cycle, and through perturbations of the system in humans by the use of drugs. Indeed, an explicit phase-response curve of the system to cholinergic agonists has been developed; this will permit experimental tests of the model in both animals and humans.

McCarley and Massaquoi successfully simulated human REM-NREM cycle characteristics by extending the McCarley-Hobson model with two sets of assumptions, one creating limit cycle behavior, the other introducing two sources of circadian variation. We argue that the limit cycle assumptions, due to freedom in choosing parameter values, suffice to explain variation in REM across the night. Nonmonotonic circadian variation in REM latency requires a circadian cycle dependence only of initial conditions at sleep onset.

The limit cycle feature and the grounding of our model in physiology are endorsed by Daan and Beersma [Am. J. Physiol. 251 (Regulatory Integrative Comp. Physiol. 20): R1030-R1032, 1986.] as well as the fundamental postulate of the model that the latency, duration, and intensity of the first rapid-eye-movement (REM) period depends on whether the limit cycle is entered from an internal or external trajectory, and the fact that this trajectory is determined by circadian modulation of conditions at sleep onset. We describe our reasons for preferring a more explicit formulation of the sleep onset conditions than provided in our earlier “Karmal” version of this model and provide additional details of how the control of the REM-off population decline is modeled. Additional empirical evidence is cited for the continuous circadian modulation of REM cycle parameters. We emphasize that, compared with the original simple model, the present version of the model adds only one additional “free” initial condition parameter (circadian phase) that is used to model normal sleep begun at different circadian phases and the resultant variations in REM latency, duration, intensity, and period length. We present specific predictions of the model and new supporting empirical data.

Sleep states and electroencephalographic (EEG) parameters were determined in unrestrained rats that had been implanted with electrodes under deep pentobarbital sodium anesthesia. Two base-line days with a light-dark cycle (LD) and 2 days under continuous darkness (DD) were followed by 24 h of sleep deprivation (SD) ending in the middle of the circadian activity period and by 2 recovery days in DD. In the base-line LD rest period, the amount of rapid-eye-movement sleep (REMS) and the EEG amplitude of non-REMS (NREMS) were lower than in the corresponding DD period. SD caused an immediate enhancement of REMS, NREMS, the slow-wave sleep (SWS) fraction of NREMS, and NREMS EEG amplitude. Although REMS, NREMS, and SWS showed a second peak at habitual light onset, they did not exceed base line. Subsequently, all parameters exhibited a marked negative rebound. We conclude that REMS and the EEG amplitude of NREMS are suppressed by light, amplitude and frequency parameters of NREMS are differently affected by light as well as by SD, and the short duration of the SD-induced increase of SWS may reflect a circadian influence on sleep homeostasis.

The bronchiolar epithelium of rats is anatomically immature at birth. We now ask whether postnatal hyperoxia impairs the normal development of bronchiolar epithelium; and, if development is impaired, is the impairment permanent? To answer these questions, we exposed newborn rats to hyperoxia (greater than 95% O2, 1 atm) or air for 7 days and killed the rats at age 7 or 30 days. We used ultrastructural and morphometric means to assess maturation of the bronchiolar epithelium. Hyperoxia substantially diminished the postnatal increase in nuclear numerical density of bronchiolar Clara cells and ciliated cells. Hyperoxia also markedly delayed the rise in volume density of Clara cell secretory granules and rough endoplasmic reticulum but accelerated the increase in volume density of Clara and ciliated cell mitochondria. When rats exposed to hyperoxia from age 1 to 7 days were thereafter allowed to breathe air, by age 30 days all the differences were eliminated that were detected between the air- and O2-breathing groups at age 7 days. We conclude hyperoxia causes a marked but nonpermanent suppression of maturation of the bronchiolar epithelium.

Results of radioimmunoassays for the Ca2+-binding protein, calmodulin, revealed that this receptor constitutes 0.53 +/- 0.12% of the total protein in adult male Schistosoma mansoni. Schistosome calmodulin purified by Ca2+-dependent hydrophobic interaction chromatography showed an apparent molecular weight of 19 kDa, and its mobility on sodium dodecyl sulfate polyacrylamide gels was influenced by the presence of Ca2+ but not the antischistosomal drug praziquantel. Calmodulin from the parasite effected a four-fold stimulation of bovine heart adenosine 3',5'-cyclic monophosphate phosphodiesterase; this process was inhibited by removal of Ca2+ with ethyleneglycol-bis(B-aminoethylether)-N,N'-tetraacetic acid but not by praziquantel. Inhibition of calmodulin-activated processes with antipsychotic compounds in vitro resulted in a number of time- and concentration-dependent changes, including inhibition of schistosome calmodulin stimulation of bovine heart phosphodiesterase, disruption and depolarization of the parasite's tegument, and positive inotropic effects on longitudinal musculature. Results of this study indicate that calmodulin is a functional component of schistosomes and suggest that the role it serves is analogous to that obtained in other eukaryotes; i.e., it is an important component of numerous processes regulated, in part, by Ca2+.

