Does α1-adrenergic blockade influence regional blood flow regulation in hearts with coronary artery occlusion?

Summary. The effects of selective α₁-adrenergic blockade with doxazosin on regional myocardial tissue blood flow was studied in anaesthetized cats with acute coronary artery occlusion. Reflex tachycardia was prevented by selective β₁-adrenergic blockade with atenolol and coronary perfusion pressure was kept constant by partial stenosis of the descending aorta. Administration of atenolol reduced cardiac mechanical work-load by its negative inotropic and chronotropic effects, and reduced myocardial tissue blood flow in normally perfused myocardium. This reduction was most pronounced in the endocardial half-layer of the myocardium adjacent to the ischaemic region. Administration of doxazosin in this situation clearly reduced peak systolic and coronary perfusion pressure. But when coronary perfusion pressure was raised to pre-administration values, measurements of regional blood flow revealed no changes either in ischaemic or non-ischaemic myocardium. Also, there was no sign of redistribution of blood flow between endocardial and epicardial tissue in any area. This study, therefore, indicates that α₁-adrenoceptors play a minor role in the regulation of coronary blood flow in normal myocardium as well as ischaemic myocardium.     

Regional myocardial tissue blood flow during β-adrenergic blockade in cat hearts with acute ischaemia

Summary. Selective β₁ or β₂-adrenergic blockade was achieved by practolol or IPS 339, respectively, in cats with acute ligation of a coronary artery. During blockade, heart rate was kept constant by atrial pacing and blood pressure reduction was prevented by aortic clamping. Regional myocardial blood flow was measured by the distribution of 15 μm labelled microspheres. Practolol slightly reduced epicardial blood flow in ischaemic myocardium, while blood flow in border and normally perfused myocardium remained unchanged. Following IPS 339, myocardial tissue flow increased in normally perfused myocardium, on average by 37% in the endocardium and 30% in the epicardium. No changes occurred in the other regions. The flow changes brought about by IPS 339 were unrelated to haemodynamic changes, and the coronary vascular resistance was reduced. These results are indicative of coronary vasodilation related to β₂-adrenergic receptor blockade and was confined to well-oxygenated areas surrounding the acutely ischaemic zone.     

Effect of practolol on blood flow distribution in the myocardium during acute regional ischaemia in cats

The β-adrenergic blocking agent practolol was given to 11 cats with acute coronary artery ligation, and regional myocardial tissue blood flow was measured by the distribution of 15 μm labelled microspheres. Practolol reduced heart rate and cardiac contractility, but left ventricular end-diastolic pressure rose in eight animals. In three animals, however, the haemodynamics were essentially unchanged and these are referred to as non-responders. No changes in regional myocardial blood flow were observed after practolol administration, either in ischaemic, border or normal areas of the left ventricle. This indicates less serious imbalance between oxygen demand and delivery in ischaemic tissue. There was no endocardial/epicardial redistribution of tissue flow. Practolol did not appear to improve coronary perfusion, and beneficial clinical effects of practolol are therefore probably related to reduction of myocardial oxygen demands.     

β-adrenergic blockade improves uniformity of local contraction in the anterior wall of feline left ventricles

