IL-6 and IL-1 receptor antagonist in stable angina pectoris and relation of IL-6 to clinical findings in acute myocardial infarction.

OBJECTIVES: To determine if increased inflammatory activity, as reflected by interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) levels, is present in patients with stable angina pectoris and if IL-6 levels on admission to the coronary care unit in patients with acute myocardial infarction (AMI) are related to heart failure and fever response. SUBJECTS AND METHODS: We studied 28 patients with stable angina pectoris enrolled for coronary angiography, and compared them with sex- and age-matched controls. Thirty-four patients with AMI were studied and samples for determination of IL-6 levels were taken on admission within 36 h of onset of symptoms. IL-6 and IL-1ra were determined in serum by enzyme immunoassay. RESULTS: Levels of IL-6 and IL-1ra were higher in patients with stable angina pectoris than in controls (mean 4.6 +/- 3.6 vs. 3.0 +/- 2.9 ng L-1, P < 0.03, and 774 +/- 509 vs. 490 +/- 511 ng L-1, P < 0.01, respectively). IL-6 and IL-1ra levels were not related to angiographic findings. IL-6 levels were high in patients with AMI (38.9 +/- 75.6 ng L-1). Patients with prolonged fever (duration > 4 days) had higher IL-6 levels (94.7 +/- 138.2 vs. 21.7 +/- 29.7 ng L-1, P < 0.05). IL-6 levels were not related to heart failure. CONCLUSIONS: Our results indicate that increased inflammatory activity is present not only in acute coronary syndromes, but also in a chronic form of ischaemic heart disease, giving further evidence for a central role of inflammatory processes in coronary artery disease. With regard to AMI, we found increased inflammatory activity in patients with prolonged fever.

The prevalence of chronic Chlamydia pneumoniae infection as detected by polymerase chain reaction in pharyngeal samples from patients with ischaemic heart disease.

AIMS: Cross-sectional serological studies have suggested an association between ischaemic heart disease and infections from Chlamydia pneumoniae and Helicobacter pylori. We therefore sought to find out if patients with ischaemic heart disease had an increased prevalence of C. pneumoniae in the pharynx. As the course of the C. pneumoniae infection remains unclear, both acute and follow-up samples were taken and compared with antibody levels. METHODS AND RESULTS: We studied 282 patients with ischaemic heart disease. One hundred and two subjects without history or symptoms of ischaemic heart disease served as controls. Pharyngeal specimens for polymerase chain reaction detection of C. pneumoniae, and blood samples for C. pneumoniae and H. pylori antibody detection, were collected. In patients with positive polymerase chain reaction or C. pneumoniae IgA titres > or = 32, indicating current infection, convalescent samples were taken at least 6 weeks later. An immunofluorescent antigen detection test was used to confirm the presence of C. pneumoniae elementary bodies in specimens found to be polymerase chain reaction positive. The prevalence of positive polymerase chain reaction tests was 36% among patients and 22% among controls (P<0.05). Forty-seven percent of patients with positive polymerase chain reaction remained positive in the convalescent test. Elevated C. pneumoniae IgG titres > or = 512 were found in 39% of patients and 26% of the controls (P<0.05). IgA titres > or = 32 were found in 46% of the patients and 44% of the controls (ns). Antibody titres remained largely unchanged at convalescent testing. Two patients and none of the controls had IgM titres > 16. There was no link between positive H. pylori serology and positive C. pneumoniae polymerase chain reaction tests. CONCLUSIONS: The high prevalence and persistence of positive pharyngeal C. pneumoniae polymerase chain reaction and elevated antibody titres in patients with ischaemic heart disease indicate a chronic infection. The pharyngeal presence of C. pneumoniae might contribute to a low grade inflammatory activation or be a source for further spread of the bacteria to atherosclerotic vessels.

The glycoprotein IIb/IIIa platelet receptor blocker tirofiban, but not heparin, counteracts platelet aggregation in unstable angina pectoris.

