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Myocardial oxygen utilization has been shown to be impaired following prolonged global ischemia in experimental and clinical studies. The precise nature of this defect in O2 utilization has not been well defined and the present study was designed in an attempt to elucidate the defect. Forty-six isolated, isovolumic feline heart preparations were utilized and three groups of 10 hearts each were subjected to 60 min of normothermic ischemic arrest. Left ventricular function, assessed by developed pressure (DP) and dP dt , coronary blood flow (CBF), myocardial oxygen consumption ( M V O 2 ), and oxygen extraction (O2E) were measured before and after ischemia. One group (I) had unmodified reperfusion; the second group (II) received epinephrine during reperfusion to increase contractility, and the third group (III) received nitroprusside post-ischemia to increase CBF. The remaining hearts, none of which underwent ischemic arrest, were divided into two groups, one of which (IV) was subjected to a period of reduced perfusion pressure with the above parameters examined, and in the final group (V) a period of epinephrine infusion was performed. In Group I hearts after ischemia, dP dt , CBF, M V O 2 , and O2E were all significantly reduced when compared to preischemic levels. Epinephrine infusion postarrest (Group II), although increasing dP dt , CBF, and M V O 2 , did not change the postischemic depression of O2E. With nitroprusside infusion to postischemic depression of oxygen extraction was still apparent. By contrast, epinephrine infusion in the nonarrested hearts (V) increased oxygen extraction as well as dP dt , CBF, and M V O 2 . These data suggest that the primary defect in postischemic oxygen utilization after prolonged ischemia is an impairment in oxygen extraction. Furthermore, the data demonstrate that oxygen extraction remains depressed following arrest in spite of changes in CBF and ventricular function.

31P was used to investigate correlations between intracellular pH (pHi) and myocardial contractility in the normal and ischemic isolated, perfused isovolumic rabbit heart. Intracellular pH was calculated from the chemical shift of Pi in hearts perfused with phosphate-free buffer. Normal intracellular pH was 7.22 ± 0.02 (n = 15). To calibrate the relationship between pHi and left ventricular developed pressure (LVDP), respiratory acidosis was induced by mixing 65% O2: 30% N2: 5% CO2 with 65% O2: 35% CO2 using Krebs buffer containing 24 m m HCO3−. The results show that a 0.22 pH unit acidification correlates with a 50% reduction in LVDP. The correlation between pHi and LVDP was also studied in two models of ischemia: total global ischemia and steady state partial ischemia (50% reduction of LVDP). In both ischemic conditions, a 50% lowering in LVDP correlated with only a 0.09 pH unit acidification. Thus, while intracellular acidosis may account for 40 to 50% of the depression of LVDP oberved during the early phases of ischemia, other factor must also play a role. Mass spectrometry was used to examine the potential regulatory role of tissue oxygen (PmO2). The model of steady-state partial ischemia was employed. Changes in LVDP and MVO2 correlated quite closely with reductions in coronary flow. However, up to a 50% reduction in flow, pHi remained near normal, and tissue PmO2 was normal or slightly elevated. These latter results suggest that an efficient autoregulatory mechanism controls both function and MVO2 in close parallel to changes in flow. As a result, the metabolic supply/demand balance is maintained. However, beyond a 50% reduction in flow, this mechanism fails and metabolic indicies of ischemia are expressed.

To evaluate the myocardial protection afforded by multiple-dose versus single-dose administration of potassium cardioplegic solution, we studied 24 isolated feline hearts before, during, and after 1 hour of ischemic arrest. Intramyocardial gas tensions, ventricular function, histologic preservation, and postischemic myocardial edema were compared in hearts maintained at 27° C during the ischemic period. Equal groups of hearts received no infusion of cardioplegic solution, a single dose of potassium solution at the onset of ischemia, or multiple infusions of the cardioplegic solution throughout the arrest period. During ischemia, single-dose cardioplegic administration resulted in less accumulation of myocardial carbon dioxide (Pmco2) than did hypothermia alone, reflecting a reduction in metabolic activity during ischemia. The fact that multiple-dose cardioplegia further reduced Pmco2 accumulation suggests an intermittent washout of metabolic end products. During reperfusion, hearts protected by multidose cardioplegia demonstrated superior preservation of ventricular performance compared to hearts protected by single-dose cardioplegia or hypothermia alone. In addition, multiple infusions of the cardioplegic solution resulted in optimal structural preservation in both light and electron microscopic studies.

To assess the effects of left ventricular distention during the early reperfusion period following ischemic arrest, 16 canine heart preparations were subjected to 45 minutes of hypothermic (27 degree C) cardioplegic arrest and normothermic reperfusion. Isovolumic left ventricular developed pressure and rate of rise of left ventricular pressure (dp/dt) were measured with an intraventricular balloon; endocardial/epicardial flow ratios were determined with microspheres; and myocardial gas tensions were monitored with mass spectrometry. During early reperfusion, Group 1 hearts (n = 8) were not distended (end-diastolic pressure = 0). Group 2 hearts (n = 8) were subjected to an enddiastolic pressure of 20 mm Hg for the initial 15 minutes of reperfusion. Group 2 hearts demonstrated impaired subendocardial blood flow after 5 minutes of reflow (0.75 +/- 0.06 vs 0.96 +/- 0.04, endocardial/epicardial flow rates, Group 2 vs Group 1) and persistent elevation of intramyocardial carbon dioxide (CO2) tension (68 +/- 4 vs 51 +/- 4 mm Hg, Group 2 vs Group 1). In addition, postischemic ventricular function was significantly worse in Group 2 hearts (60 +/- 7 vs 79 +/- 3% of control dP/dt, Group 2 vs Group 1, and 53 +/- 6 vs 81 +/- 5% of control left ventricular developed pressure, Group 2 vs Group 1). These data demonstrate that even mild distention during early reperfusion can result in reduced subendocardial perfusion and delayed washout of tissue CO2. Although myocardial blood flow and CO2 tension subsequently returned to normal in the distended hearts, left ventricular performance remained significantly depressed. This injury can occur clinically in nonvented hearts prior to the resumption of effective ventricular contraction.

The effectiveness of 60 mg b.i.d. of a novel antihistamine, terfenadine, was compared with an active control, 4 mg t.i.d. of chlorpheniramine, and placebo in 560 patients with seasonal allergic rhinitis. In contrast to the gradual decrease in seasonal symptoms observed over a 7 day period of study in placebo-treated patients, both antihistamines produced a prompt significant decrease in sneezing and rhinorrhea, and a gradual decrease in nasopharyngeal pruritus. Terfenadine-related sedation did not differ from that produced by the placebo and was less than the sedation produced by the active control.