Exposure to conditions of weightlessness has been associated with decrements in muscle mass and strength. The present studies were undertaken to determine muscle responses at the cellular level. Male Sprague-Dawley rats (360–410 g) were exposed to 7 days of weightlessness during the Spacelab-3 shuttle flight (May 1985). Animals were killed 12 h postflight, and soleus (S), gastrocnemius (G), and extensor digitorum longus (EDL) muscles were excised. Muscle protein, RNA, and DNA were extracted and quantified. Differential muscle atrophy was accompanied by a significant (P less than 0.05) reduction in total protein only in S muscles. There were no significant changes in protein concentration (mg/g) in the muscles examined. In S muscles from flight animals, sarcoplasmic protein accounted for a significantly greater proportion of total protein that in ground controls (37.5 vs. 32.5%). Tissue concentrations (nmol/g) of asparagine-aspartate, glutamine-glutamate, glycine, histidine, and lysine were significantly reduced (from 17 to 63%) in S muscles from flight animals, but only glutamine-glutamate levels were decreased in the G and EDL. Muscle DNA content (microgram) was unchanged in the tissues examined, but S muscle DNA concentration (micrograms/mg) increased 27%. RNA content (micrograms) was significantly (P less than 0.025) reduced in S (-28%) and G(-22%) muscles following spaceflight. These results identify specific alterations in rat skeletal muscle during short term (7-day) exposure to weightlessness and compare favorably with observations previously obtained from ground-based suspension simulations.

The mechanisms of inhibition of branchial ion transport by epinephrine and somatostatin were investigated in the isolated perfused gill preparation of seawater-adapted flounder Platichthys flesus. The electrogenic transepithelial potential recorded in gills perfused and bathed with identical salines was stimulated by glucagon, forskolin, or a cyclic adenosine 5' monophosphate (AMP) derivative, each administered at a concentration identified in preliminary experiments as being submaximally effective. The subsequent abilities of epinephrine and somatostatin to inhibit the stimulated potential were found to be dependent on the site of action of the stimulatory agent with respect to the formation of cyclic AMP. Thus the maximal adrenergic or peptidergic inhibition of the potential stimulated by exogenous cyclic AMP was significantly reduced compared with the maximal inhibition of the potential stimulated by either forskolin or glucagon. The data indicate dual modes of action by which epinephrine and somatostatin achieve maximal inhibition of branchial ion transport; a cyclic AMP-independent mechanism that is effective in the presence of cyclic AMP and an additional mechanism to inhibit cyclic AMP synthesis.

We investigated whether the increased intake of water during dietary electrolyte depletion is related to activation of the renin-angiotensin system. Young adult male rats were fed a low Na-, Cl-, K-free (low-salt) diet for 2 wk during which measurements were made of daily water intake and urine volume, plasma osmolality (Posm) and electrolytes, and plasma renin activity (PRA) and angiotensin I (ANG I) concentration. Water intake and urine output increased on day 3 of the low-salt diet, reached a maximum on day 4, and remained elevated, paralleling the time course of increases in PRA and ANG I plasma concentrations. Posm was normal after 2 days on the low-salt, although it was significantly lower by day 11. Renal concentrating ability was not different from controls after 6 days, but was significantly reduced after 11 days of treatment. Electrolytic lesions of the subfornical organ (SFO) abolished the low-salt diet-induced polydipsia, but had no effect on the diet-induced increases in PRA and plasma ANG I concentration. These data demonstrate that polydipsia induced by feeding a low-salt diet can develop in the presence of a normal or reduced Posm and precedes the development of a renal concentrating defect. The primary polydipsia is associated with elevated PRA and ANG I and appears to be mediated by angiotensin receptors in the SFO.