Summary. Uniformity of myocardial contraction has been put forward as an important regulatory mechanism of myocardial contraction, and we have previously demonstrated reduced uniformity of local myocardial contraction in the midwall of left ventricles during preload reduction combined with increased inotropy. The aim of the present study was to explore the isolated inotropic influence on uniformity of contraction, keeping loading conditions constant. Segment performance was measured by implanted piezo-electric crystals in ten open-chest, anaesthetized cats. One crystal pair, circumferential segment, aligned with midwall and epicardial fibres, whereas another perpendicular segment, longitudinal, ran close to endocardial fibre direction. Maximal systolic shortening of longitudinal segments remained unchanged following inotropic interventions, isoprenaline and timolol, whereas circumferential segments revealed reduced performance with timolol (8.4 ±1.0% compared with 14.0 ±1.3% during control; P<0.001). In the control state the longitudinal-to-circumferential ratio (LONG/CIRC) a quantitative measure of uniformity, was 0.32 ± 0.08. No change in uniformity occurred during isoprenaline infusion (0.32 ±0.11) but during β-adrenergic blockade with timolol a clearly higher LONG/CIRC ratio was observed (0.56±0.06, P<0–005). Myocardial tissue blood flow measurement by radioactive microspheres showed a shift in transmural distribution with interventions so that subepicardial blood flow was markedly reduced during 0-adrenergic blockade. The direction of subepicardial fibres approximates our circumferential segments. Thus, there may well exist a relationship between segmental shortening and perfusion. In conclusion, circumferential segments were most influenced by changes in inotropy in contrast to previous observations where pronounced changes in longitudinal segments with loading occur. Furthermore, this study demonstrates that reduced inotropy with timolol helped uniform local contraction as estimated by the increased LONG/CIRC ratio, a transition that could improve contraction efficacy.     

Prostacyclin and regional coronary blood flow in experimental myocardial infarction

Infusion of prostacyclin (PGI₂) has been reported to affect infarct size and myocardial blood flow favourably in various animal models of myocardial ischaemia. Recent data suggest that a similar effect of PGI₂ may occur also in humans with acute myocardial infarction. We addressed the hypothesis that PGI₂ redistributes myocardial blood flow following coronary ligation, and that this effect favours perfusion of myocardium at risk and thereby limits infarct size. Following ligation of a distal branch of the left coronary artery in anaesthetized dogs, PGI₂ (2–4 ng/kg/min) was infused for 72 h. Regional myocardial blood flow was assessed immediately after the coronary ligation and at the end of the drug infusion, by injection of ⁵⁷Co- and ¹¹³Sn-labelled microspheres, respectively. Coronary ligation reduced regional coronary blood flow by 40–70%. During the subsequent 72 h the blood flow increased, being at the end of the period 50–70% of the flow in the non-ischaemic myocardium. PGI₂ did not affect the spontaneous improvement of regional myocardial blood flow, as assessed at the end of the infusion. PGI₂ also failed to affect infarct size, either when expressed in relation to total left ventricular mass, or in relation to area at risk. We conclude that PGI₂, when infused immediately after coronary ligation in dogs in a clinically relevant dose, neither affects regional myocardial blood flow in the ischaemic regions, nor the size of the myocardial infarction.     

Regional myocardial tissue blood flow during sequential beta 1- and beta 2-adrenergic blockade in cat hearts with acute ischaemia

beta-Adrenergic blockade was imposed on cats with ischaemic regions of the left ventricle produced by coronary artery occlusion. Ten animals first received a beta 1-blocking agent (atenolol) followed by a beta 2-blocking agent (IPS 339). In ten more animals this sequence was reversed. Combined blockade, obtained after both agents were administered, showed clear reduction of tissue blood flow in all areas of the ventricle, except for the central ischaemic zone. The flow reduction could be ascribed to bradycardia and reduced coronary perfusion pressure. By analysing the sequential changes it was evident that blockade of beta 1-adrenergic receptors was responsible for the haemodynamic changes, and the coronary vascular resistance rose so as to match the quantity of blood flow to the functional state of the ventricle. Blockade of beta 2-receptors by IPS 339, however, showed no evidence of coronary vasoconstriction but rather maintained vascular resistance at an unchanged level despite a weak beta 1-adrenergic blocking effect.     

Association of β‐1 and β‐2 adrenergic receptor gene polymorphisms with myocardial infarction

