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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Local vasodilation in response to hypoxia or ischemia improves perfusion and O2 supply of the affected tissue. This local vasodilation thus constitutes the most important mechanism in the prevention of ischemic cell injury. The regulation of vascular tone has mainly been attributed to changes of cytoplasmatic Ca2+ ((Ca2+)i) concentrations in vascular smooth muscle cells. The mechanism underlying these changes has not, however, been elucidated so far. Using aortic strips of guinea pigs (transversally cut in spirals; normal Tyrode, in mM: NaCl 150, KCl 4.5, MgCl2 2, CaCl2 2.5, glucose 10; buffered with 10 mM HEPES at pH 7.4; equilibrated with 100% O2 at 31 degrees C) the authors could show that metabolic blockade (glucose replaced by 10 mM 2-deoxyglucose (DOG) led to a relaxation of the preparation. Thus, in four experiments, resting tension decreased from 0.75 g by 27% +/- 12% within two hours (% of maximal contractile force developed by each preparation when depolarized with 43 mM KCl and 101.5 mM NaCl). When the same experiment was carried out in the presence of 1 mM tolbutamide (a known blocker of ATP-dependent K+ channels) in vascular smooth muscle no such relaxation could be seen (n = 4). Furthermore, in the same type of preparation, similar results have been obtained upon hypoxic relaxation (100% O2 replaced by 100% N2), where 1 mM tolbutamide also prevented vasodilation. Thus, hypoxic/ischemic vasodilation in response to glycolytic inhibition (DOG) and hypoxia (N2) is based upon the opening of K+ ATP channels and hence can be prevented by sulfonylureas (the opening of K+ ATP channels would lead to hyperpolarization (increased K+ conductance, Goldmann equation), thus diminishing the open probability of voltage-gated Ca2+ channels with subsequent vasodilation). This inhibition by sulfonylureas of vasodilative response to ischemia may also constitute the so far unknown cause of the increased cardiovascular mortality seen under sulfonylurea treatment.
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PMID:Vasodilative response to hypoxia and simulated ischemia is mediated by ATP-sensitive K+ channels in guinea pig thoracic aorta. 844 33

We have studied the effects of adding 0.5 mmol/L CaCl2 to University of Wisconsin solution (0.08 mmol/L free Ca++) on hypothermic heart preservation. Isolated pig hearts were subjected to 8 hours of preservation at 12 degrees C; eight hearts were arrested with Ca++ free University of Wisconsin solution, and seven hearts were arrested with Ca(++)-containing University of Wisconsin solution. The recovery of contractile function was evaluated by measuring isovolumic ventricular pressure development. 31P nuclear magnetic resonance spectroscopy was used to monitor the changes in high-energy phosphates. Compared to the hearts arrested with the Ca(++)-free University of Wisconsin solution, the heart arrested with the Ca(++)-containing University of Wisconsin solution showed significantly improved (p < 0.001) contractile functional recovery. No "stone heart" or loss of high-energy phosphates was observed on reperfusion. The hearts showed an increase in diastolic pressure during infusion of the Ca(++)-containing University of Wisconsin solution, however, to show the relationship between the addition of calcium and the increase in diastolic pressure, a second protocol was performed. A 30-minute period of ischemia was induced in thirteen hearts that were arrested at 12 degrees C with either Ca(++)-containing University of Wisconsin solution (n = 8) or Ca(++)-free University of Wisconsin solution (n = 5). Diastolic pressure was monitored during ischemia while ventricular volume was maintained constant with a balloon. The hearts arrested with the Ca(++)-containing University of Wisconsin solution showed a mean rise of 5 mm Hg in diastolic pressure and a rapid decline of phosphocreatine (p < 0.001). Our results suggest that, although 0.08 mmol/L free Ca++ improves functional recovery after 8 hours of heart preservation with University of Wisconsin solution at 12 degrees C, it can increase diastolic pressure during ischemia and accelerate breakdown of the high-energy phosphate stores in the myocardium, suggesting that use of University of Wisconsin solution containing 0.5 mmol/L CaCl2 may result in a significant increase in the intracellular calcium level.
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PMID:The effects of Ca++ on the preservation of myocardial energy and function with University of Wisconsin solution. A 31P nuclear magnetic resonance study of isolated blood perfused Langendorff pig hearts. 844 6