Effects of endotoxin administration on the Na+-Ca2+ exchange in canine cardiac sarcolemma were characterized. In addition, roles of phospholipase A2 and phosphorylation on the endotoxin-induced impairment in Na+-Ca2+ exchange were investigated. The results show that intravesicular sodium (Nai+)-dependent 45Ca2+ uptake was decreased by 39-66% (P less than 0.05) and extravesicular sodium (Nao+)-induced 45Ca2+ efflux was decreased by 36-52% (P less than 0.05) at 2 h following endotoxin administration. Ca2+o-induced 45Ca2+ efflux in the absence of Ko+ was not affected, but Ca2+o-induced 45Ca2+ efflux in the presence of Ko+ was significantly reduced by endotoxin administration. The stoichiometry of Na+-Ca2+ exchange was altered from 3 Na+ for 1 Ca2+ for the control to 2 Na+ for 1 Ca2+ for the endotoxin-treated dogs. The ATP-dependent 22Na+ uptake and Na+-Ca2+ exchange in inside-out vesicles remained unchanged after endotoxin injection. Digestion of control heart sarcolemmal vesicles with exogenous phospholipase A2 (0.02-0.06 unit/500 micrograms protein) inhibited Na+-Ca2+ exchange activity measured as Nai+-dependent 45Ca2+ uptake, and the inhibition was concentration dependent. Lysophosphatidylcholine addition to the control cardiac sarcolemma had no effect on Na+-Ca2+ exchange. The inhibition of Na+-Ca2+ exchange caused by phospholipase A2 digestion in the control heart sarcolemma was completely reversible by the addition of phosphatidylcholine (0.1 mM). The inhibition of Na+-Ca2+ exchange caused by the in vivo administration of endotoxin was completely reversible by the addition of phosphatidylcholine (0.1-0.15 mM).(ABSTRACT TRUNCATED AT 250 WORDS)

A variety of methods has been used experimentally to increase baroreceptor activity and provoke transient, vagally mediated cardiac slowing in humans. We studied baroreceptor-cardiac reflex physiology in eight resting volunteers by measuring R-R interval changes during and after spontaneous brief elevations of arterial pressure, preceded by bursts of muscle sympathetic nerve activity. Arterial pressure was measured with a catheter in a brachial artery, and muscle sympathetic activity was measured with a microelectrode positioned transcutaneously in a peroneal nerve. R-R intervals were related to preceding systolic pressures with linear regression analysis. When systolic pressures were correlated with R-R intervals of the next cardiac cycle, slopes (+/- SE) averaged 12.4 +/- 2.2 ms/mmHg and correlation coefficients averaged 0.81 +/- 0.09. Baroreflex slopes were inversely related to base-line systolic pressures. These results are similar to those obtained when baroreceptors are stimulated experimentally; they suggest that elevations of arterial pressure, which are preceded by bursts of muscle sympathetic activity, trigger with one heart-beat latency highly linear increases of efferent vagal-cardiac nerve activity.

This study was undertaken to define the changes in plasma levels of atrial natriuretic peptide (ANP) induced by hypertonic saline infusion followed by spontaneous water drinking and to determine whether these changes in ANP are correlated with changes in right atrial pressure (RAP) and plasma levels of vasopressin (AVP). Conscious dogs (n = 5) were infused with hypertonic saline (6%) at a rate of 1.4 ml/min for 4 h. Water was withheld for the first 2 h and administered ad libitum for the final 2 h. Hypertonic saline infusion induced increases (P less than 0.05) in plasma osmolality (posM), pAVP, mean arterial pressure (MAP), and RAP (1.9 +/- 0.6 to 3.1 +/- 0.7 mmHg). These changes were accompanied by an increase of pANP (68 +/- 14 to 120 +/- 33 pg/ml, P less than 0.05). Spontaneous water drinking (1,410 +/- 127 ml) returned posM and pAVP to control levels and produced a further and significant increment in RAP (150%) and pANP (100%). During the water-drinking phase MAP was not further altered, and hematocrit decreased by 11.1% (P less than 0.05). A positive linear correlation (P less than 0.001) was found between increases in RAP and pANP. The administration of an AVP vasopressor antagonist in a similar protocol, and before hypertonic saline infusion, inhibited the increase of MAP, but it did not alter the changes of posM, hematocrit, RAP, nor pANP. These results suggest that changes in the release of ANP during increases in posM and after spontaneous water drinking are predominantly controlled by changes in RAP.(ABSTRACT TRUNCATED AT 250 WORDS)

We examined the influence of hepatic-portal vein infusion of NaCl and of hepatic vagotomy on 3% NaCl solution drinking by sodium-deficient rats. Combined dietary sodium restriction and administration of the natriuretic agent, furosemide (5 mg), produced a vigorous appetite for 3% NaCl solution that was attenuated by portal infusion of NaCl. Whereas infusions (1 ml/30 min) of NaCl into the hepatic-portal vein in concentrations as low as 0.15 M (isotonic) significantly reduced 3% NaCl consumption, a higher concentration (0.6 M) infused into the jugular vein, or portal infusions of KCl (0.6 M) or sucrose (1.2 M), were ineffective. Rats with selective hepatic vagotomy displayed an attenuated appetite for salt whether or not they received hepatic-portal NaCl. This was not due to altered excretion of sodium. Taken together, these results suggest that the liver or portal vein can provide a sodium-specific neural signal capable of attenuating the appetite for salt and this information is transferred to the brain by fibers in the hepatic vagus that fire in reciprocal relationship with portal sodium concentration.

