Circulatory control in hypoxia by the sympathetic nerves and adrenal medulla

1. The effects of severe arterial and primary tissue (carbon monoxide) hypoxia on cardiac output, arterial and right atrial pressures, heart rate and ventilation, have been studied in unanaesthetized normal rabbits, and in animals subjected to adrenalectomy, ;sympathectomy' (guanethidine), adrenalectomy + ;sympathectomy', and section of the carotid sinus and aortic nerves.2. In both arterial and primary tissue hypoxia the sympathetic nerves play a more important part in the normal circulatory response than the adrenal medullary hormones.3. Provided one adrenergic effector pathway remains intact, animals with intact chemoreceptors and baroreceptors tolerate both types of hypoxia well. Circulatory control during both types of hypoxia by means of sympathetic nerves alone produces relatively more peripheral vasoconstriction than is observed during reflex control through increased adrenal catecholamine secretion.4. The occurrence of tonic sympathetic activity in animals with section of carotid sinus and aortic nerves permits maintenance of a high cardiac output during hypoxia but the arterial pressure is low and there is probably less selective distribution of blood flow to the periphery than in animals with normal reflex control.5. Absence of any adrenergic activity in adrenalectomized and ;sympathectomized' animals results in a gradual fall in cardiac output during prolonged hypoxia, after an initial small rise.6. The results in guanethidine-treated animals suggest that the sympathetic discharge to the arterial chemoreceptors is a factor sustaining chemoreceptor discharge during prolonged arterial hypoxia.     

Local and reflex factors affecting the distribution of the peripheral blood flow during arterial hypoxia in the rabbit

1. The effects of severe arterial hypoxia on the blood flow in the portal vein, and in kidney, muscle and skin beds have been determined in normal unanaesthetized rabbits, in animals without functioning autonomic effectors, and in rabbits with section of the carotid sinus and aortic nerves.

2. The resting blood flows in the above regions were not significantly different in the three groups.

3. The susceptibilities of the various beds to the local dilator effects of arterial hypoxia (assessed from the responses of animals without functioning autonomic effectors) were markedly different; vasodilatation was by far the greatest in the portal bed, followed in order by the renal, skin and muscle beds.

4. Section of the carotid sinus and aortic nerves completely abolished reflex activity, and the pattern of peripheral blood flow changes was similar to that of animals without functioning autonomic effectors. The findings suggest that the arterial chemoreceptors are the primary afferent source of reflex control of the peripheral circulation in arterial hypoxia.

5. In normal animals with intact reflexes there was sustained vasoconstriction throughout the treatment period in the portal and renal bed. The net vasomotor effects in muscle and limb skin were small owing to the operation of a number of factors, which opposed the effects of reflexly increased sympathetic nerve activity.

     

Effects of haemorrhage on the distribution of the peripheral blood flow in the rabbit

1. The effects of bleeding unanaesthetized rabbits by 26% of their blood volume on the blood flow in the portal, renal, muscle and skin beds were investigated in normal animals, in animals without functioning autonomic effectors, and in animals with section of the carotid sinus and aortic nerves.2. In animals without functioning autonomic effectors there was progressive vasodilatation during the 4 hr following haemorrhage, which differed markedly in the different regional beds studied. The dilatation was greatest in the portal bed, followed by kidney and skin, but there was no significant change in the vascular resistance in muscle.3. In normal animals with intact reflexes the vascular resistance either increases or remains at control values, suggesting that reflex constrictor effects oppose locally acting dilator mechanisms. During the 4 hr following haemorrhage reflex vasoconstrictor effects were greatest in kidney, followed by muscle, portal bed and skin.4. In animals with section of the carotid sinus and aortic nerves reflex constrictor effects were absent in the portal, muscle and skin beds, but significant vasoconstriction was still evident in the renal bed, though of smaller magnitude than in normal animals. The results suggest that the arterial baroreceptors are a major source of reflex activity following haemorrhage, but that other reflexogenic zones contribute to the renal effects in normal animals.     