Both β₁‐ and β2‐adrenergic receptors (β₁‐ and β₂‐AR) have important roles in heart function mainly in response to catecholamines. Some specific polymorphisms in the β₁‐ and β₂‐AR genes, named ADRB1 and ADRB2, respectively, have been implicated in several cardiovascular and noncardiovascular phenotypes. In this study, we aimed to investigate the possible relationship between Ser49Gly and Arg389Gly polymorphisms of the ADRB1 and Arg16Gly and Gln27Glu polymorphisms of the ADRB2 gene with ST elevation myocardial infarction (MI) in a Turkish population. One hundred patients with ST elevation MI and 100 healthy control subjects were genotyped using the PCR‐RFLP method. Although the Arg389 allele of the ADRB1 gene was associated with an elevated risk of MI, the Glu27 allele of the ADRB2 gene was associated with a decreased risk of MI. Carriers of the ADRB1 Arg389 allele (heterozygotes+homozygotes) had an approximately 3.5‐fold increased risk for MI than Gly389 homozygotes (OR=3.59, 95% CI=0.96–13.47, P=0.045). For the ADRB2 Gln27Glu polymorphism, subjects having one or two copies of the Glu27 allele showed a decreased risk of MI compared with Gln27 homozygote subjects (OR=0.48, 95% CI=0.24–0.94, P=0.03). Haplotype analysis of these polymorphisms showed no significant differences between groups. These results suggest that the Arg389Gly and Gln27Glu polymorphisms may be associated with an altered risk of MI in this Turkish population. J. Clin. Lab. Anal. 23:237–243, 2009. © 2009 Wiley‐Liss, Inc.     

Effect of β1-selective and non-selective β-blockade on work capacity and muscle metabolism

Summary. Six well-trained men were studied while performing a maximal bicycle exercise. The seven experiments included in this study were randomized in a double-blind cross-over fashion. On each occasion the subjects were given either placebo or 40, 80, or 160 mg propranolol (non-selective blockade) or 25,50, or 100 mg atenolol (β₁-selective blockade). After completion of the study each subject had performed once under each of the seven treatments. Heart rate, maximal oxygen uptake (V?_o2max), blood lactate and performance time to exhaustion were measured. A muscle biopsy from vastus lateralis was taken at exhaustion after placebo, 80 mg propranolol and 50 mg atenolol trials, for analysis of ATP, creatine phosphate (CP), glucose-6-phosphate (G-6-P), glucose and lactate. The performance time was reduced (P<0·05—0·001) with both blockers compared to placebo. At an equal heart rate reduction, V?_o2max was equally reduced by both blockers. Performance time, on the other hand, was reduced to a greater extent (P<0·05) with propranolol. ATP and CP levels were decreased (P<0·05) by both drugs. G-6-P, however, was lower (P<0·05) with propranolol than with either placebo or atenolol. No difference was observed between placebo and atenolol. In conclusion, both pVselective and non-selective blockade reduced short-term maximal exercise capacity. The major limiting factor seems to be the reduction in oxygen transport. The finding that at an equivalent reduction in V?_o2max propranolol reduced performance time to a greater extent than atenolol suggests that β₂-blockade may reduce performance by mechanisms additional to those that affect oxygen transport. One possible mechanism is a retardation of glycolysis.     

Glucose-induced thermogenesis in patients with small cell lung carcinoma. The effect of acute β-adrenergic inhibition

Summary. Seven patients with histologically verified small cell lung carcinoma were given an oral glucose load of 75 g on two occasions to examine the effect of glucose on whole body and forearm thermogenesis with and without acute (3-adrenergic inhibition with propranolol. Whole body energy expenditure was measured by the open circuit ventilated hood system. Forearm blood flow was measured by venous occlusion strain-gauge plethysmography. The uptake of oxygen in the forearm was calculated as the product of the forearm blood flow and the difference in arteriovenous oxygen concentration. The glucose-induced thermogenesis in the 120 min following the glucose load was significantly reduced by β-adrenergic inhibition with approximately 50% from 63–9 ± 5–8 kJ 120 min^-1 (mean ± SE) to 27–8 ± 9–8 kJ 120 min^-1 (P<0–01). Almost the entire reduction took place from 60 to 120 min (P<0–005). The integrated glucose-induced forearm oxygen uptake in the period 60–120 min following the glucose load was significantly reduced after β-adrenergicinhibition from 103 ± 28 μmol 100 g^-160 min^-1 to 29 ± 29 μmol 100 g^-1 60 min^-1 (P<0–05). The noreadrenaline concentration in the arterial blood was not increased in the baseline period compared to healthy elderly; it increased following the glucose load while there was no demonstrable increase in adrenaline concentration in the two experiments. It is suggested that these patients have increased sensitivity of the β-adrenergic receptors and an early facultative component of the glucose-induced thermogenesis in part takes place in the forearm.     

