Geir Falck

Increased contractility and calcium sensitivity in cardiac myocytes isolated from endurance trained rats

OBJECTIVE Regular exercise enhances cardiac function and modulates myocyte growth in healthy individuals. The purpose of the present study was to assess contractile function and expression of selected genes associated with intracellular Ca2+ regulation after intensity controlled aerobic endurance training in the rat. METHODS Female Sprague-Dawley rats were randomly assigned to sedentary control (SED) or treadmill running (TR) 2 h per day, 5 days per week for 2, 4 or 13 weeks. Rats ran 8-min intervals at 85-90% of VO2max separated by 2 min at 50-60%. Myocyte length, intracellular Ca2+ (Fura-2), and intracellular pH (BCECF) were measured in dissociated cells in response to electrical stimulation at a range of stimulation rates. RESULTS The increase in VO2max plateaued after 6-8 weeks, 60% above SED. After 13 weeks, left and right ventricular weights were 39 and 36% higher than in SED. Left ventricular myocytes were 13% longer, whereas width remained unchanged. After 4 weeks training, myocyte contractility was approximately 20% higher in TR. Peak systolic intracellular Ca2+ and time for the decay from systole were 20-35 and 12-17% lower, respectively. These results suggest that increased myofilament Ca2+ sensitivity is the dominant effect responsible for enhanced myocyte contractility in TR. Intracellular pH progressively decreased as stimulation frequency was increased in the SED group. This decrease was markedly attenuated in TR and the intracellular pH was significantly higher in the TR group at a stimulation rate of 5-10 Hz. This effect may contribute to the increased contractility observed at the higher stimulation frequencies in TR. A higher intrinsic myofilament Ca2+ sensitivity was observed in permeabilised myocytes from the TR group under conditions of constant pH and [Ca2+]. Western blot analysis indicated 21 and 46% higher myocardial SERCA-2 and phospholamban, but unaltered Na+/Ca(2+)-exchanger levels. Competitive RT-PCR revealed that TR significantly increased Na+/H(+)-exchanger mRNA. CONCLUSION Intensity controlled interval training increases cardiomyocyte contractility. Higher myofilament Ca(2+)-sensitivity, and enhanced Ca(2+)-handling and pH-regulation are putative mechanisms. Our results suggest that physical exercise induces adaptive hypertrophy in cardiac myocytes with improved contractile function.

Hyperosmotic perfusion of the beating rat heart and the role of the Na + /K + /2CI − co-transporter and the Na + /H + exchanger

Abstract The aim of the present study was to investigate the role of the Na+/K+/2CI− co-transporter and the Na+/H+ exchanger on contractile function and electrolyte regulation during hyperosmotic perfusion of the heart.Langendorff perfused rat hearts were subjected to hyperosmolal perfusion in 10-min intervals. Perfusates were made hyperosmotic by adding mannitol to the buffer (370, 450 and 600 mOsmol/kg H2O). Cardiac contractile function was monitored with a balloon in the left ventricle (LV) coupled to a pressure transducer. Cardiac effluent was sampled repeatedly throughout and after hyperosmotic perfusion and analyzed for content of Na+, K+ and CI−.All three hyperosmotic perfusates initially reduced LV developed pressure (LVDP), but for 370 and 450 mOsmol/kg H2, LVDP recovered to baseline within 4 min of perfusion. With 600 mOsmol/kg H2, LVDP recovered slowly and was 50% below baseline after 10 min of hyperosmotic perfusion. Inhibition of the Na+/H+ exchanger with 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and 3-methyl-sulfonyl-4-piperidinobenzoyl-guanidine methanesulfonate (HOE 694) abolished the recovery of LVDP to the 600 mOsmol/kg H2 perfusate, whereas inhibition of the Na+/K+/2CI− co-transporter had no impact on LVDP. Potassium was taken up by the heart during hyperosmotic perfusion and this uptake was significantly reduced with inhibition of the Na+/H+ exchanger. Intracellular pH was assessed with 31P magnetic resonance spectroscopy and hyperosmolality induced a significant alkalosis that was dependent upon the Na+/H+ exchanger.The rat heart responds to moderate elevations in osmolality with a transient reduction in contractile function, whereas an elevation of 300 mOsmol/kg H2 persistently reduces contractile function. The Na+/H+ exchanger, but not the Na+/K+/2CI− co-transporter, is of importance in contractile recovery and electrolyte regulation during hyperosmotic perfusion in the rat heart.

Biophysical factors and contractile function during coronary bolus perfusion: An experimental study in the isolated guinea pig heart

RATIONALE AND OBJECTIVES The purpose of this study was to evaluate the role of biophysical factors (viscosity, temperature, osmalality, perfusion pressure, and ionic washout) on cardiac contractility during coronary bolus perfusions. METHODS Guinea pig hearts were perfused in the osmolality mode at constant and high flow (30 mL/min) and were subjected to boluses (injected in 1-8 seconds) of purely nonionic media: mannitol and iohexol (in hyposmolal, isosmolal, and twice isosmolal forms) and iodixanol (in a hyposmolal form). RESULTS All contrast media elicited a dose-dependent increase in aortic pressure and contractile variables that was attenuated by an increased osmolality. Elevation of aortic pressure was followed by an increase in left ventricular systolic pressure and, with iodixamol and iohexol, a subsequent elevation of left ventricular end-diastolic pressure. Moderate hypothermic solutions (29 degrees C) did not alter the responses. The ionic washout profile was the same for the three substances, as were the individual washout profiles for sodium, potassium, chloride, magnesium, and calcium. CONCLUSION An increase in osmolality attenuates the increased contractility induced by a purely nonionic medium. A viscosity-induced rise in perfusion pressure may increase contractility. A moderate reduction in bolus temperature does not alter the contractile responses. The ionic washout profile is the same for the main cardioactive electrolytes.