The relative roles of the aortic and carotid sinus nerves in the rabbit in the control of respiration and circulation during arterial hypoxia and hypercapnia

1. The respiratory and circulatory effects of graded arterial hypoxia, alone or with superadded hypercapnia, were studied in four groups of unanaesthetized rabbits including normal animals and those with selective section of the aortic nerves, selective section of the carotid sinus nerves and section of both sets of nerves.

2. When measured 2-4 days after selective section of the carotid sinus nerves the resting respiratory minute volume and arterial P_O2 were lower and the P_CO2 higher than normal. These effects were not observed after selective section of the aortic nerves. Selective aortic nerve section, and selective carotid sinus nerve section each produced a similar increase in the resting arterial pressure and heart rate, but were without effect on the resting cardiac output.

3. During arterial hypoxia reflex respiratory and circulatory effects ascribable to arterial chemoreceptor stimulation (hyperventilation, bradycardia, vasoconstriction) were mediated for the most part through the carotid sinus nerve. In animals with only the aortic nerves intact the circulatory response was determined largely by the opposing effects of aortic baroreceptor reflexes and the local peripheral dilator action of hypoxia.

4. The circulatory effects of hyperventilation induced by hypercapnia during arterial hypoxia, in animals with both aortic and carotid sinus nerves cut were small.

5. The results suggest that relatively few chemoreceptor fibres originate from the aortic region in the rabbit, though the carotid sinus and aortic nerves both contain baroreceptor fibres.

     

Circulatory effects of chloralose-urethane and sodium pentobarbitone anaesthesia in the rabbit

1. The effects of chloralose-urethane and sodium pentobarbitone anaesthesia on heart rate, blood pressure and cardiac output were studied in normal rabbits, in animals given atropine and in animals without functioning autonomic effectors. The findings under anaesthesia were compared during spontaneous and artificial intermittent positive pressure respiration.2. The circulatory effects of chloralose-urethane and sodium pentobarbitone anaesthesia differed significantly for the first hour after induction of anaesthesia. During the subsequent 3 hr of maintained anaesthesia differences in the circulatory effects of the two anaesthetics were small.3. The direct local effects of these anaesthetics were assessed during the maintenance phase from the responses of animals without functioning autonomic effectors. With both anaesthetics there was peripheral vasodilatation and minimal effects on heart rate.4. The autonomic activity in the normal animal was assessed by comparing the changes in normal, atropinized and ;de-efferented' rabbits without functioning autonomic effectors. During chloralose-urethane anaesthesia there was reduction in cardiac vagal efferent activity and no change in cardiac sympatho-adrenal activity. With both anaesthetics there was an increase in peripheral sympatho-adrenal constrictor activity, tending to minimize the local vasodilator effects.     

The kidneys and arterial pressure in immature and adult rabbits

1. The effect of stepwise haemorrhage on arterial pressure in adult and immature (9-15 days old) rabbits lightly anaesthetized with sodium pentobarbitone is described.2. Bethanidine (1 or 3 mg/kg) lowered initial arterial pressure but did not impair the maintenance of arterial pressure in immature or adult rabbits during stepwise haemorrhage.3. Arterial pressure was only slightly lower in nephrectomized than in intact adult rabbits; in some immature rabbits nephrectomy caused a substantial fall of resting arterial pressure. This fall was largest in animals of low body weight and low haematocrit. Nephrectomy reduced the ability of both immature and adult rabbits to maintain arterial pressure during haemorrhage.4. Arterial pressure fell more precipitately on stepwise haemorrhage in adult rabbits in which the carotid sinus and depressor nerves had been cut than in intact rabbits. No such difference was seen in immature rabbits despite the fact that initial arterial pressure was higher in denervated animals at all ages.5. The responses to stepwise haemorrhage were compared in dummy operated and nephrectomized immature and adult rabbits with carotid sinus and depressor nerves cut to minimize changes of sympathetic tone. Under these conditions the presence or absence of kidneys made no significant difference in the response to stepwise bleeding in adult rabbits. In immature rabbits maintenance of arterial pressure was greatly impaired in the absence of the kidneys.6. The results suggest that a pressor mechanism of renal origin may be relatively more important in the maintenance of arterial pressure in the face of haemorrhage in immature than in adult rabbits.7. Resting arterial pressure in small and anaemic immature rabbits may partly depend on the presence of the kidneys. At birth arterial pressure is higher in rabbits of higher haematocrit but this relationship reverses in the second week of life when the haematocrit level is falling.     