In this study, despite concomitant aspirin treatment, tirofiban, but not heparin, reduced platelet aggregation in patients with acute myocardial ischemia. Platelet aggregation was determined with 2 independent methods, filtragometry and whole blood aggregometry.

Effect of epinephrine infusion on chest pain in syndrome X in the absence of signs of myocardial ischemia.

Eight female patients (aged 51 to 65 years) with New York Heart Association class II angina pectoris, normal coronary angiograms, normal hyperventilation, and abnormal exercise stress tests (chest pain and ST depression), and 5 sex- and age-matched controls participated in this study. Epinephrine was given intravenously to both patients and controls at 5-minute intervals in doses of 0.1, 0.2, 0.3, 0.4, and 0.6 nmol/kg/min. After rest (15 minutes), the alpha-adrenoceptor antagonist phentolamine or placebo was administered intravenously to patients in a double-blind, crossover study on 2 separate occasions in doses of 250 micrograms/min for 5 minutes and 500 micrograms/min for the next 10 minutes; the epinephrine infusion was repeated. Blood pressure, heart rate, and electrocardiogram were monitored continuously and pain was estimated on the Borg CR-10 scale. On a third occasion, chest pain was induced in patients using the same epinephrine protocol during echocardiographic monitoring. In the control group, all patients received the maximal epinephrine dose. No chest discomfort or pain developed. In the patient group, the maximal tolerable epinephrine dose (0.39 +/- 0.19 nmol/kg/min) decreased diastolic pressure (-14 +/- 9 mm Hg, p < 0.01) and increased heart rate (+24 +/- 10 beats/min, p < 0.01), not statistically different from the control group. Pulse pressure increased in the patient group (27 +/- 17 mm Hg, p < 0.01) but not in the controls. Left ventricular ejection fraction at baseline was within reference limits (58% to 75%) and did not change during epinephrine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Significance of platelet beta-adrenoceptors for platelet responses in vivo and in vitro.

The significance of platelet beta-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the beta-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed alpha- and beta-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma beta-thromboglobulin levels. Adrenaline levels were 3-4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels. beta-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that beta-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an alpha-adrenoceptor mediated proaggregatory action.

Influence of beta-adrenergic receptor function during terbutaline treatment on allergen sensitivity and bronchodilator response to terbutaline in asthmatic subjects.

Nine asthmatic patients with an allergy to birch or timothy underwent bronchial allergen provocations on three different trial days, with intervals of 2 to 5 wk. Two weeks prior to one of the provocations, no medication was allowed. Before the other two provocations the patients had been on continuous treatment with oral terbutaline (7.5-mg slow-release pill bid) for 2 wk, which was discontinued 12 or 48 h before the allergen provocation. After allergen challenges, terbutaline was inhaled in increasing doses (0.5 mg, 1.0 mg, and 2.0 mg), and pulmonary function was measured after each dose. Before each allergen provocation, blood samples were drawn for measurements of catecholamine and terbutaline concentrations and for in vitro measurements of beta-adrenergic receptor function on lymphocytes (isoproterenol-induced accumulation of cyclic AMP). Beta-adrenergic receptor function on blood lymphocytes was impaired after the two treatment periods, compared with the drug-free period, and was significantly more depressed at 12 h than 48 h after dosing. The bronchial responsiveness to allergen, defined as PC20PEF (median values), was 1,700 biologic units (BU) after the period of no treatment and 220 BU and 445 BU at 12 and 48 h after discontinuation of the terbutaline treatment (p less than 0.1 after 48 h). Five of the nine patients exhibited increased bronchial responsiveness 48 h after treatment, compared to results without treatment. The responsiveness was similar on all occasions in three patients. The bronchodilator response to inhaled terbutaline after allergen-induced bronchoconstriction was attenuated (p less than 0.01) at both 12 and 48 h after terbutaline, compared to results without treatment, indicating desensitization also of the bronchial beta-adrenergic receptors. We conclude that the early bronchial responsiveness to allergen is increased following a period of continuous treatment with a beta-adrenergic receptor agonist in some asthmatic patients and that the capability of a beta-agonist to reverse allergen-induced bronchoconstriction is attenuated after beta-agonist treatment.

