Evidence for antipyretic vasopressinergic pathways and their modulation by noradrenergic afferents.

The experimental evidence for the antipyretic action of arginine vasopressin (AVP) in guinea-pigs can be summarized as follows: The febrile response to a bacterial pyrogen can be reduced by a microinfusions of exogenous AVP into the ventral septal area of the limbic system. Immunohistochemical studies indicate increased activity of AVP terminals in the ventral septal area (VSA) and in parvocellular AVP neurones of the hypothalamic paraventricular nucleus (PVN) in several stressful situations accompanied by reduced febrile responses (late stage of pregnancy, immobilization, cold adaptation, osmotic stimulation). Also the peripheral and/or central release of AVP measured in some of these situations is increased. Electrical stimulation of the PVN suppresses fever, this suppression can, at least partly, be cancelled by simultaneous intraseptal application of the vasopressinergic V1 receptor antagonist. The documented AVP pathways from the PVN to the septum receive noradrenergic afferents from the lower brainstem. Chronic destruction of these afferents by microinjections of 6-hydroxydopamine (6-OHDA) significantly reduced the fever responses to pyrogen application, while microinfusion of noradrenaline (NA) enhances the fever reaction.     

Intracerebroventricular and septal injections of arginine vasopressin are not antipyretic in the rabbit

Arginine vasopressin (AVP) has been reported to have an antipyretic effect in the ewe and guinea pig near term. Perfusions with AVP of sites in the septal region also reduced fever in non-pregnant sheep. In the present experiments adult rabbits with third cerebral ventricular or septal cannulas were restrained in a 23°C environment, and rectal temperature was recorded every 10 min. Fever induced by IV administration of leukocytic pyrogen was not reduced by AVP (25–100 ng) given intraventricularly 20 min later. Doses of 1–5 μg AVP injected into the septum likewise were not antipyretic but actually caused an increase in fever. This augmentation of the febrile response is consistent with results of previous studies in this laboratory in which AVP increased hyperthermia in a hot environment and enhanced hyperthermic responses to PGE₂. The data from these experiments provide no evidence that central AVP is an endogenous antipyretic in rabbits; rather, it may be that central AVP augments fever in this species.     

家兔发热时脑脊液和血浆中精氨酸加压素含量的变化及禁水的抗热作用

本实验观察了发热家兔脑脊液(CSF)和血浆中精氨酸加压素(AVP)含量的变化及禁水对家兔内毒素(ET)发热效应的影响。实验结果表明:1.隔区注射AVP可明显抑制家兔ET性发热效应;2.发热组家兔CSF和血浆中AVP含量较正常组明显降低;3.禁水可明显对抗家兔ET性发热效应,其抗热作用与CSF和血浆中AVP含量升高有关;4.禁水也可使正常家兔体温水平下移。上述实验结果提示,AVP可能是家兔体内一种内源性退热物质,同时在正常体温调节中也可能发挥一定的作用。     

Central arginine vasopressin and endogenous antipyresis.

Arginine vasopressin (AVP) is a centrally synthesized nonapeptide that exerts classical endocrine effects as well as a host of centrally mediated actions. A strong case can be argued in support of a neurotransmitter-neuromodulator role for AVP. Acting within the central nervous system (CNS), AVP has been demonstrated to be involved in the modulation of febrile body temperature. Because AVP acts to reduce pyrogen-induced fevers, but not normal body temperature, its actions are deemed to be antipyretic. However, to demonstrate an endogenous antipyretic function, AVP must be shown to be active during conditions where fever is naturally suppressed. This review will focus on five such conditions where the absence of pyrogen-induced fever can be linked to the endogenous activity of AVP within the brain. In the neonatal rat pup, the use of specific antagonists to the AVP receptor has revealed a role for CNS AVP in the absence of fever following peripheral injections of bacterial endotoxin. These results may help to explain a similar lack of fever in other newborn species. In parturient animals a reduced or absent febrile response has been linked to the increased presence of AVP within the septal area of the brain. The combined use of AVP receptor antagonism as well as immunohistochemistry has shown enhanced AVP activity within the ventral septal area of the rat and guinea pig brain during tolerance to intravenous pyrogens. These results suggest that the mechanism of fever suppression following repeated systemic injections of bacterial pyrogen includes centrally acting AVP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of electrical stimulation of ventral septal area on firing rates of pyrogen-treated thermosensitive neurons in preoptic anterior hypothalamus from rabbits

