Decompensatory Phase Research Articles

Determination of Optimal Dose of Arginine Vasopressin in Hemorrhagic Shock in Dogs

The hemodynamic effects of vasopressin of high/low doses on dogs were investigated using experimentally induced hemorrhagic shock model. Experimental groups were categorized according to administered doses of vasopressin (0.1, 0.4 and 1.6 IU/kg) and hemodynamic parameters were measured before and after the graded-dose administration of vasopressin. Administration of high- and middle-dose vasopressin (0.4 and 1.6 IU/kg) showed superior increase in blood pressure and systemic vascular resistance, compared with those of low-dose one (0.1 IU/kg). Results of systolic arterial pressure and mean arterial pressure in 1.6 IU/kg-administered group revealed lower efficacy than that in 0.4 IU/kg group in spite of administration of higher dose. This study demonstrates that 0.4 IU/kg of vasopressin can be used as the most effective dose for improving hemodynamic condition in the decompensatory phase of hemorrhagic shock in dogs.

Activation of central opioid receptors determines the timing of hypotension during acute hemorrhage-induced hypovolemia in conscious sheep

After an initial compensatory phase, hemorrhage reduces blood pressure due to a widespread reduction of sympathetic nerve activity (decompensatory phase). Here, we investigate the influence of intracerebroventricular naloxone (opioid-receptor antagonist) and morphine (opioid-receptor agonist) on the two phases of hemorrhage, central and peripheral hemodynamics, and release of vasopressin and renin in chronically instrumented conscious sheep. Adult ewes were bled (0.7 ml x kg(-1) x min(-1)) from a jugular vein until mean arterial blood pressure (MAP) reached 50 mmHg. Starting 30 min before and continuing until 60 min after hemorrhage, either artificial cerebrospinal fluid (aCSF), naloxone, or morphine was infused intracerebroventricularly. Naloxone (200 microg/min but not 20 or 2.0 microg/min) significantly increased the hemorrhage volume compared with aCSF (19.5 +/- 3.2 vs. 13.9 +/- 1.1 ml/kg). Naloxone also increased heart rate and cardiac index. Morphine (2.0 microg/min) increased femoral blood flow and decreased hemorrhage volume needed to reduce MAP to 50 mmHg (8.9 +/- 1.5 vs. 13.9 +/- 1.1 ml/kg). The effects of morphine were abolished by naloxone at 20 microg/min. It is concluded that the commencement of the decompensatory phase of hemorrhage in conscious sheep involves endogenous activation of central opioid receptors. The effective dose of morphine most likely activated mu-opioid receptors, but they appear not to have been responsible for initiating decompensation as 1) naloxone only inhibited an endogenous mechanism at a dose much higher than the effective dose of morphine, and 2) the effects of morphine were blocked by a dose of naloxone, which, by itself, did not delay the decompensatory phase.

Impact of Vasopressin on Hemodynamic and Metabolic Function in the Decompensatory Phase of Hemorrhagic Shock

To explore how the potent vasoconstrictive features of vasopressin impact the rate of cardiovascular collapse and metabolic derangements associated with prolonged hemorrhagic shock. A prospective randomized trial. University hospital-based animal laboratory. Sixteen swine. Swine were bled in an isobaric fashion to achieve a linear decrease in the mean arterial blood pressure to 40 mmHg. The mean arterial blood pressure was then maintained at 40 mmHg until the onset of cardiovascular decompensation, defined as the need to reinfuse shed blood to maintain the blood pressure at 40 mmHg. Once at the onset of cardiovascular decompensation, animals were randomly assigned to 2 resuscitation groups: the crystalloid group received lactated Ringer's solution and the vasopressin group received lactated Ringer's solution and arginine vasopressin. Resuscitation consisted of infusing lactated Ringer's solution with and without vasopressin (0.05 U/kg/min) to maintain a blood pressure of 70 mmHg for 60 minutes. The rate of crystalloid infusion was compared between groups using an unpaired 2-tailed t test. Metabolic and hemodynamic parameters between groups over time were compared with a repeated measures analysis of variance. Vasopressin decreased the rate of crystalloid infusion during resuscitation by 50%. During resuscitation, the cardiac index in the crystalloid group was restored to near baseline levels and was decreased to near half of baseline levels in the vasopressin group. Animals in the vasopressin group developed a lactic acidemia, but animals in the crystalloid group revealed no change from baseline in the arterial pH and a slight decrease in the plasma lactate. Administration of vasopressin used as an adjunct to maintain blood pressure in the decompensatory phase of hemorrhagic shock slows cardiovascular collapse, but has an adverse effect on metabolic and hemodynamic function. Further investigation is warranted to clarify the role of vasopressin in the delayed management of severe hemorrhagic shock.

