Gunnar Ronquist

Glucagon-like peptide-1 (7–36) amide prevents the accumulation of pyruvate and lactate in the ischemic and non-ischemic porcine myocardium

Glucagon-like peptide-1 (7-36) amide (GLP-1) has been studied as a treatment option in diabetic patients. We investigated the effect of recombinant GLP-1 infusion on hemodynamic parameters, myocardial metabolism, and infarct size during normoxic conditions as well as during ischemia and reperfusion using an open-chest porcine heart model. In the presence of rGLP-1, interstitial levels of pyruvate and lactate decreased during ischemia and reperfusion both in ischemic and non-ischemic tissue. Moreover, rGLP-1 infusion resulted in increased plasma insulin levels and decreased blood glucose levels. Neither hemodynamic variables nor the consequent infarct size were influenced by rGLP-1 infusion. We conclude that rGLP-1 altered myocardial glucose utilization during ischemia and reperfusion. It did not exert any untoward hemodynamic effects.

Neuro- and cardioprotective effects of blockade of nitric oxide action by administration of methylene blue.

Methylene blue (MB), generic name methylthioninium (C16H18ClN3 S · 3H2O), is a blue dye synthesized in 1876 by Heinrich Caro for use as a textile dye and used in the laboratory and clinically since the 1890s, with well‐known toxicity and pharmacokinetics. It has experimentally proven neuroprotective and cardioprotective effects in a porcine model of global ischemia–reperfusion in experimental cardiac arrest. This effect has been attributed to MBs blocking effect on nitric oxide synthase and guanylyl cyclase, the latter blocking the synthesis of the second messenger of nitric oxide. The physiological effects during reperfusion include stabilization of the systemic circulation without significantly increased total peripheral resistance, moderately increased cerebral cortical blood flow, a decrease of lipid peroxidation and inflammation, and less anoxic tissue injury in the brain and the heart. The last two effects are recorded as less increase in plasma concentrations of astroglial protein S‐100β, as well as troponin I and creatine kinase isoenzyme MB, respectively.

Neurological outcome after experimental cardiopulmonary resuscitation: a result of delayed and potentially treatable neuronal injury?

Background: In experimental cardiopulmonary resuscitation (CPR) aortic balloon occlusion, vasopressin, and hypertonic saline dextran administration improve cerebral blood flow. Free radical scavenger α‐phenyl‐N‐tert‐butyl‐nitrone (PBN) and cyclosporine‐A (CsA) alleviate neuronal damage after global ischemia. Combining these treatments, we investigated neurological outcome after experimental cardiac arrest.

Low energy charge in human uterine muscle

Six pregnant and 10 non-pregnant patients undergoing Caesarean section and laparatomy, respectively participated in this study which was aimed at determining the energy status of human uterine muscle and comparing it to that of striated muscle from the same individual. Biopsies were taken from the fundus uteri between the ligamenta rotunda and from the rectus abdominis muscle. A low energy charge of 0.55 in pregnant patients and 0.64 in non-pregnant patients was observed in uterine biopsies, compared to the expected value of 0.90 found in rectus biopsies. The main determinant of this finding was a 4-8 times lower level of ATP in uterine biopsies compared to that in rectus biopsies. The same pattern was apparent for total nucleotide content and creatine phosphate. The ADP and AMP contents were of the same order of magnitude in both tissues. The lactate content in uterine biopsies from pregnant patients was significantly higher than that found in biopsies from rectus muscle and from uterine tissue of non-pregnant patients, indicating an increased glycogenolysis in pregnant uterus. The low energy charge and low level of phospho-compounds observed in uterine muscle, regardless of the functional state, are new and unexpected findings.

Effects of alkaline buffer administration on survival and myocardial energy metabolism in pigs subjected to ventricular fibrillation and closed chest CPR

Nineteen anaesthetized piglets were investigated. After characterization and a stabilization period, ventricular fibrillation was induced by a transthoracic DC shock, after which a 10‐min period of cardiopulmonary resuscitation (CPR) took place. CPR included manual chest compression and mechanical ventilation with pure oxygen. After 1 min of CPR an infusion of alkaline buffer was begun and was completed within 5 min. A total of 50 mmol of one of two different buffer solutions was given, either sodium bicarbonate (n=6) or tris buffer mixture (n=7). These two groups were compared with a third control group (n=6) receiving the same volume of normal saline. After 8 min of CPR all animals were given 0.5 mg adrenaline i.v., and after 10 min DC shocks were used to return the heart to normal sinus rhythm. If this procedure was successful, the heart was rapidly (within 15 s) stopped again by another DC shock. Myocardial biopsies were then taken immediately in all animals. Successful CPR was more frequent in the animals given normal saline or tris buffer mixture and no effect was seen in the group given sodium bicarbonate. Survival was statistically correlated to low myocardial content of creatine phosphate and low base excess values in blood. Such parameters as myocardial content of ATP or ACP (adenylate charge potential) had no direct correlation to survival. Sodium bicarbonate induced significantly higher base excess and Pco2 values, while the tris buffer mixture seemed to have a greater alkalizing effect intracellularly. We consider it probable that the poor results regarding survival after experimental CPR combined with a rapid infusion of sodium bicarbonate were a result of the excessive alkalosis created in combination with the higher resulting Pco2. Indirect evidence was given that a slightly alkaline pH also intracellularly supported critical reactions including ATPases essential for cellular survival.