Although there is considerable evidence supporting that fever evolved as a host defense response, it is important that the rise in body temperature would not be too high. Many endogenous cryogens or antipyretics that limit the rise in body temperature have been identified. Endogenous antipyretics attenuate fever by influencing the thermoregulatory neurons in the preoptic anterior hypothalamus (POAH) and in adjacent septal areas including ventral septal area (VSA). Our previous study showed that intracerebroventricular (I.C.V.) injection of interleukin-1beta (IL-1beta) affected electrophysiological activities of thermosensitive neurons in VSA regions, and electrical stimulation of POAH reversed the effect of IL-1beta. To further investigate the functional electrophysiological connection between POAH and VSA and its mechanisms in thermoregulation, the firing rates of thermosensitive neurons in POAH of forty-seven unit discharge were recorded by using extracellular microelectrode technique in New Zealand white rabbits. Our results show that the firing rates of the warm-sensitive neurons decreased significantly and those of the cold-sensitive neurons increased in POAH when the pyrogen (IL-1beta) was injected I.C.V. The effects of IL-1beta on firing rates in thermosensitive neurons of POAH were reversed by electrical stimulation of VSA. An arginine vasopressin (AVP) V1 antagonist abolished the regulatory effects of VSA on the firing rates in thermosensitive neurons of POAH evoked by IL-1beta. However, an AVP V2 antagonist had no effects. These data indicated that VSA regulates the activities of the thermosensitive neurons of POAH through AVP V1 but not AVP V2 receptor.     

Evidence for a contribution by brown adipose tissue to the development of fever in the young rabbit

This study was undertaken to determine if brown adipose tissue was involved in heat production during fever produced by S. abortus equi (1 micrograms) in unanesthetized rabbits aged 19-26 days. The fever (0.9-1.6 degrees C) occurred after a delay of 20-30 min and was frequently biphasic. Radiolabelled microspheres for measuring tissue blood flow were injected intraventricularly into three groups of animals: rabbits not given pyrogen, rabbits in which the febrile response to pyrogen was developing, and rabbits in which the febrile response had peaked. Blood flow to brown fat deposits and other organs was calculated from the fractional distribution of the microspheres and the recovery of microspheres in a reference arterial blood sample. At the fever peak, blood flow to brown fat was not significantly different (p greater than 0.05) from the control value (0.9 +/- 0.2), but during the rising phase of the fever the flow increased significantly (p less than 0.01) to 2.6 +/- 0.4 mL min-1 g-1. The blood flow to muscles of the forelimbs and hind limbs was also increased significantly (p less than 0.05) during the rising phase of the fever. No significant change in blood flow to other organs or tissues was found during the rising phase of the fever. These results indicate that both nonshivering as well as shivering thermogenesis contribute to heat production during development of fever in the young rabbit. However, nonshivering thermogenesis was not involved in the maintenance of the elevated body temperature after the fever had peaked.     

Vasopressin and fever: evidence supporting the existence of an endogenous antipyretic system in the brain