Haemorrhage-evoked decompensation and recompensation mediated by distinct projections from rostral and caudal midline medulla in the rat.

The haemodynamic response to blood loss consists of three phases: (i) an initial compensatory phase during which resting arterial pressure is maintained; (ii) a decompensatory phase characterized by a sudden, life-threatening hypotension and bradycardia; and (iii) if blood loss ceases, a recompensatory phase during which arterial pressure returns to normal. Previous research indicates that topographically distinct, rostral and caudal parts of the caudal midline medulla (CMM) contain neurons that differentially regulate the timing and magnitude of each of the three phases. Specifically, decompensation depends critically on the integrity of the rostral CMM; whereas compensation and recompensation depend upon the integrity of the caudal CMM. This study aimed to determine, using retrograde and anterograde tracing techniques, if the rostral and caudal CMM gave rise to different sets of projections to the major cardiovascular region of the ventrolateral medulla (VLM) and spinal cord. It was found that rostral and caudal CMM each have projections of varying density to the region containing bulbospinal (presympathetic) motor neurons in the rostral VLM and preganglionic sympathetic motor neurons in the intermediolateral cell column of the spinal cord. Via these projections vasomotor tone and hence arterial pressure can be regulated. More strikingly: (i) consistent with a role in mediating bradycardia during decompensation, the rostral CMM projects uniquely to VLM regions containing vagal cardiac motor neurons; and (ii) consistent with its role in mediating recompensation, the caudal CMM projects uniquely onto tyrosine hydroxylase-containing, caudal VLM (A1) neurons whose activity mediates vasopressin release, on which recompensation depends.

Hemorrhagic shock in swine: nitric oxide and potassium sensitive adenosine triphosphate channel activation.

To determine the role of nitric oxide and adenosine triphosphate-sensitive potassium (KATP) vascular channels in vascular decompensation during controlled hemorrhagic shock in swine. Thirty instrumented, anesthetized adolescent Yorkshire swine were subjected to controlled isobaric hemorrhage to a mean arterial pressure of 40 mmHg for 2 h (n = 6) or 4 h (n = 10) or 50 mmHg for 4 h (n = 8). An additional six animals were used as anesthetized instrumented time controls. During controlled hemorrhage, plasma and tissue samples were obtained every 30 to 60 min. Before euthanasia, tissue (carotid artery, lung, liver, and aorta) was obtained for analysis of nitrate concentrations and nitric oxide synthase activity. Isolated carotid artery ring reactivity to norepinephrine was also determined with and without glibenclamide. Animals hemorrhaged to 40 mmHg decompensated earlier than animals hemorrhaged to 50 mmHg. Plasma nitrate concentrations and nitric oxide synthase activity rose consistently throughout hemorrhage in both groups. However, they were substantially higher in the mean arterial pressure 40 group. Constitutive nitric oxide synthase activity was the major contributor to total nitric oxide synthase activity throughout the protocol with only the animals maintained at 40 mmHg for 4 h showing evidence of inducible nitric oxide synthase activity. Profound KATP channel activation and hyporeactivity of isolated vessel rings to norepinephrine was not observed until 4 h after the initiation of hemorrhagic shock. Only those animals with inducible nitric oxide synthase activity showed a decreased response to norepinephrine, and this hyporeactivity was reversed with the KATP channel inhibitor, glibenclamide. The data indicate that profound KATP activation associated with increased nitric oxide concentrations and inducible nitric oxide synthase induction is a key factor in vascular smooth muscle hyporeactivity characteristic of the late decompensatory phase of hemorrhagic shock in swine.

