Central hemodynamic effects of adrenaline with special reference to β2-adrenergic influence on heart rate and cardiac afterload in anesthetized cats

Central hemodynamic responses evoked by i. v.infusions of adrenaline and noradrenaline were studied in normovolemic anesthetized cats with intact adrenoceptors, after selective β₂-blockade (ICI 118,551), and after nonselective β-blockade (propranolol).The results demonstrated the presence of an important β₂-adrenergic component in the integrated response to ‘physiological’ doses of adrenaline contributing to increased cardiac output, decreased total peripheral resistance and virtually unchanged mean arterial blood pressure. Corresponding β₂-adrenergic effects of noradrenaline were small. The β₂-adrenergic effects of adrenaline on the heart seemed to be both direct and indirect. A moderate direct chronotropic response mediated by β₂-adrenoceptors apparently was present but there was no evidence of a direct β₂-adrenergic inotropic effect. An indirect, quite marked effect on the heart was accomplished by a β₂-adrenergic vasodilator interaction with the α-adrenergic vasoconstrictor influence on the systemic resistance vessels. This caused a net decrease in total peripheral resistance, thereby preventing an undue increase in cardiac afterload (arterial pressure) which seemed to be essential for evoking ‘optimal’ increases in cardiac output. It is suggested that such adrenaline evoked indirect, β₂-adrenergic improvement of cardiac performance is of functional importance in reflex sympatho-adrenal circulatory control.     

Calcitonin gene-related peptide (CGRP) and leg vascular resistance during head-up tilt induced hypovolaemic shock in man

Calcitonin gene-related peptide is a potent vasodilator and its distribution in perivascular nerves suggests a role in the regulation of vascular tone. We evaluated leg vascular resistance together with total peripheral resistance and the arterial plasma concentrations of calcitonin gene-related peptide and catecholamines during 50 degrees head-up tilt induced hypotension in 7 males. During tilt mean arterial pressure, heart rate, total peripheral resistance, leg vascular resistance and plasma noradrenaline increased, while cardiac output and leg blood flow decreased. After 45 +/- 9 min (mean +/- SE) presyncopal symptoms appeared together with decreases in mean arterial pressure (81 +/- 6 to 56 +/- 9 mmHg), heart rate (97 +/- 6 to 73 +/- 8 beats min-1), leg vascular resistance (158 +/- 9 to 109 +/- 8 mmHg min l-1) and total peripheral resistance (17 +/- 3 to 10 +/- 2 mmHg min l-1) (P less than 0.01). Plasma calcitonin gene-related peptide increased from 32 +/- 3 to 35 +/- 3 pmol l-1 (P less than 0.01) and adrenaline from 1.1 +/- 0.2 to 1.7 +/- 0.3 nmol l-1 (P less than 0.01), while noradrenaline did not change. The results indicate that presyncopal symptoms induced by head-up tilt are associated with regional as well as total decreases in vascular resistance accompanied by moderate increases in arterial plasma concentrations of calcitonin gene-related peptide and adrenaline.     

Circulatory effects of noise

Thirteen patients with mild essential hypertension, mean age 44 years (range 21-59), were studied during "stress" before and after postsynaptic alpha-adrenoceptor blockade and combined postsynaptic alpha- and non-selective beta-adrenoceptor blockade. Loud broad band noise (100 dBA for 10 min) was used as the stress stimulus. Exposure to noise caused a significant increase in systolic (7%, p less than 0.05), diastolic (9%, p less than 0.01) and mean arterial pressure (6%, p less than 0.01). The blood pressure elevation was caused by an increase in total peripheral resistance (12%, p less than 0.05). There was no significant change in heart rate, stroke volume or cardiac output. The blood pressure response during noise stimulation was not affected by postsynaptic alpha-adrenoceptor blockade (prazosin, 2 mg orally). The hemodynamic reaction pattern, however, was totally reversed. Thus, the cardiac output increased significantly (9%, p less than 0.05), while the total peripheral resistance tended to decrease. Combined postsynaptic alpha- and non-selective beta-adrenoceptor blockade (labetalol, 200 mg orally) inhibited the increase in systolic blood pressure caused by noise, while the diastolic and mean arterial pressures still increased significantly (5%, p less than 0.01). Labetalol effectively blocked the stress-induced increase in total peripheral resistance and there was no significant increase in cardiac output after combined alpha- and beta-adrenoceptor blockade. Exposure to noise caused a significant increase in circulating noradrenaline (20%, p less than 0.05). Plasma adrenaline and plasma renin activity were not affected by noise stimulation. These results suggest that blood pressure elevation is essential during "stress" but that the hemodynamic pattern causing blood pressure elevation may vary and may be affected by pharmacological blockade of various parts of the sympathetic nervous system.     

