Defense reaction alters the response to blood loss in the conscious rabbit.

The interaction of sensory stressors with the cardiovascular response to blood loss has not been studied. The cardiovascular response to a stressor (i.e., the defense reaction) includes increased skeletal muscle blood flow and perhaps a reduction in arterial baroreflex function. Arterial pressure maintenance during blood loss requires baroreflex-mediated skeletal muscle vasoconstriction. Therefore, we hypothesized that the defense reaction would limit arterial pressure maintenance during blood loss. Male, New Zealand White rabbits were chronically prepared with arterial and venous catheters and Doppler flow probes. We removed venous blood in conscious rabbits until mean arterial pressure decreased to <40 mmHg. We repeated the experiment with (air) and without (sham) simultaneous exposure to an air jet stressor. Air resulted in a defense reaction (e.g., mean arterial pressure = 94 +/- 1 and 67 +/- 1 mmHg for air and sham, respectively). Contrary to our hypothesis, air increased the blood loss necessary to produce hypotension (19.3 +/- 0.2 vs. 16.9 +/- 0.2 ml/kg for sham). Air did not reduce skeletal muscle vasoconstriction during normotensive hemorrhage. However, air did enhance renal vasoconstriction (97 +/- 3 and 59 +/- 3% of baseline for sham and air, respectively) during the normotensive phase. Thus the defense reaction did not limit but rather extended defense of arterial pressure during hemorrhage.

Altered central nervous system processing of baroreceptor input following hindlimb unloading in rats.

The effect of cardiovascular deconditioning on central nervous system processing of baroreceptor afferent activity was evaluated following 14 days of hindlimb unloading (HU). Inactin-anesthetized rats were instrumented with catheters, renal sympathetic nerve electrodes, and aortic depressor nerve electrodes for measurement of mean arterial pressure, heart rate, renal sympathetic nerve activity (RSNA), and aortic depressor nerve activity (ADNA). Baroreceptor and baroreflex functions were assessed during infusion of phenylephrine and sodium nitroprusside. Central processing of baroreceptor afferent input was evaluated by linear regression relating RSNA to ADNA. The maximum baroreflex-elicited increase in RSNA was significantly reduced in HU rats (122 +/- 3.8 vs. 144 +/- 4.9% of baseline RSNA), whereas ADNA was not altered. The slope (-0.18 +/- 0.04 vs. -0.40 +/- 0.04) and y-intercept (121 +/- 3.2 vs. 146 +/- 4.3) of the linear regression relating increases in efferent RSNA to decreases in afferent ADNA during hypotension were significantly reduced in HU rats. There were no differences during increases in arterial pressure. Results demonstrate that the attenuation in baroreflex-mediated increases in RSNA following HU is due to changes in central processing of baroreceptor afferent information rather than aortic baroreceptor function.

Attenuated baroreflex control of sympathetic nerve activity after cardiovascular deconditioning in rats.

The effect of cardiovascular deconditioning on baroreflex control of the sympathetic nervous system was evaluated after 14 days of hindlimb unloading (HU) or the control condition. Rats were chronically instrumented with catheters and sympathetic nerve recording electrodes for measurement of mean arterial pressure (MAP) and heart rate (HR) and recording of lumbar (LSNA) or renal (RSNA) sympathetic nerve activity. Experiments were conducted 24 h after surgery, with the animals in a normal posture. Baroreflex function was assessed using a logistic function that related HR and LSNA or RSNA to MAP during infusion of phenylephrine and nitroprusside. Baroreflex influence on HR was not affected by HU. Maximum baroreflex-elicited LSNA was significantly reduced in HU rats (204 +/- 11.9 vs. 342 +/- 30.6% baseline LSNA), as was maximum reflex gain (-4.0 +/- 0.6 vs. -7.8 +/- 1.3 %LSNA/mmHg). Maximum baroreflex-elicited RSNA (259 +/- 10.8 vs. 453 +/- 28.0% baseline RSNA), minimum baroreflex-elicited RSNA (-2 +/- 2.8 vs. 13 +/- 4.5% baseline RSNA), and maximum gain (-5.8 +/- 0.5 vs. -13.6 +/- 3.1 %RSNA/mmHg) were significantly decreased in HU rats. Results demonstrate that baroreflex modulation of sympathetic nervous system activity is attenuated after cardiovascular deconditioning in rodents. Data suggest that alterations in the arterial baroreflex may contribute to orthostatic intolerance after a period of bedrest or spaceflight in humans.