Experiments were conducted in the freshwater turtle, Pseudemys scripta, to study the effect of autonomic agents on the control of renin in this primitive species. The unique finding in these studies was that, unlike mammals, isoproterenol infusion fails to increase renin activity even though heart rate and arterial pressure patterns indicated that systemic responses were similar to that in mammals. On the other hand, acetylcholine (ACh) infusion resulted in a prompt threefold elevation (P less than 0.01) of renin activity. This response was blocked by propranolol but not atropine. Other experiments demonstrated that ACh elicited a prompt elevation of circulating norepinephrine and epinephrine in these turtles and led to the hypothesis that the renin response to ACh was secondary to the release of endogenous catecholamines. This hypothesis was supported by the fact that, in reserpinized turtles, ACh failed to elicit the usual renin response. Further evidence stemmed from the fact that epinephrine administration led to a prompt fourfold increase (P less than 0.01) in renin, which could be blocked by propranolol. On the other hand, phenoxybenzamine failed to block the response under identical conditions. Taken as a whole, these data suggest that in this primitive species renin activity is elevated by endogenous catecholamines even though isoproterenol, a classical beta-adrenergic agonist, is without effect. These data illustrate again the need for caution when assuming analogy when comparing responses in primitive species with that of mammals.

The role of insulin and brown adipose tissue (BAT) thermogenesis in metabolic efficiency (ME, the efficiency of body wt gain) was examined in rats with varied basal insulin status. Long-lasting insulin was administered using a protocol that did not alter food intake, yet increased ME in both groups. Half the rats were fed sucrose to stimulate BAT growth and thermogenesis. Insulin overrode the exaggerated decrease in ME in sucrose-fed diabetics, with only partial attenuation in controls. Interscapular BAT (IBAT) lipoprotein lipase activity was decreased in diabetic rats, restored by insulin treatment, and not affected in controls. Sucrose-fed diabetics and controls had their IBAT sham or bilaterally surgically denervated. Insulin decreased the thermogenic potential of BAT [cytochrome oxidase activity (COA)] in intact controls and diabetics; in the latter, insulin restored COA independent of BAT innervation. We conclude that insulin can increase ME without an associated increase in energy intake, regardless of basal insulin status, both insulin deficiency and excess decrease BAT thermogenic potential (COA), and hyperinsulinemia-induced increases in ME may result from decreased BAT mitochondrial proliferation.

The role of insulin in metabolic efficiency (ME, i.e., efficiency of body wt gain) was examined under conditions of maximal energy expenditure in control and diabetic rats. Long-lasting insulin was administered using a protocol that did not affect food intake and increased ME in both groups. Half the animals were injected chronically with norepinephrine (NE). NE alone in controls decreased body weight and ME and increased brown adipose tissue (BAT) growth, thermogenic potential [cytochrome c oxidase activity (COA)], and lipoprotein lipases (LPL) activity; however, in diabetics, body weight, ME, and food intake all decreased and only BAT LPL activity and DNA content increased. The combination of NE and insulin increased BAT protein and COA in diabetics; in controls, all BAT measures were further increased and ME was intermediate to that of either treatment alone. Cold exposure decreased body weight and ME, increased food intake and qualitatively produced similar increases in BAT growth, COA, and LPL activity in both controls and diabetics. In diabetics, combined cold exposure and insulin did not affect the increase in BAT growth or LPL activity resulting from either treatment alone, but in controls this combination decreased BAT growth and COA. It is concluded that, even under conditions of maximal energy expenditure, both extremes of basal insulin status result in decreased BAT growth and thermogenic potential, but have opposite effects on ME.

The shapes and frequencies of spontaneous contractions of circular muscle strips of the human oviduct differ during the menstrual cycles. However, under given conditions, the frequency and amplitude of the contractions were continuously reduced during perfusion with Krebs solution. In the presence of prostaglandin (PG) synthesis inhibitors or an antagonist, a gradual and continuous reduction was no longer observed, and low concentrations (10(-15)-10(-10) M) of PGE2 markedly suppressed the amplitude and frequency of the spontaneous contractions. The highest sensitivity of smooth muscle cells to PGE2 was observed during the periovulatory phases. Spontaneous prepotentials followed by slow waves were observed, and the latter potentials triggered contraction of the tissue. PGE2 (10(-14)-10(-12) M) inhibited, and PGF2 alpha (10(-9)-10(-7) M) enhanced the frequency of these slow waves. The amount of PGE series released from the tissues was twice of PGF series. These results suggest that endogenous prostaglandins play a physiological role in the transport of ovum in the human fallopian tube as a result of the regulation of spontaneous membrane and mechanical activities.