Altered cardiovascular responsiveness to adrenoceptor agonists in endurance-trained men.

The influence of physical training on responses to intravenous infusions of phenylephrine (Phe) and isoproterenol (Iso) were investigated in 10 well-trained runners (WT) and 10 age-matched untrained controls (UT). The latter were reinvestigated after a 4-mo training period. The venous plasma Iso and Phe concentrations attained during infusions were lower in WT than in UT. Responses were related to the corresponding plasma concentrations. Phe-induced decreases and Iso-induced increases in heart rate were less pronounced (P less than 0.01) in WT than in UT. At venous plasma concentrations of 100 nM Phe and 0.8 nM Iso, the responses were -9 +/- 1 and 30 +/- 2, and -17 +/- 2 and 44 +/- 4 beats/min, respectively. Increases in blood pressures during Phe infusions were greater in WT than in UT (100 nM Phe: systolic 36 +/- 3 vs. 25 +/- 3 mmHg, P less than 0.05). The Iso-induced decrease in diastolic blood pressure was also more pronounced in WT (0.8 nM Iso: -29 +/- 3 vs. -15 +/- 2 mmHg, P less than 0.01). Iso-induced changes in systolic time intervals showed no consistent differences between training states. Increases in plasma adenosine 3',5'-cyclic monophosphate during Iso infusions were smaller (P less than 0.05) in WT than in UT, whereas increases in plasma glycerol were larger (P less than 0.05). Lymphocyte beta 2-adrenoceptor function and binding characteristics did not differ between training states. In summary, the present results indicate that beta-adrenergic vasodilator and alpha-adrenergic vasopressor responses are enhanced in endurance-trained subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison between isoprenaline infusions and bolus injections to assess beta-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 responses. 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 micrograms. 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', delta responses at 1 nmol l-1 isoprenaline (infusions) were increased for diastolic blood pressure and decreased for systolic blood pressure and stroke volume. Bolus injections of 2 micrograms isoprenaline caused enhanced delta responses after 'autonomic blockade' of diastolic blood pressure, left ventricular diameter in systole, ventricular circumferential fibre shortening, mean posterior wall velocity (Vmean 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 beta-blockade (propranolol), pre-ejection period and left ventricular diameter in systole were unaffected, and Vmean 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 Vmean PW and ventricular circumferential fibre shortening are parameters which can be useful in order to evaluate cardiac beta-adrenoceptor sensitivity in vivo in man.

Altered adrenoceptor responsiveness during adrenaline infusion but not during mental stress: differences between receptor subtypes and tissues.

