Central hemodynamic effects of adrenaline with special reference to beta 2-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 beta 2-blockade (ICI 118,551), and after nonselective beta-blockade propranolol). The results demonstrated the presence of an important beta 2-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 beta 2-adrenergic effects of noradrenaline were small. The beta 2-adrenergic effects of adrenaline on the heart seemed to be both direct and indirect. A moderate direct chronotropic response mediated by beta 2-adrenoceptors apparently was present but there was no evidence of a direct beta 2-adrenergic inotropic effect. An indirect, quite marked effect on the heart was accomplished by a beta 2-adrenergic vasodilator interaction with the alpha-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, beta 2-adrenergic improvement of cardiac performance is of functional importance in reflex sympatho-adrenal circulatory control.     

Microsphere analysis of β2-adrenergic control of resistance in different vascular areas after hemorrhage

In cats exposed to bleeding (exsanguination of 15 ml×kg bwt^-1) the microsphere technique was used to determine regional vascular resistances in a large number of tissues before and after i.v. administration of the ‘selective’β₂-adrenoceptor antagonist ICI 118,551. β₂-blockade significantly raised vascular resistance in the stomach (+26%), small (+25%) and large (+38%) intestine, pancreas (+29%), kidney (+39%), omental (+33%) and subcutaneous (+26%) fat, ‘white’ skeletal muscle (+19%), and skin (+24%). These findings indicate that, with intact β-adrenoceptors, β₂-adrenergic dilator interaction counteracted the hemorrhage evoked vasoconstrictor influences. β₂-blockade also evoked quite a strong increase of total peripheral resistance (19%) and led to some redistribution of cardiac output. It is concluded that β₂-adrenergic inhibition of vascular tone significantly seems to improve tissue perfusion during bleeding in several vascular areas. Such effects may be of special significance during severe hemorrhage. In the intestine, pancreas, and adipose tissue, for example, protection against excessive vasoconstriction may serve to minimize the severe metabolic disturbances with secondary release of toxic factors into the circulation reported during hemorrhagic shock.     

Influences on central hemodynamics in hemorrhage of β2-adrenergic vascular control mechanisms

Central hemodynamic responses evoked by standardized hemorrhage (exsanguination of 20 ml×kg bwt^-1) were followed during 2 h in cats with intact and blocked vascular β₂-adrenoceptors using the ‘selective’β₂-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 β₂-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 β₂-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 β₂-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 β₂-adrenergic dilator interaction with constrictor influences on the resistance vessels. It is concluded that β-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, β₂-adrenergic circulatory events are similar to those aimed at in current shock therapy by transfusion and vasodilator treatment.     

Functional β1 - and β2-adrenoceptors in the human myocardium

Functional β-adrenoceptor populations in the human heart were studied in vitro in electrically-paced strips of the right auricular and ventricular myocardium. The relative potency of selected agonists in producing inotropic responses (T_max, T′_max) in the presence of blockers for neuronal and extraneuronal uptakes was found to be as follows: isoprenaline > noradrenaline = adrenaline = salbutamol > dobutamine. Prenalterol had a negative inotropic effect in these preparations. The selective β₁ -(practoloI) and β₂-(H 35/25) blockers reduced inotropic responses to adrenaline (T_max, T′_max) and noradrenaline (T′_max) in the auricular strips. These results indicate the participation of β₂-adrenoceptors in inotropic responses in the human auricular and ventricular myocardium. For comparison, inotropic responses of electrically-paced rat myocardium to β-adrenergic agonists in the presence of blockers for neuronal and extraneuronal uptakes were likewise studied. The relative potencies for T_max were: noradrenaline = adrenaline > prenalterol > dobutamine = salbutamol. Given the high relative potency of salbutamol in the human myocardial strips (analogous to that previous shown in the β₂-dominated atria of the frog and trout) and the low relative potency of salbutamol in the rat tissue, these findings indicate a greater population of functionally active β₂-adrenoceptors in the human than in the rat myocardium.     

Decrease in survival time in β2-adrenoceptor blocked cats exposed to bleeding

Our previous investigations have indicated that β₂-adrenergic regulatory mechanisms contribute to important compensatory hemodynamic adjustments in hemorrhage. In the present study an attempt was made to examine, by comparative observations after standardized fatal hemorrhage on cats with intact and ‘selectively’ blocked β₂-adrenoceptors (ICI 118,551), whether such compensatory effects are crucial for survival. On the average, the survival time after bleeding was 686 min in cats with intact and 427 min in cats with blocked β₂-adrenoceptors (p < 0.05), the difference thus approaching 4.5 h. It is suggested that the reduced survival time after β₂-blockade, at least partly, can be ascribed to interference with the circulatory β₂-adrenergic control in hemorrhage aimed at improving tissue perfusion.     