The accuracy and precision of the doubly labeled water method for measuring energy expenditure are influenced by isotope fractionation during evaporative water loss and CO2 excretion. To characterize in vivo isotope fractionation, we collected and isotopically analyzed physiological fluids and gases. Breath and transcutaneous water vapor were isotopically fractionated. The degree of fractionation indicated that the former was fractionated under equilibrium control at 37 degrees C, and the latter was kinetically fractionated. Sweat and urine were unfractionated. By use of isotopic balance models, the fraction of water lost via fractionating routes was estimated from the isotopic abundances of body water, local drinking water, and dietary solids. Fractionated water loss averaged 23% (SD = 10%) of water turnover, which agreed with our previous estimates based on metabolic rate, but there was a systematic difference between the results based on O2 and hydrogen. Corrections for isotopic fractionation of water lost in breath and (nonsweat) transcutaneous loss should be made when using labeled water to measure water turnover or CO2 production.

Myoglobin, an intracellular O2-binding protein, plays a protective role in maintaining performance of isolated fish hearts under hypoxic conditions. This study was designed to test the hypothesis that the protein contributes to O2 consumption under conditions of increased O2 demand or hypoxia. Isolated myoglobin-rich sea raven (Hemitripterus americanus) hearts and myoglobin-poor ocean pout (Macrozoarces americanus) hearts were perfused under conditions of changing partial pressure of O2 (PO2) and afterload. Sea raven hearts maintained O2 consumption and cardiac performance at low PO2 and high afterload, whereas ocean pout hearts did not. In other cases sea raven and ocean pout hearts were treated with hydroxylamine, which renders myoglobin incapable of binding O2, and subjected to changing PO2 and afterload. Sea raven hearts could not maintain O2 consumption and cardiac performance, whereas hydroxylamine treatment had no effect on O2 consumption in ocean pout hearts under these conditions. These data provide the first evidence to support the concept that myoglobin plays a role in O2 consumption of hearts.

Previous studies have shown that adrenodemedullation has no effect on the rate of liver glycogenolysis during exercise in male rats. Mature female rats have been reported to have a higher hepatic beta-adrenergic receptor activity than do male rats of the same age. The present study was undertaken to determine the role of plasma epinephrine in stimulating liver glycogenolysis during exercise in female rats. Both male and female rats were adrenodemedullated or sham operated. Three weeks later rats were run for 60 min at 21 m/min up a 15% grade. The rate of liver glycogenolysis during exercise was not affected by adrenodemedullation in either female rats or male rats. Hepatic adenosine 3',5'-cyclic monophosphate increased to approximately the same extent in sham operated as in adrenodemedullated female rats during exercise. Adrenodemedullation caused a significant reduction in the amount of glycogen utilized by the soleus muscle and in the degree of hyperglycemia during exercise. We conclude that epinephrine is unessential for stimulation of liver glycogenolysis during exercise in either male or female rats.

Circadian responses to photoperiod were studied in house sparrows (Passer domesticus) by subjecting them to 4-h light pulses and measuring the subsequent phases of their circadian rhythms. The direction and magnitude of phase shifts in response to 4-h light pulses following pretreatment with light-dark cycles (LD) 16:8 or LD 8:16 varied with time of day; advances (3.4 h) occurred when pulses were imposed in the late subjective night on both groups of birds; delays (-2.1 h) occurred when the pulses were imposed in the early subjective night on the LD 8:16 birds. The time profiles for responses to light pulses that scanned 24 h (phase-response curves) were modified by long and short photoperiod. Short photoperiod 1) increased amplitude (1.7 h), 2) increased time from the prior lights-out to the peak of advances (6 h), and 3) decreased the mean phase shift (0.9 h).

The present study was undertaken to determine the regional hemodynamic basis for increased mean arterial pressure (MAP) variability produced by sinoaortic baroreceptor denervation (SAD) in the conscious rat. Sinoaortic-denervated and intact rats were instrumented chronically with a catheter placed in the femoral artery and pulsed-Doppler flow probes positioned on the renal and superior mesenteric arteries and the lower abdominal aorta to determine MAP, heart rate, and regional vascular resistance. Each cardiovascular variable was sampled once per minute during a 1-h recording period. Compared with control animals, baroreceptor-denervated animals exhibited greater variability of MAP and mesenteric, renal, and hindquarter resistances 7–9 days after SAD. The variability of heart rate was similar when animals from the two groups were compared. The pattern of significant correlation for the relationship of MAP to vascular resistance in the different beds was not consistent for individual SAD and intact animals. Finally, a wider distribution of mean values was observed for the individuals within the SAD group for MAP, heart rate, and hindquarter and renal vascular resistances. We conclude that SAD produces greater fluctuation of vascular resistance in several beds which contributes to the increased lability of MAP; however, there is no predictable pattern of vascular resistance lability which underlies the variability of arterial pressure.