Effect of anaesthetic and rat strain on heart rate responses to simulated haemorrhage.

Haemorrhage is characterized by two distinct responses, sympathoexcitation that evokes tachycardia and supports blood pressure, followed by sympathoinhibition contributing to bradycardia and hypotension. It has been shown that anaesthetics alter the response to haemorrhage and we hypothesized that rat strain may also influence the response. We investigated the effect of simulated haemorrhage on heart rate (HR) responses in three strains of conscious rats, and the effect of three common anaesthetics, by comparing HR responses under anaesthesia to the conscious response. Haemorrhage was simulated by constricting the inferior vena cava. We demonstrate differential effects of anaesthetics, including both maintenance and elimination of HR responses to haemorrhage depending on anaesthetic. We also show that both phases of the HR response differ in different conscious rat strains, and we have demonstrated a transient increase in HR during the decompensatory phase of haemorrhage, a novel 'second HR peak' with advanced hypotension. Both rat strain and anaesthetic influence HR responses to haemorrhage, and some anaesthetics appear less suitable than others for studies of haemodynamic responses in rats. There was evidence of an additional compensatory mechanism that operates at advanced levels of hypotension in the rat.

Haemodynamic response to haemorrhage: distinct contributions of midbrain and forebrain structures

The haemodynamic response to a fixed volume haemorrhage passes through three distinct phases: a normotensive, compensatory phase; a hypotensive, decompensatory phase; and a post-haemorrhage, recompensatory phase. The role of the forebrain and midbrain in regulating the triphasic response to a ‘fast’ (1.5%/min) or ‘slow’ (0.75%/min) rate of blood withdrawal (30% haemorrhage) was evaluated by comparing, in unanaesthetised rats, the effects of pre-collicular (PCD) vs. pre-trigeminal decerebrations (PTD). It was found that pre-trigeminal decerebration attenuated the decompensatory (hypotensive) phase to either a fast or slow haemorrhage. In contrast, pre-collicular decerebration attenuated the compensatory and recompensatory phases of the response to a ‘fast’ (but not a slow) haemorrhage. These results suggest that the integrity of (i) forebrain structure(s) are critical for compensatory and recompensatory responses to ‘rapid’ blood loss; and (ii) midbrain structure(s) are critical for the decompensatory response to progressive blood loss irrespective of rate.

ABSENT-END-DIASTOLIC FLOW VELOCITY IN THE UMBILICAL ARTERY

Fetal growth restriction (FGR) as a consequence of uteroplacental insufficiency is an important contributor to perinatal death, neonatal morbidity and long-term health problems. Progressive uteroplacental dysfunction leads to placental respiratory failure and fetal hypoxaemia, which triggers compensatory fetal haemodynamic changes including blood flow redistribution towards essential fetal organs (brain, heart and adrenal glands) at the expense of the other body systems. The duration of the compensatory phase is variable, sometimes lasting weeks, and appears not to have deleterious short-term consequences. With further disease progression, the compensatory mechanisms reach their limit and myocardial dysfunction occurs. Once the disease enters this decompensatory phase, the fetus is at high risk of multisystem organ failure and in-utero demise. There is no effective in-utero therapeutic intervention. The main aim of management is to deliver the baby when the risks of antenatal demise and irreversible end-organ dysfunction associated with further prolongation of the pregnancy are greater than the risks from delivery.

The role of inducible nitric oxide synthase inhibitor on the arteriolar hyporesponsiveness in hemorrhagic-shocked rats