Oxygen transport of colloidal fluorocarbon suspensions in asanguineous rabbits.

In anesthetized, oxygen-breathing rabbits, the entire blood volume was exchanged with a 20% colloidal fluorocarbon fluid suspension of high gas solubility. In contrast to the control animals with acute isovolemic and hypervolemic hemodilution, the fluorocarbon suspension prevented the decrease in arterial oxygen content below a hematocrit of 13%. However, the more pronounced effect of the fluorocarbon suspension on oxygen delivery occurred at higher hematocrits and was due to its efficiency as a plasma expander, since it increased the cardiac output even above the level of the hypervolemic hemodilution group. The fluorocarbon suspension also raised arterial blood pressure and total peripheral resistance due to its increased viscosity. Thus, in mild hemodilution, the fluorocarbon suspension kept oxygen utilization in the normal range by increasing cardiac output, and in extreme hemodilution it improved oxygen utilization by also raising the arterial oxygen content and arterial blood pressure. The survival time of the isovolemic control animals was 31.6 min, it was extended to 57.8 min in the hypervolemic control animals, and the rabbits with the fluorocarbon suspension lived for 124.8 min.     

Haemodynamic and other studies on the renoprival hypertensive rat

1. The optimal conditions for the development of hypertension after total nephrectomy were defined in the rat. Under these conditions, haemodynamic changes were then studied before and for 3 days after total nephrectomy in the unanaesthetized animal and compared with mock-nephrectomized controls.

2. Changes in cardiac output were followed with an electromagnetic flowmeter chronically implanted on the ascending aorta, and mean arterial pressure with an indwelling aortic cannula.

3. Haematocrit fell in animals developing hypertension, due to plasma volume expansion. Restriction of administered saline did not reduce the fall in haematocrit without also preventing development of the hypertension.

4. Cardiac output and stroke volume increased significantly on the second and third days after nephrectomy. Peripheral resistance remained unchanged and pulse rate tended to fall.

5. The increase in cardiac output appeared to be more than could be accounted for by anaemia alone, and it is suggested that plasma volume expansion was partly responsible.

6. In another group of rats developing renoprival hypertension a correlation was found between changes in plasma volume and arterial pressure over the three days.

7. Renoprival hypertension was accompanied by a slight but significant reduction in oxygen consumption in comparison with the controls.

8. No relationship was found between the changes in blood pressure, and plasma sodium and potassium levels.

9. It is concluded that the observed rise in cardiac output associated with renoprival hypertension as induced in this study was not attributable to anaemia nor to a rise in metabolic rate. The implications of this situation are discussed in relation to a theory of the pathogenesis of hypertension and the findings of other workers.

     

Effects of brainstem lesions on the nasopharyngeal reflex in the conscious rabbit

The cardiovascular responses evoked through the nasopharyngeal reflex by the inhalation of formaldehyde vapour were studied in conscious rabbits after bilateral electrolytic lesions of the ventrolateral medulla coinciding with the A1 group of catecholamine cells. Arterial blood pressure was measured in the central ear artery, heart rate was determined from the arterial pressure trace, and iliac blood flow was determined using a Doppler ultrasonic flow meter placed around the lower abdominal aorta. There were no significant changes in the heart rate, blood pressure and iliac conductance responses elicited through the nasopharyngeal reflexes of sham operated animals in which electrodes were inserted without the passage of current. The blood pressure changes produced by inhalation of formaldehyde in control rabbits were not significantly altered in animals with ventrolateral medullary lesions. However, the magnitude of the bradycardia and of the fall in iliac conductance evoked by the inhalation of formaldehyde were approximately halved 4 h and 1 day after the lesions but were fully restored at 2 weeks. These experiments suggest that the A1 group of catecholamine neurones help mediate the bradycardia and vasoconstriction elicited through nasopharyngeal reflexes in terrestial animals exposed to noxious vapours.     