Effect of β1-adrenoceptor blockade on plasma levels of atrial natriuretic peptide during exercise in normal man

Summary. Increased plasma levels of atrial natriuretic peptide (ANP) during exercise have been reported. To investigate the role of tachycardia as a stimulus for release of ANP during exercise the following study was undertaken. Graded exercise was performed in six healthy volunteers before and after β₁-adrenoceptor blockade. Plasma levels of ANP were determined at different workloads in both cases. At rest and at all workloads during exercise plasma levels of ANP were higher after β₁-adrenoceptor blockade than without. Therefore, it is unlikely that tachycardia is a major stimulus for secretion of ANP during exercise. It is suggested that increased right atrial pressure and/or pulmonary arterial blood pressure and increased plasma levels of catecholamines are important secretory stimuli for ANP during exercise.     

Role of Propranolol in Improvement of the Relationship between O2 Supply and Consumption in an Ischemic Region of the Dog Heart

Several aspects of the myocardial O₂ supply/consumption relationship were determined after coronary artery occlusion and subsequent β-adrenergic blockade in 16 anesthetized open-chest dogs. Small artery and vein O₂ saturations, and hence extraction, were obtained microspectrophotometrically and combined with radioactive microsphere blood flow determinations to calculate regional myocardial O₂ consumption. Eight dogs remained untreated after coronary artery ligation while another group was given 2 mg/kg propranolol, 10 min after occlusion. Untreated occlusion resulted in decreased arterial and especially venous O₂ saturations, indicating an increased O₂ extraction. Ischemic O₂ consumption was reduced and the subendocardial/subepicardial consumption ratio was reversed (1.26 vs. 0.37) due to the pattern of occluded area flow. Calculated O₂ supply/consumption also decreased. Propranolol produced no significant changes in volume or distribution of flow within the ischemic region while reducing flow, extraction, and consumption in the unoccluded region. The heterogeneity of arterial and particularly venous O₂ saturations within the ischemic region decreased dramatically. Venous O₂ saturations were elevated relative to the control group resulting in a reduced O₂ extraction. The decrease in heterogeneity of arterial and venous O₂ saturations suggest that propranolol eliminates microregions of relatively high O₂ extraction, consumption, and/or a majority of vessels with extremely low flow. This leads to a significant improvement in the O₂ supply/consumption ratio in the ischemic myocardium of the dog. This may be due to a reduction in the heterogeneity and level of β₁-adrenergic receptor activity within the heart.     

Redox control of β2‐glycoprotein I–von Willebrand factor interaction by thioredoxin‐1

Summary. Background: β₂‐Glycoprotein I (β₂GPI) is an abundant plasma protein that is closely linked to blood clotting, as it interacts with various protein and cellular components of the coagulation system. However, the role of β₂GPI in thrombus formation is unknown. We have recently shown that β₂GPI is susceptible to reduction by the thiol oxidoreductases thioredoxin‐1 and protein disulfide isomerase, and that reduction of β₂GPI can take place on the platelet surface. Methods: β₂GPI, reduced by thioredoxin‐1, was labeled with the selective sulfhydryl probe N^a‐(3‐maleimidylpropionyl)biocytin and subjected to mass spectrometry to identify the specific cysteines involved in the thiol exchange reaction. Binding assays were used to examine the affinity of reduced β₂GPI for von Willebrand factor (VWF) and the effect of reduced β2GPI on glycoprotein (GP)Ibα binding to VWF. Platelet adhesion to ristocetin‐activated VWF was studied in the presence of reduced β₂GPI. Results: We demonstrate that the Cys288–Cys326 disulfide in domain V of β₂GPI is the predominant disulfide reduced by thioredoxin‐1. Reduced β₂GPI in vitro displays increased binding to VWF that is dependent on disulfide bond formation. β₂GPI reduced by thioredoxin‐1, in comparison with non‐reduced β₂GPI, leads to increased binding of GPIbα to VWF and increased platelet adhesion to activated VWF. Conclusions: Given the importance of thiol oxidoreductases in thrombus formation, we provide preliminary evidence that the thiol‐dependent interaction of β₂GPI with VWF may contribute to the redox regulation of platelet adhesion.     