Ischaemic preconditioning is related to decreasing levels of extracellular adenosine that may be metabolically useful in the at-risk myocardium: an experimental study in the pig.

Aim:  ‘Pre‐treatment’ with short repetitive periods of ischaemia (ischaemic preconditioning) has proved to be a powerful mechanism for modification of the extent of myocardial damage following acute coronary artery occlusion. The exact mechanism of protection induced by ischaemic preconditioning is not known. We herewith put forward a contributing component for protection with preconditioning involving a shift in the adenylate kinase (AK) equilibrium reaction in favour of adenosine triphosphate (ATP) formation.

Energy economy in the pregnant human uterus at term: studies on arteriovenous differences in metabolites of carbohydrate, fat and nucleotides

Metabolic regulation was studied in the pregnant human uterus by determining its uptake and release of various substrates, some of which are commonly used as a fuel and some are markers of disturbed energy status in cells. Ten healthy women with normal pregnancy were examined when undergoing elective Caesarean section at term, before onset of labour. Carbohydrate metabolites (glucose, lactate and pyruvate), fat metabolites (free fatty acids (FFA) and glycerol) and nucleotide metabolites (hypoxanthine, xanthine and urate) were determined in arterial (radial artery) and venous (plexus of the uterine and ovarian veins) blood. In addition the arteriovenous difference in each substance across the uterus was calculated. A distinct uptake of glucose was a typical finding in the pregnant uterus as reflected by a positive difference. On the other hand, glycerol and FFA were released from the pregnant uterus. Similarly, a degradation of adenine-containing nucleotides seemed to be continuously ongoing in the pregnant uterus, since oxypurines displayed a negative difference as well.

Inherited, non-spherocytic haemolysis due to deficiency of glucose-6-phosphate dehydrogenase

The about 400 million individuals worldwide suffering from a hereditary deficiency of the enzyme glucose‐6‐phosphate dehydrogenase (G6PD) may experience different degrees of haemolytic anaemia. Haemoglobin is present in very high concentrations in the erythrocyte cytoplasm, at risk of falling out of solution if the internal environment or the haemoglobin itself is changed. G6PD is a crucial enzyme producing reduced glutathione in the erythrocyte cytoplasm for the purpose of protecting haemoglobin against oxidative damage. The presence of unopposed oxidizing agents leading to oxidation of the sulfhydryl bridges between parts of the haemoglobin molecule decrease the solubility of haemoglobin, leading to precipitations called Heinz bodies. The laboratory investigation of G6PD deficiency is commonly done by a quantitative spectrophotometric analysis or by a rapid fluorescent spot test detecting the generation of NADPH from NADP. Genetic tests based on polymerase chain reaction detect specific mutations and may be used for population screening, family studies, or prenatal diagnosis.

Glyburide enhancement of lactate production in ischemic heart is modified by preconditioning : An in vivo experimental study in pigs by microdialysis technique

The concentrations of lactate, pyruvate, and adenosine, together with some of their derivatives, were determined in microdialysates from 12 pig hearts, 6 of which were subjected to preconditioning and 40 min of ischemia (index ischemia) and 6 of which were subjected to only 40 min of index ischemia. Two microdialysis probes were inserted in ischemic myocardium. Glyburide (10 mu M) in a modified isotonic Krebs-Ringer phosphate buffer was administered through one of the probes and plain isotonic phosphate buffer was administered through the other. Accordingly, the experimental setup permitted us to study the metabolic effects of glyburide on ischemic myocardium constituting two groups that were either preconditioned or unpreconditioned. The preconditioning effect was validated with area at risk and infarction area measurements in 12 other pigs. We noted no functional differences between the groups. In the unpreconditioned group glyburide infusion resulted in enhanced 60% lactate production during index ischemia. However, preconditioning attenuated the enhancing effect of glyburide on lactate production. The interplay between the effects of glyburide and preconditioning on ischemic myocardium is suggested to be dependent on the different modes of action on the K(+)(ATP) channel.

Metabolic responses in ischemic myocardium after inhalation of carbon monoxide

Background: To clarify the mechanisms of carbon monoxide (CO) tissue‐protective effects, we studied energy metabolism in an animal model of acute coronary occlusion and pre‐treatment with CO.