The reflex effects of alterations in lung volume on systemic vascular resistance in the dog

1. The reflex effects of alterations in lung volume on systemic vascular resistance have been studied in anaesthetized dogs under conditions in which the systemic circulation was perfused at constant blood flow. The pressures in the isolated perfused carotid sinuses and aortic arch, and the arterial blood P_O2 and P_CO2 were maintained constant.

2. A maintained inflation of the lungs produced by injection of air into the trachea caused a fall in systemic arterial perfusion pressure, indicating vasodilatation. The size of the systemic vasodilator response varied directly with the pressure and volume of gas used to inflate the lungs. A similar effect was observed when the tidal volume of lungs ventilated by an intermittent positive pressure was increased.

3. Collapse of the lungs by creating a pneumothorax in closed-chest spontaneously breathing animals evoked a systemic vasoconstrictor response which was reversed when the lungs were re-expanded.

4. These vasodilator responses were abolished by dividing the pulmonary branches of the thoracic vagosympathetic nerves. Evidence is presented that the afferent fibres run in the cervical vagosympathetic nerves and through the stellate ganglia.

5. The responses were unaffected by atropine, but were abolished by hexamethonium, guanethidine and by bretylium tosylate, indicating that they are mediated via the sympathetic nervous system.

6. Evidence is presented that the lungs are a constant course of afferent impulses inhibiting the `vasomotor centre', and that the lung inflation—systemic vasodilator reflex is a potential mechanism operating in eupnoeic breathing.

     

The effects of hypotension and hypovolaemia on the liberation of vasopressin during haemorrhage in the unanaesthetized monkey (Macaca Mulatta)

Summary Using unanaesthetized monkeys, experiments were performed to examine the effects of haemorrhage on the liberation of arginine vasopressin (AVP). Haemorrhages of 10%, 15% or 20% total blood volume were performed via a catheter with its tip in the abdominal vena cava. A catheter in the left internal jugular vein was used for blood sampling. Arterial blood pressure was monitored via a catheter whose tip rested in an iliac artery. The monkeys showed no signs of discomfort from this catheterisation. Blood samples for AVP assay were taken at different times from 0–90 min after the end of the haemorrhage. At the end of the experiment, blood removed was reinfused. Results show that haemorrhage resulted in liberation of AVP, but only if there was a fall in arterial blood pressure. AVP release occured more readily as the total volume of blood withdrawn increased, but the absolute rise in hormone concentration was not related to the total volume of blood withdrawn. However, comparing the area under the curve of mean arterial blood pressure with that for AVP concentration showed the two to have a significant exponential relationship. It is concluded that, as in other species, haemorrhage is a potent stimulus for AVP liberation in the monkey. However, in contrast to some other species, the fall in arterial pressure seems to be the prime stimulus rather than hypovolemia per se.     

Cardiovascular responses to blockade of angiotensin and alpha-adrenergic receptors.

Both angiotensin and alpha-adrenergic blocking agents reduce arterial blood pressure in hypovolemic states. We have compared the effects of an angiotensin antagonist (saralasin) and an alpha-adrenergic blocking agent (phenoxybenzamine) in supramaximal dosage on cardiac output, total peripheral resistance, and venous tone in rabbits rendered hypovolemic by restriction of sodium intake, supplemented by a furosemide-induced diuresis 48 h prior to study. Saralasin (10 microgram/kg per min) reduced arterial blood pressure significantly (-15 +/- 1.2 mmHg) despite an unchanged cardiac output (P less than 0.025) due to a fall in total peripheral resistance. Phenoxybenzamine (5 mg/kg) induced a much larger fall in arterial blood pressure (-28 +/- 3.6 mmHg), despite an identical reduction in total peripheral resistance, because cardiac output also fell (+/- 9 ml/kg per min). The reduction in cardiac output was associated with a significant increase in hindlimb venous distensibility (P less than 0.001) after alpha-adrenergic blockade. Saralasin, conversely, had no influence on venous tone. Adrenergic mechanisms contribute to cardiovascular homeostasis through an influence on both arteriolar and venous tone, whereas the effect of angiotensin is directed entirely to the arteriolar side of the circulation.     