The contribution of alterations in cardiac output to changes in arterial pressure reflexly evoked from the carotid sinus in the rabbit.

1. The reflex cardiovascular effects of changes in pressure within the vascularly isolated carotid sinus were examined in seventeen anaesthetized rabbits. The opposite sinus was denervated and both aortic nerves were divided, 2. Comparison of the mean values at sinus pressures of 40 and 200 mmHg showed a large reduction in systemic arterial pressure from 126 to 58 mmHg and a moderate reduction in heart rate, from 287 to 253 beats min-1. Cardiac output, measured by thermal dilution, showed only a small change, a fall from 160 to 148 ml. min-1 kg-1. 3. By contrast with this reduction in cardiac output of just over 7%, total peripheral resistance, derived by dividing mean arterial pressure by cardiac output, was halved, falling from 0-48 to 0-41 mmHg ml.-1 min kg. 4. Thus in the anaesthetized rabbit changes in cardiac output make only a small contribution to the changes in systemic pressure evoked by alterations in carotid sinus pressure. Changes in total peripheral resistance are principally responsible for the effect on systemic pressure. 5. Though the changes in output of the heart were small, there were considerable changes in the work done by the left ventricle which was approximately halved when carotid sinus pressure was raised from 40 to 200 mmHg.     

Effects of diazepam on the carotid sinus baroreflex control of circulation in rabbits

To examine the effects of diazepam on the carotid sinus baroreflex control of circulation, bilateral carotid occlusion was performed on 14 conscious rabbits with aortic denervation. The responses of mean arterial pressure, heart rate, cardiac output and total peripheral resistance were obtained. The haemodynamic responses to carotid occlusion were evaluated at cumulative doses of 0.5 and 1.0 mg kg-1 of diazepam. The administration of diazepam decreased cardiac output and increased total peripheral resistance significantly, but did not affect the arterial pressure and heart rate. The response of total peripheral resistance to carotid occlusion was significantly increased from 0.118 +/- 0.018 (mean +/- SE) to 0.154 +/- 0.026 mmHg min ml-1 at 1.0 mg kg-1 of diazepam. The heart rate response was attenuated significantly from 41 +/- 5 to 24 +/- 4 beats min-1 at 1.0 mg kg-1 of diazepam. Diazepam did not alter the response of arterial pressure to carotid occlusion. We suggest that the dissociated effects of diazepam on the reflex control of circulation reflect the dissociated influences of diazepam on the central sympathetic and vagal-mediated pathways.     

The control of the circulation in skeletal muscle during arterial hypoxia in the rabbit

1. The effects of arterial hypoxia on muscle blood flow were examined in normal unanaesthetized rabbits in relation to simultaneously determined changes in cardiac output, arterial pressure and heart rate. Muscle blood flow was estimated from the difference between total limb flow (local thermodilution) and the estimated skin flow (using a calibrated heat conductivity method). The role of the arterial chemoreceptors and baro-receptors in the control of muscle blood flow was examined and the nature of the sympathetic efferent discharge analysed.2. In mild hypoxia (P(O2) > 35 mm Hg) in the rabbit, muscle blood flow did not change, although cardiac output increased. During moderate hypoxia (P(O2) 30-35 mm Hg) there was initial vasoconstriction in muscle, followed by a return to control values paralleling the changes in cardiac output. In severe arterial hypoxia (P(O2) < 30 mm Hg) the initial vasoconstriction was less marked, and during the ;steady state' there was a large vasodilatation and increase in muscle blood flow, at a time when the cardiac output was not elevated.3. The early vasoconstriction in arterial hypoxia is mediated mainly through sympathetic vasoconstrictor nerves as a result of strong arterial chemoreceptor stimulation.4. Increased secretion of adrenaline is an important factor in restoring muscle blood flow to control values during moderate arterial hypoxia, and in elevating the muscle blood flow above these values in severe hypoxia. The peripheral dilator (beta-) effects of adrenaline oppose the peripheral constrictor (alpha-) effects resulting from increased activation of sympathetic constrictor nerves during arterial hypoxia.     