1. Effects of 3 h infusions of adrenaline (0.4 nmol kg-1 min-1) or placebo and of mental stress evoked by a colour word test (CWT) on adrenergic receptor function were investigated in healthy men. Responses of heart rate, blood pressure, plasma catecholamines, plasma cyclic AMP and plasma free fatty acids (FFA) were evaluated during infusions and CWT. In vitro beta 2-adrenoceptor numbers [( 125I]-HYP binding) and function (isoprenaline induced cyclic AMP accumulation) were studied on lymphocytes in all experiments. alpha 2-adrenoceptor binding [( 3H]-yohimbine and adrenaline) to intact platelets was evaluated in the infusion experiments only. 2. Placebo infusion evoked no major alterations of any parameter. 3. Adrenaline infusion raised venous plasma adrenaline levels to 4-5 nmol l-1, increased heart rate by 14 +/- 3 beats min-1 and plasma cyclic AMP by 17 +/- 3 nmol l-1, and decreased diastolic blood pressure by 15 +/- 5 mm Hg. These responses persisted throughout the infusion. Plasma FFA levels, on the other hand, increased at 30 min of infusion (from 236 +/- 44 to 717 +/- 92 mumol l-1) and returned to basal levels after 3 h of infusion. 4. In vitro, lymphocytes showed increased beta 2-responsiveness after 30 min of adrenaline infusion (delta cyclic AMP increased from 1.86 +/- 0.24 to 3.06 +/- 0.58 pmol/10(6) cells), but a decreased response (0.47 +/- 0.10 pmol/10(6) cells) after 3 h of infusion. [125I]-HYP binding to lymphocyte membranes showed a three-fold increase of Bmax at 30 min of adrenaline infusion followed by a return to basal values after 3 h of infusion. [125I]-HYP binding reflected the functional responsiveness of the lymphocytes in vitro poorly. alpha 2-adrenoceptors on platelets were not altered with regard to Bmax or Kd for [3H]-yohimbine binding or Ki for adrenaline displacement of [3H]-yohimbine binding. 5. CWT evoked marked circulatory changes, a four-fold increase in plasma adrenaline and a 60% increase in beta 2-adrenoceptor binding sites without changes in functional responsiveness of the lymphocytes. 6. We conclude that exposure to high physiological levels of adrenaline in vivo alters lymphocyte beta-adrenoceptor responsiveness in a biphasic manner, with an early increase followed by a later decrease, but that most beta-adrenoceptor mediated responses to adrenaline in vivo remain intact. Lymphocyte alterations may reflect recruitment of cells into the circulation during sympathoadrenal stimulation. Platelet alpha 2-adrenoceptors are apparently not easily subjected to agonist induced dynamic receptor regulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Beta-adrenergic receptor responsiveness to isoprenaline in humans: concentration-effect, as compared with dose-effect evaluation and influence of autonomic reflexes.

1. Different techniques of assessing beta-adrenoceptor sensitivity in vivo, by use of i.v. infusions or bolus injections of isoprenaline (ISO), were compared in healthy volunteers. The importance of autonomic reflexes for responses to ISO was evaluated by studying the influence of 'autonomic blockade' by atropine and clonidine, which antagonize muscarinic effects and reduce sympathetic activity, respectively. Estimates of in vivo responsiveness to ISO were compared with parameters reflecting beta 2-adrenoceptor function in vitro in lymphocytes. 2. Heart rate responses to infused ISO were not significantly altered by 'autonomic blockade' when evaluated from concentration-effect curves. When related to the infused dose of ISO, however, sensitivity was artefactually increased (P less than 0.05), as the plasma concentrations of ISO were 40% higher after atropine and clonidine. Heart rate responses to bolus injections of ISO were attenuated (P less than 0.05) by 'autonomic blockade', suggesting that facilitatory reflexes contribute to these non-steady state responses. Intersubject variations in heart rate responsiveness to ISO were greater than the intrasubject variability caused by counterregulatory reflexes. 3. 'Autonomic blockade' lowered venous plasma noradrenaline at rest. The noradrenaline response to ISO infusion was attenuated and the diastolic blood pressure response enhanced, indicating that a counterregulatory vasoconstrictor reflex normally is activated by ISO-induced vasodilatation. The plasma cyclic AMP response to ISO, on the other hand, was unaffected by atropine and clonidine and reflects beta 2-adrenoceptor responsiveness in vivo. 4. In vitro data for beta-adrenoceptor binding sites (Bmax;[125I]-IHYP binding) and cyclic AMP responses to ISO in lymphocytes correlated with DBP and noradrenaline responses to infused ISO. No correlations were found between in vitro data and heart rate, plasma cyclic AMP or plasma glycerol responses to infused ISO in vivo. 5. During prolonged ISO infusions (in six other healthy subjects) physiological responses reached greater than 90% of their steady state level after 8 min, but no definite steady state level could be defined for the plasma concentration of ISO during 40 min of infusion. 6. The ISO infusion test showed a good reproducibility, especially when repeated on the same day. Evaluation of plasma concentration-effect relationships increase the precision of the ISO infusion test as confounding inter- and intra-individual variations in ISO concentrations (as caused by e.g. autonomic blockade) will be taken into account.(ABSTRACT TRUNCATED AT 400 WORDS)

Reduced beta 2-adrenoceptor sensitivity in normal pregnancy but not in pregnancy-induced hypertension.