Comparison of β-adrenoceptors mediating vasodilatation in canine subcutaneous adipose tissue and skeletal muscle

Blood flow changes in response to various drugs in simultaneously autoperfused canine subcutaneous adipose tissue and gracilis muscle were compared to study the vascular β-adrenoceptors. Compared to isoprenaline the β₂-selective agonist salbutamol was 4–6 times more potent as a vasodilator in the muscle than in adipose tissue. Furthermore two β₁-selective agonists (Tazolol and H80/62) caused vasodilatation in adipose tissue but not in the gracilis muscle. When given by close i.a. injection after β-adrenoceptor blockade, adrenaline was a more potent vasoconstrictor than noradrenaline in both tissues. Before β-blockade, however, noradrenaline was the more potent vasoconstrictor in the gracilis muscle whereas adrenaline was more potent in adipose tissue. Intravenous infusion of adrenaline in doses causing vasodilatation in the muscle caused vasoconstriction in adipose tissue whereas intravenous infusion of noradrenaline caused vasoconstriction in both tissues. The present findings suggest that the β-adrenoceptors mediating vasodilatation in skeletal muscle are mainly of the β₂-type, whereas β₁-adrenoceptors seem to predominate in subcutaneous adipose tissue. Since adrenaline is a much more potent β₂- than β₁-agonist, these differences point to different roles of intravascular adrenaline in the two sites. In skeletal muscle circulating adrenaline is mainly a vasodilator whereas in subcutaneous adipose tissue it mainly acts as a vasoconstrictor.     

The mechanism of neuronal noradrenaline and dopamine β-hydroxylase release by a sodium-deficient solution substituted with urea

Isolated rabbit hearts were perfused with a ‘low Na-urea’ solution (the substitution of 132 mM NaCl of Tyrode's solution by 242 mM urea) for 1–30 min. The effect on noradrenaline overflow was compared with that evoked by other NaCl substitutes.‘Low Na’ solutions released noradrenaline at greatly differing rates and time courses. ‘Low Na-urea’ medium caused a large noradrenaline overflow which in time course and magnitude was similar to that evoked by ‘high K-low Na’. However, the effect of ‘high K-low Na’ was largely dependent on calcium and little affected by lowering the temperature from 36 to 16°C (Q₁₀ = 1.1) while the noradrenaline output evoked by ‘low Na-urea’ medium was only transiently calcium-dependent and greatly reduced by a drop in temperature (Q₁₀ = 6.7).Both ‘low Na-urea’ and calcium-free ‘high K-low Na’ solutions evoked the release of α-methyladrenaline which had been incorporated into adrenergic nerves of the hearts of rabbits previously treated with reserpine. Since reserpine blocks the vesicular storage mechanism the amine must have been released from the axoplasm through the neuronal membrane. The re-introduction of Tyrode's solution did not reverse the α-methyladrenaline output evoked by ‘low Na-urea’ although it abolished that after ‘low Na-sucrose’ or calcium-free ‘high K-low Na’ solutions. Similarly, the noradrenaline loss from the normal heart evoked by ‘low Na-urea’ medium was also unaltered by returning to Tyrode's solution. The irreversibility of the action of ‘low Na-urea’ solution on amine release, an initial loss of potassium into the perfusate and previous morphological evidence of myocardial cell damage suggested that the medium produced a hyposmotic shock. As a result, there was a brief calcium-dependent release of noradrenaline and of dopamine β-hydroxylase that was superimposed upon a much larger and persisting non-exocytotic amine overflow which was unaccompanied by release of dopamine β-hydroxylase.The present findings corroborate our previous observation that electron-dense cores in the small vesicles of adrenergic neurons of the rabbit heart are preserved while most of the cardiac noradrenaline is depleted by perfusion with ‘low Na-urea’ solution, and the suggestion by other authors that proteins, such as dopamine β-hydroxylase, rather than amine constitute the electron-dense material.     