The role of the vagus nerves in the respiratory and circulatory responses to intravenous histamine and phenyl diguanide in rabbits

1. The responses of rabbits, anaesthetized with pentobarbitone sodium, to intravenous injections of histamine and phenyl diguanide have been studied. Total lung conductance, lung compliance, breathing frequency, tidal volume, end-tidal CO(2)%, systemic arterial and right atrial blood pressures and heart rate were measured. Some of the rabbits were first paralysed and artificially ventilated.2. The role of vagal afferent nerves was determined by observing the responses before and after bilateral vagotomy, and before and during cooling the vagus nerves to 8-10 degrees C; such cooling selectively blocks some vagal afferent pathways.3. Histamine decreased conductance (bronchoconstriction), in spontaneously breathing and in paralysed, artificially ventilated animals, and caused rapid shallow breathing. The responses were considerably reduced or abolished by vagal cooling and vagotomy and are thought to be mainly vagal reflexes due to stimulation by histamine of irritant receptors in the lungs.4. Phenyl diguanide also decreased conductance, in spontaneously breathing and in paralysed, artificially ventilated animals, and caused rapid shallow breathing. Vagotomy abolished the respiratory changes and considerably reduced the bronchoconstriction. Vagal cooling caused an equal reduction of the bronchoconstriction but an increase in minute volume persisted. This respiratory response to phenyl diguanide which persists during vagal cooling is thought to be due to stimulation of deflation receptors in the lungs; it was associated with vagal reflex hypotension and bradycardia.5. Both histamine and phenyl diguanide decreased lung compliance when vagal conduction was unimpaired. The effects were largely secondary to changes in the pattern of breathing, although histamine also had a weak direct action on lung tissue leading to a fall in compliance.6. Both histamine and phenyl diguanide decreased end-tidal CO(2)% and increased right atrial pressure by direct (non-vagal) actions on lung tissues. Histamine also caused a non-vagal hypertension.     

Circulatory responses of supine subjects to the exposure of parts of the body below the xiphisternum to subatmospheric pressure

1. Observations are reported on the effects of exposure of parts of the body below the level of the xiphisternum of supine subjects to a pressure 70 mm Hg below atmospheric for 1 min.

2. The stress on the circulation was greater than when parts below the iliac crests were similarly exposed. Heart rate increased by 15-20 beats/min, there was a sustained fall in arterial blood pressure, and forearm blood flow fell profoundly and in some subjects was reduced to below 0·1 ml./100 ml. min.

3. In arms that were sympathectomized, or had received an intraarterial infusion of an adrenergic blocking drug, the fall in forearm blood flow was much less and could be related to the fall in arterial pressure.

4. When the suction was released there was a brief overshoot of arterial blood pressure and brief cardiac slowing. Forearm blood flow rose to reach a peak some 15 sec after the release.

5. In the sympathectomized forearm on release of suction there was an immediate rise in blood flow which was proportionately much greater than the rise in arterial blood pressure.

6. This rise was not due to circulating vasodilator substances or to the activity of cholinergic vasodilator nerves. The possibility that it was the result of a change in the tone of the resistance vessels occurring in response to the sudden change in transmural pressure is discussed.

     

Elevated arterial blood pressure in cardiac tamponade.