Hemorrhagic shock (HS) has been implicated in the induction of inducible nitric oxide synthase (iNOS) that leads to increase production of nitric oxide (NO). Recently, NO has been implicated to cause hyporesponsiveness of blood vessel in vitro towards vasoconstrictors in refractory (decompensated) HS. In our in vivo model, we examined the effects of aminoguanidine (AG), a known iNOS inhibitor, with angiotensin II (ANG II), a vasoconstrictor, following hemorrhagic shock decompensatory phase (HSDP) on percentage survival, vascular responsiveness, mean arterial blood pressure (MABP), heart rate and mean nitrate/nitrite levels in anaesthetized rats. HSDP (3 h) was achieved via constant pressure method (40–45 mmHg). MABP and heart rate was measured via the left carotid artery. Plasma collected from HSDP rats was used to measure nitrate/nitrite levels. Vascular hyporeactivity to ANG II was carried out using HSDP aortic strips, precontracted with KCl and noradrenaline. Sham-operated rats served as controls. HSDP rats decreased percentage survival, vascular contractility to ANG II and noradrenaline, MABP, heart rate while showing increased levels of nitrate/nitrite. Infusion of AG with ANG II, increased percentage survival and had reversed these cardiovascular effects of HSDP rats. This study indicates that excessive NO formation from iNOS activity induces vascular hyporeactivity and decompensation in HSDP. This might suggest that selective NOS inhibitor, AG, when coupled with ANG II, show reduction in NO's effect in HSDP.

Evidence that hemorrhagic hypotension is mediated by the ventrolateral periaqueductal gray region.

Severe hemorrhage lowers arterial pressure by suppressing sympathetic activity. This study tested the hypothesis that the decompensatory phase of hemorrhage is mediated by the ventrolateral periaqueductal gray (vlPAG), a region importantly involved in the autonomic and behavioral responses to stress and trauma. Neuronal activity in the vlPAG was inhibited with either lidocaine or cobalt chloride 5 min before hemorrhage (2.5 ml/100 g body wt) was initiated in conscious, unrestrained rats. Bilateral injection of lidocaine (0.5 microl of a 2% or 1 microl of a 5% solution) into the caudal vlPAG delayed the onset and reduced the magnitude of the hypotension produced by hemorrhage significantly. In contrast, inactivation of the dorsolateral PAG with lidocaine was ineffective. Cobalt chloride (5 mM; 0.5 microl), which inhibits synaptic transmission but not axonal conductance, also attenuated hemorrhagic hypotension significantly. Microinjection of lidocaine or cobalt chloride into the vlPAG of normotensive, nonhemorrhaged rats did not influence cardiovascular function. These data indicate that the vlPAG plays an important role in the response to hemorrhage.

Pyruvate improves cerebral metabolism during hemorrhagic shock.

Pyruvate (PYR) improves cellular and organ function hypoxia and ischemia by stabilizing the reduced nicotinamide adenine dinucleotide redox state and cytosolic ATP phosphorylation potential. In this in vivo study, we evaluated the effects of intravenous pyruvate on neocortical function, indexes of the cytosolic redox state, cellular energy state, and ischemia during a prolonged (4 h) controlled arterial hemorrhage (40 mmHg) in swine. Thirty minutes after the onset of hemorrhagic shock, sodium PYR (n = 8) was infused (0.5 g x kg(-1) x h(-1)) to attain arterial levels of 5 mM. The volume and osmotic effects were matched with 10% NaCl [hypertonic saline (HTS)] (n = 8) or 0.9% NaCl [normal saline (NS)] (n = 8). During the hemorrhage protocol, the time to peak hemorrhage volume was significantly delayed in the PYR group compared with the HTS and NS groups (94 +/- 5 vs. 73 +/- 6 and 72 +/- 4 min, P < 0.05). In addition to the early onset of the decompensatory phase of hemorrhagic shock, the complete return of the hemorrhage volume during decompensatory shock resulted in the death of five and four animals, respectively, in the HTS and NS groups. In contrast, in the PYR group, reinfusion of the hemorrhage volume was slower and all animals survived the 4-h hemorrhage protocol. During hemorrhage, the PYR group also exhibited improved cerebral cortical metabolic and function status. PYR slowed and reduced the rise in neocortical microdialysis levels of adenosine, inosine, and hypoxanthine and delayed the loss of cerebral cortical biopsy ATP and phosphocreatine content. This improvement in energetic status was evident in the improved preservation of the electrocorticogram in the PYR group. PYR also prevented the eightfold increase in the excitotoxic amino acid glutamate observed in the HTS group. The findings show that PYR administered after the onset of hemorrhagic shock markedly improves cerebral metabolic and functional status for at least 4 h.

