Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Local inhibition of angiotensin-converting enzyme (ACE, kininase II) produces both attenuation of angiotensin (Ang) II generation and bradykinin (BK) degradation. To delineate the participation of BK in the cardioprotective actions of ACE inhibitors, experiments were performed in rats and dogs with cardiac ischemia-reperfusion injuries. (I) In rat isolated perfused working hearts with regional myocardial ischemia, BK in concentrations as low as 1 X 10(-9) M increased coronary flow (CF) and reduced the incidence and duration of reperfusion ventricular fibrillation (VF). In addition, enzyme activities of lactate dehydrogenase (LDH) and creatine kinase as well as lactate output were decreased in the venous effluent of BK-perfused hearts, which also showed improved cardiodynamic and metabolic parameters. Even concentrations of BK lower than 1 X 10(-10) M, which were without influence on coronary flow, exerted comparable beneficial metabolic effects connected with reduced incidence and duration of VF. Combined perfusions with threshold concentrations of BK (1 X 10(-12) M) and the ACE inhibitor ramiprilat (2.58 X 10(-9) M), which were ineffective given alone, resulted in a marked cardioprotective effect. Perfusion with Ang II (1 X 10(-9) M) aggravated reperfusion arrhythmias and worsened myocardial metabolism. BK perfusion prevented this deterioration in a concentration-dependent manner, whereas the Ang II receptor antagonist saralasin was only marginally effective. The BK antagonist D-Arg-[Hyp2, Thi5,8, D-Phe7]-BK (1 X 10(-5) M) completely abolished the cardioprotective effects of BK or the ACE inhibitor. However, higher concentrations of BK (1 X 10(-7) M) or ramiprilat (2.58 X 10(-5) M) competitively reversed these properties of the BK antagonist. (II) In anesthetized dogs, BK was infused into the coronary artery in a dose of 1 ng/kg/min during occlusion (90 min) and reperfusion (30 min) of the left descending coronary artery (LAD)--a dose without effects on cardiovascular parameters. In line with the findings in isolated ischemic rat hearts, BK infusion reduced LDH activities and lactate concentrations in the coronary sinus blood, whereas myocardial tissue levels of glycogen and energy-rich phosphates were increased in the infarcted area. The cardioprotective effects produced by perfusion with BK or by reduction of BK degradation through local interference with ACE favor a role for BK in ischemia-reperfusion injuries in rats and dogs.
 ...
PMID:Local inhibition of bradykinin degradation in ischemic hearts. 169 70

In this study, the effect of bradykinin or saline infusion during ischemia and reperfusion on electrical stability, 2 weeks after myocardial infarction, was assessed. Acute myocardial infarction was induced in 21 pigs by a transluminal occlusion of the left coronary artery with a catheter balloon, inflated for 45 min. Bradykinin was administered by a 30-min infusion that started after 30 min of coronary occlusion and was continued until 15 min after reperfusion. Although creatine kinase levels in bradykinin-treated animals were significantly lower (p less than 0.001), 2 week survival was not different between groups. In survivors, the filtered QRS (ventricular deflection) duration (detected using signal-averaged electrocardiography) was significantly prolonged in saline-treated pigs, whereas in bradykinin-treated pigs this prolongation was prevented. The terminal voltage of the QRS complex was significantly lower in saline-treated pigs than in bradykinin-treated pigs. These two parameters signify an improved electrical stability after bradykinin treatment. Refractory periods in saline-treated hearts were longer than in bradykinin-treated hearts (106 +/- 10% vs. 95 +/- 13%, p less than 0.05). Also, current thresholds in the infarct border zones showed a greater variance in saline-treated hearts (p less than 0.001), pointing toward more tissue heterogeneity of the infarct border zone. Programmed electrical stimulation showed a trend toward reduced inducibility of sustained ventricular tachycardia in bradykinin-treated hearts. Therefore, bradykinin improves electrical stability weeks after experimental myocardial infarction.
 ...
PMID:In vivo effect of bradykinin during ischemia and reperfusion: improved electrical stability two weeks after myocardial infarction in the pig. 171 27