Structure‐activity relationships of acetylcholine derivatives with Lucilia cuprina nicotinic acetylcholine receptor α1 and α2 subunits in chicken β2 subunit hybrid receptors in comparison with chicken nicotinic acetylcholine receptor α4/β2

Insect nicotinic acetylcholine (ACh) receptors (nAChRs) are the targets of several insecticide classes. In the present study, we report the gene identification and cloning of nAChR α1 and α2 subunits (Lcα1 and Lcα2) from the sheep blowfly Lucilia cuprina. Xenopus oocytes voltage clamp experiments as hybrids with the chicken β2 nAChR (Ggβ2) subunit resulted in ACh‐gated ion channels with distinct dose–response curves for Lcα1/Ggβ2 (effective concentration 50% [EC₅₀] = 80 nM; n_H = 1.05), and Lcα2/Ggβ2 (EC₅₀ = 5.37 μM, n_H = 1.46). The neonicotinoid imidacloprid was a potent agonist for the α‐bungarotoxin‐sensitive Lcα1/Ggβ2 (EC₅₀ ～ 20 nM), while the α‐bungarotoxin‐resistant Lcα2/Ggβ2 showed a 30‐fold lower sensitivity to this insecticide (EC₅₀ = 0.62 μM). Thirteen close derivatives of ACh were analysed in EC₅₀, Hill coefficient and maximum current (relative to ACh) determinations for Lcα1/Ggβ2 and Lcα2/Ggβ2 and the chicken Ggα4/Ggβ2 nAChRs, and comparisons relative to ACh allowed the definition of novel structure‐activity and structure‐selectivity relationships. In the case of N‐ethyl‐acetylcholine, the EC₅₀ of the chicken Ggα4/Ggβ2 rose by a factor of 1000, while for both Lcα1/Ggβ2 and Lcα2/Ggβ2, potency remained unchanged. Further derivatives with insect nAChR selectivity potential were acetyl‐α‐methylcholine and trimethyl‐(3‐methoxy‐3‐oxopropyl)ammonium, followed by acetylhomocholine and trimethyl‐(4‐oxopentyl) ammonium. Our results may provide guidance for the identification or design of insect‐specific nAChR agonists using structure‐based or in silico methods.     

β2‐Glycoprotein I: evolution,structure and function

Summary. β₂‐Glycoprotein I (β₂‐GPI) is a protein that circulates in blood at high concentrations. The function of β₂‐GPI has long been an enigma. More than 20 years ago, it was discovered that β₂‐GPI is the major antigen for the circulating antibodies in the antiphospholipid syndrome. However, this knowledge has not advanced our understanding of the physiologic role of the protein. In recent years, new insights have suggested an important function of this protein in innate immunity. β₂‐GPI was found to scavenge lipopolysaccharide and was able to clear unwanted anionic cellular remnants such as microparticles from the circulation. The function of β₂‐GPI seems to depend on the structural conformation of the protein, and it has been established that β₂‐GPI can exist in at least two conformations. In this review, we will highlight and summarize the current knowledge on this protein.     