BACKGROUND. In cardiac tamponade cardiac output falls, but peripheral vascular resistance increases, so that systemic blood pressure may be maintained at normal or near-normal levels. We recently observed a patient with cardiac tamponade whose blood pressure was markedly elevated. METHODS. To determine the frequency of elevated blood pressure in patients with cardiac tamponade and their hemodynamic characteristics, we studied 18 consecutive patients with cardiac tamponade from a variety of causes using right heart catheterization. RESULTS. Six of the 18 patients had systolic arterial blood pressures ranging from 150 to 210 mm Hg (mean [+/- SD], 176 +/- 26) and diastolic pressures ranging from 100 to 130 mm Hg (mean, 113 +/- 14). All six had previously been hypertensive. After pericardiocentesis there was a significant decrease in blood pressure (to 139 +/- 13 mm Hg systolic, P less than 0.05; and 83 +/- 6 mm Hg diastolic, P less than 0.01) and peripheral vascular resistance (from 2150 +/- 588 to 1207 +/- 345 dyn.sec.cm-5, P less than 0.01). Cardiac output increased in all six. The other 12 patients, 3 of whom had a history of hypertension, had significant increases in cardiac output and systolic blood pressure (from 119 +/- 13 to 127 +/- 7 mm Hg, P less than 0.05) after pericardiocentesis, whereas peripheral vascular resistance decreased. Both groups had similar degrees of cardiac tamponade, as indicated by measurements of cardiac output and intrapericardial, right atrial, and pulmonary-artery wedge pressures. CONCLUSIONS. Elevated blood pressure may occur in some patients with cardiac tamponade who have preexisting hypertension. Moreover, blood pressure may fall after pericardiocentesis in patients who have elevated blood pressure associated with tamponade.     

The effect of haemorrhage on haemoglobin concentration, blood volume and arterial pressure in kittens and cats

1. The arterial haemoglobin concentration in kittens less than 24 hr old was inversely related to body weight. There was about twice as much haemoglobin/unit body weight at birth as in adult cats. Haemoglobin concentrations were minimal at 3-6 weeks of age.2. In animals lightly anaesthetized with sodium pentobarbitone, arterial pressure rose from 52 mm Hg at birth in kittens to 133 mm Hg in adult cats. Blood volume decreased from 73 ml./kg at birth to 60 ml./kg in adults.3. When kittens less than a fortnight old were subjected to stepwise blood letting, arterial pressure fell proportionately with blood volume; in older kittens and in cats, arterial pressure was less well maintained at similar proportionate reductions of blood volume than in young kittens.4. The responses to haemorrhage of kittens and cats were compared with those of rabbits similarly treated and with those of adult cats anaesthetized with urethane and chloralose reported in the literature.     

Acute effects of haemorrhage on the composition of arterial blood in immature and adult rabbits, kittens and cats

1. The fall of haematocrit after stepwise bleeding in rabbits and young kittens was not accompanied by an equivalent fall of plasma nitrogen. The relative failure of plasma nitrogen to decrease after haemorrhage was not attributable to the entry of diffusible nitrogen into the circulation.2. Plasma protein recovery by a combination of stepwise bleeding and viviperfusion was such as to yield values for the whole body/great vessel haematocrit ratio (F(cells)) in the normal range in adult cats but significantly below the normal range in young kittens and rabbits. If viviperfusion was not preceded by stepwise bleeding F(cells) in the normal range was obtained in young kittens and rabbits.3. The results of electrophoretic examination of pre- and post-haemorrhagic plasma were consistent with the entry of fresh protein into the circulation after haemorrhage occurring preferentially in the albumin fraction, but increase of albumin/globulin ratio was small in adult cats.4. It was concluded that the fall of haematocrit after haemorrhage in young kittens and rabbits was mainly due to the entry of protein rich tissue fluid into the circulation. In adult cats, however, the haematocrit did not always fall and any such fall may have been partly due to a shift of plasma from the periphery to the great vessels.5. The bearing of these observations on the validity of calculation of blood volume from red cell mass and haematocrit during stepwise haemorrhage was considered.     

Inefficiency of intracerebroventricular ANP to alter haemodynamic,plasma vasopressin and renin responses to haemorrhage in sheep

Whether intracerebroventricular (i.e.v.) infusion of atrial natriuretic peptide (human-ANP, 1–28) 25 pmol min^-1 influences the tolerance to blood loss and haemorrhage induced cardiovascular, vasopressin and renin responses were studied in five conscious sheep. The i.e. v. infusion was started 60 min prior to a slow (0.7 ml kg^-1 min^-1) venous haemorrhage, was run concurrently with bleeding, and for 90 min thereafter. Venous blood was removed until the mean systemic arterial pressure suddenly fell to about 50 mmHg. There were no statistically significant differences in either the bleeding volume necessary to induce the sudden decrease in blood pressure, or in cardiovascular parameters measured by venous heart thermodilution catheterization, compared with control experiments with i.e.v. infusion of artificial CSF. The plasma protein and vasopressin concentrations and renin activity were unaffected by the i.c.v. infusion of ANP as were the changes in these parameters occurring during the subsequent haemorrhage. The same negative findings were obtained with a three times higher dose of ANP(l-28) (75 pmol min^-1), tested in three of the animals. Thus the i.c.v. infusion of ANP(l-28), in amounts expected to elevate the CSF concentration far above basal levels does apparently not influence normal blood pressure regulation or alter haemodynamic, vasopressin and renin responses to haemorrhage in conscious sheep.     

