bq-123 and Heart-Arrest

Evidence as to how ACE inhibitors attenuate ischemia-reperfusion injury (IR) after cardioplegic arrest remains scarce. Twenty-four rabbit hearts were perfused on a Langendorff apparatus. Control hearts (n = 6) were arrested with pure histidine-tryptophan-ketoglutarate (HTK)-Bretschneider. Treatment groups received added to the cardioplegic solution (n = 6) captopril (100 μmol/l) and losartan (100 μmol/l) for selective AT1-receptor antagonism or BQ123 (100 nmol/l) for selective ETA-receptor antagonism. Pre-ischemic equilibration of 45 min was followed by 90 min of cardioplegic arrest and 30 min of reperfusion. Indices of myocardial contractility (LVP, dp/dt max, dp/dt min), coronary flow, heart rate, and O2 consumption were recorded before and after ischemic arrest. Tissue adenosine triphosphate (ATP) and malondialdehyde (MDA) contents were measured to evaluate energy content and oxidative stress, respectively. After selective cardiac arrest with Bretschneider, captopril-treated hearts showed improved hemodynamics compared to control and the other treatment groups. Oxygen consumption was significantly decreased during early reperfusion in captopril-treated hearts (34 ± 3 μmol/min/g/mmHg) compared to controls and losartan- and BQ123-treated hearts (controls: 77 ± 9 μmol/min/g/mmHg, p = 0.003; losartan: 54 ± 9 μmol/min/g/mmHg, p = 0.015; BQ123: 64 ± 13 μmol/min/g/mmHg, p = 0.046). The ATP content of the reperfused tissue was significantly elevated after captopril treatment compared to control group (24 ± 2 vs. 16 ± 2 μmol/g, p = 0.033), whereas the level of MDA was substantially decreased (0.58 ± 0.163 vs. 1.5 ± 0.28 μmol/g, p = 0.009). ACE inhibition leads to a significantly greater and faster recovery of myocardial contractility after prolonged cardiac arrest with Bretschneider solution. Due to decreased oxygen consumption, myocardial protection is enhanced. The association between ACE and ischemia cannot be clarified by selective blockade of angiotensin-II receptor type 1 (AT1-R) or ETa receptor (ETa-R).

Topics: Adenosine Triphosphate; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Endothelin Receptor Antagonists; Glucose; Heart Arrest; Hemodynamics; Losartan; Male; Malondialdehyde; Mannitol; Myocardial Reperfusion Injury; Oxygen Consumption; Peptides, Cyclic; Potassium Chloride; Procaine; Rabbits

Haemodynamic effects of saline-extracted venom from nematocysts isolated from Chiropsalmus quadrigatus (Habu-kurage) were studied in anaesthetized rats. Intravenous administration of venom (0.2-5 microg protein/kg) produced immediately dose-dependent hypertension and bradycardia. Femoral blood flow transiently increased but calculated femoral vascular conductance decreased. Changes caused by 1 microg/kg of venom were reproducible, and were not affected by prazosin, atropine or BQ123 (ET(A) receptor antagonist) but were significantly attenuated by nicardipine. At doses over 2 microg/kg, hypotension and a decrease in pulse pressure were observed subsequent to transient hypertension. In 5 of 8 rats received 5 microg/kg venom and 6 of 6 rats at 10 microg/kg, death due to irreversible cardiac arrest occurred within 30 min after intravenous injection. However, during nicardipine infusion, venom (10 microg/kg) exerted only modest effects and the rats survived. Heating venom (50 degrees C for 10 min) before injection practically abolished the haemodynamic effects of 10 microg/kg venom, indicating its thermolability. Data show that C. quadrigatus venom has both vasoconstrictor and cardiodepressive effects in rats, and suggest that a calcium channel blocker can protect against the cardiovascular and lethal effects of the venom.