Aversive conditioning of elevations in total peripheral resistance in dogs.

Operant conditioning experiments were performed with 12 chronically instrumented dogs to which aversive stimulation was presented whenever total peripheral resistance (mean pressure/cardiac output) decreased acutely below a criterion level. Initial experiments in which aversive stimulation occurred whenever total peripheral resistance decreased below mean base-line levels resulted in sustained decreases in total peripheral resistance, accompanied by elevations in heart rate, cardiac output, and arterial pressure. Subsequent experiments showed, however, that if aversive stimulation occurred only following large-magnitude decreases in resistance (30% below base-line levels), a progressive cardiovascular response pattern emerged during daily sessions of 5--16 h. This cardiovascular pattern included progressive elevations in resistance (10--50%), accompanied by progressive decreases or no change in heart rate and cardiac output and moderate increases in arterial (up to 20 mmHg) and pulse pressure. These within-session cardiovascular changes were accompanied by sustained inhibition of overt behavioral acitivity and progressive inhibition in respiratory activity. Implications of these observation for behavioral regulation of circulatory function are discussed.     

Effect of Carotid Sinus Stimulation on Cardiac Output and Peripheral Vascular Resistance during Changes in Blood Volume Distribution in Man

In ten healthy subjects (mean age 29.6 years) the hemodynamic response to carotid sinus stimulation (neck suction - 40 mmHg) was studied under control conditions and during peripheral pooling of blood (lower body negative pressure). Heart rate, arterial and central venous pressure, cardiac output and forearm blood flow were measured. The time sequence of the heart rate response was studied separately in six healthy subjects. During control conditions, carotid sinus stimulation induced a significant decrease in arterial pressure and heart rate. The blood pressure decrease mainly reflected a reduction in cardiac output, total peripheral vascular resistance being essentially unchanged. However, in the skeletal muscle, represented by a forearm segment, vascular resistance decreased significantly. During lower body negative pressure (LBNP) the same stimulation of the carotid sinus induced a significantly greater fall in mean arterial pressure even though the reduction in cardiac output was slightly smaller on the average than in the control condition. The heart rate increased, probably secondary to a time dependent increase in heart rate elicited by the continuous LBNP stimulus. Total peripheral vascular resistance decreased significantly during LBNP, the reaction likewise differing significantly from that in the control condition. Thus the augmented blood pressure response was due to a more pronounced vasodilatation when the carotid sinus was stimulated during lower body negative pressure. The results indicate that the hemodynamic changes elicited by carotid sinus stimulation are modified by changes in the distribution of blood volume and in the tone of resistance vessels.     

Changes in the systemic hemodynamics after injection of synthetic angiotensin II into dogs of different ages

The arterial pressure, cardiac output, total peripheral resistance, and heart rate were studied in experiments on puppies aged 18–22 days and 2–3 months and on adult dogs receiving injections of synthetic angiotensin II-amide in a dose of 2 μg/kg body weight/min. Elevation of the arterial pressure in the adult dogs as a result of the action of angiotensin was due to an increase in the total peripheral resistance, but in puppies it was due to an increase both in the total peripheral resistance and in the cardiac output.     

Influences on central hemodynamics in hemorrhage of beta 2-adrenergic vascular control mechanisms

Central hemodynamic responses evoked by standardized hemorrhage (exsanguination of 20 ml x kg bwt-1) were followed during 2 h in cats with intact and blocked vascular beta 2-adrenoceptors using the 'selective' beta 2-blocker, ICI 118, 551. In the first 10 min after bleeding blood pressure and cardiac output (CO) decreased and total peripheral resistance (TPR) increased by the same amount in the 'intact' and beta 2-blocked animals. Whereas blood pressure later on reached approximately the same hypotension level in both groups, other hemodynamic variables were distinctly different. In the 'intact' animals there was a gradual, partial recovery of stroke volume (SV) and CO in the face of a restoration to control of TPR. In the beta 2-blocked animals TPR continued to increase in the face of a maintained low CO and declining SV. The lower SV in the latter group was ascribed to abolition of beta 2-adrenergic restoration of plasma volume via absorption of tissue fluid into the circulation. The gradual decline of TPR in the 'intact' animals was attributed to beta 2-adrenergic dilator interaction with constrictor influences on the resistance vessels. It is concluded that beta-adrenergic vascular control mechanisms help to improve nutritional tissue blood flow during hemorrhage by increasing plasma volume, and hence venous return and CO, and by decreasing TPR. These reflex, beta 2-adrenergic circulatory events are similar to those aimed at in current shock therapy by transfusion and vasodilator treatment.     