Relative rates of oxidation of glucose and free fatty acids by ischaemic and non-ischaemic myocardium after coronary artery ligation in the dog

Abstract. 1. Small regional ischaemic lesions, involving about 7 % of the volume of the whole heart, were produced in the greyhound dog by ligation of a branch of the anterior descending coronary artery. Arteriovenous differences across ischaemic tissue were studied by cannulation of a local vein visibly draining the ischaemic area, whereas arteriovenous differences across the non-ischaemic tissue were obtained by coronary sinus samples. This system permitted study of those ischaemic cells draining into the local vein and perfused by residual collateral circulation. Flow factors were common to all metabolites measured in local venous blood, thereby allowing detection of changes in substrate metabolism relative to each other. As the contribution of local venous blood to coronary sinus blood was negligible, it was possible to use coronary sinus values as non-ischaemic control data for each local venous sample.—2. The contributions of glucose, free fatty acids (FFA) and other substrates (lactate, pyruvate, ketones, triglycerides) to the residual oxidative metabolism of the ischaemic, infarcting dog myocardium were indirectly assessed by calculations of the oxygen extraction ratio (OER), and directly by the rate of ¹⁴CO₂ formation from ¹⁴C-labelled glucose or palmitic acid.—3. Within two hours of arterial ligation, the arteriovenous difference of glucose across the ischaemic tissue was increased relative to that of IT A. Whether calculated from OER or from ¹⁴CO₂ data, there was an increase in the oxidation rate of glucose relative to that of FFA. In absolute terms the oxygen uptake of ischaemic tissue fell almost as much as the flow rate, and the glucose uptake probably fell too. Nevertheless, glucose competed more favourably than did FFA for the residual oxidative metabolism of the ischaemic tissue.—4. In coronary sinus blood, draining predominantly non-ischaemic tissue, formation of ¹⁴CO₂ accounted for about half the uptake of ¹⁴C-glucose and formation of ¹⁴C-lactate was very low. In local venous blood draining predominantly ischaemic tissue, ¹⁴CO₂ formation accounted for about 30–40% and ¹⁴C-lactate for about 10% of the arteriovenous difference of ¹⁴C-glucose. The chemical oxygen extraction ratio of glucose and FFA could account for 90–100% of the residual oxygen uptake of the ischaemic myocardium 60–100 min. post-ligation, with glucose accounting for nearly twice as much oxygen as FFA. Thus an unexpected finding was that a major part of the glucose extracted by the ischaemic myocardium was oxidized, possibly because local venous blood drained the less severely ischaemic areas.—5. The major fate of labelled FFA extracted by the non-ischaemic myocardium also appeared to be oxidation. After arterial ligation, rates of FFA oxidation fell as assessed by both OER calculation and by rates of ¹⁴CO₂ formation. More ¹⁴C-label was recovered in the “mitochondrial” and less in the “microsomal” lipid fractions of the ischaemic tissue.—6. Lactate uptake by the normal myocardium was changed to lactate discharge by the ischaemic myocardium. Initially, tissue glycogen was the major source of the lactate formed, but 60–120 min. after arterial ligation there was less discharge of lactate and circulating ¹⁴C-gIucose became a major source of venous lactate.—7. It was concluded that not only was anaerobic metabolism of glucose accelerated by coronary artery ligation, but the aerobic metabolism of glucose increased relative to that of FFA.     

Gradual reduction of coronary perfusion pressure in cats: Changes in transmural distribution of blood flow

We evaluated a model for regional myocardial hypoperfusion in cats with an extracorporeal shunt line to the left main coronary artery, and investigated the effects of reduced coronary perfusion pressure on the transmural distribution of left ventricular blood flow measured with radioactive microspheres. Shunt establishment did not alter cardiac function, myocardial tissue blood flow, or its transmural distribution. An artificial shunt stenosis, which clearly reduced coronary perfusion pressure without changing cardiac function, caused reduced endocardial blood flow, slight flow reduction in mid-myocardium, and no flow change in the epicardium. When a severe stenosis was applied, causing increased end-diastolic pressure and reduced shunt flow, endocardial and mid-myocardial flow further decreased whereas epicardial blood flow remained essentially unchanged. These results demonstrate a transmural profile of the coronary autoregulation capacity.     