The dipsogenic responsiveness to isoproterenol was studied in food-deprived male rats. Unstimulated water intake was similar between control and fasted groups, and parallel dose-response curves for the dipsogenic response induced by isoproterenol (10–50 micrograms/kg) were observed. A twofold elevation in dipsogenic responsiveness was observed in the fasted rats, and this enhanced response was correlated with a dose-dependent increase in plasma renin activity when compared with the control rats after administration of isoproterenol. beta-Adrenergic receptor binding assays were performed on both heart and renal cortical tissues. In the heart the receptor concentration was decreased after food deprivation, whereas the affinity of the receptor for the beta-adrenergic antagonist [125I]CYP remained unchanged. On the other hand, an increased beta-adrenergic receptor concentration without change in affinity was found in renal cortices of fasted rats. Results from these receptor binding studies correlated with the attenuated chronotrophic response and the increased dipsogenic response to beta-adrenergic stimulation in the fasted rat. Therefore stimulation of these increased renal receptors by isoproterenol could result in an enhanced activation of the renin-angiotensin system and thus be a factor responsible for the increased dipsogenic response induced by isoproterenol observed in the fasted rats.

The volume-evoked micturition reflex (VEMR) and the effects of anesthetics on the VEMR were studied in a chronic unanesthetized rat model. The bladder catheter was implanted chronically through a laparotomy and externalized percutaneously. An intrathecal (IT) catheter was implanted chronically in animals scheduled for an IT injection. By 2 days after implantation, infusion of saline (200 microliter/min) in the bladder reliably resulted in a low base-line pressure (BP) followed by a transient increase in bladder pressure, an opening of the sphincter (bladder opening pressure, BOP) corresponding to expression of urine (volume of urination, V), then a further rise in pressure (peak pressure, PP) and a subsequent return to base line. Seven days after implantation, values (means +/- SE) for BP, BOP, PP, and V were 10 +/- 0.3, 30 +/- 2, 67 +/- 6 cmH2O, and 1.0 +/- 0.1 ml, respectively. Residual volumes were reliably less than 2-4% of the expressed volume. The VEMR was reliably evoked up to 28 days after implantation. V values in unimplanted and implanted animals were not different. In implanted animals, VEMR parameters were not different during infusion or during spontaneous urination after oral fluid load. Administration of pentobarbital sodium (50 mg/kg ip), alpha-chloralose (130 mg/kg ip), ketamine (100 mg/kg im), halothane (in air 2%), and local anesthetics (2-chloroprocaine 3% or bupivacaine 0.75%, 10 microliter IT) produced a complete blockade of the VEMR and overflow incontinence at pressures significantly higher than BOP values. To compare overflow pressures and passive compliance of the bladder, unanesthetized animals were decapitated.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain volume is regulated during acute hypernatremia in the little skate, Raja erinacea, based on the gain of osmolytes, including sodium, chloride, and potassium [Cserr et al., Am. J. Physiol. 245 (Regulatory Integrative Comp. Physiol. 14): R853-R859, 1983]. In this study we show that this volume regulatory response is complete in 35 min and examine the mechanism of sodium influx across the blood-brain barrier over this period. Skates have a glial blood-brain barrier. Blood-to-brain transfer constants (K1) for 22Na and [14C]mannitol were measured using the integral technique of [Ohno et al.Am. J. Physiol. 235 (Heart Circ. Physiol. 4): H299-H307, 1978]. In skates injected intramuscularly with isotonic saline (controls) or with hypertonic NaCl or fructose, K1 for sodium increased linearly with osmolality. This increase was the same for hypernatremia and fructose-induced hypertonicity, and it was not affected by the “loop” diuretic bumetanide. K1 for mannitol also increased with osmolality. These results suggest that hypertonicity increases barrier permeability by a nonselective mechanism. The contribution of influx across the blood-brain barrier to tissue sodium gain during acute hypernatremia is assessed using a diffusional model of plasma-brain exchange.