Sympathetic influence on cardiovascular responses to sustained head-up tilt in humans

Sympathetic β-adrenergic influences on cardiovascular responses to 50d? head-up tilt were evaluated with metoprolol (β₁-blockade; 0.29 mg kg^-1) and propranolol (β₁ and β-₂-blockade; 0.28 mg kg^-1) in eight males. A normotensive-tachycardic phase was followed by a hypotensive-bradycardic episode associated with presyncopal symptoms after 23pL3 min (control, mean pLSE). Head-up tilt made thoracic electrical impedance (3.0pL10Ω), mean arterial pressure (MAP, 86pL4-93pL4 mmHg), heart rate (HR, 63pL3-99pL10 beats min^-1) and total peripheral resistance (TPR, 15pL1-28pL4 mmHg min L^-1) increase, while central venous oxygen saturation (74pL2-58pL4%), cardiac output (5.7pL0.1–3.1pL0.3 L min^-1), stroke volume (95pL6-41pL5 mL) and pulse pressure (55pL4-49pL4 mmHg) decreased (P < 0.05). Central venous pressure decreased during head-up tilt (7pL2-0pL1 mmHg), but it remained stable during the sustained tilt. At the appearance of preswyncopal symptoms MAP (49pL3 mmHg), HR (66pL4 beats min^-1) and TPR (15pL3 mmHg min L^-1) decreased (P < 0.05). Neither metoprolol or propranolo changed tilt tolerance or cardiovascular variables, except for HR that remained at 57pL2 (metoprolol) and 55pL3 beats min^-1 (propranolol), and MAP that remained at 87pL5 mmHg during the first phase with metoprolol. In conclusion, sympathetic activation was crucial for the heart rate elevation during normotensive head-up tilt, but not for tilt tolerance or for the associated hypotension and bradycardia.     

Acute blockade of β1-receptors in the asphyxiated sheep fetus

Acute blockade of β₁-receptors in the asphyxiated sheep fetus. Acta Physiol Scand 130 , 381–385. Received 5 November 1986, accepted 9 February 1987. ISSN 0001–6772. Department of Paediatrics, Landspitalinn, University Hospital, Reykjavik, Iceland and Department of Physiology and Department of Paediatrics I, University of Goteborg, Sweden. The effects of acute β₁-blockade on fetal cardiovascular reactions during asphyxia were evaluated in 11 exteriorized sheep fetuses. Gestational age was 110–142 days. Asphyxia was induced either by ventilating the mother with low oxygen gas mixture or by mechanical reduction of placental blood flow. During asphyxia all fetuses reacted to metoprolol injection with a decrease in heart rate, myocardial contractility, cardiac output and arterial blood pressure. Five experiments resulted in irreversible fetal cardiovascular collapse. Isoprenaline was given to the fetuses during hypoxia to test the ability to further increase heart rate and activate myocardial β-adrenoceptors. In those experiments with fetal cardiovascular demise after metoprolol, the isoprenaline injection did not result in a significant tachycardia. The surviving fetuses could increase their heart rate as a sign of a capacity to further increase the sympatho-adrenergic drive.     

Beta2-adrenergic attenuation of capillary pressure autoregulation during hemorrhagic hypo tension,a mechanism promoting transcapillary fluid absorption in skeletal muscle

The aim of this study was to evaluate a possible humoral β₂-adrenergic effect on the capillary pressure autoregulation capacity in cat skeletal muscle during bleeding. For this purpose capillary pressure autoregulation in response to graded decrease in arterial pressure was studied in sympathectomized muscle in the control state, and during haemorrhagic hypovolaemia in the presence and absence of selective β₂-adrenoceptor blockade (ICI 118,551). The study was performed with a technique that permits continuous recordings of average capillary pressure in absolute terms and of the regional pre- and postcapillary vascular resistance, from which the pre- to post capillary resistance ratio could be determined. In the pre-haemorrhagic control state, an experimental decrease in arterial pressure from 100 to 50 mmHg caused a fall of capillary pressure from 17.6 by only 1.7 mmHg (ΔP_A/ΔP_c= 29), demonstrating an efficient capillary pressure autoregulation. This autoregulation was accomplished by a decrease in pre- to post capillary resistance ratio in turn being a result of active precapillary dilatation and a passive increase in post capillary vascular resistance. Haemorrhage per se, via a humoral α-adrenergic preferentially precapillary vaso-constriction, caused a decrease in capillary pressure to 16.8 mmHg at arterial pressure 100 mmHg. A superimposed decrease in arterial pressure to 50 mmHg resulted in a capillary pressure fall by 3.7 mmHg (ΔP_A/ΔP_e= 14), indicating impaired autoregulation capacity. This attenuation to a great extent could be ascribed to adrenaline-induced B₂-adrenoceptor stimulation, since β₂-blockade restored the Δ arterial pressure/capillary pressure ratio to 20. Low-dose isoprenaline infusion in the control state similarly caused marked impairment of capillary pressure autoregulation. The β₂-adrenergic attenuation of capillary pressure autoregulation appears to be a beneficial effect in haemorrhagic hypotension, since it lowers capillary pressure passively in relation to the arterial pressure fall, thereby reinforcing the a-adrenergic active capillary pressure decrease, leading to more effective transcapillary fluid absorption and, hence, improved replenishment of plasma volume.     