The effects of stroma-free and dextran-conjugated hemoglobin on hemodynamics and carotid blood flow in hemorrhaged guinea pigs.

Hemoglobin solutions are potential resuscitative fluids with volume expanding and oxygen delivery abilities developed to reduce the use of blood transfusion. Most hemoglobin solutions in clinical trials increase transiently arterial pressure by inhibiting nitric oxide-dependent vasodilation. Our objective was to compare the effects on central hemodynamics and carotid blood flow of two hemoglobin solutions after resuscitation from hemorrhage in anesthetized guinea pigs. After anesthesia and instrumentation, severe hemorrhage was induced by withdrawing 50% of the blood volume. Resuscitation was performed after 15 min of hypovolemia with 5% albumin, stroma-free hemoglobin, or hemoglobin conjugated to dextran-benzenetetracarboxylate (Dex-BTC-Hb). The mean arterial pressure (MAP), carotid blood flow (CBF), vascular resistance index and heart rate (HR) were monitored for 3 hours after resuscitation. After hemorrhage, MAP and CBF dropped to 57.6 +/- 4.4% and 58.9 +/- 3.7% of control values respectively. Albumin failed to maintain hemodynamics in the decompensatory phase of shock. Both hemoglobin solutions gave rise to a transient increase in MAP (35%); stroma-free hemoglobin increased the CBF (150%) and resistance index (24%) whereas Dex-BTC-Hb had no effect on CBF and vascular resistances. None of the solutions affected the HR. Modified hemoglobin has attenuated effects on CBF and resistance index compared to stroma-free hemoglobin. This may be due to a balance between the stimulation of nitric oxide synthesis by shear-stress and the inhibition of vasodilation by nitric oxide trapping.

Correction of hypovolemic hypotension by centrally administered naloxone in conscious rabbits

Our goal was to test directly whether the vasoconstrictor action of naloxone during hypovolemic hypotension is centrally mediated. In eight chronically instrumented rabbits, progressive central hypovolemia and fall in cardiac output (CO) were produced by gradually inflating a cuff on the thoracic vena cava. Central hypovolemia was then sustained for 8 min by holding CO constant. In the main experiment (n = 4), each rabbit was studied eight times over 4 experimental days. Saline or naloxone treatment commenced 10 min before progressive hypovolemia (early treatment) or 2 min after the onset of sustained hypovolemia (late treatment), given by intravenous infusion or into the fourth ventricle (V4). With saline treatment, there was spontaneous recovery of systemic vasoconstriction and arterial pressure during sustained hypovolemia. Late treatment with naloxone (4 mg/kg i.v.; 4-37 micrograms/kg V4) accelerated and exaggerated these changes. Thus, under conditions of constant CO and central blood volume, the vasodilatation of the decompensatory phase of acute hypovolemia is not sustained, and intravenous nalox one's vasoconstrictor action is via a brain stem mechanism.

L-Arginine reverses the abolition of hypovolaemic decompensation by N-nitro- l-arginine methyl ester and naloxone in conscious rabbits

Graded caval occlusion in conscious rabbits caused a biphasic haemodynamic response. Phase I was characterized by a fall in systemic vascular conductance so that arterial pressure was maintained. When cardiac output had fallen to 65 ± 2% of its baseline level, phase II supervened. During phase II, conductance rose abruptly and arterial pressure fell to a life-threatening level (≤ 40 mm Hg). Fourth ventricular administration of either N-nitro- l-arginine methyl ester or naloxone prevented the occurrence of phase II. Fourth ventricular administration of l-arginine had no effect on the response to graded caval occlusion but was able to reverse the phase II blocking action of N-nitro- l-arginine methyl ester and naloxone. It is concluded that central nitrergic and opioid mechanisms interact to cause the vasodilatation characteristic of the decompensatory phase II of the cardiovascular response to acute hypovolaemia.

