Biomedical subjects

T Tønnessen

Publications and source records attributed to T Tønnessen.

At least 19 recordsLinked to original sources

PubMed2002

Gene expression of colony-stimulating factors and stem cell factor after myocardial infarction in the mouse.

Recent studies have suggested that cytokines such as macrophage colony-stimulating factor (M-CSF) might be involved in the pathogenesis of ischaemic heart disease. Macrophage colony-stimulating factor, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-colony stimulating factor (GM-CSF), stem cell factor (SCF), interleukin-3 (IL-3) and interleukin-7 (IL-7) are potent cytokines belonging to the same structual class that may affect function, growth and apoptosis both in the heart and other organs. The aims of the present study were to characterize a post-infarction model in the mouse and to examine mRNA expression of M-CSF, GM-CSF, SCF, IL-3 and IL-7 during the development of heart failure. Myocardial infarction (MI) was induced in mice by ligation of the left coronary artery. Average infarct size was 40% and the mice developed myocardial hypertrophy and pulmonary oedema. Ribonuclease (RNAase) protection assays showed abundant cardiac expression of M-CSF and SCF. After MI, we measured down-regulation of cytokine mRNA expression in the heart (M-CSF, SCF), lung (M-CSF), liver (M-CSF) and spleen (M-CSF) compared with sham. Cardiac G-CSF, GM-CSF and IL-7 mRNAs were not detected. In conclusion, abundant cardiac gene expression of M-CSF and SCF was found. In our mouse model of MI, M-CSF and SCF were down-regulated in the heart and several other organs suggesting specific roles for these cytokines during development of ischaemic heart failure.

Animals↗

PubMed2001

[Perforated ulcer].

BACKGROUND: We wanted to review patients operated for perforated peptic ulcer at Ullevål University Hospital, Oslo, Norway in the period 1992-1997. MATERIAL AND METHODS: Data from 84 operated patients (43 men) were obtained retrospectively from patient and hospital files. Median age was 69 years (range 20-92 years). RESULTS: 41 patients had perforated duodenal ulcer and 43 had perforated gastric ulcer (pylorus included). Median time from start of symptoms until admission to hospital was 5 hours (range 2-24 hours; n = 40) and from admission to start of surgery 5 hours (range 1 1/2-48 hours; n = 69). 64 out of 74 patients had pneumoperitoneum on preoperative abdominal X-ray examination. 77 patients were operated with rafi and/or tegmentation of the perforation; six patients with Billroth II or Billroth I; one patient was treated with percutaneous drainage. Median duration of surgery was 68 minutes (range 40-240 minutes). Thirteen patients died in hospital. Post-operative complications were recorded in 30 patients. INTERPRETATION: Early surgical intervention is important to reduce lethality from ulcus perforatum. A patient with clinical peritonitis and suspected perforated peptic ulcer should be operated without time-consuming examinations.

Adult↗

PubMed2001

Myocardial gene expression of leukaemia inhibitory factor, interleukin-6 and glycoprotein 130 in end-stage human heart failure.

BACKGROUND: Studies in different animal models and plasma analyses in humans suggest that members of the interleukin-6 (IL-6) cytokine family may be involved in the pathogenesis of congestive heart failure (CHF). Accordingly, we have examined IL-6-related cytokines in chronic CHF in humans by analysing gene and protein expression in myocardium derived from patients with end-stage heart failure and donor hearts. METHODS: Gene expression of cytokines/receptors of the IL-6 family was documented in myocardial samples using cDNA array hybridization and RNase protection assays. Immunohistochemistry was used to detect leukaemia inhibitory factor (LIF), IL-6 and glycoprotein 130 (gp130) in myocardial tissues. RESULTS: Myocardial gene activity was documented for the majority of IL-6 family cytokines and their receptors. Immunohistochemical analysis localized IL-6, LIF and their common receptor subunit gp130 to myocytes and vascular smooth muscle cells. LIF mRNA levels were enhanced in the left ventricles of CHF patients relative to the left ventricles of donor hearts (patients 4.6 +/- 4.7 vs. donors 0.3 +/- 0.3, P < 0.005). Myocardial IL-6 and gp130 mRNA levels were not statistically different between patients and donors, but in contrast to LIF mRNA expression in heart explants, gp130 mRNA levels were significantly higher in left atrium compared with left ventricle in both patients and donors. CONCLUSIONS: Both mRNA and proteins of gp130 and its ligands IL-6 and LIF are expressed in both nonfailing and failing human myocardium. The elevated LIF mRNA levels in left ventricles from patients with end-stage heart failure suggest a role for LIF in the pathogenesis of CHF.

