Total Autonomic Blockade Research Articles

The role of the autonomic nervous system in control of cardiac and air-breathing responses to sustained aerobic exercise in the African sharptooth catfish Clarias gariepinus

Clarias gariepinus is a facultative air-breathing catfish that exhibits changes in heart rate (ƒH) associated with air-breaths (AB). A transient bradycardia prior to the AB is followed by sustained tachycardia during breath-hold. This study evaluated air-breathing and cardiac responses to sustained aerobic exercise in juveniles (total length~20cm), and how exercise influenced variations in fH associated with AB. In particular, it investigated the role of adrenergic and cholinergic control in cardiac responses, and effects of pharmacological abolition of this control on air-breathing responses. Sustained exercise at 15, 30 and 45cms−1 in a swim tunnel caused significant increases in fAB and fH, from approximately 5breathsh−1 and 60heartbeatsmin−1 at the lowest speed, to over 60breathsh−1 and 100beatsmin−1 at the highest, respectively. There was a progressive decline in the degree of variation in fH, around each AB, as fAB increased with exercise intensity. Total autonomic blockade abolished all variation in fH during exercise, and around each AB, but fAB responses were the same as in untreated animals. Cardiac responses were exclusively due to modulation of inhibitory cholinergic tone, which varied from >100% at the lowest speed to <10% at the highest. Cholinergic blockade had no effect on fAB compared to untreated fish. Excitatory β-adrenergic tone was approximately 20% and did not vary with swimming speed, but its blockade increased fAB at all speeds, compared to untreated animals. This reveals complex effects of autonomic control on air-breathing during exercise in C. gariepinus, which deserve further investigation.

Cardioacceleratory responses to hypocretin-1 injections into rostral ventromedial medulla

Intracisternal injections of hypocretin-1 (hcrt-1) have been shown to elicit sympathoexciatory responses. However, the location of central sites that may mediate these cardiovascular effects have not been clearly elucidated. This study was done in male Wistar rats to investigate the effects of microinjections of hcrt-1 into the rostral ventromedial medulla (RVMM) on mean arterial pressure (MAP), heart rate (HR) and the arterial baroreflex. An initial series of experiments was done to provide a detailed mapping of the location of hcrt-1- and hcrt-1 receptors (hcrtR-1)-like immunoreactivity (ir) in the RVMM region. Hcrt-1 and hcrtR-1 ir were found throughout the RVMM region, but primarily within the magnocellular reticular nucleus and the adjacent nucleus paragigantocellularis lateralis. In the second series, this region containing hcrt-1 and hcrtR-1 ir was explored for sites that elicited changes in MAP and HR in the anaesthetized rat. Microinjection of hcrt-1 (0.5–2.5 pmol) into the region of magnocellular reticular nucleus elicited a dose-dependent increase in HR, with little or no change in MAP. Administration (iv) of the muscarinic receptor antagonist atropine methyl bromide significantly attenuated (∼62%) the HR response whereas, the total autonomic blockade abolished the HR response. Finally, unilateral or bilateral microinjection of hcrt-1 into the magnocellular reticular nucleus significantly attenuated the reflex bradycardia resulting from the activation of the baroreflex following the increase in MAP from an iv injection of phenylephrine. These data suggest that hcrt-1 in the RVMM region activates neuronal circuits that both inhibit vagal activity and increase sympathetic activity to the heart, and that it alters the excitability of central circuits that reflexly control the circulation.

An American contribution to German anesthesia.

An American contribution to German anesthesia.

Pharmacological profile of depressor response elicited by sarthran in rat ventrolateral medulla.