In an attempt to separate the cardiac effects of converting-enzyme (CE) inhibition from those on blood pressure, experiments were performed in rats and dogs with nonantihypertensive (subhypotensive) doses of the CE inhibitor ramipril. (a) Left ventricular hypertrophy: Rats with aortic constriction treated with a nonantihypertensive dose of ramipril (10 micrograms/kg/day) for 6 weeks showed the same prevention and regression of cardiac hypertrophy as groups receiving the antihypertensive dose of 1 mg/kg/day. Comparable results were obtained in animals treated for 1 year. (b) Ischemia-reperfusion injuries: In rats, subchronic oral administration of ramipril in a subhypotensive dose (10 micrograms/kg/day) prevented ex vivo postischemic reperfusion arrhythmias and improved cardiodynamic and metabolic parameters. Almost complete inhibition of cardiac CE was achieved with this low dose. (c) Acute myocardial infarction: Ramiprilat (40 ng/kg/min) was infused for 6 h into the left coronary artery of anesthetized dogs with a ligation of the descending branch of this artery. This route and the low dose were chosen to achieve local cardiac effects without affecting systemic hemodynamics. Ramiprilat significantly reduced the infarct area expressed as a percentage of the area at risk. This cardioprotective effect of ramiprilat was mimicked by bradykinin and abolished by coadministration of a bradykinin antagonist. Thus, factors beyond blood pressure reduction and load changes may add to the cardiovascular benefits of CE inhibitors. This may indicate local (cardiac) paracrine and/or autocrine effects of the renin-angiotensin system and/or participation of kinins.
 ...
PMID:Experimental cardiovascular benefits of angiotensin-converting enzyme inhibitors: beyond blood pressure reduction. 172 38

We hypothesized that coronary artery endothelial cell function and smooth muscle function are modified by global myocardial ischemia and used bradykinin-induced secretion of endothelium-derived relaxing factor as a marker of endothelial cell function. Bradykinin and sodium nitroprusside together determined maximum smooth muscle relaxation. Potassium chloride-induced contraction determined smooth muscle contractility. Endothelium-mediated smooth muscle relaxation expressed as a ratio of total coronary smooth muscle relaxation before and after ischemia quantified endothelial cell function. The effect of global normothermic ischemia on in situ coronary arteries from 7 swine hearts was studied. Coronary arterial rings taken from 0 to 220 minutes of ischemia at 20-minute intervals were studied in vitro. The data revealed unexpected tolerance of endothelium-mediated relaxation to ischemia. Endothelium-derived relaxing factor function was maintained to 160 minutes and smooth muscle function, to 120 minutes of ischemia. Coronary artery dysfunction seen in other studies after less ischemia may be the result of injury introduced during reperfusion, may be the consequence of myocardial injury, or may be due to events operative at the level of small arterioles.
 ...
PMID:Coronary artery endothelial cell and smooth muscle dysfunction after global myocardial ischemia. 173 74

The adjunctive use of angiotensin-converting enzyme (ACE) inhibitors with thrombolytic therapy early during acute myocardial infarction offers theoretic advantages. In the acute phase, captopril may scavenge free radicals, blunt the catecholamine response, elicit coronary vasodilation, and increase prostacyclin and bradykinin levels. In the chronic phase, ventricular remodeling may be attenuated. At present, a large number of controlled clinical trials mainly focusing on the effects of ACE inhibition in the chronic phase are underway. Only a few studies concentrate on the effect of acute intervention with ACE inhibitors in ischemia-reperfusion, i.e., thrombolysis in myocardial infarction. In April 1990 under auspices of the Interuniversity Cardiology Institute of the Netherlands, a large nationwide acute intervention trial with captopril in 280 patients receiving thrombolytic therapy was started, the Captopril and Thrombolysis Study (CATS). The primary hypothesis of CATS supposes a very early effect of ACE inhibition on evolving myocardial damage due to ischemia and the consequences of early reperfusion. This will be evaluated by serial echocardiography, Holter monitoring and neurohumoral measurements immediately on thrombolysis and during the first year after myocardial infarction.
 ...
PMID:Early intervention with angiotensin-converting enzyme inhibitors during thrombolytic therapy in acute myocardial infarction: rationale and design of captopril and thrombolysis study. CATS investigators group. 174 15