Adult↗

PubMed2000

[Traditional surgery of inguinal hernia].

Inguinal hernia repair is associated with a variety of complications of which the recurrence rate is one of the most important. The aim of this study was to examine all patients one year after surgery for inguinal hernia in an outpatient clinic. 12 months after the operation patients were interviewed and physically examined. 172 hernias in 166 patients were repaired in 1996 in our outpatient unit. 17 surgeons used nine different techniques. Follow-up was achieved in 93.9% of patients alive. Ten recurrences were found (6.3%). Four of the patients were not aware of their recurrence. 11% of the patients still had discomfort or pain after twelve months, whereas 5.2% had not resumed full activity. Other complications occurred in more than 20% of the operations. A "free to do policy" in inguinal hernia repair results in high recurrence and complication rates even in the hands of experienced surgeons in our clinic. The present study shows that an interview as well as a physical examination are necessary in evaluating recurrences, postoperative complications, postoperative pain and time to full mobilisation. Without physical examination, the recurrence rate would have been underreported.

Adolescent↗

PubMed2000

Cardiac endothelin-like immunoreactivity and preproendothelin-1 mRNA expression in human heart failure.

Endothelin (ET) induces hypertrophy of cardiomyocytes and increases synthesis of collagen in vitro. Interestingly, these features are hallmarks of the cardiac remodeling taking place in heart failure. The aim of the present study was to examine cardiac ET peptide and preproET-1 mRNA synthesis in human heart failure. Cardiac tissue was obtained from 11 patients with end-stage heart failure undergoing orthothopic heart transplantation (NYHA III-IV). Cardiac tissue from nine organ donors served as controls. The specimens were examined by immunohistochemistry and mRNA slot blot analyses. Significantly stronger ET-1-like immunoreactivity (ET-1-ir) was seen in the left atrial myocardium of failing hearts compared to the left atrial myocardium of donor hearts. Within each heart, the epicardium showed the strongest ET-1-ir. Left ventricular preproET-1 mRNA expression in the entire group of patients did not differ significantly from that of donor hearts. However, hypertrophic obstructive cardiomyopathy may be associated with a twofold increase in left ventricular preproET-1 mRNA. We report an increase in cardiac ET peptide in human heart failure.

Adolescent↗

PubMed1998

Reduced myocardial Na+, K(+)-pump capacity in congestive heart failure following myocardial infarction in rats.

We examined changes in expression and function of the cardiac Na+, K(+)-pump in a post-infarction rat model of hypertrophy and congestive heart failure (CHF). Myocardial infarction was induced by ligation of the left coronary artery in Wistar rats and hearts were obtained from animals with CHF and from sham operated rats after 6 weeks. In the CHF group the ratio of heart weight to body weight was 70% greater compared to sham (*P < 0.05) and all left-ventricular end-diastolic pressures (LVEDP) were above 15 mmHg. The expression of the alpha 1- and beta 1-subunits (mRNA and protein) of the Na+, K(+)-pump was not significantly different in CHF and sham. As compared to sham the alpha 2 isoform, mRNA and protein levels were lower in CHF hearts by 25 and 55%, respectively, whereas the alpha 3 isoform mRNA was greater by 120% in CHF. The alpha 3 protein was not detectable in sham but a prominent band was seen in CHF. Cell volume of isolated cardiomyocytes was 30% larger in CHF. Cardiomyocytes containing the Na+ sensitive fluorescent dye SBFI were loaded to an intracellular Na+ concentration ([Na+]i] of about 140 mM in a K(+)- and Mg(2+)-free medium (140 mM Na+, free Ca2+ of 10(-8) M). To avoid back leak of Na+ and to ensure no voltage effects on the Na+, K(+)-pump extracellular Na+ was subsequently removed, and 6 mM Mg2+ was added to the superfusate, The Na+, K(+)-pump was then reactivated by 10 mM Rb+. SBFI fluorescence ratio decreased mono-exponentially with a time constant (tau) of 191 +/- 15 s in sham (n = 8) and 320 +/- 38 s in CHF (n = 9) rats (P < 0.01). These changes in fluorescence indicate that the maximum rate of decline of [Na+]i from 100 to 35 mM was 39% (P < 0.005) slower in CHF compared to sham, whereas maximum pump rate per cell was not significantly altered (9.0 +/- 0.7 fmol/s in sham and 7.1 +/- 0.7 fmol/s in CHF cells). The [Na+]i which caused 50% pump activation (k0.5) was also not altered in CHF (40 mM in both groups). We conclude that the number of Na+, K(+)-pumps per cell was maintained in CHF but an isoform switch of the alpha 3-replacing the alpha 2-isoform occurred. However, maximum Na+, K(+)-pump rate in terms of rate of change of [Na+]i was significantly attenuated in CHF, most likely as a result of increased cell size.