beta 2-Adrenoceptors on lymphocytes from healthy nonpregnant and pregnant women and patients with pregnancy-induced hypertension (PIH) were studied in vitro by a radioligand binding technique (125I-hydroxybenzylpindolol) and related to in vivo responses to infused adrenaline. Healthy pregnant women had significantly fewer beta 2-adrenoceptor binding sites than nonpregnant controls (47.1 +/- 5.6 vs. 73.6 +/- 10.5 fmol X mg-1 protein), PIH patients displaying intermediate values. Adrenaline-induced increases in plasma cyclic AMP (a beta 2-mediated in vivo response) also tended to be reduced during normal pregnancy. The systemic vasodilatation evoked by intravenously infused adrenaline and the density of lymphocyte beta 2-adrenoceptor binding sites were positively related in the nonpregnant controls (r = 0.50), but inversely related in both the pregnant controls (r = -0.40) and the PIH patients (r = -0.70). These regression lines differed significantly. The present results indicate a reduction of beta 2-adrenoceptor function during normal pregnancy, which is less pronounced in PIH, as well as an altered relationship between beta 2-mediated vasodilator responses and densities of beta 2-adrenoceptors on lymphocytes during pregnancy.

Studies in vivo and in vitro of terbutaline-induced beta-adrenoceptor desensitization in healthy subjects.

Beta-Adrenoceptor function was studied in eight healthy subjects before, during and 24 and 72 h after cessation of 2 weeks continuous oral treatment with the beta 2-adrenoceptor agonist terbutaline (sustained release, 7.5 mg twice daily). In vivo, blood pressure, heart rate, plasma noradrenaline and plasma cyclic AMP responses to isoprenaline (0.01, 0.02 and 0.05 microgram min-1 kg-1 intravenously) were related to the plasma concentrations of isoprenaline. for comparison, beta 2-adrenoceptor function was evaluated in lymphocytes in vitro by studies of isoprenaline-induced accumulation of cyclic AMP and radioligand binding studies using 125I-iodohydroxybenzylpindolol. In vivo, the beta 2-mediated plasma cyclic AMP response to isoprenaline was markedly attenuated during terbutaline treatment and was still reduced by 38% (P less than 0.05) 72 h after discontinuation of treatment. The blood pressure and heart rate responses to isoprenaline were unaffected by treatment. Isoprenaline-induced elevations of plasma noradrenaline concentrations were markedly reduced during terbutaline treatment. This indicates an attenuation of isoprenaline-induced increases in sympathetic nerve function and could explain why no attenuation of the isoprenaline-induced vasodilatation was observed. Thus, plasma cyclic AMP seems to be a better marker than diastolic blood pressure when evaluating beta 2-adrenoceptor responsiveness in vivo in man, since it is not influenced by counter-regulatory increases in sympathetic nerve activity and/or noradrenaline overflow from sympathetic nerves. In lymphocytes, the isoprenaline-stimulated cyclic AMP accumulation was reduced by 75% and the beta-adrenoceptor binding sites were reduced by 40% 12 h after dosing. Also the lymphocyte beta 2-adrenoceptors recovered slowly after withdrawal of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma neuropeptide Y-like immunoreactivity and catecholamines during various degrees of sympathetic activation in man.