The stimulation of NMDA receptor activates NO dependent cGMP biosynthesis with dynamic and extent different for hippocampus and brain cortex. The significantly higher NO mediated cGMP level was observed in hippocampus than in brain cortex. NMDA receptor stimulation increases NO mediated cGMP formation about 8 fold in hippocampus and 2.5 fold in brain cortex as compared to basal value (2 mM CaCl2). The activity of NO synthase and the basal level of cGMP in unstimulated slices were only slightly higher in hippocampus then in brain cortex. The CA2+ calmodulin dependent NO synthase was found in brain membrane and cytosol fraction. The enzyme activity was not affected by glucocorticoids, even after 20 days of hydrocortisone treatment in a dose of 40 mg/kg b.w. Brain ischemia induced by ligation of both common carotid arteries in gerbils increases significantly NOS activities as well as the level of cGMP and putrescine but decreases mono-ADP-ribosylation of brain proteins during reperfusion period. The ischemia evoked changes of NOS/cGMP were eliminated by specific inhibitor of neuronal form of NOS, 7-Nitrodazole (7NI) administered in a dose of 25 mg/kg b.w. 5 min. before ischemia. This inhibitor has no effect on the level of putrescine enhanced during ischemia and also biphasically during reperfusion. The inhibitor of guanylate cyclase, LY 83583 administered in a dose of 6 mg/kg b.w. 5 min before ischemia diminishes not only the enhanced level of cGMP but also NOS activity stimulated by ischemia. These results indicate that activation of NMDA receptor stimulates more significantly NO/cGMP production in hippocampus than in brain cortex suggesting the role of NO in neuronal form of NOS and inhibitor of guanylate cyclase protect the brain against excessive production of nitric oxide and cGMP during ischemia-reperfusion. These compounds may offer a new strategy in the therapy of brain ischemia.
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PMID:NMDA receptor mediated nitric oxide dependent cGMP synthesis in brain cortex and hippocampus. Effect of ischemia on NO related biochemical processes during reperfusion. 910 Feb 45

The compound 2,3,5,6-Tetramethylpyrazine (TMP; Ligustrazine), a flavouring component and sweetness enhancer for beverages constitutes a commonly used food additive. Now we studied the effect of TMP on coronary artery dilation during ischemia: In our experiments we used isolated, Langendorff-perfused guinea pig hearts, arrested with K(+)-rich Normal Tyrode solution (in mM: NaCl 129.5, KCl 15, MgCl2 0.8, CaCl2 1.0, glucose 10), buffered with 10 mM HEPES to pH 7.4 at 37 degrees C, equilibrated with 100% O2. Ischemia was simulated by equimolar replacement of glucose by 2-deoxyglucose (DOG), an inhibitor of oxydative phosphorylation. We found that coronary perfusion pressure (CPP) decreased by 20 +/- 1.2 cm H2O (from initially 90 cm H2O; n = 6, +/- SEM) within 15 min from the onset of DOG. In the presence of 1 mM TMP the decrease in CPP was largely attenuated and CPP declined by 1.4 +/- 1.0 cm H2O (n = 6, +/- SEM; p < 0.01). In 2 out of the 6 TMP experiments even as light increase in CPP (< 2 cm H2O) could be seen. We conclude that TMP, a blocker of ATP-dependent K(+)-channels in pancreatic beta-cells and possibly in arterial smooth muscle cells, prevents coronary dilation in response to ischemia. The possible suppression of this vital mobilization of coronary reserve during ischemia in patients with coronary artery disease certainly merits further attention and may question the use of this compound as a food additive.
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PMID:First description of the effect of a non-sulfonylurea compound, tetramethylpyrazine, on coronary response to desoxyglucose-induced ischemia. 957 20