Animals↗

PubMed1998

Mechanisms of cardiomyocyte dysfunction in heart failure following myocardial infarction in rats.

Available information regarding the cellular and molecular mechanisms for reduced myocardial function after myocardial infarction (MI) is scarce. In rats with congestive heart failure (CHF), we examined cardiomyocytes isolated from the non-infarcted region of the left ventricle 6 weeks after ligation of the left coronary artery. Systolic left-ventricular pressure was reduced and diastolic pressure was markedly increased in the CHF-rats. The cardiomyocytes isolated from the CHF-hearts had increased resting length, reduced fractional shortening by 31% and a 34% increase in time to 90% relaxation compared to sham cells (P<0.01 for all). Peak L-type calcium currents were not significantly changed, but peak calcium transients measured with fura-2 were reduced by 19% (P<0.01). Moreover, the decline of the calcium transients as measured by the time constant of a monoexponential function was significantly increased by 26% (P<0.01). We also examined the contribution of the Ca2+-ATPase of the sarcoplasmic reticulum (SR) in the removal of cytosolic Ca2+ during relaxation by superfusing cells with 1 microM thapsigargin that effectively inhibits the Ca2+-ATPase. Relaxation time in CHF-cells was significantly less prolonged when this drug was used (P<0.01). This suggests that other mechanisms, probably the Na+-Ca2+ exchanger, contribute significantly to the relaxation rate in CHF. Simultaneous measurements of fura-2 transients and mechanical shortening did not reveal any alteration in the calcium-myofilament sensitivity in CHF. Our study clearly shows reduced shortening and prolonged relaxation in cardiomyocytes isolated from non-infarcted region of the left ventricle in heart failure. Moreover, we were able to relate the observed cardiomyocyte dysfunction to changes in specific steps in the excitation-contraction coupling.

Actin Cytoskeleton↗

PubMed1998

Pulmonary and cardiac expression of preproendothelin-1 mRNA are increased in heart failure after myocardial infarction in rats. Localization of preproendothelin-1 mRNA and endothelin peptide.

OBJECTIVES: Recent reports indicate that endothelin (ET) plays an important pathophysiological role in congestive heart failure (CHF). However, existing data on local cardiopulmonary ET production are few. No studies have hitherto examined the specific anatomic localization of cardiopulmonary ET synthesis in CHF. Thus, the aims of the present study were to examine whether cardiopulmonary preproET-1 mRNA synthesis is upregulated in CHF and to determine the anatomic localization of preproET-1 mRNA and the mature peptide. METHODS: CHF was induced in rats by occluding the left coronary artery. Only animals with a left ventricular end-diastolic pressure above 15 mmHg after one week were included (n = 28). Sham-operated animals served as controls (n = 24). Hearts and lungs were examined by mRNA slot blot analyses, in situ hybridization (ISH) and immunohistochemistry (IHC). RESULTS: In CHF-rats, slot blot analyses revealed a 3.5 +/- 1.1-fold and a 6.4 +/- 0.8-fold upregulation of preproET-1 mRNA in the noninfarcted and the infarcted area of the left ventricles, respectively (p < 0.05 for both). ISH revealed that the preproET-1 mRNA was localized predominantly over the granulation tissue in the infarcted region. The ET peptide was predominantly localized to inflammatory cells and remaining cardiomyocytes in the infarcted region as determined by IHC. Lungs from CHF-rats showed a 1.5 +/- 0.1-fold upregulation of preproET-1 mRNA (p = 0.01). The most abundant preproET-1 mRNA and ET-1-like-immunoreactivity (ET-1-ir) was seen over inflammatory cells and over airway epithelial cells. Some ET-1-ir was also located to bronchial and vascular smooth muscle cells. CONCLUSION: Increased cardiopulmonary ET synthesis strongly suggest a pathophysiological role for ET in CHF.