Hemodynamic effects of acute stressors in the conscious rabbit.

Chronically instrumented, conscious rabbits were used to test the hypothesis that sensory stimulation with an air jet or oscillation produces differential hemodynamic changes that may be appropriate for an active or a passive behavioral response, respectively. Both stressors increased arterial pressure, central venous pressure, and hindquarters blood flow and produced visceral vasoconstriction. Neither stimulus altered hindquarters conductance. Although air jet increased heart rate and cardiac output, oscillation did not. The two stressors affected arterial baroreflex control of heart rate differently. Oscillation reset arterial pressure to a higher level with no change in heart rate maximum or minimum, whereas air jet reset both heart rate and arterial pressure to higher levels. Neither stressor affected baroreflex sensitivity. We conclude that the conscious rabbit shows at least two distinct cardiovascular responses when exposed to acute stressors. Air jet produces a cardiovascular response including tachycardia, which resembles the defense reaction and appears appropriate for active defense or flight. The response to oscillation, on the other hand, appears better suited for a passive response such as "freezing" behavior. During exposure to either stressor, the baroreflex is altered to allow simultaneous increases in heart rate and arterial blood pressure, but the sensitivity is maintained, allowing normal moment to moment control of heart rate.

Total and regional cerebral blood flow during recovery from G-LOC.

INTRODUCTION: This study measured total and regional cerebral blood flow (BF) in baboons during +Gz-induced loss of consciousness (G-LOC) and during recovery from G-LOC. METHODS: Flowprobes (Transonic Inc., T201, Ithaca, NY) were placed on the common carotid and internal carotid arteries of five male baboons for continuous measurement of total cephalic and cerebral BF, respectively. Radiolabeled microspheres were used to measure regional central nervous system BF at discrete timepoints. G-LOC was determined from visual observations of the animals and from EEG recordings. RESULTS: Cerebral blood flow was maintained and animals remained conscious during 60 s exposure to +4 Gz. In contrast, G-LOC was observed during the first 16-25 s (mean = 20.3 +/- 3.7 s) of exposure to +8 Gz in all five animals. Internal and common carotid artery BF decreased rapidly to zero during the first few seconds of +8 Gz. BF always appeared to cease prior to the occurrence of G-LOC. During early recovery from G-LOC there was no hyperemic response recorded with flowprobes, whereas a hyperemic response was recorded following 60 s exposures to +4 Gz in which the animals did not experience G-LOC. Microsphere measurements of the regional distribution of BF are consistent with the hypothesis of a +Gz-induced differential perfusion deficit throughout the brain and central nervous system during G-LOC. CONCLUSIONS: We conclude that G-LOC is preceded by cessation of cerebral BF. The fact that the hyperemic response following +Gz exposure is less when G-LOC occurs than when G-LOC does not occur suggests CNS energy conservation during G-LOC.

Influence of nitric oxide on the hemodynamic response to hemorrhage in conscious rabbits.

We investigated the role of nitric oxide, an endothelium-derived relaxing factor, in the hemodynamic response to acute hemorrhage in conscious rabbits. Chronically instrumented rabbits were treated with the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) or vehicle and hemorrhaged until mean arterial pressure fell below 40 mmHg. Control animals were treated with L-NAME or vehicle but not subjected to hemorrhage. L-NAME increased mean arterial pressure and decreased heart rate in control animals. Hindquarters and mesenteric blood flow velocity and conductance were reduced by L-NAME. Nitric oxide synthase inhibition also produced significant changes in the hemodynamic response to hypotensive hemorrhage. Mean arterial pressure was higher and regional vascular conductances were lower throughout hemorrhage and during recovery. L-NAME treatment significantly (but in some cases, subtly) altered the characteristic pattern of changes in vascular conductance associated with acute hypotensive hemorrhage and recovery. Similar experiments with other arginine analogues or phenylephrine infusion showed that L-NAME's effects during hemorrhage were due to nitric oxide synthase inhibition. We conclude that nitric oxide plays a role in the hemodynamic response to acute hemorrhage in the rabbit and is essential for the full expression of the vasodilation associated with hypotensive hemorrhage.