Vasopressin administered into the ventral septum exerts a dose-related antipyresis. This site of action is similar in a number of species. The fever-reducing properties of vasopressin are both site and neuropeptide specific. Evidence supporting a role for endogenous vasopressin in fever suppression is the demonstration that the release of the peptide from the ventral septal area is altered during fever: the amount released correlates negatively with febrile changes in body temperature. In addition, changes in the concentration of vasopressin in the septum and amygdala have been demonstrated immunocytochemically during fever: an activation of vasopressinergic neurons occurs which is similar to that observed in pregnant animals at term when fever is absent. Specific antibodies directed against vasopressin or specific vasopressin antagonist analogues (e.g., d(CH2)5Tyr(Me)AVP) enhanced the febrile response to a pyrogen challenge when injected into the ventral septum. The same antagonist also can antagonize the antipyretic effect of exogenously administered vasopressin. The use of relatively specific antagonists and agonists of vasopressin, directed against the V1 and V2 subtypes of the peripheral vasopressin receptor, suggests that the central receptor responsible for the antipyretic effect of vasopressin may resemble the V1 subtype. Recent experiments using electrophysiological techniques have demonstrated the existence of thermoresponsive units in the ventral septal area whose activity may be altered by vasopressin which is possibly derived from the paraventricular nucleus and bed nucleus of the stria terminalis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pre-existing bacterial infections, not stress fever, influenced previous studies which labeled Gerrhosaurus major an afebrile lizard species

Early studies indicated that the Sudan plated lizard, Gerrhosaurus major, did not exhibit a febrile response when challenged with bacterial pyrogen. More recent results indicated that a 14-day antibiotic treatment regime produced a significant decrease (0.5 +/- 0.1 degree C) in the mean selected body temperature (MSBT) for this species (31.3 +/- 0.2-30.8 +/- 0.2 degrees C). The antibiotic treatment results suggested that G. major already had a fever caused by a pre-existing bacterial infection. The current study was designed first to determine if a sub-population of G. major, with a higher mean pre-antibiotic treatment MSBT would exhibit a greater decrease in MSBT after antibiotic treatment. A 14-day antibiotic treatment regime for G. major (N = 7) with MSBTs > or = 31.9 degrees C (mean 32.4 +/- 0.2 degrees C) produced a significant decrease of 1.7 +/- 0.4 degrees C in MSBT to 30.7 +/- 0.3 degrees C. Analysis of the combined antibiotic treatment MSBT data from [13] and the current study demonstrated that the magnitude of the change in MSBT after antibiotic treatment was dependent upon the pre-antibiotic treatment MSBT. These data imply that animals with a greater pre-treatment MSBT and greater MSBT change had a greater magnitude fever. In the second portion of this study the MSBT for individual lizards was measured during separate experiments using both indwelling cloacal thermocouples taped to the tail of the lizard and telemeters implanted into the peritoneal cavity of the lizard. This second study was designed to determine if measurement of Tb using thermocouples induced a stress fever which may have masked a portion of the pyrogen-induced fever. The MSBT measured using indwelling cloacal thermocouples (30.5 +/- 0.3 degrees C) was not significantly greater (T > 0.05) than the MSBT increased using telemeters (31.0 +/- 0.2 degrees C). The results of the experiments from this study demonstrate that the previously reported afebrile state for G. major was the result of animals having pre-existing bacterial infections. G. major does exhibit a febrile response similar to other lizard species.     

The fever reaction of the polecat Mustela putorius x Mustela putorius furo to a bacterial pyrogen: the hypo- and hyperthermic phases]

It has been demonstrated that the ferret (Mustela putorius x Mustela putorius furo) responds to intramuscular injection of Salmonella typhi lipopolysaccharide (30 ng/kg-100 micrograms/kg) by biphasic change in the body temperature (Tb): the initial decrease in the latter is followed by hyperthermia. Maximum rise in Tb (1.6 +/- 0.1 degrees C) was observed after the injection of lipopolysaccharide in the highest dose. Rabbit leucocytic pyrogen/interleukin-1 (1 ml from 3.5 x 10(7) peritoneal phagocytes, 3 ml/kg) induces a pronounced (1.1 +/- 0.3 degrees C) decrease in Tb. Mechanisms of hypothermic effects of pyrogens are discussed. The described pattern (hypothermia-hyperthermia) of Tb response to lipopolysaccharide in the ferret presumably reflects the central thermoregulatory process which is the same for different changes in Tb during fever.     