Injection of sarthran, an angiotensin receptor antagonist, bilaterally into the rostral ventrolateral medulla (RVLM) of alpha-chloralose-anesthetized rats decreases arterial pressure (AP) to the same extent as total autonomic blockade. This response is not reproduced by selective AT(1) antagonists. To examine the pharmacological profile of the response elicited by [Sar(1), Thr(8)]ANG II (sarthran), the ability of angiotensin analogs to inhibit the effect of sarthran injected into the RVLM was tested. Coinjection of angiotensin II (ANG II) prevented the sarthran-evoked decrease in AP, but this action of ANG II was markedly attenuated by pretreatment of the RVLM with the aminopeptidase inhibitor amastatin. Coinjection of ANG(3-8) or a selective agonist of AT(4) receptors prevented the effect of sarthran injected into the RVLM. ANG(1-7) was also able to prevent the effect of sarthran. None of the angiotensin fragments tested substantially altered blood pressure when injected alone into the RVLM. These results suggest that the depressor action of sarthran injected into the RVLM is not dependent on ANG II receptors, though the nature of the site or sites of action of sarthran within the RVLM remains uncertain.

Abnormality of alpha-adrenergic vascular response in patients with neurally mediated syncope

Although diagnosis of neurally mediated syncope (NMS) using the head-up tilt (HUT) test has been established, the precise etiologic mechanism of NMS is still obscure. Previously, we reported the contribution of impaired α-adrenergic vascular response to syncope in patients with various arrhythmias. This study evaluates α-adrenergic vascular response in 21 NMS patients with syncope and a positive HUT test (80 degrees, 30 minutes, and low-dose isoproterenol, NMS group, mean age 31 ± 14 years) and 21 control subjects (C group, 33 ± 14 years) who had no evidence of syncope and no structural heart disease. After 30 minutes in a recumbent position, pharmacologic total autonomic blockade was attained using atropine and propranolol. Thereafter, increased systolic blood pressure with 0.4 μg/kg/min phenylephrine (designated as ΔBPphenyl) and decreased systolic blood pressure with 0.5 μg/kg/30 seconds of phentolamine (designated as ΔBPphent) were measured as indexes of α-adrenergic vascular sensitivity and activity, respectively. ΔBPphenyl in the NMS group (70.0 ± 37) was significantly less than that in C group (107 ± 38, p <0.005). ΔBPphent was significantly greater in the NMS group than in the C group (33.5 ± 10 vs 21.0 ± 14, p <0.005). Thus, decreased α-adrenergic vascular sensitivity and elevated α-adrenergic vascular tone were observed in patients with NMS. Although it is not known whether the mechanism causing NMS can be attributed to this abnormal α-adrenergic vascular response, the abnormality could at least contribute to augmenting the symptoms of NMS.

Tonic glutamate-mediated control of rostral ventrolateral medulla and sympathetic vasomotor tone.

Sympathoexcitatory neurons in the rostral ventrolateral medulla (RVLM) play a key role in the tonic maintenance of resting arterial pressure. Removal of tonically active inhibitory inputs to the RVLM provided by the caudal ventrolateral medulla (CVLM) elicits a large increase in arterial pressure. The present study addresses the hypothesis that excitatory amino acids (EAA) provide the excitation of the RVLM responsible for the increase in arterial pressure that occurs after withdrawal of CVLM-mediated inhibition of the RVLM. In rats anesthetized with either alpha-chloralose or urethan, inhibition of the CVLM by local injection of muscimol markedly elevated arterial pressure. Subsequent injection of the EAA receptor antagonist kynurenic acid into the RVLM caused arterial pressure to fall to levels comparable to those that occur-with total autonomic blockade. In contrast, injection of kynurenic acid into the RVLM of control rats had little effect on arterial pressure. These results indicate that the large increase in arterial pressure produced by inhibition of the CVLM is mediated by EAA excitation of RVLM neurons. Furthermore, these data suggest that EAA play a prominent role in the tonic excitation of RVLM neurons, but, in intact rats, inhibition of EAA in the RVLM elicits no change in arterial pressure because of removal of inhibitory as well as excitatory drives of the RVLM.