Neuropeptide Y-like immunoreactivity (NPY-LI) and catecholamine concentrations in plasma were analysed during and after 60 min of physical exercise at a work load corresponding to 70% of individual maximal oxygen uptake in nine healthy men of average physical fitness. Systemic plasma NPY-LI increased progressively from 18 +/- 3 to 81 +/- 19 pmol X 1(-1) in parallel with a 10-fold increase in noradrenaline (NA) concentration. The increase in plasma NPY-LI during exercise and the decrease after completion of exercise were much slower than the corresponding changes in NA concentration. This difference is probably related to a slower diffusion of NPY into systemic circulation after release, as well as to a longer half-life of NPY than of NA in plasma. Reversed phase HPLC and sephadex G-50 gel-filtration chromatography revealed that the main component of NPY-LI in plasma during exercise eluted in a similar position as synthetic human NPY. During exercise plasma NPY-LI correlated well with the plasma concentration of NA (r = 0.80), but not with that of adrenaline (ADR), suggesting a neuronal origin of NPY. The self-ratings of perceived exertion (RPE) were well correlated with the plasma concentrations of both NPY-LI and NA. No clear-cut veno-arterial concentration difference was observed for NPY-LI. Isometric handgrip and orthostatic test doubled plasma NA concentrations but did not cause any increase in plasma NPY-LI. No change in plasma tachykinin-like immunoreactivity was detected during exercise. The present data suggest that NPY is released together with NA during strong, but probably not during mild, sympathetic activation under physiological conditions in man.

Beta-adrenoceptor function in white blood cells from newborn infants: no relation to plasma catecholamine levels.

The maturity of beta-adrenoceptors in newborn infants was studied in relation to the catecholamine surge during labor. Umbilical blood was collected at birth from 12 infants delivered vaginally and 13 infants delivered by elective cesarean section. Granulocytes and lymphocytes were isolated. Receptor numbers and binding affinity were determined in the granulocytes by incubation with 125I-iodohydroxybenzylpindolol. Receptor responsiveness was tested by assessing isoproterenol-induced cyclic AMP accumulation in lymphocytes. Significantly higher plasma noradrenaline, adrenaline, and dopamine concentrations were found in infants born vaginally (108; 8.9; 0.9 nmol/liter, liter, respectively, median values) as compared with those delivered by cesarean section (11.0; 2.4; 0.2 nmol/liter). No significant differences in beta-adrenoceptor binding sites (receptor number: 39.2 +/- 2.6 versus 44.7 +/- 5.9 fmol/mg protein and binding affinity: 66.6 +/- 7.8 versus 65.0 +/- 6.2 pM) or responsiveness (maximal isoprenaline induced cAMP formation 52.4 +/- 10.3 versus 40.6 +/- 8.9 pmol/10(6) cells) were found between the two groups of infants. Lymphocyte beta-adrenoceptor sensitivity was similar to that found in adults. The beta-adrenoceptors on whole blood cells seem to be mature at birth and have the same responsiveness as in adults. The higher catecholamine surge during vaginal delivery as compared to elective cesarean section does not seem to affect beta-adrenoceptor function. Our results do not support the idea that reduced beta-adrenoceptor function is the cause of the previously observed inappropriately small cardiovascular and metabolic responses to the exceptionally high plasma catecholamine concentrations at birth.

Temperature-induced changes in metabolic and hormonal responses to intensive dynamic exercise.

Seven male subjects performed intensive cycle exercise to exhaustion at subnormal muscle temperature (Tm, 29 +/- 2.8 degrees C). Exercise at exactly the same rate of exercise and duration (370 +/- 34 W, 1.5 +/- 0.15 min) was then repeated with normal Tm (35 +/- 0.9 degrees C). During exercise both the arterial (a) and femoral venous (fv) contents of oxygen were significantly higher at subnormal than at normal Tm, because of the higher haemoglobin concentration, but the a-fv oxygen difference was the same in the two situations. The rate of increase in lactate concentration in both arterial and venous blood during exercise was the same in two situations. During exercise the plasma concentrations of adrenaline and noradrenaline in arterial and venous blood were significantly higher at subnormal than at normal Tm. At rest and after exercise the calf blood flow was significantly reduced at subnormal Tm. At the end of exercise the concentrations of glucose-6-phosphate and lactate in the muscle were significantly higher at subnormal Tm than in the muscle of normal temperature. These findings suggest that there was a greater increase in glycolysis in the muscle of subnormal temperature during exercise, possibly as a result of impaired work efficiency and/or reduced blood flow in the cold muscle.

Improvement of the isoprenaline infusion test by plasma concentration measurements.