The aim of this study was to determine whether endogenous adenosine has antiarrhythmic effects on ischemia-induced ventricular tachyarrhythmias. We therefore modulated the effect of endogenous adenosine in isolated rat hearts using four different approaches. First, interstitial adenosine was elevated by metabolic inhibition with either EHNA (erythro-9-(2-hydroxy-3-nonly)adenine) or acadesine [5-amino-1-beta-D-imidazole-4-carboxamide). Second, cardiac effects of A1 adenosine receptors were allosterically enhanced with PD81,723 (2-amino-4,5-dimethyl-3-thienyl)[3-(trifluoromethyl)phenyl]-methanone . Third, endogenous adenosine release was suppressed with NBMPR (S-(4-nitrobenzyl)-6-thioinosine), and fourth, adenosine receptor subtypes were blocked with antagonists of different selectivity. Regional ischemia, induced by coronary artery ligation, caused ventricular fibrillation of a reproducible kind in about 20% of untreated hearts with a low calcium concentration in the perfusion medium (0.80 mmol/l CaCl2) and in about 75% with high calcium (1.85 mmol/l) within an observation period of 30 min. At high calcium, EHNA (1 and 10 micromol/l) and acadesine (500 micromol/l) suppressed the occurrence of ventricular fibrillation from 68% (controls) to 47%, 33% and 38%, respectively. Conversely, PD81,723 (10 micromol/l) did not influence the occurrence of ventricular fibrillation. At low calcium, NBMPR (0.1 and 1 micromol/l) resulted in a concentration-dependent rise of ventricular fibrillation from 13% (controls) to 40% and 57%, respectively. The adenosine receptor antagonists theophylline (100 micromol/l), XAC (Xanthine Amine Congener; 1 micromol/l) and 8-PT (8-phenyltheophylline; 1 micromol/l) caused a rise in the occurrence of ventricular fibrillation from 25%, 15% and 18% (controls) to 57%, 39% and 44%, respectively, and the selective A2a receptors antagonist CSC (8-(3-chlorostyryl)caffeine; 5 micromol/l) from 20% to 56%. Conversely, the selective A1 receptor blocker DPCPX (8-cyclopentyl-1,3-dipropyl-xanthine; 1 micromol/l) was ineffective. NBMPR or EHNA concentration-dependent suppressed or increased ischemia-induced adenosine overflow, respectively, in a concentration-dependent manner, whereas the adenosine receptor antagonists did not influence adenosine overflow. We conclude that endogenous adenosine is an antiarrhythmic mediator accumulating in acute ischemic myocardium to a level which effectively decreases the occurrence of ventricular fibrillation by an A2 adenosine receptor activation in the isolated rat heart.
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PMID:Endogenous adenosine reduces the occurrence of ischemia-induced ventricular fibrillation in rat heart. 1007 21

Previous investigators have suggested that calcium may play a role in the pathogenesis of myocardial cell damage following ischemia and reperfusion. Twenty-six in-situ blood perfused isovolumic canine preparations were divided into four groups. Group I dogs were maintained normocalcemic during 45 min of reperfusion following 45 min of hypothermic (27 degrees C) ischemic arrest; Group II dogs received CaCl2 (7 mg/kg) after 15 min of reperfusion; Group III dogs received citrate solution (0.8 ml/kg citrate-phosphate-dextrose [CPD]) after 15 min of reperfusion; Group IV dogs received 7 mg/kg of CaCl2 at 5 min after receiving the same citrate dose as Group III after 15 min of reperfusion. In Group II hearts, calcium improved the left ventricular contractility (P < 0.05 vs Group I) without causing additional cellular or subcellular injury. Calcium also appeared to increase myocardial stiffness (alpha(n)) compared to Group I hearts (P < 0.01). In Group III hearts, citrate reduced contractility (P < 0.01 vs Group I) and increased myocardial edema (P < 0.005 vs Group I) without any apparent improvement in cellular or subcellular preservation. In Group IV hearts, calcium reversed the depression of contractility caused by citrate, resulted in no additional morphologic injury, increased myocardial stiffness compared to Group I or Group III (P < 0.005), and minimized myocardial edema (P < 0.005 vs Group I or III). These results suggest that calcium administered after 15 min of reperfusion improves the depression of contractility that follows hypothermic ischemic arrest without causing additional myocardial damage.
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PMID:Effects of calcium administration during post-ischemic reperfusion on myocardial contractility, stiffness, edema, and ultrastructure. 1474 Jul 1