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.     

Long-term hemodynamic effects of antihypertensive treatment

The cardinal hemodynamic disorder in established essential hypertension is increased total peripheral resistance. During exercise, the increase in stroke volume of the heart is abnormal. A 20-year follow-up study of the hemodynamics in essential hypertension demonstrated a progressive increase in total peripheral resistance and deterioration of the heart pump function. Long-term treatment with antihypertensive agents modifies the circulatory system in different ways. Vasodilators (angiotensin converting enzyme inhibitors, ₁-blockers, and calcium antagonists) all reduce total peripheral resistance, and in general, cardiac output, heart rate, and stroke volume remain unchanged. Calcium antagonists like verapamil and diltiazem reduce the heart rate approximately 10% during exercise, but since stroke volume increases, cardiac output is unchanged. Chronic treatment with conventional -blockers induces a permanent reduction in cardiac output and heart rate during exercise. In contrast, carvedilol — a ₁,₂-blocker with ₁-blocking activity — prevents the immediate increase in total peripheral resistance during acute -blockade. In 19 patients followed by hemodynamic measurements over 6–9 months, blood pressure was well controlled by carvedilol. During exercise, total peripheral resistance decreased 6% (P<0.05), and=" the=" reductions=" in=" heart=" rate=" and=" cardiac=" index=" were=" less=" than=" on=" conventional=">-blockade. Echo-Doppler studies showed a significant reduction in the intraventricular septum of 13%.     

Adrenergic control of post-exercise metabolism

After strenuous exercise there is a sustained increase in resting O₂ consumption. The magnitude and duration of the excess post-exercise O₂ consumption (EPOC) is a function of exercise intensity and exercise duration. Some of the mechanisms underlying the rapid EPOC component (<1 h) are well defined, while the mechanisms causing the prolonged EPOC component (>1 h) are not fully understood. It has been suggested that β-adrenergic stimulation is of importance for the prolonged component. There is an increased level of plasma adrenaline and noradrenaline during exercise, and it is shown that catecholamines stimulate energy expenditure through β-adrenoceptors. After exercise an increased fat oxidation and an increased rate of triglyceride fatty acid (TG–FA) cycling may account for a significant part of the prolonged EPOC component. These processes may be stimulated by catecholamines. However, the return of plasma concentration of catecholamines to resting levels after exercise is more rapid than the return of O₂ uptake. But plasma concentration of catecholamines may be an insensitive indicator of sympathetic activity, since the clearance rate of catecholamines is high. Also, the sensitivity to catecholamines may be increased after exercise. A decreased post-exercise O₂ uptake has been shown when β-blockade is administered in dogs before the exercise bout. In a pilot study in humans, administration of β-antagonist after exercise did not seem to change EPOC.     

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.     

β2-adrenergic control of plasma volume in hemorrhage

Hemorrhage is associated with absorption of extravascular fluid from skeletal muscle to blood in order to compensate for the loss of intravascular volume. Our previous studies have shown that this fluid gain is mainly linked to β-adrenergic microvascular adjustments leading to decrease in capillary hydrostatic pressure and to precapillary ‘sphincter’ mediated increase in the capillary surface area available for fluid exchange. In the present study the importance of β-adrenergic control of plasma volume in bleeding was confirmed by measurement of changes in plasma volume after graded hemorrhage in animals with intact and blocked vascular β₂-adrenoceptors (i. v. administration of the ‘selective’β₂-blocking agent ICI 118, 551). With intact β₂-adrenoceptors plasma volume was gradually restored after bleeding so that about 50% of the shed plasma volume (about 35% of the shed blood volume) had been compensated for at two hours after exsanguination of 20% as well as 40% of the blood volume. The corresponding figures in animals with blocked β₂-adrenoceptors were only 14% of the shed plasma volume and 8% of the shed blood volume at both degrees of hemorrhage.     