Effect of magnesium infusion on bleeding time in healthy male volunteers.

Intravenous magnesium has proved to be valuable in the treatment of cardiac arrhythmias and eclampsia, but the specific mode of action is not established. In this study the effect of magnesium sulphate (MgSO4) infusion on bleeding time and endogenous prostacyclin (PGI2) production in healthy male volunteers was investigated. Thirty-five males (age 18-30 years) randomized in a double-blind, placebo-controlled, cross-over study were investigated. MgSO4 was given as a bolus (8 mmol, 12 min) followed by continuous infusion (8 mmol in 108 ml saline, 120 min). Control was equal volumes of physiological saline. Heart rate, blood pressure and bleeding time (according to Ivy) were recorded as well as blood concentrations of magnesium and creatinine. Urine PGI2 was analysed as the stable metabolite 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha). Treatment with MgSO4 did not affect bleeding time (MgSO4; 8.4+/-3.5 vs. control 8.0+/-2.7 min) nor the production of PGI2 (MgSO4; 1.2 microg 6-keto-PGF1alpha/g creatinine vs. control; 1.1 microg 6-keto-PGF1alpha/g creatinine). Intravenous infusion of MgSO4 does not affect the PGI2/platelet axis in healthy male volunteers. Studies in patients with endothelium dysfunction and/or concomitant drug therapy are required before the anti-thrombogenic effect of MgSO4 in vivo is discarded.

Skills of pre-registration house officers: gender differences reported in Norway

During training pre‐registration house officers should acquire skills, practical clinical procedures, and good clinical judgement, in order to be able to practice on their own. This is not always the case ( Flaatten et al. 1987 ). Ten years ago the Norwegian Health Authorities issued a regulation regarding the content of hospital training (6 months internal medicine and surgery, respectively). A number of practical skills to be learned were listed. As part of an assessment of the quality of the internship, a study was carried out into what extent the pre‐registration house officers had acquired these clinical skills.

Protective Effects of Repetitive Injections of Radiographic Contrast Media on the Subsequent Tolerance to Ischemia in the Isolated Rat Heart

AbstractPurpose: Despite detailed knowledge of the effects of X-ray contrast media on cardiac function, no studies have examined the effect of contrast media injections on the subsequent tolerance to ischemia in the heart. Methods: Isolated perfused rat hearts were exposed to repetitive injections of iohexol, iodixanol, or ioxaglate before 30 min of global ischemia and 120 min of reperfusion. These groups were compared with control (no pretreatment) and ischemic preconditioning known to reduce infarct size. Physiologic variables and infarct size were measured Results: Pretreatment with iodixanol reduced infarct size significantly compared with control and thus afforded protection against ischemia. Injections with iohexol and ioxaglate reduced infarct size, although not significantly, compared with control. Conclusion: Pretreatment of the isolated rat heart with commonly used contrast media enhances the cardiac tolerance to subsequent ischemia. The mechanism behind this protective effect could not be determined, but could involve stretching of the heart and/or generation of nitric oxide.

Young female doctors report achieving fewer surgical skills than young male doctors

EDITOR,—In their paper on the career preferences of British doctors Trevor W Lambert and colleagues highlight the different choices of career between men and women.1 As in the United Kingdom, in Norway the proportion of female graduates has increased in recent decades and is currently 50% (roughly 200 graduates); this change greatly influences recruitment …

Mast cells in human coronary arteries; is there any correlation with luminal narrowing?

Histamine in the human coronary arteries is harboured in mast cells and possibly in a non‐mast cell store. Upon histamine exposure atherosclerotic coronary arteries react differently than normal coronary arteries, and histamine has been proposed to provoke vasospasms, ischaemia and sudden cardiac death. Previous reports have indicated a correlation between the mast cell density and the histamine content on the one hand and the degree of atherosclerosis on the other hand. Since previous reports applied visual assessment of the luminal narrowing only, we reexamined these results utilising plani‐metric methods. The study was accomplished by examining coronary arteries from autopsy cases (50–70 years, N=29) with a diagnosis of sudden death, myocardial infarction or a non‐cardiac cause. The mast cell density was calculated as the ratio between the mast cell count and the adventitial area as seen by light microscopy, and was compared to the degree of luminal narrowing. We were not able to find any correlation between the mast cell density and the luminal narrowing. The myocardial infarction group had the most severe degree of luminal narrowing, but there was no significant difference in mast cell density between the groups. We therefore question the previous notion that there is a correlation between the adventitial mast cell density in the coronary arteries and the luminal narrowing. Earlier reports may have been biased by visual assessment and by erroneously treating several measurements from the same person as independent samples.