Ischemically sensitive abdominal visceral afferents are known to reflexly stimulate the cardiovascular system. These nerve endings respond to severe hypoxia as well as to exogenously administered bradykinin and prostaglandins such as PGI2, PGE, and PGF2 alpha. We have shown previously that these prostaglandins can sensitize some previously unresponsive afferents to respond to ischemia. To determine if endogenously produced prostaglandins contribute to the observed increase in activity during ischemia, we recorded activity of 6 A delta- and 23 C-fiber sympathetic afferents in anesthetized cats during 5 min of ischemia before and 15-30 min after intravenous administration of either indomethacin (5 mg/kg) or aspirin (50 mg/kg). Before cyclooxygenase inhibition, we noted repeatable increases of 1.44 +/- 0.22 and 1.44 +/- 0.36 impulses/s in the A delta- and C-fibers, respectively, in response to ischemia. After indomethacin or aspirin, these increases were significantly reduced (P less than 0.05) in both thinly myelinated and unmyelinated afferents (0.69 +/- 0.36 and 0.46 +/- 0.21 impulses/s, respectively). In a second protocol, we observed that the activity of six A delta- and seven C-fibers was significantly reduced by aspirin or indomethacin when a single period of ischemia preceded cyclooxygenase blockade. These data, in conjunction with our previous observations, indicate that prostaglandins significantly contribute to the increased afferent discharge activity associated with ischemia of the abdominal visceral region.
 ...
PMID:Ischemically sensitive abdominal visceral afferents: response to cyclooxygenase blockade. 175 May 53

1. A total of 59 medullary raphespinal neurons antidromically activated from the T2-T5 segments were tested for responses to coronary artery occlusion, epicardial application of bradykinin, and mechanical probing of the epicardium in cats anesthetized with alpha-chloralose. With the exception of five neurons, only those neurons that were responsive to electrical stimulation of the left stellate ganglion were tested for responses to these stimuli. Neurons in this study are a subset of those in the companion report. 2. Six neurons (12%) responded to epicardial bradykinin. Five cells were excited, and one was inhibited. Nine neurons (18%) had cardiac receptive fields, and one neuron (2%) had a field confined to the pericardium. 3. Neurons were tested for responses to separate occlusions of the left anterior descending (LAD) and circumflex (CX) coronary arteries. Overall, 13/34 (38%) of tested raphespinal neurons were responsive to coronary artery occlusion. Responses to coronary artery occlusion consisted of two major patterns. One pattern consisted of either an increase or decrease in neuronal firing rate after the heart became ischemic; this pattern was termed an ischemic (IS) response. Ten neurons (29%) exhibited an IS response to occlusion of the LAD and/or CX coronary arteries. Because four neurons exhibited IS responses to occlusion of each artery, there were a total of 14 IS responses. Of these, 10 were inhibitory, and 4 were excitatory. The second pattern of response consisted of a rapidly adapting excitation or inhibition at the onset or release of occlusion, but cell activity was unchanged during cardiac ischemia; this pattern was termed an onset (ON) response. Three neurons (9%) exhibited ON responses; two were excited, and one was inhibited. No neurons demonstrated both ON and IS responses during occlusion. 4. Twenty-one neurons were tested for responses to occlusion of each artery. Seventeen neurons (81%) exhibited similar patterns of responses to occlusion of each artery; that is, they either showed the same pattern of response to occlusion of each artery or they were unresponsive to either occlusion. For the 5 of these 17 neurons that were responsive, direction of change in neuronal activity (excitation or inhibition) was the same for occlusion of each artery. 5. All raphespinal neurons tested for responses to epicardial bradykinin and coronary artery occlusion were responsive to electrical stimulation of the left stellate ganglion. In addition, 16/28 (57%) of neurons tested for responses to occlusion were responsive to electrical stimulation of the right cervical vagus nerve.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Responses of medullary raphespinal neurons to coronary artery occlusion, epicardial bradykinin, and cardiac mechanical stimuli in cats. 181 39

The purpose of this investigation was to study the effect of an angiotensin converting enzyme inhibitor (enalaprilat) on the morphologic manifestations of experimentally induced necrotizing tracheobronchitis (NTB). Twenty piglets were anesthetized before saline lung lavage. High frequency flow interrupter (HFFI) ventilation was used with a strategy known to produce NTB. Animals were randomly assigned to receive IV enalaprilat 0.1 mg/kg (ENP-Hi), enalaprilat 0.01 mg/kg (ENP-Lo), or saline (C). After 8 hours of ventilation, the piglets were sacrificed. Total airway injury scores (mean +/- S.D.) were 1.2 +/- 0.7 for ENP-Hi, 0.2 +/- 0.2 for ENP-Lo, and 21.3 +/- 16 for group C. Enalaprilat minimizes NTB lesions in neonatal piglets exposed to high frequency oscillatory ventilation. Although the origin of NTB is multifactorial, airway mucosa ischemia may play an important role. Enalaprilat may compensate for the reduction of mucosal blood flow by limiting formation of angiotensin II and/or preventing degradation of bradykinin.
 ...
PMID:Necrotizing tracheobronchitis (NTB) following high frequency ventilation: role of an angiotensin converting enzyme inhibitor. 184 39