Gradual reduction of coronary perfusion pressure in cats: changes in transmural distribution of blood flow

We evaluated a model for regional myocardial hypoperfusion in cats with an extracorporeal shunt line to the left main coronary artery, and investigated the effects of reduced coronary perfusion pressure on the transmural distribution of left ventricular blood flow measured with radioactive microspheres. Shunt establishment did not alter cardiac function, myocardial tissue blood flow, or its transmural distribution. An artificial shunt stenosis, which clearly reduced coronary perfusion pressure without changing cardiac function, caused reduced endocardial blood flow, slight flow reduction in mid-myocardium, and no flow change in the epicardium. When a severe stenosis was applied, causing increased end-diastolic pressure and reduced shunt flow, endocardial and mid-myocardial flow further decreased whereas epicardial blood flow remained essentially unchanged. These results demonstrate a transmural profile of the coronary autoregulation capacity.     

Formation of prostacyclin during administration of β1-selective and non-selective β-adrenergic antagonists in healthy humans

Summary. Vascular formation of prostacyclin is increased by propranolol in patients with essential hypertension. However the possible effect of β-adrenoceptor blocking drugs in healthy subjects is, however, not known. We studied this issue by analysis of the urinary excretion of the prostacyclin metabolite, 2,3-dinor-6-keto-prostaglandin F_la during intake of a (β₁-selective (metoprolol) or a non-selective (propranolol) (3-adrenoceptor antagonist. After 14 days of metoprolol treatment (100 mg d^-1) the urinary excretion of PGI-M did not differ from control (253 ± 77 vs. 220 ± 33 pg mg^-1 creatinine, respectively). Five days of randomized cross-over treatment with propranolol (80 mg day^-1) or placebo did not affect urinary PGI-M significantly either (177 ± 11 vs. 202 ± 11 pg mg^-1 creatinine, respectively). Furthermore, a daily increasing dose of propranolol (80–480 mg) progressively lowered resting blood pressure and heart rate, but failed to influence urinary excretion of PGI-M. The data demonstrate that metoprolol and propranolol do not affect basal cardiovascular formation of prostacyclin in healthy subjects. Thus, the biosynthesis of prostacyclin does not appear to be regulated by p-adrenoceptor activity under normal conditions.     

Distribution of coronary blood flow during acute coronary occlusion in dogs. Effect of nicotinic acid and sodium salicylate

The effects of the antilipolytic agents nicotinic acid (NA) and sodium salicylate (SS) on the distribution of coronary blood flow during acute myocardial ischaemia were studied in open chest dogs. Fifteen min following experimental coronary artery occlusion, blood flow in the ischaemic myocardium was on average 28% of flow in the non-ischaemic myocardium. The reduction in blood flow in the ischaemic mycardium was more pronounced in the endocardial than in epicardial halves of the myocardium. No significant change in blood flow was observed after administration of NA or SS in either the ischemic or nonischemic part of the myocardium. Both drugs reduced the extent of myocardial ischaemic injury as shown by reduced epicardial ST-segment elevations. Arterial concentrations of fatty acids were lowered by NA or SS, whereas the mechanical activity of the heart remained unchanged. It is concluded that the reduction of acute myocardial ischaemic injury effected by NA or SS is not due to changes in myocardial blood flow, but more likely to lower myocardial oxygen demand related to reduced fatty acid utilization.     

Distribution of coronary blood flow during acute coronary occlusion in dogs. Effect of nicotinic acid and sodium salicylate

The effects of the antilipolytic agents nicotinic acid (NA) and sodium salicylate (SS) on the distribution of coronary blood flow during acute myocardial ischaemia were studied in open chest dogs. Fifteen min following experimental coronary artery occlusion, blood flow in the ischaemic myocardium was on average 28% of flow in the non-ischaemic myocardium. The reduction in blood flow in the ischaemic mycardium was more pronounced in the endocardial than in epicardial halves of the myocardium. No significant change in blood flow was observed after administration of NA or SS in either the ischemic or nonischemic part of the myocardium. Both drugs reduced the extent of myocardial ischaemic injury as shown by reduced epicardial ST-segment elevations. Arterial concentrations of fatty acids were lowered by NA or SS, whereas the mechanical activity of the heart remained unchanged. It is concluded that the reduction of acute myocardial ischaemic injury effected by NA or SS is not due to changes in myocardial blood flow, but more likely to lower myocardial oxygen demand related to reduced fatty acid utilization.