Potentiated adrenal responses to the second of two identical hemorrhages spaced 24 h apart are seen in the pentobarbital sodium-anesthetized dog. Although pentobarbital effectively reduces environmental influences, barbiturates affect hemodynamic and hormonal responses and preclude normal daily feeding and activity patterns. To determine the role of anesthesia in these earlier results, we prepared awake trained dogs with chronic adrenal venous catheters. Animals were bled 8.7-21.8% of measured blood volume [131] over 3 min, and peripheral and adrenal blood was sampled. Blood was reinfused 1 h later, and the dogs were fed. The protocol was repeated 24 h later. Dogs with small hemorrhage (11.6 +/- 2.3% blood vol; n = 9) showed no difference in catecholamine secretion on the 2 days. Dogs with large hemorrhage (18.9 +/- 2.1% blood vol; n = 9) showed a greater epinephrine and norepinephrine secretory response to hemorrhage on day 2. No differences were detected in the hemodynamic response to bleeding on the 2 days. Whereas potentiation was seen in epinephrine and norepinephrine responses to a second 10% hemorrhage in anesthetized dogs, larger hemorrhage was needed to elicit this effect in awake dogs. Thus potential adrenal medullary responses to repeated hemorrhage occur in both awake and pentobarbital-anesthetized dogs, but important differences in the threshold and manifestation of this effect are seen.

Potentiated pituitary-adrenocortical responses to the second of two identical small hemorrhages, spaced 24 h apart, are seen in the pentobarbital sodium-anesthetized dog. To investigate the role of pentobarbital anesthesia in these results and to better define the range of the effect, we studied awake trained dogs with chronic adrenal venous catheters. Each dog was bled an amount between 8.7 and 21.8% of measured blood volume [131I] (MBV) over 3 min, and peripheral and adrenal blood were sampled. Blood was reinfused 1 h later, and the dogs were fed. The same hemorrhage and experimental protocol were repeated 24 h later. Steroids were assayed by high-performance liquid chromatography-ultraviolet (HPLC-UV) and adrenocorticotropic hormone (ACTH) by radioimmunoassay (RIA). Secretory rates of cortisol were calculated using measured adrenal blood flow rates. Maximal secretion of cortisol was determined after injection of 100 mU ACTH following each experiment. Dogs whose day 1 cortisol secretion after hemorrhage was submaximal (hem volume = 14.8 +/- 3.7% MBV; n = 7) showed a greater cortisol secretory response to the same hemorrhage on day 2 (P less than 0.005). This increased cortisol response on day 2 was accompanied by an increased ACTH presentation rate (APR) (P less than 0.025) and by increased adrenal sensitivity to ACTH (P less than 0.025). The increased APR was caused by both an increased venous ACTH and by an increased adrenal blood flow. If posthemorrhage cortisol secretion was maximal on day 1, ACTH, APR, and ABF were not different on the 2 days. No hemodynamic differences were seen to explain these findings. These results confirm and extend our previous results.(ABSTRACT TRUNCATED AT 250 WORDS)

When male Golden hamsters are maintained on short days (less than 12.5 h of light/day) the testes gradually regress. This testicular regression is due to an inhibitory effect of pineal gland melatonin on gonadotropin secretion. A previous report from the author's laboratory has indicated that olfactory bulbectomy (BX) will prevent the testicular regression associated with short photoperiod. The present study examined whether BX would also prevent the testicular regression associated with exogenous melatonin (MEL) injections. Male Golden hamsters were BX or sham (SH) BX at 23–28 days of age and were maintained on 14:10 light-dark cycle. Six weeks following surgery, one half of each surgical group began receiving injections of melatonin (15 micrograms sc), whereas the other half was injected with vehicle at 1600 daily. The testes size of the SH group injected with MEL progressively decreased, whereas the testes of all other groups remained large. These results indicate that BX prevents the testicular regression associated with short photoperiod by interfering with the antigonadotropic effect of melatonin.

A mathematical model describing the kinetics of binding and release of substances by plasma proteins is presented. The effects of protein binding on the uptake of substances such as drugs from the capillary network of the brain are discussed. The model assumes equilibration between bound and free forms of drug in arterial blood and incorporates the on-off rate constants for the drug-protein complex and rate constants for passage of free drug across the blood-brain barrier and for drug metabolism in the brain. Regional cerebral blood flow and the related capillary transit time are important parameters in the model. Analytical expressions for bound and free drug concentrations and for the net extraction of drug are derived where practicable, and numerical solutions also are presented. Effects of changes in the total drug and protein concentrations in the plasma are discussed with special reference to the uptake of bilirubin by the brain.

