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Biomedical subjects

H H Klein

Publications and source records attributed to H H Klein.

At least 37 records · Page 2Linked to original sources
PubMed2001

[Recurrent hypoglycemia caused by malignant insulinoma: chemoembolization as a therapeutic option].

HISTORY AND CLINICAL FINDINGS: A 73-year-old previously healthy woman presented with recurrent weakness, vertigo and perioral paresthesia of 3 months' duration. Physical examination on admission was unremarkable and revealed a patient in good condition. INVESTIGATIONS: Recurrent episodes of fasting hypoglycemia let us to proceed with a fasting test. The test was stopped after 24 hours when the patient became presyncopal and was found to have a blood sugar value of 2.2 mmol/l (accompanied by inadequately increased values for proinsulin, insulin and C-peptide). Ultrasound and computertomography of the abdomen showed a huge inhomogeneous mass in the tail of pancreas and multiple lesions in the liver, respectively. Core needle biopsies revealed typical histopathological findings of a neuroendocrine carcinoma. TREATMENT AND COURSE: Eight cycles of chemotherapy were given using streptozotocin/doxorubicin for three cycles and streptozotocin/5-fluorouracil for the remaining therapy over a period of 16 months resulting in a reduction in size of liver metastases and improvement of symptoms. Following 6 months without any therapy new episodes of severe hypoglycemia and progression of the liver metastases occurred. Despite seven further cycles of chemotherapy and additional treatment with diazoxide/octreotide the patient remained hypoglycemic and continuous glucose infusions became necessary. Therefore, chemoembolization of the liver with streptozotocin/5-fluorouracil and lipiodol-emulsion was performed. This resulted in a significant improvement of symptoms and the patient could subsequently be discharged. The patient died 4 months later. CONCLUSION: Chemoembolization is an effective possibility in the palliative treatment of advanced malignant insulinoma.

Aged↗
PubMed2001

[Stress and myocardial infarction].

BACKGROUND: Stress is characterized by an increase in plasma catecholamines and cortisol associated with a rise in heart rate and blood pressure. Plasma epinephrine can increase by a factor of 8 through emotional or physical stress. In contrast, the rise in plasma norepinephrine following physical stress is much higher than that following emotional stress. STRESS AS A TRIGGER: Experimental studies in monkeys suggest a causal relationship between emotional stress and coronary atherosclerosis. This relationship has not yet been convincingly proven in clinical studies. However, clinical studies have clearly demonstrated that emotional stress can trigger the onset of acute myocardial infarction. Life threatening situations like earthquakes are able to increase the risk for myocardial infarction about sixfold. Anger or sexual activity may double this risk. The occurrence of myocardial infarction is not evenly distributed throughout the day. The highest risk in non-treated, non-smoking patients lies between 6 a.m. and noon with a predominance on Monday morning. High physical stress in untrained persons carries a much greater risk for myocardial infarction than extreme emotional stress. This difference may be due to a greater degree of coronary vasoconstriction induced by the higher levels of norepinephrine in physical exercise compared to those during emotional stress. CONCLUSION: A causal relationship between stress and atherosclerosis has not yet been demonstrated in clinical studies. However, there is convincing evidence to accept emotional stress as a potential trigger for the onset of acute myocardial infarction. High physical stress of untrained persons carries an even greater risk for the development of acute myocardial infarction.

Anger↗
PubMed2000

Na(+)/H(+) exchange inhibitor cariporide attenuates cell injury predominantly during ischemia and not at onset of reperfusion in porcine hearts with low residual blood flow.

BACKGROUND: This study investigated whether myocardial protection by inhibition of Na(+)/H(+) exchange (NHE) occurs during ischemia and/or during reperfusion. METHODS AND RESULTS: The left anterior descending coronary artery was occluded in 32 pigs for 60 minutes and then reperfused for 24 hours. Infarct sizes (nitroblue tetrazolium [NBT] stain, histology) were determined at the end of the experiments. An extracorporeal bypass was used to achieve a constant residual blood flow of 3 mL/min in the myocardium at risk during ischemia. The NHE-1 inhibitor cariporide or distilled water was infused into the extracorporeal bypass system. In group 1, active treatment was administered from the onset of ischemia until 10 minutes of reperfusion (n=8). In group 2, active treatment was infused during the first 30 minutes of ischemia only (n=8). The group 3 animals (n=8) received intracoronary cariporide after 45 minutes of ischemia until 10 minutes of reperfusion. The control animals (group 4, n=7) were treated similarly to group 1 animals, with the cariporide solution being replaced by distilled water. Infarct sizes of group 1 (NBT stain, 41.5+/-20%; histology, 44. 6+/-12%) and group 2 (NBT stain, 33.5+/-14%; histology 34.9+/-15%) differed significantly (at least P:=0.012) from infarct sizes of group 3 (NBT stain, 71.6+/-15%; histology, 69.2+/-12%) and the control group (NBT stain, 76+/-9%; histology 72.4+/-12%). Cariporide treatment in group 1 and group 2 significantly improved functional recovery after 24 hours of reperfusion. CONCLUSIONS: Myocardial protection by cariporide is predominantly achieved by NHE inhibition during ischemia and not during early reperfusion.