Cerebral and spinal cord blood flow dynamics during high sustained +Gz.

This study had two purposes. First, the use of Transonic flowprobes placed on the common carotid and internal carotid arteries of seven male baboons was evaluated for measuring cerebral blood flow (BF) during +Gz stress. The approach was to compare BF's obtained with these flowprobes to microsphere measurements of total cerebral BF. The second purpose was to measure regional variations in cerebral and spinal cord BF during +Gz to test the hypothesis that +Gz produces a differential perfusion deficit throughout the central nervous system so that BF's at the superior portion of the brain are decreased more than in areas of the brain that are nearer to the heart. The results indicate that internal carotid artery and microsphere measurements of total brain BF were related so that the relative decrease in internal carotid artery BF was consistently comparable to that measured with the labeled microsphere technique. Thus, Transonic flowprobes placed on the internal carotid artery of the baboon give reliable estimates of cerebral BF during +Gz stress. The microsphere BF data demonstrated that there were no regional differences in the relative decrease in BF measured in the brain or spinal cord during +Gz. We conclude that our results do not support the hypothesis of a gradient of BF deficit within the brain or spinal cord during +Gz.

Peripheral opioidergic mechanisms do not mediate naloxone's pressor effect in the conscious rabbit.

We tested the hypothesis that the pressor effect of naloxone during acute hemorrhagic hypotension is mediated in part at peripheral sites. Experiments were performed in conscious, chronically prepared rabbits. First, we compared the hemodynamic response to peripheral injections of naloxone and naloxone methobromide during acute hemorrhagic hypotension. Naloxone methobromide, which does not enter the central nervous system, produced a lesser pressor effect than naloxone. Second, we looked for peripheral effects of naloxone after close-arterial injection into the hindquarter vasculature. Unlike i.v. injections, close-arterial injection of naloxone did not produce any significant hemodynamic changes during hemorrhagic hypotension. Finally, we compared the capacities of naloxone and naloxone methobromide to block the peripherally mediated cardiovascular response to i.v. methionine-enkephalin in nonhemorrhaged animals. The potency of the two compounds, in terms of their blockade of this peripherally mediated response, was similar. The results of the present study do not support a predominant peripheral role for naloxone during acute hemorrhagic hypotension in conscious rabbits.

Sympathoinhibition and its reversal by naloxone during hemorrhage.

During hemorrhagic hypotension, vascular resistance, plasma norepinephrine, and sympathetic nerve activity decrease. Naloxone reverses these effects. We hypothesized that increased sympathetic nerve activity was specific to naloxone and not secondary to the pressor response. Conscious rabbits were hemorrhaged until mean arterial pressure (MAP) was less than 40 mmHg, given naloxone (3 mg/kg) or saline, and monitored for 5 min. In some animals, we attenuated naloxone's pressor response with alpha-adrenergic blockade or mimicked the pressor response by infusion of phenylephrine. During nonhypotensive hemorrhage, heart rate and renal sympathetic nerve activity (RSNA) increased significantly. During hypotensive hemorrhage, RSNA decreased to significantly less than prehemorrhage control values. After saline treatment, RSNA did not increase. Naloxone significantly increased MAP and RSNA. alpha-Blockade reduced the pressor response to naloxone but not the increase in RSNA. Phenylephrine increased MAP to a level similar to naloxone, but RSNA remained suppressed. Reinfusion of hemorrhaged blood reduced RSNA in all groups treated with naloxone. These data suggest that hypotensive hemorrhage is associated with sympathoinhibition that is not transient. In addition, the pressor response to naloxone is not required for its sympathoexcitatory effects.

Cold- and ethanol-induced hypothermia reduces cellular levels of mRNA-encoding Thyrotropin-Releasing Hormone (TRH) in neurons of the preoptic area.