Cardiovascular effects of neurotensin microinjections into the nucleus of the solitary tract

Neurotensin (NT) immunoreactivity and binding sites have been demonstrated to be extensively distributed throughout the caudal nucleus of the solitary tract (NTS). In this study, the cardiovascular effects of microinjecting the tridecapeptide neurotensin (NT) or its analogues NT 1–8 and [ d-Trp 11]NT into NTS were investigated in the chloralose-anesthetized, paralyzed and artificially ventilated rat. Microinjection of NT (10 pmol) elicited decreases in arterial pressure (AP) (−34 ± 3 mm Hg) and heart rate (HR) (−28 ± 2 beats/min), whereas microinjection of equimolar amounts of the NT fragment NT 1–8 elicited a significantly smaller depressor response (−14 ± 3 mm Hg), but the bradycardic (−22 ± 4 beats/min) response was similar in magnitude to that elicited by NT. On the other hand, microinjection of [ d-Trp 11]NT did not elicit cardiovascular responses from sites in NTS. In addition, the prior injection of [ d-Trp 11]NT into cardiovascular responsive sites in the NTS did not significantly reduce the AP or HR response to NT. The depressor response elicited by NT was not affected by bilateral vagotomy but was abolished by either C1–C2 spinal cord transection or the i.v. administration of the nicotinic receptor blocker hexamethonium bromide. The cardiac slowing was partially attenuated by either bilateral vagotomy (−19 ± 2 beats/min, i.v. administration of atropine methyl bromide (−17 ± 4 beats/min), i.v. administration of hexamethonium bromide (−11 ± 4 beats/min) or by spinal cord transection (−12 ± 3 beats/min), and completely abolished after total autonomic blockade or by combined bilateral vagotomy and spinal cord transection. These data have demonstrated that within a restricted region of the caudal NTS NT activates neurons that contribute to vasodepressor responses as a result of sympatho-inhibition and to bradycardia responses as a result of vagal excitation and sympatho-inhibition. Furthermore, these data suggest that NT may act as a neurotransmitter or modulator in central cardiovascular reflex pathways.

Autonomic blockade amplifies cortisol-induced hypertension in man.

1. We investigated the role of the autonomic nervous system (ANS) in cortisol induced hypertension using the technique of total autonomic blockade (AB). 2. Four healthy young males were given 50 mg cortisol 6 hourly for 6 days. On the day prior to, and the last day of, cortisol treatment, AB was produced using oral prazosin 1 mg, intravenous clonidine 300 micrograms, propranolol 0.2 mg/kg and atropine 2 mg. The adequacy of blockade was assessed using the haemodynamic response to Valsalva manoeuvre. 3. Cortisol produced a significant rise in systolic blood pressure (130 +/- 2 vs 110 +/- 1 mmHg, pre vs post cortisol; P < 0.01). On the final treatment day, AB augmented the increase in diastolic blood pressure (delta DBP), mean arterial pressure (delta MAP) and heart rate (delta HR) compared to the pretreatment day, delta DBP: 43 +/- 6 vs 17 +/- 4 mmHg, post vs pre cortisol, P < 0.005, delta MAP: 39 +/- 4 vs 14 +/- 4 mmHg, P < 0.001, delta HR: 45 +/- 5 vs 26 +/- 4 b.p.m., P < 0.05. The change in systolic blood pressure (delta SBP) was not statistically significant (32 +/- 4 vs 7 +/- 3 mmHg, P = 0.065). 4. These results suggest that the ANS exerts a modulating influence on the hypertensive effect of cortisol.