Animals↗
PubMed2000

[Severe vitamin D deficiency osteomalacia by coincidence of multiple risk factors].

HISTORY: An 82-year-old woman was admitted with bilateral clavicular fractures after falling out of bed. She complained of pain in all her bones. She reported having undergone a partial gastrectomy (Billroth II) 40 years ago with subsequent milk intolerance and a dislike of direct sun light. INVESTIGATIONS: Scintigraphy revealed multiple areas of abnormal uptake. Conventional radiography showed in both ulnae transverse zones of increased density with a central translucent band. Laboratory tests demonstrated the constellation of increased bone turnover in secondary hyperparathyroidism with hypocalcaemia (1.49 mmol/l) and hypophyosphataemia (0.62 mmol/l). The 25-hydroxyvitamin D-level was too low to be measured. Ileal crest biopsy indicated osteomalacia. TREATMENT AND COURSE: Serum levels of calcium, alkaline phosphatase and vitamin D became normal after 7 weeks of daily administration of 10,000 IU vitamin D and 1000 mg calcium. The severe pains had subsided after two weeks and no longer required analgesics. CONCLUSION: Multiple areas of increased uptake on skeletal scintigraphy, combined with diffuse bone pain and increased alkaline phosphatase, were at first misinterpreted as extensive skeletal metastases. But the history, at first seemingly of little significance, contained three long-term risk factors for the development of vitamin D and calcium deficiency and thus of osteomalacia, namely partial gastrectomy, milk intolerance and inadequate exposure to sun light. Early recognition of risk factors for bone changes will rapidly lead to the correct diagnosis and immediate treatment of the treatable underlying disease.

Aged↗
PubMed2000

Serine residues 994 and 1023/25 are important for insulin receptor kinase inhibition by protein kinase C isoforms beta2 and theta.

AIMS/HYPOTHESIS: Inhibition of the signalling function of the human insulin receptor (HIR) is one of the principle mechanisms which induce cellular insulin resistance. It is speculated that serine residues in the insulin receptor beta-subunit are involved in receptor inhibition either as inhibitory phosphorylation sites or as part of receptor domains which bind inhibitory proteins or tyrosine phosphatases. As reported earlier we prepared 16 serine to alanine point mutations of the HIR and found that serine to alanine mutants HIR-994 and HIR-1023/25 showed increased tyrosine autophosphorylation when expressed in human embryonic kidney (HEK) 293 cells. In this study we examined whether these mutant receptors have a different susceptibility to inhibition by serine kinases or an altered tyrosine kinase activity. METHODS: Tyrosine kinase assay and transfection studies. RESULTS: In an in vitro kinase assay using IRS-1 as a substrate we could detect a higher intrinsic tyrosine kinase activity of both receptor constructs. Additionally, a higher capacity to phosphorylate the adapter protein Shc in intact cells was seen. To test the inhibition by serine kinases, the receptor constructs were expressed in HEK 293 cells together with IRS-1 and protein kinase C isoforms beta2 and theta. Phorbol ester stimulation of these cells reduced wild-type receptor autophosphorylation to 58 % or 55 % of the insulin simulated state, respectively. This inhibitory effect was not observed with HIR-994 and HIR-1023/25, although all other tested HIR mutants showed similar inhibition induced by protein kinase C. CONCLUSION/INTERPRETATION: The data suggest that the HIR-domain which contains the serine residues 994 and 1023/25 is important for the inhibitory effect of protein kinase C isoforms beta2 and theta on insulin receptor autophosphorylation.

Adenosine Triphosphate↗
PubMed2000

The HIV-1 protease inhibitor indinavir impairs insulin signalling in HepG2 hepatoma cells.