Lesions in the ventromedial hypothalamus (VMH) uniformly produced obesity, but lesions in the paraventricular nucleus (PVN) produced obesity in only half of the animals. The obesity in the PVN-lesioned animals was related to the extent of PVN damage and was attenuated by concurrent damage to the dorsomedial nucleus. Comparing the PVN-lesioned rats that became obese with the VMH-lesioned rats that showed comparable weight gain, revealed several differences. The nocturnal intake of food in rats eating ad libitum was lower in the VMH-lesioned rats. Glucose concentrations were also lower in the VMH-lesioned rats, whether eating ad libitum or pair fed. Insulin concentrations were higher in the fatter animals fed ad libitum regardless of the location of the lesion. After pair feeding the insulin values were lower in both VMH- and PVN-lesioned rats than in controls. The diurnal excursion of corticosterone was blunted by both hypothalamic lesions in rats fed ad libitum, but after pair feeding there was less distortion of the diurnal rhythm. These data show that the characteristics of obesity produced by PVN lesions differ from those resulting from VMH damage.

The ionic compensatory response to CO2 breathing for 3 days was studied on intact and cystectomized turtles at 10 and 20 degrees C. Arterial blood gases, pH, ionized calcium, and the plasma concentrations of Na+, K+, Cl-, total Ca2+, and total Mg2+ were measured periodically. At 20 degrees C, ureteral urine was also collected from bladderless turtles and was analyzed for pH, ions, NH3+, total CO2, osmolality, and titratable acid. When CO2 was breathed there was a compensatory change in the strong-ion difference as manifest by an increase in plasma [HCO3-] that was approximately 10 meq/l both in the 10 and 20 degrees C turtles. The only significant associated strong-ion changes observed consistent with the ionic compensatory response were increases in total and ionized Ca2+ and total Mg2+. These results were unaffected at either temperature by surgical removal of the urinary bladder. Urine collected from cystectomized turtles showed no compensatory increase in acid excretion during hypercapnia; in fact, changes occurred in the opposite direction. Urinary excretion of HCO3- and urine pH increased significantly, whereas titratable acidity decreased significantly. No significant change occurred in ammonia excretion over the three days of hypercapnia. These data argue against compensatory roles for the kidneys and urinary bladder in this species and point to internal ionic exchanges involving bone and shell.

We recently reported that ovine corticotropin releasing factor (CRF) infusion in conscious dogs elevated plasma vasopressin. The present study examines the vasopressin, adrenocorticotropic hormone (ACTH), and cortisol responses to CRF infusion (20 ng X kg-1 X min-1), to hypertonic saline infusion (NaCl 0.054 meq X kg-1 X min-1), and to simultaneous coinfusion of CRF and NaCl (CRF + NaCl) without (no-dex) or with (dex-treated) dexamethasone pretreatment in six conscious dogs (6-8 experiments/dog). CRF had no significant effect on plasma sodium or osmolality, blood pressure, or heart rate. NaCl increased plasma sodium from 146 +/- 1 to 151 +/- 1 meq/l and plasma osmolality from 298 +/- 3 to 305 +/- 3 mosmol/kg. Vasopressin increased significantly during CRF (2.1 +/- 0.5 to 4.8 +/- 1.1 pg/ml) and NaCl (1.9 +/- 0.3 to 5.0 +/- 0.8 pg/ml). Coinfusion of CRF and NaCl resulted in a response larger than the sum of the two infusions alone (3.0 +/- 1.6 to 31.4 +/- 18.5 pg/ml). The ACTH response to CRF (45 +/- 8 to 288 +/- 88 pg/ml) was not augmented by coinfusion with NaCl. DEX attenuated the vasopressin and ACTH responses to each infusion. We conclude that CRF-induced increases in vasopressin are augmented by a simultaneous osmotic stimulus. In addition, the plasma vasopressin responses to CRF and/or hypertonic saline infusion are inhibited by glucocorticoid pretreatment.

Page R178: Gary O. Zerbe, Philip G. Archer, Natalio Banchero, and Andrew J. Lechner. “On comparing regression lines with unequal slopes.” Page R179: first column, the paragraph after Equation 7 should read Case II. If A < 0 and D > 0, then the tests will be significant for X's satisfying (See PDF)

Page R783: Gloria D. Massaro and Donald Massaro. “Development of bronchiolar epithelium in rats.” Pages R785–R786: the values for the nuclear numerical density in Fig. 1 and Tables 1 and 2 of the original article should be multiplied by 4. The error does not effect in any way the statistical calculations or the conclusions. Corrected Fig. 1 and Tables 1 and 2 should be substituted. (See PDF)

Page 192: Michael E. Tordoff and Mark I. Friedman. “Hepatic portal glucose infusions decrease food intake and increase food preference.” Page R195: first paragraph, the first four sentences should read In addition to the theoretical implications of these results, several practical implications are apparent. The data suggest that repeated tests of the same subject must be interpreted with caution, because the response during later tests may well be determined by previous infusions. It is interesting to note in this regard that several previous studies finding no change in feeding after hepatic portal glucose infusion have used daily tests according to counterbalanced designs (Refs. 2, 13, and 17–20 and perhaps Refs. 26, 27, and 29).