Comparison between isoprenaline infusions and bolus injections to assess β-adrenoceptor function in man,with special reference to cardiac contractility and the influence of autonomic reflexes

The present study was performed to characterize cardiovascular responses to isoprenaline and the influence of autonomic reflexes on these reponses. Nine healthy volunteers received infusions and bolus injections of isoprenaline before and after ‘autonomic blockade’ produced by intravenous atropine 0.04 mg kg^-1 and clonidine 300 μg. Heart rate, blood pressures, systolic time intervals and various echocardiographic measures of cardiac contractility were registered. No significant differences in responsiveness to isoprenaline were seen when infusions were repeated on the same day without ‘autonomic blockade’. After ‘blockade’, Δ responses at 1 nmol 1^-1 isoprenaline (infusions) were increased for diastolic blood pressure and decreased for systolic blood pressure and stroke volume. Bolus injections of 2 μg isoprenaline caused enhanced Δ responses after ‘autonomic blockade’ of diastolic blood pressure, left ventricular diameter in systole, ventricular circumferential fibre shortening, mean posterior wall velocity (V_{mean pw}), stroke volume, systemic vascular resistance, electromechanical systole (QS₂) and pre-ejection period. Systolic blood pressure decreased, in contrast to a small increase without ‘blockade’. These findings are explained by differences in haemodynamic effects of isoprenaline and by the dependence of responses on reflexes when isoprenaline is administered in different ways. When heart rate was increased by bolus doses of atropine, in the presence of β-blockade (propranolol), pre-ejection period and left ventricular diameter in systole were unaffected, and V_{mean pw} and ventricular circumferential fibre shortening showed only small increases (compared with alterations induced by isoprenaline). However, left ventricular ejection time, QS₂ and ejection time (by echocardiography), were markedly dependent on heart rate alterations. Thus, pre-ejection period, left ventricular diameter in systole V_{mean pw} and ventricular circumferential fibre shortening are parameters which can be useful in order to evaluate cardiac β-adrenoceptor sensitivity in vivo in man.     

Haemodynamic and humoral responses to repeated hypotensive haemorrhage in conscious sheep

Haemodynamic and humoral responses to two subsequent hypotensive haemorrhages, separated by 3 hours and each followed by retransfusion, were studied in unanaesthetized sheep. Haemorrhage was induced by removal of blood from a jugular vein at a rate of 0.7 ml kg-1 min-1 until the mean systemic arterial pressure suddenly decreased by 35 mmHg or more. In addition to the mean systemic arterial pressure, the cardiac output, the mean pulmonary arterial pressure, the central venous pressure and the pulmonary capillary wedge pressure decreased in response to each haemorrhage. The recovery of the systemic and pulmonary arterial pressure was slower and/or less efficient after the second haemorrhage, due to a less pronounced increase of the vascular resistance. Relative bradycardia, in association with the abrupt fall of the mean systemic arterial pressure, was more apparent during the first haemorrhage. The plasma levels of vasopressin, renin activity and angiotensin II were increased by each blood removal, but the vasopressin response to the second haemorrhage was significantly reduced. The plasma noradrenaline concentration was slightly and transiently elevated only in response to the second haemorrhage. The concentration of neuropeptide Y-like immunoreactivity in plasma was unaffected by both haemorrhages. It is suggested that the reduced and delayed increase in the systemic vascular resistance, accompanied by impaired recovery of the arterial pressure, and the relative absence of 'bleeding bradycardia', during the second haemorrhage, were due to the diminished vasopressin response.