AIMS/HYPOTHESIS: Patients treated with human immunodeficiency virus-1 protease inhibitors often develop impaired glucose tolerance or diabetes, most likely due to an induction of insulin resistance. We therefore investigated whether the protease inhibitor indinavir alters insulin signalling. METHODS: We incubated HepG2 cells for 48 h without or with indinavir (100 micromol/l). Subsequently 125I-insulin binding to the cells and the effects of insulin stimulation on insulin-receptor substrate-1-phosphorylation, association of phosphatidylinositol 3-kinase with insulin-receptor substrate-1 and Akt-Thr308-phosphorylation were measured. RESULTS: In cells not exposed to indinavir, insulin (100 nmol/l) led to rapid increases of insulin-receptor substrate-1-phosphorylation, association of phosphatidylinositol 3-kinase with insulin-receptor substrate-1 and Akt-phosphorylation during the first 75 s, followed by subsequent decreases. In indinavir-treated cells, these insulin-stimulated increases during the first 75 s were reduced by 30-60% and this was not associated with alterations in cell number or viability, insulin binding to the cells or cellular insulin-receptor substrate-1-content. CONCLUSION/INTERPRETATION: Effects of indinavir on initial insulin signalling could cause, or contribute to, the metabolic effects of human immunodeficiency virus-1 protease inhibitors.

Carcinoma, Hepatocellular↗
PubMed2000

Ramipril increases the protein level of skeletal muscle IRS-1 and alters protein tyrosine phosphatase activity in spontaneously hypertensive rats.

To investigate mechanisms by which angiotensin converting enzyme (ACE)-inhibition increases insulin sensitivity, spontaneously hypertensive (SH) rats were treated with or without ramipril (1 mg/kg per day) for 12 weeks. Insulin binding and protein levels of insulin receptor substrate-1 (IRS-1), p85-subunit of phosphatidylinositol 3'-kinase (p85) and Src homology 2 domain-containing phosphatase-2 (SHP2) were then determined in hindlimb muscle and liver. Additionally, protein tyrosine phosphatase (PTPase) activities towards immobilized phosphorylated insulin receptor or phosphorylated IRS-1 of membrane (MF) and cytosolic fractions (CF) of these tissues were measured. Ramipril treatment increased IRS-1-protein content in muscle by 31+/-9% (P<0.05). No effects were observed on IRS-1 content in liver or on insulin binding or protein expression of p85 or SHP2 in both tissues. Ramipril treatment also increased dephosphorylation of insulin receptor by muscle CF (22.0+/-1.0%/60 min compared to 16.8+/-1.5%/60 min; P<0.05), and of IRS-1 by liver MF (37.2+/-1.7%/7.5 min compared to 33.8+/-1.7%/7.5 min; P<0.05) and CF (36.8+/-1.0%/7.5 min compared to 33.2+/-1.0%/7.5 min; P<0.05). We conclude that the observed effects of ACE-inhibition by ramipril on the protein expression of IRS-1 and on PTPase activity might contribute to its effect on insulin sensitivity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Serum leptin concentrations throughout the menstrual cycle.

Leptin is a cytokine involved in the regulation of food intake and fertility in rodents and in humans. No data exist about serum leptin serum levels during the spontaneous menstrual cycle. In this study 16 ovulatory cycles of endocrinologically normal volunteers were analyzed. Blood samples were taken on alternate days throughout the menstrual cycle for measurement of serum estradiol, progesterone, LH, FSH and leptin serum levels. No correlation of leptin values with estradiol values (r = 0.07) or progesterone values (r = 0.14) were seen. Mean leptin values during the luteal phase were significantly higher (16.67 +/- 9.45 ng/mL) compared to the follicular phase (13.50 +/- 8.75 ng/mL) (P < 0.02). A strongly positive correlation with the progression of the menstrual cycle could be seen (r = 0.91). The physiological significance of higher luteal phase leptin levels is unknown.

Adult↗
PubMed2000

Functional characteristics of insulin receptors with a Thr-->Ser1200 mutation overexpressed in Chinese hamster ovary cells.