THE ROLE OF HISTAMINE IN MEDIATING THE DECOMPENSATORY PHASE OF HEMORRHAGIC SHOCK IN THE RAT

Our laboratory has previously reported that plasma histamine levels rise significantly and coincidentally with the onset of the decompensatory phase of isobaric hemorrhagic shock in rats. The histamine levels seen in shock were comparable to those that induce profound vasodilatation in many vascular beds under normovolemic conditions. We, therefore, sought to determine whether the elevation in plasma histamine contributes to the cardiovascular collapse seen in the decompensatory phase of hemorrhagic shock. Sprague-Dawley rats were bled according to an isobaric bleeding protocol which maintained the mean arterial blood pressure (MAP) at 40 mmHg until death. Selected H1 (diphenhydramine) and/or H2 (cimetidine and famotidine) antagonists were administered at 75% of the estimated peak shed blood volume (PSBV), a point preceding the rise in plasma histamine. Plasma histamine levels in all groups were similar throughout the time course of hemorrhagic shock. None of the histamine receptor antagonists affected the time of onset or the rate of decompensation. Suspecting that hypotension may alter the animal's response to histamine, we investigated the effect of exogenous histamine administration on MAP before and after hemorrhage. In unbled animals, bolus histamine infusions (.6 mg/kg) dropped the MAP by 62.0 +/- 2.7 mmHg, however, in animals bled to 40 mmHg, histamine dropped the MAP by 7.2 +/- 2.7 mmHg (p = .002). On the basis of the results of these two interventions, we conclude that histamine is not an important mediator of the cardiovascular collapse seen in the decompensatory phase of hemorrhagic shock in the rat.

N-Nitro- l-arginine methyl ester blocks the decompensatory phase of acute hypovolaemia in conscious rabbits by a brainstem mechanism

Graded caval occlusion in conscious rabbits caused a biphasic response. Phase I was characterized by a fall in conductance so that arterial pressure was maintained. When cardiac output had fallen to 71 ± 4% of its baseline level, phase II supervened. During phase II, conductance rose abruptly and arterial pressure fell to a life threatening level (< 40 mm Hg). When administered into the fourth ventricle, the nitric oxide synthase inhibitor N-nitro- l-arginine methyl ester prevented the onset of phase II. The mean threshold dose for this effect was 4 μmol (range: 0.4–11). When administered intravenously, a dose of 275 μmol N-nitro- l-arginine methyl ester prevented the onset of phase II in only one out of six rabbits. It is concluded that a central brainstem nitrergic mechanism is involved in the onset of the decompensatory phase II of the haemodynamic response to hypovolaemia.

ACTH-(1–24) blocks the decompensatory phase of the haemodynamic response to acute hypovolaemia in conscious rabbits

Graded caval occlusion in conscious rabbits caused a biphasic cardiovascular response. Phase I was characterized by a fall in systemic vascular conductance so that arterial pressure was maintained. When cardiac output had fallen to 64 ± 3% of its baseline level, phase II supervened. During phase II, conductance rose abruptly and arterial pressure fell to a life-threatening level (< 40 mm Hg). Intravenous (i.v.) or central (fourth ventricular) administration of the adrenocorticotrophin (ACTH) fragment ACTH-(1–24) prevented the occurrence of phase II. The central dose of ACTH-(1–24) needed to block the occurrence of phase II was ∼ 39 times less than the i.v. dose. Central administration of the δ 1-opioid receptor agonist [ d-Pen 2, d-Pen 5]enkephalin (DPDPE) reversed this effect of both central and i.v. ACTH-(1–24). I.v. ACTH-(1–24) also lowered arterial pressure while raising cardiac output and vascular conductance. These effects were insensitive to propranolol and hyoscine methyl bromide, and were not mimicked by cortisol or adrenaline. It is concluded that ACTH-(1–24) has an acute, adrenal-independent, peripheral vasodilator effect as well as a central, anti-shock, effect.