Subcellular Localization and Characterization of Vasopressin Binding Sites in the Ventral Septal Area, Lateral Septum, and Hippocampus of the Rat Brain

[Arg8]-Vasopressin (AVP) has been shown to exert characteristic central physiological actions in the ventral septal area of the rat brain. This study reports the characterization of receptors for AVP in synaptic plasma membranes prepared from the ventral septal area, the lateral septum, and the hippocampus. Binding of [3H]AVP was temperature and time dependent, linearly related to protein concentration, saturable, and specific. Scatchard plot analysis suggested the presence of a population of binding sites in the three brain areas with dissociation constants and maximal binding capacities, respectively, of 1.06 +/- 0.39 nM and 24.0 +/- 7.01 fmol/mg of protein (mean +/- SEM; n = 3 for the ventral septal area, 0.92 +/- 0.13 nM and 47.0 +/- 4.96 fmol/mg of protein (n = 3) for the lateral septum, and 0.91 +/- 0.14 nM and 25 +/- 5.02 fmol/mg of protein (n = 3) for the hippocampus. In all three brain regions, the rank order of potencies of several vasopressin analogs, unrelated peptides, and other compounds for competitive displacement of ligand indicated a receptor with properties resembling those of the V1-like receptor for AVP. These data document the presence of a high-affinity, V1-like vasopressin receptor in the rat ventral septal area for which the pharmacological properties are similar to those previously reported in physiological studies.     

A study of the variability in the febrile responses of rabbits to endogenous pyrogen

The range of body temperature increases elicited by a standard dose of endogenous pyrogen (0.5 ml/kg iv) was examined in a population of 26 male New Zealand White rabbits. Although the mean maximum increase in rectal temperature was 0.88 +/- 0.06 degree C (SE), individual responses varied from 0.4 degree to 1.5 degree C. Three representative animals that responded to the standard dose of pyrogen with small, intermediate, and large febrile responses were selected and challenged with the same dose of pyrogen on eight separate occasions, and the variability of these responses was examined. There was little variability within the characteristic responses of any particular animal to the repeated challenges. The variability of the febrile responses elicited by both intravenous and intracerebroventricular administration of the same pyrogen was examined and compared using another group of 11 rabbits. The variability in response to the intravenous route was similar to that found in the larger population, whereas the variation in response to the intracerebroventricular route was smaller, and all 11 animals had fevers that were greater than 1 degrees C. It is concluded that the variability of the febrile responses of rabbits to intravenous pyrogen was due to differences between individual sensitivities of animals to the intravenously administered pyrogen. This difference in sensitivity may be due to a difference in the amount of pyrogen that reaches the putative receptor sites, or to a difference in the density or effectiveness of receptor sites in translating the pyrogenic stimulus into a fever response.     

中枢精氨酸加压素在大鼠促肾上腺皮质激素释放激素释放激素引起发热机制中的作用

实验对大鼠进行第三脑室和脑腹中隔区插管,用数字体温计测量大鼠的结肠温度,用放射免疫分析法测定脑中隔区精氨酸加压素（arginine vasopressin,AVP）含量,观察脑中隔区AVP在大鼠促肾上腺皮质激素释放激素（corticotrophin releasing hormone,CRH）性发热机制中的作用。结果发现：脑室注射CRH（5.0μg）引起大鼠结肠温度明显升高,同时明显增高脑中隔区AVP的含量。脑腹中隔区注射AVP V1受体拮抗剂本身并不导致大鼠结肠温度明显改变,但能显著增强脑室注射CRH引起的发热反应。而且,腹中隔区注射AVP显著抑制大鼠CRH性发热。结果提示：发热时CRH是引起脑腹中隔区AVP释放的因素之一,脑腹中隔区内源性AVP抑制中枢注射CRH引起的体温升高。     

α-MSH injected into the septal region reduces fever in rabbits

In previous research the concentration of α-MSH within the septal region of rabbits increased with fever. This finding raises the possibility that the septal concentration of this peptide, which reduces fever when given both peripherally and intracerebroventricularly, is important to limitation of fever. To test this idea, rabbits with cannulas in the septal region were made febrile by IV injections of leukocytic pyrogen (LP). Injection of α-MSH (1 μg bilaterally) into the septal region did reduce fever, consistent with the idea that the increase in septal α-MSH concentration which occurs naturally in fever limits the febrile response. We also noted late rises in body temperature when experimental and control septal injections were given close together in time. These increases in temperature were similar to those known to occur after injections into the primary temperature control in the PO/AH region. This commonality further strengthens the possibility that septal neurons are important to central modulation of body temperature.     