A simple and sensitive method for the determination of isoprenaline (ISO) in plasma by high performance liquid chromatography (HPLC) with electrochemical detection is presented. Blood pressure and heart rate responses to i.v. infusion of ISO (15, 38 and 76 ng/kg/min) were studied in 15 subjects. Blood samples for ISO analyses were drawn after 7.5 min infusions on each dose level. A four- to six-fold interindividual variation in the venous plasma concentrations of ISO was found. Comparisons were made between estimates of the sensitivity to ISO from concentration-effect and dose-effect curves for both heart rate and diastolic blood pressure responses. Despite an overall correlation between the two methods of estimating ISO sensitivity, individual estimates of sensitivity differed markedly due to the differences in the plasma concentrations attained during infusions of standardized doses of ISO. The venous plasma concentration of ISO required to elevate heart rate by 25 beats/min (CC25) varied between 0.3 and 1.7 nM, whereas the corresponding dose of ISO (CD25) varied between 10 and 27 ng/kg/min.

Influence of circulating alpha adrenoceptor agonists on lung function in patients with exercise induced asthma and healthy subjects.

The influence of circulating noradrenaline (in this context primarily a non-selective alpha agonist) and the alpha 1 selective agonist phenylephrine on bronchial tone, blood pressure, and heart rate was studied in eight patients with exercise induced asthma and eight age and sex matched controls. All subjects refrained from taking treatment for at least one week before the trial. The agonists were infused intravenously in stepwise increasing doses of 0.04, 0.085, 0.17, and 0.34 micrograms/kg a minute for noradrenaline and 0.5, 1.0, 2.0, and 4.0 micrograms/kg a minute for phenylephrine. At the highest dose the plasma concentration of noradrenaline was about 30 nmol/l, resembling the concentrations found during intense exercise, and that of phenylephrine was about 400 nmol/l. Both agonists caused dose dependent and similar increases in blood pressure in the two groups. Despite clearcut cardiovascular effects (systolic and diastolic blood pressure increased by about 40-50/25-30 mm Hg), neither agonist altered lung function, as assessed by measurements of specific airway compliance (sGaw), peak expiratory flow (PEF), or end expiratory flow rate, in either group. It is concluded that circulating alpha agonists, whether alpha 1 selective (phenylephrine) or non-selective (noradrenaline), fail to alter basal bronchial tone in patients with exercise induced asthma or in healthy subjects.

Altered cardiovascular responsiveness to adrenaline in endurance-trained subjects.

The influence of physical training on responses to i.v. adrenaline infusions and to exercise were investigated in 10 endurance-trained men (mean age: 35 y; VO2max: 61.9 ml kg-1 min-1) and 10 age-matched and sedentary controls (36 y, 37.5 ml kg-1 min-1). The untrained subjects were reinvestigated after a 4 month training period which increased their VO2max by 18%. Resting heart rate and diastolic blood pressure were significantly lower in the trained state. The venous plasma adrenaline concentrations attained during infusions (4 dose levels, 8 min each) were lower in the well-trained than in the untrained subjects (2.15 vs. 3.59 nmol l-1 at the highest dose level, P less than 0.01). The adrenaline-induced increases in heart rate and in plasma cAMP and decreases in pre-ejection period (PEP) and PEP/LVET ratio were not dependent on the training state. The adrenaline-induced decrease in diastolic blood pressure was more pronounced (P less than 0.05) in the well-trained than in the untrained group and tended (0.05 less than P less than 0.1) to be enhanced by training in the latter group. The increases in systolic blood pressure were greater in the well-trained subjects (P less than 0.01) but training did not alter this response in the untrained subjects. The plasma noradrenaline response to maximal cycle ergometer exercise (VO2max test) was significantly greater in the well-trained than in the untrained subjects, while no difference was seen for adrenaline. The submaximal exercise systolic blood pressure was similar in all training conditions when related to the absolute rate of work. In summary, the present results indicate that both the vasodilator and systolic pressor responses to adrenaline are enhanced in endurance-trained subjects. The cardiac chronotropic and inotropic effects of adrenaline seem, however, to be independent of the training state.