Animals↗

PubMed1998

Circulating levels of endothelin-1 during acute hyperinsulinemia in patients with essential hypertension treated with type 1 angiotensin receptor antagonist or placebo.

Insulin and angiotensin II (Ang II) are involved in the regulation of endothelin-1 (ET-1). This study investigates their possible influence on plasma levels of ET-1 in humans. Twenty patients with essential hypertension were included in a randomized, double-blind, placebo-controlled crossover study of 4 weeks' treatment with losartan, a selective type 1 angiotensin (AT1) receptor antagonist. The effect was evaluated in the fasting state and during acute hyperinsulinemia physiologically induced by oral glucose ingestion (OGTT) and by euglycemic glucose clamp. Losartan lowered blood pressure significantly, but did not influence plasma levels of ET-1 in the fasting condition (5.2 +/- 0.2 fmol/mL on placebo and 5.6 +/- 0.3 fmol/mL after losartan treatment). During both models of acute hyperinsulinemia, there was a significant decrease in plasma ET-1. In the OGTT the mean values after placebo treatment decreased from 5.2 +/- 0.2 fmol/mL at time 0 to 4.7 +/- 0.4 (P = .001) and 4.0 +/- 0.5 (P = .001) at 60 and 120 minutes, respectively. During the clamp the mean ET-1 values decreased from 5.7 +/- 0.4 fmol/mL at time 0 to 4.6 +/- 0.2 (P < .001) and 4.3 +/- 0.3 (P = .006) at 60 and 120 minutes, respectively. No differences in these profiles occurred after losartan treatment. Significant inverse correlation between fasting levels of ET-1 and insulin sensitivity index was found, r = -.51, P = .003. In conclusion, losartan did not influence the circulating levels of ET-1 in basal condition or during acute hyperinsulinemia, whereas a significant decrease in plasma ET-1 occurred during acute hyperinsulinemia. A significant inverse correlation demonstrated between basal levels of plasma ET-1 and the insulin-stimulated glucose uptake could point to a possible regulatory influence of ET-1 production on glucose metabolism or vice versa.

Adult↗

PubMed1998

Cardiac accumulation of citrate during brief myocardial ischaemia and reperfusion in the pig in vivo.

Citrate is a key intermediate in energy metabolism and an inhibitor of phosphofructokinase of the glycolytic pathway. During myocardial ischaemia glycolysis is the main source of cardiac ATP. The aim of the present study was to determine if myocardial ischaemia and reperfusion alter cardiac tissue levels of citrate. Open-chest, anaesthetized pigs were subjected to 10 min of regional myocardial ischaemia by occlusion of the left anterior descending coronary artery, with and without reperfusion, and to 10 min of global ischaemia by circulatory arrest. Citrate, amino acids, glucose and NH3 were measured in biopsies. Ischaemia, whether regional or global, caused a 60-70% increase in tissue levels of citrate. During 1 min of reperfusion following regional ischaemia the level of citrate increased 460%, to approximately 600 nmol g-1 wet weight. The level of glutamate decreased by 20-33% (corresponding to 1300-2200 nmol g-1 wet weight), indicating net consumption of this amino acid during ischaemia. The level of aspartate decreased 50% indicating conversion of aspartate to oxaloacetate for the synthesis of citrate. Theoretically, the accumulation of myocardial citrate during brief ischaemia and early reperfusion is large enough to significantly inhibit phosphofructokinase activity and could therefore affect the ability of the myocardium to increase the glycolytic rate in response to ischaemia. This could, however, be partly compensated by the metabolism of myocardial glutamate.

Amino Acids↗

PubMed1998

Hypertonic saline and dextran in normovolaemic and hypovolaemic healthy volunteers increases interstitial and intravascular fluid volumes.