Topics: Animals; Atropine; Cardiovascular System; Cnidarian Venoms; Cubozoa; Dose-Response Relationship, Drug; Heart Arrest; Hemodynamics; Male; Nicardipine; Peptides, Cyclic; Prazosin; Rats; Rats, Wistar; Temperature

Successful resuscitation of the brain after cardiac arrest requires unimpaired microcirculatory reperfusion. Postischemic cerebral hypoperfusion presumably is mediated through activation of endothelin type A receptors (ET(A)). The effect of the selective ET(A) antagonist BQ123 on cerebral blood flow and function was studied in a rat model of cardiac arrest.. Prospective, randomized trial.. Experimental animal laboratory.. Twelve male Sprague-Dawley rats (290-350 g).. Cardiac arrest for 12 mins was induced by electrical fibrillation of the heart, followed by standardized cardiopulmonary resuscitation. BQ123 (0.8 mg/kg; n = 6) or its vehicle (saline; n = 6) was injected intravenously at 15 mins after the return of spontaneous circulation.. Cortical blood flow was measured by laser-Doppler flowmetry, electrophysiological function by recording the amplitude of somatosensory evoked potentials, vascular reactivity by ventilation with 6% CO2, and the functional coupling of blood flow by recording the laser-Doppler flow (LDF) changes during somatosensory stimulation. Hemodynamic and functional cerebral recovery was monitored for 3 hrs after the return of spontaneous circulation.. Forty-five minutes after the return of spontaneous circulation, postischemic hypoperfusion developed in both groups, as reflected by a decrease of the LDF signal to about 60% of the preischemic level. In untreated animals, hypoperfusion persisted throughout the observation time, but in animals receiving BQ123, LDF gradually returned to normal. CO2 reactivity in untreated animals was severely reduced for 2-3 hrs after the onset of recirculation, whereas after BQ123 treatment it returned to normal and after 2 hrs even above normal. The ET(A) antagonist also induced a more rapid recovery of the somatosensory evoked potentials amplitude and of the functional blood flow response to somatosensory stimulation, but these parameters did not recover completely within the observation period.. Application of the ET(A) antagonist BQ123 during the early reperfusion period after cardiac arrest shortens postischemic cerebral hypoperfusion and accelerates the restoration of the cerebrovascular CO2 reactivity and the recovery of electrophysiologic function.

Topics: Animals; Carbon Dioxide; Cardiopulmonary Resuscitation; Cerebrovascular Circulation; Endothelin Receptor Antagonists; Heart Arrest; Hemodynamics; Male; Peptides, Cyclic; Prospective Studies; Random Allocation; Rats; Rats, Sprague-Dawley

Antagonists of endothelin (ET(A)) receptors improve postischemic hypoperfusion. In this study we investigated whether the selective ET(A)-antagonist BQ123 also improves postischemic functional recovery.. Cardiac arrest of 12 mins duration was induced in rats by electrical fibrillation of the heart, followed by advanced cardiopulmonary resuscitation. BQ123 (0.8 mg/kg; n = 9) or its vehicle (saline; n = 9) was injected intravenously at 15 mins after the return of spontaneous circulation. The neurologic deficit was scored daily for 7 days after resuscitation by rating consciousness, various sensory and motor functions, and coordination tests. On day 7, we measured functional coupling of cerebral blood flow under halothane anesthesia by recording laser-Doppler flow during electrical forepaw stimulation, and we measured vascular reactivity to CO2 by measuring the laser-Doppler flow change during ventilation with 6% CO2. The brains were perfusion-fixated with 4% paraformaldehyde, and the histopathologic damage was evaluated in the CA1 sector of hippocampus, in the motor cortex, and in the cerebellum.. Treatment with BQ123 had no effect on histopathologic damage, but it significantly improved neurologic recovery. In all nine treated rats, neurologic performance returned to near normal within 2 days whereas four of nine untreated animals developed spastic paralysis of the hind limbs and severe coordination deficits. BQ123 also normalized CO2 reactivity and improved the functional cerebral blood flow response to somatosensory stimulation.. The ET(A)-antagonist BQ123 significantly improves neurologic outcome after 12 mins of cardiac arrest. The apparent restoration of vascular reactivity demonstrates a correlation between hemodynamic factors and functional recovery.

Topics: Animals; Brain; Cardiopulmonary Resuscitation; Electrophysiology; Endothelin Receptor Antagonists; Heart Arrest; Hemodynamics; Male; Nervous System; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Recovery of Function; Time Factors