Influence of angiotensin II, α- and β-adrenoceptors on peripheral noradrenergic neurotransmission in canine gracilis muscle in vivo

Interactions between angiotensin II and adrenoceptor-mediated effects on peripheral sympathetic neurotransmission were investigated in constant flow blood-perfused canine gracilis muscle in situ, without and with pretreatment by non-competitive α- adrenoceptor blockade. Angiotensin converting enzyme (ACE)-inhibition by benazeprilat increased nerve stimulation (2 Hz, 4 min)-evoked noradrenaline (NA) overflow (+21 ± 5 yo) with α- adrenoceptors intact, but reduced NA overflow (– 18 ± 6%) when α-adrenoceptors were blocked. Vasoconstrictor responses were slightly reduced by benazeprilat. Subsequent infusion of angiotensin II (Ang 11, 20 and 500 ng kg_-1 min_-1 i.v., raising arterial concentrations from 0.6 ± 0.2 PM to 1390 ± 240 and 25 110 ± 3980 PM, respectively) failed to increase NA overflow or to enhance stimulation-evoked vasoconstriction. Adrenaline (0.4 nmol kg_-1 min_-1 i.v.) did not change evoked NA overflow before or after benazeprilat, either with or without α-adrenoceptor blockade, despite high concentrations (± 10 nM) in arterial plasma. Following benazeprilat, propranolol reduced NA overflow (–24 ± 3 yo) only if the α-adrenoceptors were blocked. In conclusion, benazeprilat reduced evoked NA overflow in the presence of α- adrenoceptor blockade to a similar degree as previously shown in the presence of neuronal uptake inhibition in this model. However, contrasting to our previous findings, benazeprilat enhanced NA overflow and reduced the post-junctional response to nerve stimulation in the absence of α-adrenoceptor blockade. This could be related to bradykinin accumulation during ACE-inhibition, in addition to the reduction of Ang II generation. Our data are not compatible with facilitation of NA release by circulating Ang II even at pharmacological dose levels. Although activation of prejunctional β-adrenoceptors may facilitate evoked NA overflow in this model, circulating adrenaline is ineffective under physiological conditions even after α-adrenoceptor blockade. Also, β-adrenoceptor-mediated prejunctional effects do not seem to involve Ang II in canine skeletal muscle in vivo.     

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.     

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.     

Classification of β-adrenoceptors in the microcirculation of skeletal muscle

Nervous and humoral β-adrenergic, postjunctional effects on microvascular resistance, on precapillary sphincter tone, and on transcapillary fluid exchange in cat skeletal muscle (Lundvall & Järhult 1974, 1976 a, Lundvall & Hillman 1978 a, b) were evaluated with regard to the β₁-or β₂,-specificity of the adrenoceptors. Marked β₂-dilator responses but no significant β₁-effects were observed. The conclusion was therefore reached that neurogenic as well as humoral β-adrenergic control of the microcirculation in skeletal muscle is exerted via activation of β₂-adrenoceptors.     

Enhanced transglutaminase 2 expression in response to stress-related catecholamines in macrophages

Transglutaminase 2 (TG2) is a multifunctional protein that contributes to inflammatory disease when aberrantly expressed. Although macrophages express TG2, the factor stimulating TG2 expression remains poorly characterized in these cells. In the present study, we examined the effects of the stress-related catecholamines adrenaline and noradrenaline on macrophage expression of TG2 in RAW264.7 murine macrophages and murine bone marrow-derived macrophages. Treatment with adrenaline markedly increased TG2 mRNA expression and increased TG2 protein levels. While the β₂-adrenoceptor-selective antagonist ICI 118,551 completely blocked adrenaline-induced TG2 mRNA expression, the β₂-adrenoceptor specific agonist salmeterol increased TG2 expression. Noradrenaline also increased TG2 mRNA expression at higher doses than the effective doses of adrenaline. The effect of adrenaline on TG2 mRNA expression was mimicked by treatment with the membrane-permeable cAMP analog 8-Br-cAMP. Thus, increased intracellular cAMP following stimulation of β₂-adrenoceptors appeared to be responsible for adrenaline-induced TG2 expression. Because stress events activate the sympathetic nervous system and result in secretion of the catecholamines, adrenoceptor-mediated increase in macrophage TG2 expression might be associated with stress-related inflammatory disorders.