Calcium antagonists and hypothermia: the temperature dependency of the negative inotropic and anti-ischemic properties of verapamil in the isolated rat heart.

Using an isolated rat heart preparation under both aerobic and ischemic conditions we have characterized the temperature dependency of the slow calcium channel-blocking drug verapamil. In the first series of studies, isolated working rat hearts were subjected to global ischemia at 37 degrees, 34 degrees, 31 degrees, 29 degrees, 27 degrees, 25 degrees, and 20 degrees C. The duration of ischemic arrest was adjusted so that in the control group the postischemic recovery of function (aortic flow) was approximately 50% of its preischemic value.

Comparison of the protective properties of four clinical crystalloid cardioplegic solutions in the rat heart.

Although few surgeons dispute the benefits of high-potassium crystalloid cardioplegia, objective comparison of the efficacy of various formulations is difficult in clinical practice. We compared four commonly used cardioplegic solutions in the isolated rat heart (N = 6 for each solution) subjected to 180 minutes of hypothermic (20 degrees C) ischemic arrest with multidose cardioplegia (3 minutes every half-hour). The clinical solutions studied were St.

Microbiopsy metabolite and paired flow analysis: a new rapid procedure for homogenisation, extraction and analysis of high energy phosphates and other intermediates without any errors from tissue loss.

A new procedure is described which allows for the rapid homogenisation, extraction and analysis of the metabolite content of microbiopsy samples (milligram quantities) while completely overcoming the major errors arising as the consequence of the substantial and variable tissue loss associated with conventional procedures. In addition to allowing more accurate and faster analysis of much smaller quantities of tissue the procedure also allows for the coincident paired measurement of flow (radioactive microspheres) in each biopsy. An example of the application of the method to the measurement of flow and high energy phosphate content in multiple microbiopsy samples from normal and ischaemic canine myocardium is provided.

Calcium and cardioplegia. The optimal calcium content for the St. Thomas' Hospital cardioplegic solution.

The relationship between the calcium content of the St. Thomas' Hospital cardioplegic solution and the degree of tissue protection it affords has been characterized by means of an isolated working rat heart preparation subjected to normothermic ischemic arrest. With a 3 minute period of preischemic infusion of solutions containing calcium chloride concentrations of 0, 0.

Calcium delivery and time: factors affecting the progression of cellular damage during the calcium paradox in the rat heart.

Using an isolated rat heart preparation we have investigated the influence of calcium delivery and time upon the induction of cellular injury during the calcium paradox. Hearts were subjected to 10 min of calcium depletion. This was followed by calcium repletion for up to 20 min during which time the calcium concentration in the perfusate was varied between 0.

Creatine phosphate: an additive myocardial protective and antiarrhythmic agent in cardioplegia.

The potential for enhancing myocardial protection by adding high-energy phosphates to cardioplegic solutions was investigated in a rat heart model of cardiopulmonary bypass and ischemic arrest. Creatine phosphate (CP) was evaluated as an additive to the St. Thomas' Hospital cardioplegic solution.

The potential hazard of particulate contamination of cardioplegic solutions.

The potential hazard of particulate debris in unfiltered cardioplegic solutions was assessed using the isolated rat heart preparation. Five intravenous solutions were evaluated: These were manufactured by three pharmaceutical firms (two United States and one British) and are commonly used as bases for preparing clinical cardioplegic solutions. Particles were counted in each solution, and each fell well within the limits for particle contamination defined by both the United States and the British Pharmacopoeias.

The temperature-sensitivity of slow channel calcium blockers in relation to their effect upon the calcium paradox.

The isolated perfused rat heart preparation was used to investigate the interrelationship between temperature and the ability of calcium antagonists to reduce protein leakage in the calcium paradox. Exploiting the fact that although the calcium depletion phase of calcium paradox-injury is highly temperature sensitive, the calcium repletion phase, during which time the injury is manifested, is temperature independent. Verapamil (4 mumol l-1) included in a 10 min period of calcium depletion (37 degrees C) and a 20 min period of calcium repletion (37 degrees C) was known to reduce cumulative protein leakage by 22 +/- 3%.

Nifedipine and cardioplegia: rat heart studies with the St Thomas' cardioplegic solution.

The ability of nifedipine to enhance myocardial protection was assessed using an isolated rat heart model of cardiopulmonary bypass and ischaemic cardiac arrest. With normothermic ischaemic arrest (35 min, 37 degrees C), nifedipine addition improved the protective properties of the St Thomas' cardioplegic solution. Optimal protection was observed with 0.

Calcium antagonists and myocardial protection: diltiazem during cardioplegic arrest.

Using an isolated rat heart preparation as a model of cardiopulmonary bypass and ischemic arrest, the effects of the addition of the calcium antagonist, diltiazem, to St. Thomas' cardioplegic solution were investigated. Under conditions of normothermic ischemic arrest (37 degrees C, 35 min), the addition of diltiazem improved the protective properties of the St.