Lower Body Negative Pressure and Effects of Autonomic Heart Blockade on Cardiovascular Responses

Heart rate, arterial pressure and cardiac output were recorded in eight healthy male volunteers during exposure to 80 mmHg of lower body negative pressure (LBNP) in the supine position before and after beta-adrenergic and combined beta-adrenergic and parasympathetic blockade of the heart as induced by the i.v. administration of propranolol 0.25 mg/kg b.wt. and atropine 0.04 mg/kg b.wt. After propranolol, heart rate response to LBNP averaged 48 % of that observed without blockade indicating that LBNP-induced cardioacceleration is of both sympathetic and parasympathetic origin. Tolerance to LBNP was reduced by beta-adrenergic blockade, since the decrease in mean arterial pressure during LBNP was exaggerated by such blockade. Although the addition of atropine markedly elevated mean arterial pressure and cardiac output in the control situation, tolerance to LBNP was not enhanced by this drug as judged from the arterial pressure response. Post-LBNP overshoot in mean arterial pressure was strikingly augmented by combined cardiac effector blockade and was in part due to a lingering elevation of total peripheral resistance, cardiac output remaining decreased for more than 110 s after release of LBNP.     

Lower body negative pressure and effects of autonomic heart blockade on cardiovascular responses.

Heart rate, arterial pressure and cardiac output were recorded in eight healthy male volunteers during exposure to 80 mmHg of lower body negative pressure (LBNP) in the supine position before and after beta-adrenergic and combined beta-adrenergic and parasympathetic blockade of the heart as induced by the i.v. administration of propranolol 0.25 mg/kg b.wt. and atropine 0.04 mg/kg b.wt. After propranolol, heart rate response to LBNP averaged 48% of that observed without blockade indicating that LBNP-induced cardioacceleration is of both sympathetic and parasympathetic origin. Tolerance to LBNP was reduced by beta-adrenergic blockade, since the decrease in mean arterial pressure during LBNP was exaggerated by such blockade. Although the addition of atropine markedly elevated mean arterial pressure and cardiac output in the control situation, tolerance to LBNP was not enhanced by this drug as judged from the arterial pressure response. Post-LBNP overshoot in mean arterial pressure was strikingly augmented by combined cardiac effector blockade and was in part due to a lingering elevation of total peripheral resistance, cardiac output remaining decreased for more than 110 s after release of LBNP.     

Influence of changes in cardiac output on the acid-base status of arterial and mixed venous blood

While maintaining the arterial CO₂ tension constant near the normal level of the dog (4.3 kPa), we studied the influence of decreasing cardiac output on both the arterial and mixed-venous blood acid-base status in anaesthetized, artificially ventilated dogs. Cardiac output was manipulated by applying positive end-expiratory pressure (PEEP), and by -adrenergic blockade to suppress a compensatory heart rate response. The systemic vascular response was attenuated by -adrenergic blockade. Metabolic rate remained virtually unchanged when cardiac output decreased. Under these conditions a fall in cardiac output led to a shift of the arterial acid-base status in the direction of a metabolic acidosis. The changes occurring in the mixed-venous blood resembled those of an in-vivo CO₂ bufferline, with the shift being such as if a respiratory acidosis was developing.     