Thyrotropin-releasing hormone (TRH)-containing neurons have been implicated in the central control of body temperature. TRH-containing neurons are located in brain areas known to influence body temperature, and TRH injected into these areas can produce changes in body temperature. While these lines of evidence support the view that central TRH is involved in thermoregulation, it has been difficult to confirm that TRH-containing neurons of the preoptic area are involved in this process. We used a different approach to test this hypothesis, based on recent evidence that changes in cellular levels of neuropeptide mRNA are linked to changes in neurosecretory processes. Hence, we predicted that if TRH neurons of the preoptic area are involved in body temperature regulation, cellular levels of TRH mRNA would be altered in animals in which body temperature had been experimentally altered. TRH mRNA levels were measured by in situ hybridization histochemistry in neurons of the preoptic area (POA) of animals that had been exposed to cold (5 degrees C) or that had been given a hypothermic dose of ethanol. Cellular levels of TRH mRNA were reduced by both treatments. However, cellular levels of the mRNA-encoding gastrin-releasing peptide were not affected by these treatments in neurons of the POA, indicating that hypothermia exerted selective effects on TRH neurons in this brain region. Considering that both cold exposure and ethanol administration increase blood pressure, that the POA contains neurons which are both thermosensitive and barosensitive, and that TRH has been implicated in the control of blood pressure, we manipulated arterial blood pressure pharmacologically without changing body temperature to determine whether TRH neurons were also responsive to cardiovascular changes. Infusions with either nitroprusside, a vasodilator, or phenylephrine, a vasoconstrictor, produced significant changes in arterial blood pressure and heart rate, but did not affect TRH mRNA in the POA. These findings demonstrate that TRH neurons of the POA are thermoresponsive, supporting the view that they play a role in the central control of body temperature.

Hemodynamic and neurohumoral responses to acute hypovolemia in conscious mammals.

In conscious mammals including humans, the neurohumoral and hemodynamic responses to progressive acute hypovolemia have two distinct phases. There is an initial arterial baroreceptor-mediated phase in which the fall in cardiac output is nearly matched by a sympathetically mediated increase in peripheral resistance so that arterial pressure is maintained near normal levels. In most species, adrenal catecholamines and vasopressin contribute little to this phase. Increased renin release appears to augment the sympathetically mediated vasoconstriction. When blood volume has fallen by a critical amount (approximately 30%), a second phase develops abruptly. This phase is characterized by withdrawal of sympathetic vasoconstrictor drive, relative or absolute bradycardia, an increase in release of adrenal catecholamines and vasopressin, and a profound fall in arterial pressure. In rabbits and rats the signal that initiates this phase appears to travel in cardiopulmonary afferents. In dogs and humans its origin is unknown. Central opioidergic and serotonergic mechanisms may be involved.

Interaction of vasopressin and opioids during rapid hemorrhage in conscious rabbits.

We investigated possible interactions between arginine vasopressin (AVP) and endogenous opioid peptides during rapid hypotensive hemorrhage and subsequent opioid receptor blockade in conscious rabbits. Plasma AVP concentration did not change after normotensive hemorrhage but increased after hypotensive hemorrhage. Blockade of V1-AVP receptors (AVPX) did not affect prehemorrhage arterial pressure, heart rate, or hindquarter blood flow and vascular resistance. AVPX did not alter the hemodynamic response to hemorrhage or the blood loss required to reduce mean arterial pressure to less than 40 mmHg. However, hindquarter blood flow was higher and mean arterial pressure and hindquarter resistance lower after hypotensive hemorrhage in AVPX-treated animals. These differences were maintained after naloxone or saline injection. Naloxone increased mean arterial pressure and hindquarter resistance and decreased heart rate with or without AVPX. At 2 min postinjection, plasma AVP values were greater after saline than after naloxone. When naloxone's pressor response was reduced by alpha-adrenergic blockade, plasma AVP values were higher after naloxone than after saline. Thus AVP was not vital to maintenance of blood pressure during rapid normotensive hemorrhage or to the abrupt decrease in arterial blood pressure and resistance after rapid hypotensive hemorrhage. AVP release was important to spontaneous recovery from acute hypotensive hemorrhage but only of minor importance to naloxone's pressor response. Finally, AVP release appeared to be inhibited by endogenous opioids during acute hemorrhagic hypotension.

Renin-angiotensin system and opioids during acute hemorrhage in conscious rabbits.