The cardiotonic and antidysrhythmic effects of four triterpenoid derivatives, namely oleanolic acid (OA), ursolic acid (UA), and uvaol (UV), isolated from the leaves of African wild olive (Olea europaea, subsp. africana) as well as methyl maslinate (MM) isolated from the leaves of Olea europaea (Cape cultivar) were examined. The derivatives showed low toxicity on brine shrimp test. They displayed significant, dose-response vasodepressor effect and sinus bradicardia, most prominent for OA and MM. The derivatives acted as beta-adrenergic antagonists, blocking the effect of adrenaline and isoprenaline. The established positive inotropic and dromotropic effects were most distinctive for OA and MM. The antidysrhythmic effects were evaluated on CaCl2- and adrenaline-induced chemical arrhythmias, and on ischemia-reperfusion arrhythmia. OA and UA displayed antidysrhythmic effects on both types of chemical arrhythmia; OA and UV in dose 40 mg/kg conferred significant antidysrhythmic activity on ischemia and reperfusion arrhythmias. The effect was comparable to that of propranolol and suggestive of beta-adrenergic antagonistic activity. On the basis of the vasodepressor, cardiotonic and antidysrhythmic effects of these compounds, it was concluded that OA and UV isolated from wild African olive leaves, or crude extract containing all components, can provide a cheap and accessible source of additive to conventional treatment of hypertension, complicated by stenocardia and cardiac failure.
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PMID:Cardiotonic and antidysrhythmic effects of oleanolic and ursolic acids, methyl maslinate and uvaol. 1507 Jan 61

Brief ischemic episodes that induce myocardial and coronary endothelial dysfunction may alter the responses to inotropic drugs. To determine the effects of inotropic drugs in stunned myocardium, the coronary blood flow (CBF), myocardial oxygen consumption (MVO2), and regional mechanical function in response to intracoronary dobutamine, epinephrine, amrinone, and calcium chloride (CaCl2) were measured before (normal) and 30 min after a 15-min-period occlusion of the left anterior descending artery (stunned) in an open-chest canine model. Percent segment shortening (%SS) and post-systolic shortening (%PSS) were determined. Myocardial extraction of oxygen (EO2) and lactate (E(lac)) was calculated. The inotropic drugs increased %SS, CBF, and MVO2 in normal myocardium. Epinephrine and amrinone decreased, while dobutamine and CaCl2 did not affect EO2. The ischemia and reperfusion itself significantly reduced %SS and E(lac), and increased %PSS. In stunned myocardium, the responses to inotropic drugs were not significantly altered, except that they progressively reduced %PSS and epinephrine did not affect EO2. These findings indicate that a brief episode of ischemia does not affect the mechanical and metabolic coronary flow responses to inotropic drugs, although it abolishes direct vasodilator responses to epinephrine.
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PMID:Effects of inotropic drugs on mechanical function and oxygen balance in postischemic canine myocardium: comparison of dobutamine, epinephrine, amrinone, and calcium chloride. 1622 44