Plasma hyperosmolality augments peripheral vascular response to baroreceptor unloading during heat stress

The aim of this study was to elucidate the interactive effect of central hypovolemia and plasma hyperosmolality on regulation of peripheral vascular response and AVP secretion during heat stress. Seven male subjects were infused with either isotonic (0.9%; NOSM) or hypertonic (3.0%; HOSM) NaCl solution and then heated by perfusing 42 degrees C (heat stress; HT) or 34.5 degrees C water (normothermia; NT) through water perfusion suits. Sixty minutes later, subjects were exposed to progressive lower body negative pressure (LBNP) to -40 mmHg. Plasma osmolality (P(osmol)) increased by approximately 11 mosmol/kgH(2)O in HOSM conditions. The increase in esophageal temperature before LBNP was much larger in HT-HOSM (0.90 +/- 0.09 degrees C) than in HT-NOSM (0.30 +/- 0.07 degrees C) (P < 0.01) because of osmotic inhibition of thermoregulation. During LBNP, mean arterial pressure was well maintained, and changes in thoracic impedance and stroke volume were similar in all conditions. Forearm vascular conductance (FVC) before application of LBNP was higher in HT than in NT conditions (P < 0.001) and was not influenced by P(osmol) within the thermal conditions. The reduction in FVC at -40 mmHg in HT-HOSM (-9.99 +/- 0.96 units; 58.8 +/- 4.1%) was significantly larger than in HT-NOSM (-6.02 +/- 1.23 units; 44.7 +/- 8.1%) (P < 0.05), whereas the FVC response was not different between NT-NOSM and NT-HOSM. Plasma AVP response to LBNP did not interact with P(osmol) in either NT or HT conditions. These data indicate that there apparently exists an interactive effect of P(osmol) and central hypovolemia on the peripheral vascular response during heat stress, or peripheral vasodilated conditions, but not in normothermia.     

Augmentation of the push-pull effect by terminal aortic occlusion during head-down tilt.

Tolerance to positive vertical acceleration (Gz) gravitational stress is reduced when positive Gz stress is preceded by exposure to hypogravity, which is called the "push-pull effect." The purpose of this study was to test the hypothesis that baroreceptor reflexes contribute to the push-pull effect by augmenting the magnitude of simulated hypogravity and thereby augmenting the stimulus to the baroreceptors. We used eye-level blood pressure as a measure of the effectiveness of the blood pressure regulatory systems. The approach was to augment the magnitude of the carotid hypertension (and the hindbody hypotension) when hypogravity was simulated by head-down tilt by mechanically occluding the terminal aorta and the inferior vena cava. Sixteen anesthetized Sprague-Dawley rats were instrumented with a carotid artery catheter and a pneumatic vascular occluder cuff surrounding the terminal aorta and inferior vena cava. Animals were restrained and subjected to a control gravitational (G) profile that consisted of rotation from 0 Gz to 90 degrees head-up tilt (+1 Gz) for 10 s and a push-pull G profile consisting of rotation from 0 Gz to 90 degrees head-down tilt (-1 Gz) for 2 s immediately preceding 10 s of +1 Gz stress. An augmented push-pull G profile consisted of terminal aortic vascular occlusion during 2 s of head-down tilt followed by 10 s of +1 Gz stress. After the onset of head-up tilt, the magnitude of the fall in eye-level blood pressure from baseline was -20 +/- 1.3, -23 +/- 0.7, and -28 +/- 1.6 mmHg for the control, push-pull, and augmented push-pull conditions, respectively, with all three pairwise comparisons achieving statistically significant differences (P < 0.01). Thus augmentation of negative Gz stress with vascular occlusion increased the magnitude of the push-pull effect in anesthetized rats subjected to tilting.     

Hypotensive effect of push-pull gravitational stress occurs after autonomic blockade.