OBJECTIVE: To investigate the functional properties of insulin receptors with a Thr-->Ser(1200)-mutation that is associated with severe insulin resistance in humans. DESIGN AND METHODS: The effect of in situ insulin-stimulation on insulin receptor kinase activity was studied in Chinese hamster ovary cells with overexpressed human Ser(1200)-mutated, non-mutated, and ATP-binding site-mutated (Lys-->Arg(1030)) receptors using a microwell-based assay that only detects human (and not hamster) insulin receptors. Moreover, the fraction of anti-phosphotyrosine antibody-binding receptors following in situ stimulation was separated, and autophosphorylation and kinase activity resulting from in situ and/or in vitro activation evaluated in this fraction. RESULTS: Although insulin-stimulated kinase activity of human-specific anti-insulin receptor antibody-binding receptors in cells with Ser(1200)-mutated insulin receptors represented only 3.3% of that reached in cells with non-mutated receptors, a clear insulin-induced increase in kinase activity was observed (3.4-fold; P<0.05). This increase was associated with a 2.3+/-0.6% (P<0.05) increase in anti-phosphotyrosine-binding receptors with a kinase activity representing 43+/-8% of that found in activated non-mutated receptors. In vitro autophosphorylation and kinase activation proceeded much more slowly in Ser(1200)-mutated receptors (t(1/2)): 100 min) compared with non-mutated receptors (t(1/2)): 1 min) and were inhibitable by lower alkaline phosphatase concentrations (EC(50): 3 U/ml and 70 U/ml respectively). No activation of insulin receptor kinase was observed with Arg(1030)-mutated receptors. CONCLUSIONS: Overexpressed Ser(1200)-mutated human insulin receptors possess insulin-stimulated kinase activity and can be activated in situ and in vitro. They are characterized by a markedly slower autophosphorylation reaction, which, in a phosphatase-containing environment, results in a small fraction of phosphorylated and activated receptors.

Alkaline Phosphatase↗
PubMed2000

Insulin activation of insulin receptor kinase in erythrocytes is not altered in non-insulin-dependent diabetes and not influenced by hyperglycemia.

Recent studies suggest that high glucose concentrations impair insulin receptor phosphorylation and kinase activation in certain cell models. To examine whether such an effect of glucose can also be demonstrated in vivo, insulin receptor kinase activation was studied in erythrocytes from 11 patients with non-insulin-dependent diabetes (NIDDM), before and after reduction of hyperglycemia (from 14.6+/-1.6 to 6.6+/-0.5 mmol/l fasting plasma glucose within 8.6+/-0.6 days). For the measurement of receptor kinase activation, cells were incubated with insulin (0-400 nmol/l), solubilized and insulin receptors immobilized to microwells coated with anti-insulin receptor antibody. Kinase activity towards insulin receptor substrate-1 and insulin binding were then measured in these wells. Kinase activities (expressed as amol phosphate transferred per min and per fmol insulin binding activity) were similar before (2.4+/-0.4 and 32.2+/-2.0 amol/min per fmol with 0 and 400 nmol/l insulin, respectively) and after improvement of metabolic control (2.4+/-0.5 and 32.0+/-2.3 amol/min per fmol with 0 and 400 nmol/l insulin, respectively). Moreover, activities were also similar in 22 hyperglycemic patients with NIDDM (2.1+/-0.3 and 35.1+/-1.4 amol/min per fmol with 0 and 400 nmol/l insulin, respectively) compared with those in 21 non-diabetic control individuals (2.1+/-0.3 and 34.2+/-1.2 amol/min per fmol with 0 and 400 nmol/l insulin, respectively). We conclude that insulin activation of erythrocyte insulin receptor kinase is not impaired in NIDDM and is not influenced by hyperglycemia.

Blood Glucose↗
PubMed2000

Insulin signaling and action in cultured skeletal muscle cells from lean healthy humans with high and low insulin sensitivity.

The aim of these studies was to investigate whether insulin resistance is primary to skeletal muscle. Myoblasts were isolated from muscle biopsies of 8 lean insulin-resistant and 8 carefully matched insulin-sensitive subjects (metabolic clearance rates as determined by euglycemic-hyperinsulinemic clamp: 5.8 +/- 0.5 vs. 12.3 +/- 1.7 ml x kg(-1) x min(-1), respectively; P < or = 0.05) and differentiated to myotubes. In these cells, insulin stimulation of glucose uptake, glycogen synthesis, insulin receptor (IR) kinase activity, and insulin receptor substrate 1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity were measured. Furthermore, insulin activation of protein kinase B (PKB) was compared with immunoblotting of serine residues at position 473. Basal glucose uptake (1.05 +/- 0.07 vs. 0.95 +/- 0.07 relative units, respectively; P = 0.49) and basal glycogen synthesis (1.02 +/- 0.11 vs. 0.98 +/- 0.11 relative units, respectively; P = 0.89) were not different in myotubes from insulin-resistant and insulin-sensitive subjects. Maximal insulin responsiveness of glucose uptake (1.35 +/- 0.03-fold vs. 1.41 +/- 0.05-fold over basal for insulin-resistant and insulin-sensitive subjects, respectively; P = 0.43) and glycogen synthesis (2.00 +/- 0.13-fold vs. 2.10 +/- 0.16-fold over basal for insulin-resistant and insulin-sensitive subjects, respectively; P = 0.66) were also not different. Insulin stimulation (1 nmol/l) of IR kinase and PI 3-kinase were maximal within 5 min (approximately 8- and 5-fold over basal, respectively), and insulin activation of PKB was maximal within 15 min (approximately 3.5-fold over basal). These time kinetics were not significantly different between groups. In summary, our data show that insulin action and signaling in cultured skeletal muscle cells from normoglycemic lean insulin-resistant subjects is not different from that in cells from insulin-sensitive subjects. This suggests an important role of environmental factors in the development of insulin resistance in skeletal muscle.