BACKGROUND: Hypertonic saline (HS) is increasingly used for fluid resuscitation in hypovolaemic patients. Although the effects of HS have been investigated in animal models, controlled studies in healthy human individuals are few. AIM: The effects of i.v. hypertonic saline 75 mg.ml-1 in dextran 70, 60 mg.ml-1 (HSD) infusion on fluid shifts between the interstitial and intravascular fluid spaces, diuresis and haemodynamics were studied in normovolaemic and moderately hypovolaemic healthy volunteers. MATERIAL AND METHODS: Nine fasting subjects received 4 ml.kg-1 HSD as a 10-min infusion in a normovolaemic situation. Seven days later they served as their own controls in a hypovolaemic situation after 10% of the calculated blood volume had been withdrawn during a 15-min period. Before and after the HSD infusion, interstitial colloid osmotic pressure (COPi) and interstitial fluid hydrostatic pressure (Pi) were measured on the lateral part of the thorax. During the study, blood sampling and pressure measurements were performed through a radial artery cannula, and central venous pressure measured through a catheter in the cubital vein. RESULTS: In these awake and normovolaemic healthy volunteers, HSD infusion caused a transitory unpleasant sensation of headache and heat in the thorax up to the throat. A transitory haemodynamic effect was found with increased heart rate (HR), increased mean arterial pressure (MAP) from 77 +/- 5 mmHg to 92 +/- 13 mmHg (P < 0.05) and CVP increase from 5 +/- 1 mmHg to 8 +/- 1 mmHg (P < 0.05) after end of infusion. A haemodilution with increase in calculated blood volume lasting longer than the MAP increase was observed, with decreased COPi from 14.4 +/- 2.2 mmHg to 12.1 +/- 2.0 mmHg (P < 0.05). The diuresis measured at 180 min was higher in the normovolaemic than in the hypovolaemic situation. More pronounced effects of the infused fluid (HSD) on calculated blood volume, interstitial compartment and CVP were observed during moderate hypovolaemia. CONCLUSIONS: HSD infusion resulted in increased calculated blood volume with increased HR, MAP, and CVP. These effects were greater in a hypovolaemic situation. The haemodilution was most likely caused by fluid shifts from the intracellular compartment to the interstitial and vascular fluid spaces, eventually increasing diuresis.

Adult↗

PubMed1997

Increased cardiac expression of endothelin-1 mRNA in ischemic heart failure in rats.

OBJECTIVES: Plasma endothelin (ET) concentrations are increased in heart failure. The aims of the present study were to investigate to what extent cardiac ET mRNA expression is induced in ischemic heart failure and whether there may be compensatory downregulation of myocardial mRNA levels for the ETA and ETB receptor subtypes. METHODS: In rats with ischemic heart failure (left ventricular end-diastolic pressure > 15 mmHg) due to left coronary artery ligation. Northern blot analyses were performed on mRNA isolated from cardiac tissues. RESULTS: A substantial upregulation was revealed in all chambers of the failing hearts. Up to 27-fold upregulation (mean 10.6 +/- 4.0, P = 0.002) of left ventricular ET-1 mRNA levels was measured 1 week after myocardial infarction, whereas only a modest upregulation was detected after 6 weeks (mean 2.7 +/- 0.5, P < 0.05). Ribonuclease protection assay revealed 2.8 +/- 0.4-fold higher levels of ET-1 mRNA in the left ventricular area subjected to myocardial infarction compared to the non-infarcted tissue after 1 week. Left ventricular ET-1 mRNA correlated significantly with left ventricular end-diastolic pressure after 1 week (r2 = 0.86, P = 0.007). The ETA and ETB receptor mRNA levels tended to increase 1 week after myocardial infarction although these changes were not statistically significant. CONCLUSIONS: Cardiac ET-1 mRNA levels are increased in ischemic heart failure and correlate significantly with left ventricular end-diastolic pressure 1 week after myocardial infarction. The increase in cardiac ET-1 mRNA is not accompanied by a decrease in ET receptor mRNA.

Animals↗

PubMed1997

Importance of nitric oxide in hepatic arterial blood flow and total hepatic blood volume regulation in pigs.

The importance of nitric oxide in regulating basal arterial blood flow has been examined in several different vascular beds by intra-arterial infusion of inhibitors of nitric oxide synthesis, but not in the arterial vascular bed of the liver. In the present study, N(G)-nitro-L-arginine (L-NNA), in a dose of 0.5 and 1.0 mumol mL-1 of hepatic arterial blood flow, was infused for 5 min into the hepatic artery in seven pigs anaesthetized with pentobarbital sodium. The haemodynamic effects observed by the first infusion were not further enhanced by the second infusion. Hepatic arterial resistance increased by 143 +/- 38% and hepatic arterial blood flow declined by 38 +/- 10%. A systemic effect due to 'spillover' was observed, as evidenced by an increase in mean aortic blood pressure of 24 +/- 4 mmHg. However, no significant increase in arterial mesenteric resistance was observed and total liver blood flow remained unchanged. Hepatic arterial vasodilation in response to occlusion of the portal vein, the arterial buffer response, remained intact after inhibition of nitric oxide synthesis. Liver lobe thickness, measured by an ultrasonic technique, was not found to change with inhibition of arterial nitric oxide synthesis, excluding a significant direct effect of arterial nitric oxide on liver capacitance. In conclusion, nitric oxide is an important regulator of hepatic arterial resistance, but does not mediate the hepatic arterial buffer response and was not found to play any significant role in total hepatic capacitance regulation.