We measured changes in plasma renin activity (PRA) and used angiotensin-converting enzyme blockade with captopril to evaluate the role of the renin-angiotensin system during hemorrhage and after opioid receptor blockade in conscious rabbits. The increase in PRA after nonhypotensive hemorrhage was not statistically significant. PRA increased sixfold after a hypotensive hemorrhage to a mean arterial pressure less than 40 mmHg. This increase was statistically significant. Captopril altered the hemodynamic response to hemorrhage. The normal increase in vascular resistance early in hemorrhage was reduced by captopril pretreatment. After a critical blood loss, arterial pressure and heart rate decreased in both groups. The blood loss required to decrease mean arterial pressure to less than 40 mmHg was approximately 25% less in animals pretreated with captopril. The characteristic decrease in vascular resistance coincident with the onset of hypotension was still present after captopril pretreatment. Injection of naloxone or saline during acute hemorrhagic hypotension did not affect PRA. However, recovery of blood pressure after naloxone or saline was attenuated by converting-enzyme blockade. This attenuation was due primarily to a reduction in spontaneous recovery (i.e., recovery after the control saline injection) and not to a reduction in the response to naloxone. We tested whether this effect of captopril might be due to an interaction of ANG II and catecholamines. The plasma norepinephrine (NE) response to naloxone was statistically similar with and without captopril. In contrast, the response to exogenous NE after hypotensive hemorrhage was significantly reduced by captopril pretreatment. Captopril apparently did not alter baroreflex sensitivity but did reset the baroreflex to lower pressure levels during naloxone's pressor response.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic and hemodynamic adjustments to hemorrhage: a possible role for endogenous opioid peptides.

The traditional view of the decrease in blood pressure during blood loss is that it is a passive phenomenon. Blood pressure falls due to the inability of the compensatory mechanisms to keep pace with blood loss. However, recent evidence indicates that this transition from normotension to hypotension may involve an active decrease in compensation by the sympathetic nervous system. In the conscious, chronically prepared rabbit, blood pressure is maintained early in hemorrhage primarily by sympathetically mediated compensatory increases in vascular resistance and heart rate. When blood loss exceeds approximately 20% of total blood volume, hypotension develops abruptly due to a decrease in vascular resistance. This vasodilation is accompanied by decreased plasma norepinephrine (NE) levels and decreased sympathetic nerve activity. Therefore, the transition from normotension to hypotension during hemorrhage involves an active change, a decrease in vascular resistance, associated with a decrease in sympathetic nerve activity. Opioid receptor blockade with naloxone reverses acute hemorrhagic hypotension by increasing vascular resistance. The increase in resistance is accompanied by increased plasma NE and increased sympathetic nerve activity. Thus, the transition to hypotension during acute hemorrhage may be an active event brought on by a decrease in sympathetic outflow. Naloxone's reversal of the hypotension is consistent with the central involvement of endogenous opioid peptides in this phenomenon and thus in the pathogenesis of hypotension during blood loss.

Ventilatory responses of the ground squirrel, Spermophilus tridecemlineatus, to various levels of hypoxia.

1. Minute ventilation (VE) in the semifossorial ground squirrel (Spermophilus tridecemlineatus) increased with increased levels of hypoxia. 2. The increase in VE was brought about primarily by an increase in breathing frequency (f). There was no significant change in tidal volume (VT). 3. The PiO2 threshold for the ventilatory response to hypoxia and position of the ventilatory response curve in the ground squirrel were closer to the semifossorial echidna (Tachyglossus aculeatus) than the completely fossorial mole rate (Spalax ehrenbergi); both the ground squirrel and echidna had a higher PiO2 threshold than the mole rat. 4. The ventilatory response curve was shifted to the left in the mole rat. 5. These observations indicate that the mole rat is the least responsive to hypoxia of the three species.

A miniaturized ultrasonic flowmeter and telemetry transmitter for chronic animal blood flow measurements.

An ultrasonic blood flowmeter telemetry system, using only two integrated circuits and one transistor, has been designed for chronic unanesthetized animal studies. Standard components and construction techniques are utilized. The CW Doppler system employs LZT piezoelectric 10 MHZ transmitting and receiving crystals held in a lightweight polystyrene arterial transducer. The audio frequency, FM Doppler signal modulates an FM oscillator-transmitter to produce an FM/FM radio frequency carrier which is transmitted to an FM receiver at a remote location. The transmitted Doppler audio flow signal is demodulated at the receiver by a zero crossing detector. Power consumption is 48 mw. The 12.4 cc package volume can be further reduced for animal implantation.