Adult↗
PubMed1999

Implications of compound heterozygous insulin receptor mutations in congenital muscle fibre type disproportion myopathy for the receptor kinase activation.

We studied insulin receptor kinase activation in two brothers with congenital muscle fibre type disproportion myopathy and compound heterozygous mutations of the insulin receptor gene, their parents, and their unaffected brother. In the father who has a heterozygote Arg1174-->Gln mutation, in situ activation of the receptor kinase in skeletal muscle was reduced about 70%. Selection of only those receptors that bound to anti-phosphotyrosine antibody showed that these receptors had normal kinase activity and that the reduction in overall kinase activity was due to the inability of about 70% of the receptors to become insulin-dependently activated. The mother carries a point mutation at the last base pair in exon 17 which, due to abnormal alternative splicing, could lead to normally transcribed receptor or truncated receptor lacking the kinase region. Kinase activation was normal in the mother's skeletal muscle, suggesting that virtually no truncated receptor was expressed. Receptor kinase activity was, however, reduced by 95 and 91% in the compound heterozygous brothers. This suggests that the mother's mutated allele contributes little to the generation of functional receptor protein and that the receptors in the mother's skeletal muscle are transcribed almost exclusively from the non-mutated allele. The mutation in exon 17 could lead to reduced transcription or rapid degradation of a predominantly transcribed truncated gene product or both.

Adult↗
PubMed1999

Hypergravity stimulates collagen synthesis in human osteoblast-like cells: evidence for the involvement of p44/42 MAP-kinases (ERK 1/2).

The formation and organization of skeletal tissue is strongly influenced by mechanical stimulation. There is increasing evidence that gravitational stress has an impact on the expression of early response genes in mammalian cells and may play a role in the formation of extracellular matrix. In particular, osteoblasts may be unique in their response to gravitational stimuli since in these cells microgravity has been reported to reduce collagen synthesis, while in fibroblasts the opposite effect was observed. Here, we have investigated the influence of hypergravity induced by centrifugation on the collagen synthesis of human osteoblast-like cells (hOB) and studied the possible involvement of the mitogen-activated protein (MAP) kinase signaling cascade. Collagen synthesis was significantly increased by 42+/-16% under hypergravity at 13 x g, an effect paralleled by the enhanced expression of the collagen I alpha 2 (COL1A2) mRNA. No difference was seen in the proportion of collagen types I, III, and V synthesized by hOB. Hypergravity induced a markedly elevated phosphorylation of the p44/42 MAP kinases (ERK 1/2). The inhibition of this pathway suppressed the hypergravity-induced stimulation of both collagen synthesis as well as COL1A2 mRNA expression by about 50%. Our results show that the collagen synthesis of non-transformed hOB is stimulated under hypergravitational conditions. This response appears to be partially mediated by the MAP kinase pathway.

Base Sequence↗
PubMed1999

[Glucocorticoid-induced diabetes mellitus in gastrointestinal diseases].