Time‐Frequency Analysis of Heart Rate Variability

Background: The heart rate variability (HRV) signal is mainly analyzed in frequency‐domain and the signal's spectrum is estimated using either Fast Fourier Transformation (FFT) or the autoregressive (AR) model. These two methods assume that the HRV signal is stationary and additionally the AR method is based on the assumption that the model is linear and the signal is monocomponent in nature. Qualities of spectral estimates are thus closely related to the validity of the above assumptions. Evidence has accumulated indicating that HRV is a multicomponent, nonlinear and nonstationary signal. Then the spectral representations currently used would yield global, approximate, and smoothed view of HRV dynamics.Methods: We applied time‐frequency (TF) analysis methods, smoothed pseudo‐Wigner distribution (SPWD), and spectrogram and complemented for validation by FT spectrum to the HRV signal of fifteen apparently healthy volunteers (mean age 27.2 ± 5.6 years). Short‐term electrocardiograms (ECG) were recorded during supine and upright tilting positions (baseline recording). After baseline recording we induced parasympathetic, sympathetic, and total autonomic blockade correspondingly to six, nine, and four subjects. In addition, in four patients ECGs were recorded during controlled respiration.Results: SPWD and spectrogram revealed strips in frequency, or TF components, corresponding to FT components. High frequency (HF) components appeared stationary (in wide sense), with slight mean frequency shifts during spontaneous respiration, concurrent with respiratory motions. Low frequency (LF) and very low frequency (VLF) components had a nonstationary character displaying activity burst in time and interrelation in frequency. Upright tilting caused a uniform reduction in intensity and bandwidth of the HF component and enhancement of intensity and burst activity of the LF component. There was a pronounced decline of HF and LF components’intensity and decrease of HF component's bandwidth after parasympathetic blockade and total autonomic blockade, while the VLF component did not change. Sympathetic blockade was accompanied by augmentation of the LF and HF components’intensity associated with an increase in the HF component's bandwidth and the spreading of it in the region between the LF and HF. The LF component exhibited less burst activity during tilting under sympathetic blockade, as compared to baseline recordings during tilt. The VLF component's behavior did not change after sympathetic, parasympathetic, and total autonomic blockades.Conclusion: Application of TF distributions to the HRV signal offers a new representation of HRV dynamics. SPWD unveiled features in the HRV signal not available in separate time‐ and frequency‐domains. TF components display idiosyncratic behavior patterns in time and were effected by physiological and pharmacological interventions. A.N.E. 1996;1(4):411–418

Effect of autonomic blockade on pressor responses to vasopressin in pregnant rats

We tested the hypothesis that gestational changes in reflex neural control of the heart and vasculature contribute to altered cardiovascular responses to vasopressin during pregnancy. Changes in mean arterial pressure, cardiac output, total peripheral resistance, and heart rate were measured in response to constant infusion of arginine vasopressin (0.15 to 2.5 mU/kg/min) in conscious pregnant and virgin rats (n = 9) with total autonomic blockade plus restoration of baseline hemodynamics by norepinephrine infusion. Resting cardiac output was 40% higher and total peripheral resistance 30% lower in pregnant animals (p < 0.01). Constant infusion of arginine vasopressin evoked equivalent changes in mean arterial pressure in both groups, but the respective contributions of cardiac output and total peripheral resistance to mean arterial pressure differed between groups. Cardiac output was unchanged and the increase in total peripheral resistance was significantly blunted in pregnant vs virgin rats during arginine vasopressin infusion. Control data in nonblocked revealed similar pressor responses to arginine vasopressin in gravid compared with virgin rats but no differences in the contributions of cardiac output and total peripheral resistance to the change in mean arterial pressure. These findings suggest that neural modulation of arginine vasopressin-induced hypertension is altered during pregnancy and are consistent with a reduction in intrinsic vascular sensitivity to arginine vasopressin during gestation.

COMPARATIVE HAEMODYNAMIC EFFECTS OF VERAPAMIL, FLECAINIDE, AMIODARONE AND SOTALOL IN THE CONSCIOUS RABBIT

1. The effect of intravenous boluses of verapamil (0.15 mg/kg), flecainide (2 mg/kg), amiodarone (5 mg/kg), and sotalol (1.5 mg/kg) on mean arterial pressure, heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), and peak rate of change of left ventricular pressure (LV dP/dt) were assessed in the conscious rabbit. 2. All four drugs had negative inotropic effects: verapamil reduced peak LV dP/dt by 19 +/- 4% (mean +/- s.e.m.; P < 0.01), flecainide by 27 +/- 9% (P < 0.001), amiodarone by 11 +/- 2% (P < 0.01) and sotalol by 13 +/- 3% (P < 0.01). 3. The drugs had different effects on CO as a result of differences in their actions on peripheral blood vessels: verapamil and amiodarone produced, respectively, a 12 +/- 4% (P < 0.03) and 16 +/- 6% (P < 0.01) increase in CO associated with a substantial vasodilatory effect (TPR reduced 15 +/- 7% [P < 0.05] and 20 +/- 5% [P < 0.01], respectively). Flecainide caused only a small (6 +/- 1%; P < 0.01) increase in CO and sotalol had no effect on either CO or TPR. 4. Bolus intravenous injections of verapamil, flecainide and amiodarone produced an increase in HR, while sotalol reduced HR by 10 +/- 2% (P < 0.01). The increase in HR and cardiac output seen with verapamil, flecainide and amiodarone was in part secondary to reflex increase in sympathetic tone and these changes were abolished after total cardiac autonomic blockade. 5. The modest reduction in cardiac performance associated with sotalol was abolished by cardiac autonomic blockade, suggesting that the predominant effect of sotalol on contractility was mediated through its beta-adrenoceptor blocking effect.