Role of adrenal medulla in hemodynamic response to hemorrhage and naloxone.

We tested the hypothesis that enkephalins or some other compound(s) released by the adrenal medulla during hemorrhage were responsible for the resultant hypotension. We compared the hemodynamic and plasma catecholamine responses to hemorrhage and subsequent opioid receptor blockade with naloxone in intact, adrenal-denervated (ADD), and adrenalectomized (ADX) rabbits. The studies were done in conscious, chronically prepared, male New Zealand White rabbits. The hemodynamic response to hemorrhage was not different among the three groups. Plasma norepinephrine (NE) increased early in hemorrhage in all groups. In the ADD and ADX animals, NE decreased significantly at the transition to hypotension, suggesting decreased release of NE by peripheral sympathetic nerves as a possible cause of the decrease in pressure. In the intact group, NE did not decrease but reached a plateau possibly due to the release of some NE by the adrenal medulla, which obscured the decreased release by sympathetic nerves. The pressor response to naloxone, though present in all groups, was attenuated by adrenalectomy or adrenal denervation. The plasma NE response to naloxone was similar in all groups and involved a two- to threefold increase after naloxone. We conclude that enkephalins or any other compounds released by the adrenal gland are not responsible for the acute hemodynamic changes during hemorrhage in the conscious rabbit. However, some substance(s) released by the adrenal medulla, perhaps epinephrine, does play a role in naloxone's pressor effect, since this is reduced by adrenalectomy or adrenal denervation.

Decreased vascular resistance after intra-arterial injection of [met]enkephalin in the hindquarters of conscious rabbits.

The hemodynamic effects of i.a. [met]enkephalin were studied in the hindquarter vasculature of chronically prepared, conscious rabbits. A new method allowed i.a. injection while simultaneously measuring blood pressure and blood flow to this vascular bed. [Met]enkephalin produced a dose-dependent (3-300 micrograms/kg) decrease in hindquarter vascular resistance (18-42% change from base line). The duration of the response ranged from 28 sec to over 2 min. Heart rate decreased 16 to 45% over the same dose range but returned to preinjection levels in 5 sec. Only the bradycardia was abolished by pretreatment with atropine methyl nitrate. All hemodynamic changes were eliminated or significantly reduced after pretreatment with the ganglionic blocking agent, chlorisondamine hydrochloride. The opioid antagonist, naloxone hydrochloride, abolished the hemodynamic effects of [met]enkephalin. Resistance decreases in the mesenteric vasculature were coincident with those in the hindquarters. The time to onset of the response was delayed when [met]enkephalin was injected i.v. These data indicate activation of a reflex originating in the hindquarters that resulted in opioid-dependent increased efferent parasympathetic activity to the heart and decreased sympathetic tone to at least two vascular beds.

Cardiovascular responses to hemorrhage and naloxone in conscious barodenervated rabbits.

The hemodynamic and plasma catecholamine response to hypotensive hemorrhage and subsequent opioid receptor blockade with naloxone were evaluated before and after complete sinoaortic denervation (SAD). This study was done to test the general hypothesis that opioid-mediated failure of the baroreflex accounts for the hypotension of hemorrhage. The specific hypothesis we tested was that SAD would abolish the pressor effect of opioid receptor blockade with naloxone. The studies were done in conscious chronically prepared rabbits. Hemorrhage of 12 ml/kg did not change mean arterial blood pressure in intact animals due to a compensatory increase in heart rate and vascular resistance. When blood loss exceeded 12 ml/kg, pressure decreased abruptly due to a decrease in vascular resistance. Plasma norepinephrine (NE) and epinephrine (E) were higher after hemorrhage than before. Plasma E levels increased almost 70 times. After SAD, mean blood pressure began to decrease at the beginning of hemorrhage, the heart rate increase was abolished, and vascular resistance decreased throughout the blood loss. Plasma NE was no different after hemorrhage than before. Plasma E increased, but the increase was only fivefold. Naloxone increased mean arterial blood pressure, vascular resistance, cardiac index, and plasma NE before and after SAD. The increases in blood pressure and plasma norepinephrine were significantly greater after SAD. Therefore the pressor effect of naloxone in this model is not due to increased baroreflex sensitivity. Rather, intact baroreflexes buffer naloxone's effects.