Glucocorticoid excess causes insulin resistance i.e. a reduced effectiveness of insulin to suppress hepatic glucose production and to increase glucose uptake in muscle and fat tissue. Persons who cannot compensate for the resulting additional insulin need develop overt diabetes during glucocorticoid therapy. In the field of gastroenterology, glucocorticoids are mainly employed for the therapy of chronic inflammatory bowel diseases, alcoholic and autoimmune hepatitis, and after liver transplantation. The risk of developing steroid diabetes depends among other things on the genetic predisposition, the body composition, the underlying gastrointestinal disease, the age, and the steroid dose. The treatment of glucocorticoid-induced diabetes resembles essentially the treatment of type 2-diabetes. In addition to dietary measures, oral antihypoglycemic drugs and/or insulin are applied. If oral antihypoglycemic drugs are used, specific problems that might result from the gastrointestinal diseases need to be observed. In the short and medium term, the prognosis of glucocorticoid-induced diabetes is good since it is well treatable. If glucocorticoid treatment is continued for a long time, the alterations of glucose metabolism and the resulting hyperinsulinemia may lead to increased cardiovascular risk.

Adolescent↗
PubMed1998

Time-dependent protection by Na+/H+ exchange inhibition in a regionally ischemic, reperfused porcine heart preparation with low residual blood flow.

Inhibition of Na+/H+ exchange has been shown to protect the ischemic reperfused myocardium. This study investigated the time-dependent beneficial effect of the Na+/H+ exchange inhibitor HOE642 (4-isopropyl-3-methylsulphonylbenzoyl-guanedine methanesulphonite, cariporide). The left anterior descending coronary artery was ligated in 21 pigs (seven control animals) for 60 min and then reperfused for 24 h. An extracorporeal bypass system was used to achieve a constant residual blood flow of 3 ml/min within the ischemic myocardium. Cariporide (1 mg/kg) was injected intravenously in seven pigs after 15 min of ischemia (group A), and in another seven animals after 45 min of ischemia (group B). Histochemical (tetrazolium stain) and histologic infarct sizes were determined at the end of the experiments. Regional systolic shortening was determined by sonomicrometry. Mean calculated residual blood flows (ml/min/g of ischemic myocardium) amounted to 0.106 (group A), 0.093 (group B), and 0.117 (control group). Histochemical (32.9 +/- 21%) and histologic infarct sizes (36.7 +/- 17.7%) were significantly reduced in group A compared to both the control group (histochemical infarct size, 62.5 +/- 16.1%, P < 0.01; histologic infarct size. 67.8 +/- 16.3%, P = 0.013) and group B (histochemical infarct size 64.8 +/- 12.2%, P < 0.01; histologic infarct size 67.1 +/- 15.6%, P < 0.01). Infarct sizes of group B did not differ from control values. Recovery of regional systolic shortening after 24 h of reperfusion was insignificantly improved in group A compared to both other groups. In conclusion, inhibition of Na+/H+ exchange during early ischemia reduced cell death in an ischemic reperfused preparation with low residual blood flow.

Animals↗
PubMed1997

Time delay of cell death by Na+/H+-exchange inhibition in regionally ischemic, reperfused porcine hearts.

Studies in different preparations have suggested that Na+/H+ exchange is one mechanism causally involved in cell death in myocardial ischemia and reperfusion. The time delay of cell death by pretreatment with the Na+/H+-exchange inhibitor HOE642, cariporide (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate), was investigated in regionally ischemic, reperfused porcine hearts. HOE642 (1 mg/kg) was injected intravenously in 14 thoracotomized pigs 10 min before occlusion of the left anterior descending coronary artery (45 min of ischemia, six pigs; 70 min of ischemia, six pigs; 90 min of ischemia, two pigs). Ischemia was followed by 24 h of reperfusion. Six animals (45 min of ischemia) served as controls. Infarct size was determined as a ratio of infarcted (tetrazolium stain, histology) to ischemic myocardium (dye technique), and regional myocardial function was assessed by sonomicrometry. HOE642 did not affect global hemodynamic parameters. In the pretreated group with 45 min of ischemia, HOE642 significantly decreased histochemical infarct size from 51.2 +/- 12.6% (control group) to 13.2 +/- 12% (p < 0.005) and histologic infarct size from 44.5 +/- 9% to 17.1 +/- 7% (p < 0.005). Recovery of regional systolic shortening after 24 h of reperfusion was improved from 2 +/- 6% (control group) to 12 +/- 7% (p = 0.02). In addition, myocardial contracture and increase in heart rate during early reperfusion were attenuated. When ischemia was prolonged to 70 min after pretreatment with HOE642, infarct size, recovery of systolic shortening, myocardial contracture, and increase in heart rate did not differ from those of the control group. Pretreatment with HOE642 increased the tolerance to ischemia/reperfusion by approximately 20-25 min. Inhibition of Na+/H+ exchange appears to be very promising in the clinical treatment of acute myocardial ischemia and reperfusion.

Animals↗