Animals↗

PubMed1997

Transient, isopeptide-specific induction of myocardial endothelin-1 mRNA in congestive heart failure in rats.

Increased myocardial expression of preproendothelin-1 (ppET-1) mRNA has been associated with congestive heart failure (CHF) in rats. However, the time course and isoform pattern of ppET mRNA induction and the cellular localization of ET in failing hearts are unknown. Thus our aim was to investigate myocardial ppET mRNA expression in CHF rats during the first 6 wk after induction of myocardial infarction. Furthermore, performing immunohistochemical analysis, we also investigated the origin and localization of immunoreactive endothelin (ET) in different regions of the failing heart. Ribonuclease protection assays revealed a marked increase in ppET-1 mRNA levels in rat myocardial tissues during CHF. The induction of ppET-1 mRNA was isopeptide specific and transient. The most substantial upregulation was observed in the infarcted area, where maximal expression of ppET-1 mRNA was observed after 7 days (25-fold increase, P < 0.05). However, a marked and statistically significant induction of ppET-1 mRNA was also observed in the nonischemic myocardium. Immunohistochemical analysis revealed ET-1-like immunoreactivity in cardiomyocytes, vascular endothelial cells, macrophages, and proliferating fibroblasts. Thus immunohistochemistry revealed the structural basis for the dramatic upregulation of the myocardial ET system in the infarcted region, suggesting a role for ET in the healing process after myocardial infarction. However, the global upregulation of ppET-1 mRNA in the heart also suggests an autocrine/paracrine regulatory mechanism in the nonischemic myocardium during CHF.

Animals↗

PubMed1997

Endothelin production and effects of endothelin antagonism during experimental airway inflammation.

Endothelin (ET) has strong bronchoconstrictor properties, stimulate mucus secretion and mucosal edema, and may also exert proinflammatory effects. Therefore, ET may play a pathogenic role in inflammatory airway diseases such as bronchial asthma. The production and localization of ET and the effect of blocking ET receptors was investigated in rats during airway inflammation induced by intratracheal instillation of dextran (Sephadex). We observed a considerable increase in the concentration of ET in bronchoalveolar lavage fluid (BALF) during the early phase of inflammation, with an increase from 2.2 +/- 0.6 pg/ml in controls to 40.0 +/- 6.7 pg/ml at Day 1, declining to 5.3 +/- 1.1 pg/ml at Day 14. Correlated with the ET response in BALF was a considerable increase in total cell count (r = 0.61), eosinophils (r = 0.83), and neutrophils (r = 0.81). Plasma ET was not elevated. Immunohistochemical analyses revealed ET-like staining in the bronchial epithelium. Treatment with the ET receptor antagonist bosentan inhibited the increase in eosinophils in BALF and reduced the inflammatory reaction in the lung tissue. In summary, a considerable increase in the ET concentration in BALF was demonstrated during the acute phase of an experimental eosinophilic airway inflammation, coinciding with an increased ET-like immunostaining in the bronchial epithelium. Treatment with an ET receptor antagonist inhibited the inflammatory response in BALF and in the tissue.

Animals↗

PubMed1995

Nitric oxide regulates coronary blood flow at various coronary arterial pressures in intact porcine hearts.