Total autonomic blockade eliminates the attenuated pressor response to angiotensin II in pregnant rats

Pressor responses to angiotensin II (ANG II) are markedly attenuated in reflex-intact pregnant animals, a phenomenon widely attributed to intrinsic changes in vascular reactivity. To test the hypothesis that gestational augmentation of neural reflex activity contributes importantly to this phenomenon, changes in mean arterial pressure (MAP), cardiac output (CO), and total peripheral resistance (TPR) were compared during constant infusion (25-400 ng.kg-1.min-1) of ANG II in conscious virgin and pregnant rats, using a model of total autonomic blockade (chlorisondamine chloride and methscopolamine bromide), with restoration of baseline hemodynamics by infusion of norepinephrine. Basal CO was higher and TPR lower in pregnant (CO 121.8 +/- 3.8 ml/min; TPR 0.78 +/- 0.04 mmHg.ml-1.min) compared with virgin (CO 95.9 +/- 3.9 ml/min; TPR 1.05 +/- 0.08 mmHg.ml-1.min) rats (P < 0.005). Pressor responses to ANG II were similar in both groups of reflex-blocked animals due to comparable changes in TPR and CO (not significant by repeated-measures analysis of variance). Other experiments demonstrated that changes in MAP after bolus administration of ANG II did not differ in areflexic virgin and gravid rats. Thus in the absence of autonomic control ANG II has similar effects on systemic resistance in pregnant and nonpregnant rats, suggesting that reflex neural mechanisms contribute significantly to gestational changes in pressor responsiveness. These data further suggest that pregnancy is not accompanied by a generalized decrease in vascular reactivity to all pressor agents.

Autonomic regulation of heart rate and blood pressure in hemorrhaged toads.

Mean arterial blood pressure (P(a)) and heart rate (HR) were studied in normal conscious cane toads (Bufo marinus) or in autonomically blocked animals treated variously with bretylium, atropine, phentolamine, and propranolol. Partial or total autonomic blockade had no effect on resting values of the variables tested, with the exception that atropine treatment of bretylium-treated toads caused an increase of heart rate by 5.3 +/- 1.3 beats/min. In graded hemorrhage, aliquots of blood (1.68 ml/100 g body wt) were removed at 60-min intervals. There was extensive plasma recruitment, and blood could be removed up to 10.08 ml/100 g without inducing cardiovascular shock. Each hemorrhage caused an initial transient decrease in P(a) and increase in HR followed by recovery toward prehemorrhage values. Repeated hemorrhage caused a progressive rise in basal HR and fall in basal P(a). The effects of drug treatments suggest that transient increases in HR may be caused by the release of adrenal catecholamines. In addition, hemorrhage may increase sympathetic tone so that basal HR becomes elevated, which, together with sympathetic vasoconstriction, limits the progressive fall of basal P(a).

The autonomic nervous system modulates dry air-induced constriction in the canine lung periphery.