Temporal and spatial characteristics of evolving cell injury during regional myocardial ischemia in the dog: the "border zone" controversy.

An open chest dog heart with multiple coronary ligations was used to define the temporal and spatial characteristics of injury evolving during regional ischemia. With the use of a multiple (40 sample) biopsy device, adjacent transmural biopsy specimens were obtained from the transition zone between normal and ischemic tissue after 5, 30, 45, 60 and 120 minutes of ischemia. The first 1.

Myocardial cyclic AMP determinations: the importance of rapidity of sample freezing.

Using specially modified automatic freeze clamps studies were undertaken to determine the importance of rapid freeze clamping in the determination of myocardial cAMP content. Modification of the freeze clamps allowed the separation of the physical processes of clamping and freezing. When the tissue was clamped and maintained at 37 degrees C for periods in excess of 5 s before freezing cyclic AMP content increased by up to 100%.

Cardioplegia and slow calcium-channel blockers. Studies with verapamil.

The ability of dl-verapamil to enhance myocardial protection when given before, during, or after myocardial ischemia was assessed with the use of an isolated working rat heart model of cardiopulmonary bypass and ischemic cardiac arrest. Under conditions of normothermic ischemic arrest (30 minutes at 37 degrees C), the addition of verapamil enhanced the protective properties of the St. Thomas' Hospital cardioplegic solution.

Two different metabolic responses to ischaemia: inherent variability or artefact?

Guinea pig hearts, perfused with (5-3H) glucose (8 mmol . litre-1) and subjected to 30 min of reduced (6%) coronary flow, exhibited two distinctly different metabolic and electrophysiological responses to ischaemia. In 22 of the 50 hearts studied (Group 1) glucose utilisation declined during ischaemia from 2.

Metabolic and flow correlates of myocardial ischaemia.

Seven hundred and twenty three biopsies were obtained from 20 dogs after coronary artery ligation for 5, 30, 45, 60 or 120 min (n = 4 dogs for each group). Paired values for blood flow (radioactive microspheres) and tissue ATP content were obtained for each biopsy and related to the duration of ischaemia. Three states of ischaemic injury could be recognised.

Slow calcium channel blockers and the calcium paradox: comparative studies in the rat with seven drugs.

In studies of the calcium paradox, the isolated perfused rat heart was used to characterize the relationship between myocardial protein leakage and the concentration of calcium antagonist (verapamil and D600) or calcium in the perfusion fluid during a cycle of calcium depletion and repletion. The results indicated a dose-dependency such that protein leakage could be progressively reduced by decreasing the concentration of calcium during calcium repletion and/or by increasing the concentrations of drug. Detailed dose-response studies with seven calcium antagonists (verapamil, D600, nifedipine, terodiline, diltiazem, fendiline and prenylamine) and a calcium concentration of 1.

The temperature dependence of the calcium paradox: enzymatic, functional and morphological correlates of cellular injury.

An isolated rat heart preparation was used to characterize the temperature dependence of the calcium paradox and also to assess the validity of various indices of hypothermic protection. Hearts were subjected to 10-min periods of calcium depletion at various degrees of hypothermia followed by 20 min of normothermic calcium repletion. Using enzyme or protein leakage during calcium repletion as an index of hypothermic protection during calcium depletion, paradox injury was reduced extensively by relatively moderate hypothermia.

Sustained limitation of myocardial necrosis 24 hours after coronary artery occlusion: verapamil infusion in dogs with small myocardial infarcts.

Studies were undertaken to ascertain whether verapamil infusion affords a sustained limitation of myocardial injury in the dog after a 24-hour period of coronary artery occlusion. Regional myocardial ischemia was induced by an embolization procedure which did not involve thoracotomy. Immediately after embolization radioactive microspheres were administered intraventricularly to define any area of myocardial underperfusion (zone at risk of infarction).

Models and problems in the study of myocardial ischemia and tissue protection.

Myocardial protection and the control of ischemic injury has been highly successful clinically in the field of cardiac surgery where hearts are made globally ischemic. By contrast, protection of the regionally ischemic myocardium, as found during evolving myocardial infarction, has been less successful and, despite numerous experimental and clinical studies, very controversial. Confusion over the feasibility of infarct size reduction can be attributed to a number of factors including: (1) uncertainty over the nature of the interface between normal and ischemic tissue (the 'border zone controversy'), (2) the inadequacy of many indices of tissue injury and protection.

Effects of flurbiprofen in altering the size of myocardial infarcts in dogs: reduction or delay?

Anti-inflammatory agents such as flurbiprofen have been claimed to reduce infarct size in a number of models of coronary artery occlusion. However, several of the studies are controversial and also do not allow the critical distinction between reducing and delaying injury. In the present study, a closed chest method of coronary occlusion was used to generate small areas of regional myocardial ischemia in dogs.