The "push-pull" effect denotes the reduced tolerance to +Gz (hypergravity) when +Gz stress is preceded by exposure to hypogravity, i.e., fractional, zero, or negative Gz. Previous studies have implicated autonomic reflexes as a mechanism contributing to the push-pull effect. The purpose of this study was to test the hypothesis that nonautonomic mechanisms can cause a push-pull effect, by using eye-level blood pressure as a measure of G tolerance. The approach was to impose control (30 s of 30 degrees head-up tilt) and push-pull (30 s of 30 degrees head-up tilt immediately preceded by 10 s of -15 degrees headdown tilt) gravitational stress after administration of hexamethonium (10 mg/kg) to inhibit autonomic ganglionic neurotransmission in four dogs. The animals were chronically instrumented with arterial and venous catheters, an ascending aortic blood flow transducer, ventricular pacing electrodes, and atrioventicular block. The animals were paced at 75 beats/min throughout the experiment. The animals were sedated with acepromazine and lightly restrained in lateral recumbency on a tilt table. After the onset of head-up tilt, the magnitude of the fall in eye-level blood pressure from baseline was -27.6 +/- 2.3 and -37.9 +/- 2.7 mmHg for the control and push-pull trials, respectively (P < 0.05). Cardiac output fell similarly in both conditions. Thus a push-pull effect attributable to a rise in total vascular conductance occurs when autonomic function is inhibited.     

Renal resistance to vasopressin in poorly controlled type 1 diabetes mellitus

To investigate the hypothesis that diabetes induces nephrogenic diabetes insipidus, we studied the urine-concentrating ability in response to vasopressin (AVP) in 12 patients with insulin-dependent diabetes mellitus (IDDM) and 12 nondiabetic controls. Subjects were euglycemic-clamped, and after oral water loading, AVP was infused intravenously for 150 min. AVP induced a greater (P<0.001) rise in urine osmolality in controls (67.6+/-10.7 to 720+/-31.1 mosmol/kg, P<0.001) than in IDDM patients (64.3+/-21.6 to 516.7+/-89.3 mosmol/kg, P<0.001). Urinary aquaporin-2 concentrations after AVP infusion were higher in controls (611.8+/-105.6 fmol/mg creatinine) than in IDDM (462.0+/-94.9 fmol/mg creatinine, P = 0. 003). Maximum urine osmolality in IDDM was inversely related to chronic blood glucose control, as indicated by Hb A(Ic) (r = -0.87, P = 0.002). To test the hypothesis that improved glycemic control could reverse resistance to AVP, 10 IDDM subjects with poor glycemic control (Hb A(Ic) >9%) were studied before (B) and after (A) intensified glycemic control. Maximum urine osmolality in response to AVP increased with improved glycemic control (B, 443.8+/-49.0; A, 640.0+/-137.2 mosmol/kg, P<0.001), and urinary aquaporin-2 concentrations after AVP increased from 112.7 +/-69 to 375+/-280 fmol/mg creatinine (P = 0.006), with improved glycemic control. Poorly controlled IDDM is associated with reversible renal resistance to AVP.     

Peri-OVLT E-series prostaglandins and core temperature do not increase after intravenous IL-1beta in pregnant rats.