To determine the modulatory role of the autonomic nervous system on dry air-induced bronchoconstriction (AIB) in the canine lung periphery, we examined the effect of cholinergic, alpha- and beta-adrenergic, and total autonomic ganglionic blockade on AIB. Pretreatment with atropine significantly attenuated AIB by approximately 30%, indicating that AIB is partially mediated via a vagal reflex. Pretreatment with either phentolamine or propranolol did not affect AIB, indicating that alpha- and beta-adrenoceptors, respectively, were not activated in response to dry air challenge. In contrast, pretreatment with hexamethonium significantly potentiated AIB. In addition, exogenous vasoactive intestinal peptide (VIP), a potential neurotransmitter for the nonadrenergic-noncholinergic (NANC) inhibitory system, significantly inhibited AIB. We conclude that (1) neither alpha- or beta-adrenergic efferents are activated during dry air challenge, (2) total autonomic blockade potentiates the response to dry air, and (3) VIP attenuates AIB. Based on these observations, we speculate that NANC inhibitory activity may be stimulated during dry air challenge and antagonizes AIB.

Dual effect of insulin on plasma volume and transcapillary albumin transport

During the past decade it has been demonstrated that insulin, apart from its effects on metabolism and ion fluxes, has acute effects on the cardiovascular system and capillary permeability. Intravenous infusion of insulin in doses which increase plasma insulin to physiological levels, induced vascular dilatation and increased muscle sympathetic nerve activity during a euglycaemic glucose clamp. During similar conditions insulin increased the transcapillary escape rate of albumin and reduced plasma volume. Insulin has also an indirect effect on vascular permeability during hypoglycaemia, which is mediated by the increase in plasma adrenaline. Adrenaline infusion increased haematocrit and decreased plasma volume and intravascular albumin mass. In contrast to insulin adrenaline did not increase the transcapillary escape rate of albumin. Total autonomic blockade during insulin-induced hypoglycaemia abolished the increase in haematocrit, but did not influence the decrease in plasma volume and the increase in the transcapillary escape rate of albumin. Insulin administration may also increase urinary albumin excretion, and this effect was observed during a euglycaemic clamp. The mechanism of the increase in capillary permeability after insulin has not been elucidated. A number of morphological studies indicate that insulin may have effects on endothelial cell morphology and paraendothelial cell permeability. These results indicate that insulin, apart from its effect on peripheral blood flow, may play a role in a normal transfer of macromolecules from the blood to the extracellular space after food intake. This process may be greatly disturbed in insulin-dependent diabetic patients.

Plasma glucagon and glucose recovery after hypoglycemia: the effect of total autonomic blockade.

The role of the autonomic nervous system in the glucagon response to hypoglycemia has not been fully clarified. We have studied the effect of total pharmacological blockade of the autonomic nervous system (concomitant alpha- and beta-adrenergic blockade with simultaneous atropine injection) and of isolated alpha-adrenergic blockade on hormonal responses to hypoglycemia and on blood glucose recovery after hypoglycemia in healthy subjects. Neither of the pharmacological blockades had any significant effects on plasma glucagon responses to hypoglycemia nor had they any effect on the rate of blood glucose recovery after hypoglycemia. We conclude that the autonomic nervous system has no major influence on the glucagon response to hypoglycemia in healthy man. Changes in autonomic nervous activity are not essential for blood glucose recovery after hypoglycemia in healthy man.

HAEMODYNAMIC RESPONSES TO N‐NITRO‐l‐ARGININE IN CONSCIOUS RABBITS

1. The effect of N-nitro-L-arginine (NOLA) on mean arterial pressure (AP), hindlimb vascular resistance (HVR) and heart rate (HR) was examined in conscious rabbits. 2. NOLA (15 mg kg, i.v.) increased AP (delta AP = 14 +/- 3 mmHg) and HVR (delta HVR = 0.8 +/- 0.3 U) and decreased HR (delta HR = -66 +/- 8 beats/min). AP remained elevated for at least 2 h following NOLA infusion but had returned to control levels after 24 h. In contrast, the hindlimb vaso-constriction and bradycardia were sustained for at least 48 h but had returned to control levels after 72 h. 3. In the presence of total autonomic blockade (hexamethonium 30 mg/kg; propranolol 1 mg/kg and atropine 0.1 mg/kg) NOLA continued to have a pressor (delta AP = 33 +/- 9 mm Hg) and hindlimb vasoconstrictor action (delta HVR = 0.4 +/- 0.1 U) but did not affect HR (delta HR = -1 +/- 3 beats/min). 4. NOLA has a prolonged pressor and vasoconstrictor action which is independent of any action in the central nervous system and which results in a marked reflex bradycardia. These results suggest that the peripheral biosynthesis of nitric oxide is important in regulation vascular tone and arterial pressure.