Positive inotropic drugs may attenuate or exacerbate the deleterious effects of ischemia and reperfusion (IR) injury on excitation-contraction coupling in hearts. We 1) quantified the phase-space relationship between simultaneously measured myoplasmic Ca2+ concentration ([Ca2+]) and isovolumetric left ventricular pressure (LVP) using indexes of loop area, orientation, and position; and 2) quantified cooperativity by linearly modeling the phase-space relationship between [Ca2+] and rate of LVP development in intact hearts during administration of positive inotropic drugs before and after global IR injury. Unpaced, isolated guinea pig hearts were perfused at a constant pressure with Krebs-Ringer solution (37 degrees C, 1.25 mM CaCl2). [Ca2+] was measured ratiometrically by indo 1 fluorescence by using a fiber-optic probe placed at the left ventricular free wall. LVP was measured by using a saline-filled latex balloon and transducer. Drugs were infused for 2 min, 30 min before, and for 2 min, 30 min after 30-min global ischemia. IR injury worsened Ca2+-contraction coupling, as seen from decreased orientation and repositioning of the loop rightward and downward and reduced cooperativity of contraction and relaxation with or without drugs. Dobutamine (4 microM) worsened, whereas dopamine (8 microM) improved Ca2+-contraction coupling before and after IR injury. Dobutamine and dopamine improved cooperativity of contraction and relaxation after IR injury, whereas only dopamine increased cooperativity of relaxation before IR injury. Digoxin (1 microM) improved Ca2+-contraction coupling and cooperativity of contraction after but not before ischemia. Levosimendan (1 microM) did not alter Ca2+-contraction coupling or cooperativity, despite producing concomitant increases in contractility, relaxation, and Ca2+ flux before and after ischemia. Dynamic indexes based on LVP-[Ca2+] diagrams (area, shape, position) can be used to identify and measure alterations in Ca2+-contraction coupling during administration of positive inotropic drugs in isolated hearts before and after IR injury.
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PMID:Ischemia-reperfusion injury changes the dynamics of Ca2+-contraction coupling due to inotropic drugs in isolated hearts. 1628 37

Openers of K+(ATP) channels protect the myocardium from I/R injury. Sulfonylureas are known as potent blockers of K(ATP) channels. We investigated whether 1) mitochondrial permeability transition pore may be involved in the protection afforded by the mitoK+(ATP) opener nicorandil and 2) whether sulfonylureas may prevent this beneficial effect. Anesthetized New Zealand White rabbits underwent 30 min of coronary artery occlusion, followed by 60 (isolated mitochondria) or 240 min (infarct size) of reperfusion. They received an administration of either saline (control) or nicorandil (0.5 mg kg(-1), i.v.) 15 min before ischemia. Each control and nicorandil group was divided in four subgroups pretreated by either saline, glibenclamide (Glib; 1 mg kg(-1)), gliclazide (Glic; 1 mg kg(-1)), or glimepiride (Glim; 5 microg kg(-1)) 10 min before this. Infarct size was assessed by triphenyltetrazolium chloride staining. Mitochondria were isolated from the area at risk for further assessment of the calcium retention capacity. Glibenclamide (35 +/- 8), but neither Glic (61 +/- 9) nor Glim (48 +/- 7), reversed the improvement in calcium retention capacity due to nicorandil (58 +/- 10 vs. 27 +/- 8 nmoles CaCl2 mg(-1) proteins in control). Infarct size reduction by nicorandil (32% +/- 6% vs. 65% +/- 6% of area at risk) was abolished by Glib (55 +/- 5) but not by Glic (37 +/- 3) or Glim (31 +/- 5). These data suggest that 1) the protective effect of nicorandil involves the inhibition of the mitochondrial permeability transition pore and 2) that unlike Glib, second-generation sulfonylureas preserve this cardioprotection.
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PMID:Second-generation sulfonylureas preserve inhibition of mitochondrial permeability transition by the mitochondrial K+(ATP) opener nicorandil in experimental myocardial infarction. 1917 41


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