Platelet-activating factor (PAF) is an unusually potent lipid autacoid with a variety of biological activities. The growing body of evidence suggests that PAF might play an important role in modulation of central nervous system function, particularly during ischemia- and trauma-induced neuronal damage. However, the mechanisms involved in PAF actions on neuronal or other brain cells is virtually unknown. Therefore, this study was designed to characterize PAF receptor-mediated cellular signal transduction in neurohybrid NG108-15 cells with the aid of a new potent PAF antagonist, BN 50739. PAF induced an immediate and concentration-dependent increase in [Ca++]i with an EC50 of 6.8 nM. PAF-induced [Ca++]i mobilization was inhibited by several structurally unrelated PAF antagonists such as BN 50739, WEB 2086, SRI 63-441 and BN 52021, in a dose-dependent manner with IC50 values of 4.8, 6.9, 809 and 98500 nM, respectively. The calcium channel blockers nifedipine (5 microM) and diltiazem (10 microM) had no effect on the PAF-induced increase in [Ca++]i, but omission of CA++ from the incubation buffer caused an 82% reduction of PAF-induced [Ca++]i elevation; the remainder contributed from intracellular sources was completely inhibited by 10 microM TMB-8, an intracellular Ca++ blocker. NG108-15 cells exhibited homologous desensitization to sequential addition of PAF, but no heterologous desensitization between PAF and other agonists such as bradykinin, endothelin, angiotensin II and ATP was observed. PAF stimulated phosphoinositide metabolism in a dose-dependent manner with an EC50 of 5.1 nM for IP3 formation, which was also inhibited by the PAF antagonist BN 50739 in a dose-dependent manner (IC50 = 3.6 nM).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Platelet-activating factor (PAF) receptor-mediated calcium mobilization and phosphoinositide turnover in neurohybrid NG108-15 cells: studies with BN50739, a new PAF antagonist. 185 Apr 73

Local inhibition of angiotensin-converting enzyme (ACE, kininase II) produces both-attenuation of angiotensin II generation and of bradykinin degradation. To delineate the participation of bradykinin in the cardioprotective actions of ACE inhibitors, experiments were performed in rats and dogs with cardiac ischemia-reperfusion injuries. In isolated perfused working rat hearts with regional myocardial ischemia, bradykinin in concentrations as low as 1 x 10(-9) M increases coronary flow and reduces the incidence and duration of reperfusion ventricular fibrillation. In addition, enzyme activities of lactate dehydrogenase and creatine kinase as well as lactate output were decreased in the venous effluent of bradykinin-perfused hearts, which also showed improved cardiodynamic and metabolic parameters. Even concentrations of bradykinin lower than 1 x 10(-10) M, which were without influence on coronary flow, exerted comparable beneficial metabolic effects connected with reduced incidence and duration of ventricular fibrillation. Combined perfusions with threshold concentrations of bradykinin (1 x 10(-12) M) and the ACE inhibitor ramiprilat (2,58 x 10(-9) M), which were ineffective given alone, resulted in a marked cardioprotective effect. Perfusion with angiotensin II (1 x 10(-9) M) aggravated reperfusion arrhythmias and worsened myocardial metabolism. Bradykinin perfusion prevented this deterioration in a concentration-dependent manner. The bradykinin antagonist D-Arg-[Hyp2, Thi5,8, D-Phe7]-bradykinin (1 x 10(-5)) completely abolished the cardioprotective effects of bradykinin or the ACE inhibitor. However, higher concentrations of bradykinin (1 x 10(-7) M) or ramiprilat (2,58 x 10(-5) M) reversed these properties of the bradykinin antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[ACE inhibition: mechanisms of "cardioprotection" in acute myocardial ischemia]. 186 30


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>