Role of vagal afferents in the haemodynamic response to acute central hypovolaemia in unanaesthetized rabbits

In unanaesthetized mammals, including rabbits, the response to acute central hypovolaemia is biphasic. An initial phase of baroreflex-mediated systemic vasoconstriction is succeeded by an abrupt failure of sympathetic vasoconstrictor drive and haemodynamic decompensation. We have tested whether a signal travelling in the cervical vagus nerves is responsible for the second phase. An inflatable vena caval cuff, an ascending aortic flow probe, and diaphragmatic electrodes were chronically implanted into 7 rabbits. Haemorrhage was simulated by gradual caval constriction so cardiac index (CI) fell linearly at 9% per minute. In Study 1, caval constriction was performed under control conditions, after muscarinic cholinoceptor blockade (MCB), and was repeated twice under MCB after a sham operation. In Study 2, the steps were identical but bilateral cervical vagotomy plus tracheostomy was substituted for sham operation. With or without MCB, caval constriction caused a progressive fall of systemic vascular conductance index (SVCI), and a small decline in mean arterial pressure (MAP) (Phase I). When CI had fallen by ≈ 40%, there was an abrupt rise of SVCI and fall of MAP (Phase II). Sham operation had no effect on either phase. Vagotomy had no effect on Phase I, but the onset of Phase II was delayed until CI had fallen by ≈ 53% in 6 rabbits. In 1 rabbit, Phase II did not occur, even though CI had fallen by 67%. We conclude that an afferent vagal signal does not contribute to the compensatory Phase I, and is not essential for the occurrence of the decompensatory Phase II, of acute central hypovolaemia in unanaesthetized rabbits.

The decompensatory phase of acute hypovolaemia in rabbits involves a central δ1-opioid receptor

Graded caval occlusion in conscious rabbits caused a biphasic response. Phase I was characterized by a fall in conductance so that arterial pressure was maintained. When cardiac output had fallen to 69 ± 2% of its baseline level, phase II supervened. During phase II, conductance rose abruptly and arterial pressure fell to a like-threatening level (< 40 mm Hg). Centrally administered δ-opioid receptor antagonists prevented the occurence of phase II. The relative order of potency was 7-benzyl-idenenaltrexone (BNTX, δ 1-selective) > N,N-diallyl-Tyr-Aib-Phe-Leu-OH (ICI 174 864) > naltrindole (δ 2-selective). It is concluded that a central δ 1-opioid receptor is involved in the onset of the second decompensatory phase of the haemodynamic response to haemorrhage.

Effect of Alcohol, Neurohypophysectomy, and Vasopressin Antagonists on Hemorrhage-Induced Bradycardia in the Rat

During initial stages of hemorrhage in the rat, cardiovascular compensation leads to a tachycardia (mean +/- SE, 5.2 +/- 0.7%; n = 23) that helps prevent a large fall in blood pressure. This compensatory phase is followed by a decompensatory phase in which mean arterial pressure and heart rate fall. A rise in arginine vasopressin (AVP) levels has been postulated as the cause of this hemorrhage-induced bradycardia (HIB). The object of the present study was to determine whether interference with AVP release by alcohol anesthesia or neurohypophysectomy or by blockade of AVP receptors in the plasma or cerebral spinal fluid could attenuate HIB. Male Wistar rats were anesthetized with pentobarbital, surgically prepared, and bled to maintain a blood pressure of 40-50 mm Hg. After hemorrhage, heart rate decreased 15 +/- 2% (n = 6) with alcohol anesthesia compared with 32 +/- 3% (n = 7) with pentobarbital. After neurohypophysectomy, however, HIB remained unchanged (-15 +/- 2%; n = 5) compared with sham-operated controls (-19 +/- 3%; n = 6). Peripheral administration of two nonselective V1/V2 antagonists and one V2 antagonist had no effect on HIB, whereas a V1 antagonist significantly attenuated the heart rate decrease (-15 +/- 4%; n = 6) compared with controls (-32 +/- 3%; n = 7). None of the AVP antagonists tested at one tenth the peripheral dose had any effect on HIB when administered into the lateral ventricle of the brain, although a mixed serotonin, dopamine, and catecholamine antagonist, spiperone, potentiated the response. It was concluded that although peripheral release of AVP may be partially involved in the heart rate response to hemorrhage, central AVP release and central AVP receptors were not involved in HIB.