Rats have an attenuated febrile response to endogenous pyrogen near the term of pregnancy. Given the fundamental role of E-series prostaglandins (PGEs) in mediating the febrile response to blood-borne endogenous pyrogen, the present experiments were carried out to determine whether PGEs increase in the area surrounding the organum vasculosum laminae terminalis (peri-OVLT) of near-term pregnant (P) rats as in nonpregnant (NP) rats after intravenous (iv) administration of recombinant rat interleukin-1beta (rrIL-1beta). Core temperature was measured by telemetry and peri-OVLT interstitial fluid was sampled in 12 NP and 12 P chronically instrumented, Sprague-Dawley rats by microdialysis for determination of total PGEs by radioimmunoassay. Basal core temperatures were higher in NP compared with P rats (NP 37.9 degrees C +/- 0.5, P 36.9 degrees C +/- 0.4; P < 0.05), but basal peri-OVLT PGEs were similar in both groups (NP 260 +/- 153 pg/ml, P 278 +/- 177 pg/ml; P =not significant). Intravenous administration of rrIL-1beta to NP rats produced a significant increase in core temperature with a latency, magnitude, and duration of 10 min, 0.87 degrees C, and at least 170 min, respectively; peri-OVLT PGEs were increased significantly by 30 min and averaged 270% above basal levels throughout the experiment. In P rats, however, neither core temperature nor peri-OVLT PGEs increased significantly after iv administration of rrIL-1beta. Intravenous administration of vehicle did not significantly alter core temperature or peri-OVLT PGEs in either group of rats. Thus peri-OVLT PGEs do not increase in P rats as they do in NP rats after iv administration of rrIL-1beta. The mechanism of this interesting component of the maternal adaptation to pregnancy, which likely plays a major role in mediating the attenuated febrile response to endogenous pyrogen near the term of pregnancy, warrants further investigation.     

Role of the autonomic nervous system in push-pull gravitational stress in anesthetized rats.

Tolerance to +G(z) stress is reduced by preceding exposure to -G(z) (push-pull effect). The mechanism(s) responsible for this effect are not fully understood, although the arterial baroreceptor reflexes have been implicated. We investigated the integrative response of the autonomic nervous system by studying responses to gravitational stress before and after autonomic function was inhibited by hexamethonium in 10 isoflurane-anesthetized male and female Sprague-Dawley rats. Animals were restrained supine and subjected to two rotations imposed about the x-axis: 1) a control G profile consisting of rotation from 0 G(z) (+1 G(y)) to 90 degrees head-up tilt (+1 G(z)) for 10 s and 2) a push-pull G profile consisting of rotation from 0 G(z) to 90 degrees head-down tilt (-1 G(z)) for 2 s immediately preceding 10 s of +1 G(z) stress. Eight G profiles consisting of equal numbers of control and push-pull trials were imposed by using a counterbalanced design. We found that hexamethonium lowered baseline arterial pressure and abolished the push-pull effect. The lack of a push-pull effect after autonomic blockade persisted when arterial pressure was restored to baseline levels by phenylephrine infusion. Lowering baseline arterial pressure by sodium nitroprusside infusion or by hemorrhage when autonomic function was intact also abolished the push-pull effect. We conclude that intact autonomic function and a normal baseline arterial pressure are needed for expression of the push-pull effect in anesthetized rats subjected to tilting.     

Myogenic origin of the hypotension induced by rapid changes in posture in awake dogs following autonomic blockade

The "push-pull" effect denotes the reduced tolerance to +G(z) (hypergravity) when +G(z) stress is preceded by exposure to hypogravity, i.e., fractional, zero, or negative G(z). The purpose of this study was to test the hypothesis that an exaggerated, myogenically mediated rise in leg vascular conductance contributes to the push-pull effect, using heart level arterial blood pressure as a measure of G tolerance. The approach was to impose control (30 s of 30 degrees head-up tilt) and push-pull (30 s of 30 degrees head-up tilt immediately preceded by 10 s of -15 degrees head-down tilt) gravitational stress after administration of hexamethonium (5 mg/kg) to inhibit autonomic ganglionic neurotransmission in seven dogs. Cardiac output or thigh level arterial pressure (myogenic stimulus) was maintained constant by computer-controlled ventricular pacing. The animals were sedated with acepromazine and lightly restrained in lateral recumbency on a tilt table. Following the onset of head-up tilt, the magnitude of the fall in heart level arterial pressure from baseline was -11.6 +/- 2.9 and -17.1 +/- 2.2 mmHg for the control and push-pull trials, respectively (P < 0.05), when cardiac output was maintained constant. Over 40% of the exaggerated fall in heart level arterial pressure was attributable to an exaggerated rise in hindlimb vascular conductance (P < 0.05). Maintaining thigh level arterial pressure constant abolished the exaggerated rise in hindlimb blood flow. Thus a push-pull effect largely attributable to a myogenically induced rise in leg vascular conductance occurs when autonomic function is inhibited.