Plasma volume changes during hypoglycaemia: the effect of autonomic blockade

To investigate the role of the autonomic nervous system in changes in blood volume and composition induced by acute hypoglycaemia in man, seven healthy subjects participated in three experiments on separate days: insulin-induced hypoglycaemia with concomitant alpha-adrenoceptor blockade; insulin-induced hypoglycaemia with total autonomic blockade (alpha-adrenoceptor blockade combined with beta-adrenoceptor blockade and atropine); and insulin-induced hypoglycaemia without any autonomic blockade. In the experiments without autonomic blockade the peripheral venous hematocrit increased, plasma volume decreased, intravascular albumin content decreased and the transcapillary escape rate of albumin increased. In both experiments with autonomic blockade the increase in venous haematocrit was abolished, yet plasma volume decreased, intravascular albumin content decreased and the transcapillary escape rate of albumin increased in these experiments. Thus, the changes in plasma volume and composition in response to hypoglycaemia are due to the combined actions of adrenaline and of insulin.

Autonomic, hormonal, and local circulatory effects of hemorrhage in conscious rabbits

Conscious instrumented rabbits were bled at a constant rate of congruent to 3% of the blood volume (BV) per minute. We determined the BV-response relationships for mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), mesenteric and hindlimb blood flows, and for the corresponding conductances. We studied the responses 1) under normal conditions; 2) after pretreatment with captopril, arginine vasopressin (AVP) antagonist, or both; 3) during total autonomic blockade (TAB); and 4) during neurohumoral blockade (NHB, i.e., TAB + captopril + AVP antagonist). We determined the direct local response component from the responses obtained during NHB. The local chronotropic effects congruent to 0, so that the reflex rise in HR was entirely autonomically mediated. The local vascular response consisted of vasodilatation and provided the base line for assessing the estimated constrictor component from the net response from control, with the former ranging from 2 to 16 times the conventional estimates based on the net responses. In normal rabbits, the phase of good maintenance of MAP was entirely governed by autonomic mechanisms, which minimized the fall in CO and offset the local vasodilator component. During the hypotensive phase immediately after hemorrhage, when congruent to 30-35% BV had been removed, the constrictor effects of AVP and angiotensin II (ANG II) became important, whereas the role of autonomic mechanisms diminished. During TAB, the constrictor effects of AVP and ANG II were prominent even with small BV losses.

Reflex release of vasopressin and renin in hemorrhage is enhanced by autonomic blockade

We determined the relationships during hemorrhage between nominal blood volume (BV) and 1) plasma arginine vasopressin (AVP), 2) plasma renin activity (PRA), and 3) mean arterial pressure (MAP). Conscious rabbits were studied under normal conditions and during total autonomic blockade (TAB) at bleeding rates of 2 and 4 ml/min. Normally, MAP was well maintained until BV had been reduced to approximately 65% of control (termed 65% BV) after which it fell abruptly. The threshold for a rise in AVP was 80-75% BV, followed by exponential rises to levels of 14 and 24 times control at the slow and fast rate of bleeding. PRA rose earlier in hemorrhage, but this rise was more gradual, to values at 60% BV of 5.5 and 7 times control at the two rates of bleeding. During TAB, MAP fell rapidly and both BV concentration curves were shifted to the left with the rises in AVP and PRA/unit delta BV greater than normal; at 75% BV at each rate of hemorrhage, AVP and PRA had risen, respectively, to approximately 40 and 8 times control. Normally, the rises in the AVP and PRA (i.e., angiotensin II) concentrations were modest during the nonhypotensive phase, consistent with their minimal constrictor action observed in a parallel study. During the hypotensive phase, both reached high levels in the constrictor range. During TAB, high concentrations were reached with small BV loss, representing a model of near-maximum release of PRA and AVP.