Cardiovascular and sympathoadrenal responses to mental stress: a study of sensory intake and rejection reactions

Cardiovascular, sympathoadrenal and subjective responses to mental stress induced by two mental challenges eliciting sensory intake (word identification test = WIT) and sensory rejection (colour word conflict test = CWT) reactions were studied in 10 healthy males. Pressor responses to these stressors have been proposed to differ haemodynamically. Sympathoadrenal activity was assessed by arterial and femoral venous plasma catecholamine determinations and direct recordings of muscle sympathetic activity in the right peroneal nerve (MSA). Basal measurements differed little from those made during an active relaxation procedure, with the exception of MSA, which decreased. Both stress tasks elicited increases in heart rate, cardiac output, calf blood flow and brachial and pulmonary arterial blood pressures. WIT and CWT elicited qualitatively similar responses, but the amplitudes of the circulatory responses were lower with WIT, which also was rated as a weaker stressor. MSA increased during CWT, while marginal increases were seen during WIT. Arterial adrenaline showed a transient increase by 0.14 nmol l-1 during WIT. During CWT arterial adrenaline increased significantly by 50%. Increases in arterial adrenaline and subjective stress ratings were related to increases in cardiac output and reductions of systemic vascular resistance. Arterial and femoral venous noradrenaline increased during CWT, while changes during WIT were small. MSA and noradrenaline responses did not correlate to local vascular responses in the calf. Differences in the responses to mental challenges evoking sensory intake or rejection seem to be of a quantitative rather than a qualitative character.     

Stimulus dimensions of the cold pressor test and the associated patterns of cardiovascular response

Hemodynamics of the cold pressor response in relation to its pain and nonpain stimulus components were investigated in normotensive college men using the foot and forehead cold pressor tasks. Mechanisms of pain- and non-pain-related increases in blood pressure were analyzed as residual effects of concurrent changes in total peripheral resistance and cardiac output. The identified partial relationships suggested that the response pattern associated with pain included positive change both in cardiac output and in total peripheral resistance, whereas the nonpain-related response was limited to an increase in total peripheral resistance. Analyses of individual differences in car-diovascular responses to pain further indicated that pain-related increments in blood pressure were mediated by a steeper rise in total peripheral resistance, an increase in heart rate, and an apparent increase in preload. At baseline, high reactors to pain manifested relatively elevated total perpheral resistance, diminished cardiac output, and an indication of a reduced inotropic state, suggesting that altered basal homeostasis may discriminate normotensive individuals displaying heightened cardiovascular reactivity to aversive cold stimulation.     

Regional distribution of cardiac output in young lambs: effect of cold exposure and treatment with catecholamines

1. Lambs less than 3 days old, exposed to thermoneutral or intensely cold conditions in a respiration chamber, were infused with adrenaline or noradrenaline, 1 or 10 mug/kg.min; and the effects on oxygen consumption, cardiac output and its distribution to skin, skeletal and cardiac muscle, liver, spleen, kidney, gut, brown adipose tissue and brain were determined. Cardiac output was estimated by the Fick and dye dilution methods and the distribution of cardiac output by Sapirstein's method of fractional distribution of indicators.2. Under thermoneutral conditions, metabolic rate was stimulated by both doses of noradrenaline and by the low, but not the high dose of adrenaline. Under cold conditions, the low dose of catecholamines had little effect on the already elevated metabolic rate, but the high doses depressed the metabolic response to cold.3. The low dose of adrenaline increased cardiac output under thermoneutral conditions whereas the high dose decreased cardiac output; the effects of noradrenaline were less marked, in contrast to reported effects in new-born rabbits. The low doses of catecholamine given under cold conditions had little effect on the already elevated cardiac output, but the high doses, particularly of adrenaline, decreased cardiac output.4. Blood flow through the skin of the extremities was markedly reduced by cold exposure, while flow through the peri-renal fat was doubled, flow through the skeletal muscle was quadrupled and flow through the cardiac muscle was trebled. These increases, particularly in skeletal muscle, were due to increased cardiac output and to vasodilation, as indicated by the reduced ratio of blood pressure to blood flow. Results are contrasted with published reports that blood flow through brown fat in new-born rabbits was greatly increased by cold, but muscle flow was scarcely altered.5. In almost all organs examined the high doses of adrenaline infused in either environment markedly reduced blood flow, presumably by generalized vasoconstriction. Changes due to noradrenaline were small under thermoneutral conditions and flow through brown fat was increased by only 60% during infusion of 10 mug/kg.min. Much greater increases have been reported in new-born rabbits. Under cold conditions the high doses of noradrenaline tended to decrease flow in most organs including brown fat and muscle.6. The results provide likely explanations for published reports that adrenaline failed to stimulate non-shivering thermogenesis or suppressed the mobilization of metabolites and the metabolic response to cold.     

