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.

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.

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)

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)

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.

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.

Reduced beta 2-adrenoceptor responsiveness in exercise-induced asthma.

Beta-adrenoceptor responsiveness was studied both in vivo and in vitro in patients with exercise-induced asthma (EIA), asthmatic patients without EIA (NEIA), and control subjects. All subjects were age- and sex-matched and without medication at least one week prior to the tests. In vivo, beta-adrenoceptor responsiveness was evaluated by plasma concentration-effect studies for intravenously infused isoprenaline (0.02-0.1 micrograms X kg-1 X min-1). Mainly beta 2-adrenoceptor mediated responses to isoprenaline, ie, decreases in diastolic blood pressure and increases in plasma cyclic AMP, were reduced in EIA patients but not in NEIA patients. Heart rate and plasma glycerol responses to isoprenaline did not differ between the groups. In vitro, the beta 2-adrenoceptor mediated accumulation of cyclic AMP in lymphocytes stimulated by isoprenaline was attenuated (p less than 0.05) in EIA patients, whereas the beta 2-adrenoceptor responsiveness of lymphocytes from NEIA patients was normal. Thus, beta 2-adrenoceptor mediated responses were reduced both in vivo and in vitro in EIA patients, but not in NEIA patients. This finding that beta 2-adrenoceptor responsiveness was reduced only in a subgroup of asthmatic patients could explain some of the controversies in the literature concerning beta-adrenoceptor function in asthma.

Ethanol dependent interaction between prostaglandins and lipoxygenase products in human peripheral lymphocytes.

The effect of lipoxygenase products, 12-L-HETE and 15-L-HPETE, on cyclic AMP levels in human peripheral lymphocytes was examined in the absence and in the presence of a prostaglandin of the E-type (0.6-3.0 microM) or isoprenaline (33 microM). The studies were performed either in the absence or in the presence of 6 per cent ethanol. For comparison the effect of arachidonic acid and linolenic acid were studied. In the absence of ethanol 12-L-HETE and 15-L-HPETE had no significant effect on cyclic AMP accumulation. However, in the presence of ethanol 12-L-HETE (above 1 microM) inhibited prostaglandin E1 but not isoprenaline induced cyclic AMP accumulation. 15-L-HPETE had a biphasic effect on prostaglandin E2 induced cyclic AMP accumulation. Concentrations below 1 microM stimulated, those above inhibited. Virtually complete inhibition was seen at 15 microM. The two other fatty acids inhibited both prostaglandin E2 and isoprenaline induced cyclic AMP accumulation in the presence, but not in the absence of ethanol. The results show that lipoxygense products have little or no effect on cyclic AMP accumulation in human peripheral lymphocytes unless ethanol is present. In the presence of ethanol both 12-L-HETE and 15-L-HPETE appeared to selectively affect the cyclic AMP accumulation stimulated by PGE.

Sympathoadrenal reactivity in exercise-induced asthma.

The possibility that sympathoadrenal activity is altered in asthma was examined in eight patients with a history of exercise-induced asthma (EIA), eight matched patients with nonexercise induced asthma (NEIA), and eight matched healthy control subjects. No medication was allowed for at least one week before examination. In a pretrial exercise test diagnosis of EIA was confirmed and each individual's work capacity (Vo2 max) was determined. The trial consisted of an orthostatic test and a standardized exercise test at 80 to 90 percent of VO2 max on a treadmill. The trial exercise test caused a decrease in FEV1 in EIA patients only, whereas measurements of Sgaw revealed a significant but less pronounced postexercise bronchoconstriction in NEIA-patients as well. Basal plasma catecholamine levels were similar in all groups. Noradrenaline and adrenaline levels were approximately doubled by the orthostatic test and increased approximately ten-fold following exercise, with no differences between the groups. Plasma cAMP levels were approximately doubled by the exercise test. In the EIA patients there was an inverse correlation between increases in plasma cAMP and decreases in Sgaw. Our study does not support earlier claims that exaggerated catecholamine response to exercise causes postexercise bronchoconstriction by alpha-adrenoceptor stimulation in EIA. Differences in study results appear to have methodologic explanations.

Comparison of the effects of different arachidonic acid metabolites on cyclic nucleotide accumulation in human peripheral lymphocytes.

The effect of PGE1, PGE2, PGD2, PGF2 alpha, PGI2, PGG2, PGA1, 12L-HETE, arachidonic acid, 15- HPETEa and linolenic acid on the accumulation of cyclic AMP in human peripheral lymphocytes was studied. PGE1, PGE2 and PGD2 were essentially equipotent as stimulators of cyclic AMP accumulation (threshold at about 10(-8)M and EC50 about 0.15 microM), PGF2 alpha was about 20 times less potent, while PGG2, 12L-HETE, 15-HPETE, PGA1 and linolenic acid were inactive. PGI2 caused a weak stimulation between 5 and 600 nM and a secondary stimulation above 3 microM. Arachidonic acid had no effect on cyclic AMP levels up to 100 microM. PGE1, PGD2, PGI2 and PGF2 alpha increased cyclic GMP in the concentrations that produced a rise in cyclic AMP, but the cyclic GMP increase was of smaller magnitude. Exogenous arachidonic acid was converted mainly to 12L-HETE, HHT and thromboxane B2 by lymphocyte suspensions. This conversion could be accounted for by contamination with blood platelets. The results show that the degree of cyclic AMP accumulation in human lymphocytes following stimulation of arachidonic acid metabolism will be critically dependent upon which prostaglandins are in fact formed by cells surrounding the lymphocytes.