Nitric oxide (NO) is known to regulate basal coronary blood flow (CBF). The objective of the present study was to examine the importance of NO in CBF regulation at various coronary arterial pressures (CAPs) in vivo. Experiments were performed in 11 open-chest pentobarbitone sodium anesthetized pigs. CAP was reduced in steps by a hydraulic occluder on the mid left anterior descending coronary artery (LAD) before and after a 5-min intracoronary infusion of the inhibitor of NO synthesis, NG-nitro-L-arginine (NOARG, 30 mumol min-1). CAP was recorded and NOARG infused through a catheter inserted into the LAD just distal to the occluder. CBF was measured by Doppler flowmetry on the LAD. NOARG significantly reduced CBF by 11 +/- 4, 20 +/- 5, 10 +/- 3, 15 +/- 4, 19 +/- 2, 25 +/- 4 and 25 +/- 5 mL min-1 100 g-1 (mean +/- SE) at CAPs of 30 (n = 6), 40 (n = 9), 50 (n = 9), 60 (n = 9), 70 (n = 9), 80 (n = 8) and 90 (n = 6) mmHg, respectively. These decrements were not statistically different, but the percentage reductions in CBF after infusion of NOARG were significantly greatest at the lowest CAPs. The slight haemodynamic alterations induced by NOARG could not explain the reductions in CBF. Thus, the reductions in CBF after infusion of NOARG were caused by inhibition of a continuous NO release from the coronary endothelium. Coronary NO contributes significantly to CBF at all CAPs between 30 and 90 mmHg. The pronounced reduction in CBF during NO inhibition at the lower CAPs indicates an important vasodilating role of intact endothelium in a region supplied by a stenosed coronary artery.

Animals↗

PubMed1995

Modulation of systolic and diastolic function by endothelin-1: relation to coronary flow.

Different conclusions have been reached with regard to the effect of endothelin (ET-1) on cardiac contractility. We examined systolic and diastolic function in response to constant known concentrations of ET-1 with or without ET-1 induced reductions in coronary flow (CF). Rat hearts (n = 21) were buffer-perfused using constant coronary flow (cCF) or constant perfusion pressure (cPP). Left ventricular function was assessed isovolumically. Addition of ET-1 (10(-9) M) in the cCF group caused a gradual increase in PP from 61 +/- 2 to 165 +/- 6 mmHg (mean +/- SE) (P < 0.01). Within 10 min left ventricular systolic pressure (LVSP) increased from 111 +/- 2 to a maximum of 134 +/- 4 mmHg (P < 0.01) and [LVdP/dt] increased from 1640 +/- 81 to a maximum of 2020 +/- 92 mmHg s-1 (P < 0.01). After 15 min left ventricular end diastolic pressure (LVEDP), a measure of diastolic stiffness (DS), also increased. With ET-1 (10(-8) M), similar haemodynamic alterations appeared more rapidly. In the cPP group, ET-1 (10(-9) M) caused a sharp decrease in CF and LVSP fell from 115 +/- 8 to 62 +/- 12 mmHg at 10 min (P < 0.001). Systolic function remained stable at a reduced level for 1 h. DS did not change. Thus, ET-1 possesses positive inotropic effects and increases diastolic stiffness. Both effects may be masked by vasoconstriction-induced ischaemia.

Animals↗

PubMed1995

Increased in vivo expression and production of endothelin-1 by porcine cardiomyocytes subjected to ischemia.

Circulating levels of the endothelium-derived vasoconstrictor peptide endothelin-1 (ET-1) are increased in association with myocardial ischemia and infarction. The present study investigates whether ET-1 is synthesized and produced locally in the ischemic heart. Sixteen pigs were divided into three groups. In the first group, the left anterior descending coronary artery was occluded for 90 minutes, followed by 150 minutes of reperfusion (group A, n = 8). Two additional groups were subjected to 90 minutes (group B, n = 4) or 240 minutes (group C, n = 4) of ischemia without reperfusion. Biopsies from the nonischemic and ischemic myocardium were rapidly obtained from the beating heart and subsequently examined by Northern blot, in situ hybridization, and immunohistochemistry. Arterial plasma ET-1 was measured before ischemia and at the end of the experiments. Northern blot revealed a twofold increase in ET-1 mRNA in the ischemic myocardium compared with the nonischemic myocardium. In situ hybridization showed a considerable increase in ET-1 mRNA over the ischemic cardiomyocytes. Substantial ET-1-like immunoreactivity (ET-1-ir) was detected in cardiomyocytes in the ischemic region. In contrast, little or no ET-1-ir or mRNA was detected in nonischemic cardiomyocytes. Both in the ischemic and nonischemic regions, little ET-1-ir was detected in vascular endothelial cells or vascular smooth muscle cells. There was no difference in the intensity and distribution of ET-1 mRNA expression or ET-1-ir among experimental groups A, B, and C. Arterial plasma ET-1 was increased only in group A, the reperfused group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