Altered hemodynamic responses to acute hypoxemia in spontaneously hypertensive rats.

Conscious spontaneously hypertensive rats (SHR), 5--7 wk old, were studied hemodynamically by the direct Fick procedure to determine whether high total peripheral resistance (TPR) coexisted with increased oxygen consumption (QO2) at an early stage of hypertension development. Since under resting conditions cardiac output in SHR was not significantly different from normotensive controls, the elevated arterial pressure and QO2 were associated with increased TPR. Arterial hypoxemia was induced to reduce oxygen availability and to assess whether increased TPR in SHR could be reversed by this procedure. During hypoxemia, normotensive controls (WKY) responded with increased cardiac output and decreased arterial pressure and TPR. In contrast, arterial pressure and cardiac output fell in SHR; and the increased TPR persisted. QO2 fell in hypoxemic SHR demonstrating that the relationship between total body oxygen consumption and cardiac output was abnormal in young SHR, and that increased TPR in SHR was not dependent on resting levels of QO2 or oxygen availability. Although QO2 was elevated in SHR compared to age-matched WKY, this condition was not essential for maintained elevated vascular resistance.     

The cold pressor test: Vascular and myocardial response patterns and their stability

The purposes of the present study were to compare the cardiovascular response patterns evoked by three versions of the cold pressor test (either forehead stimulation or hand or foot immersion) and to determine the reproducibility of the responses over a 2-week interval. Blood pressure, heart rate, stroke volume, cardiac output, total peripheral resistance, and systolic time intervals were obtained during rest and during the cold pressor test in 42 young men. Across conditions, the pressor response was supported by peripheral resistance increases with concomitant stroke volume decreases. Although the response panerns were generally similar across sites, exceptions were apparent for heart rate. Forehead stimulation was characterized by no significant change in heart rate, whereas limb (hand or foot) immersion was associated with significant heart rate acceleration. The responses elicited by the three cold pressor test conditions were reliable and showed little evidence of attenuation over the test-retest interval.     

Effects of dobutamine and salbutamol on haemodynamics and atrial natriuretic factor in patients with severe congestive heart failure.

The influence of two cardiac inotropic drugs, dobutamine and salbutamol, on plasma atrial natriuretic factor (ANF) was investigated in 20 patients with congestive heart failure. All were in New York Heart Association class-III or IV. The patients underwent right heart catheterization with determination of central pressures, cardiac output, and pulmonary arterial plasma ANF during incremental infusions with dobutamine or salbutamol. Fourteen patients completed the study. Both drugs induced comparable increases in cardiac index and decreases in total systemic vascular resistance (P less than 0.01) without significant changes in central pressures. Heart rate rose after salbutamol (P less than 0.05), but not after dobutamine. No changes in plasma ANF were observed after either of the drug infusions. ANF secretion rate was calculated from simultaneous measurements of ANF in right atrial and pulmonary arterial plasma before and after salbutamol infusion, and median values rose more than seven-fold (P less than 0.05). The results demonstrate that ANF secretion rate is augmented after beta-adrenergic agents, possibly by a direct beta 2-adrenergic stimulation, in patients with severe congestive heart failure, and that changes in plasma ANF are an insufficient measure of ANF release when patient samples are small.     

Influence of Age on Sensitivity and Effector Mechanisms of the Carotid Baroreflex

In 30 healthy subjects aged 20–48 years the hemodynamic response to carotid sinus stimulation (neck suction -40 mmHg) was studied. Heart rate, arterial pressure and cardiac output (dye dilution technique) were measured. In order to evaluate the effect of age on carotid sinus function the material was subdivided into two arbitrary subgroups, aged up to 30 years (n = 15) respectively 30 years and above (n = 15). Carotid sinus stimulation induced a significantly greater reduction in mean arterial pressure in the younger group compared to the older group. The heart rate reduction was, on the average, slightly greater in the younger group though the difference was not significant. In both groups a significant decrease in cardiac output contributed to the demonstrated reduction in mean arterial pressure. As the decrease in cardiac output was, on the average, slightly smaller in the younger group, the results indicate that the greater blood pressure response in the younger group was due to a greater reduction in peripheral vascular resistance. This is further supported by the finding of a significant correlation between changes in total peripheral vascular resistance, elicited by carotid sinus stimulation and age.