Search

This study was designed to determine whether human hearts release adenosine, a possible regulator of coronary flow, during temporary myocardial ischemia and, if so, to examine the mechanisms involved. Release of adenosine from canine hearts had been reported during reactive hyperemia following brief coronary occlusion, and we initially confirmed this observation in six dogs hearts. Angina was then produced in 15 patients with anginal syndrome and severe coronary atherosclerosis by rapid atrial pacing during diagnostic studies. In 13 of these patients, adenosine appeared in coronary sinus blood, at a mean level of 40 nmol/100 ml blood (SE = +/-9). In 11 of these 13, adenosine was not detectable in control or recovery samples; when measured, there was concomitant production of lactate and minimal leakage of K(+), but no significant release of creatine phosphokinase, lactic acid dehydrogenase, creatine, or Na(+). THERE WAS NO DETECTABLE RELEASE OF ADENOSINE BY HEARTS DURING PACING OR EXERCISE IN THREE CONTROL GROUPS OF PATIENTS: nine with anginal syndrome and severe coronary atherosclerosis who did not develop angina or produce lactate during rapid pacing, five with normal coronaries and no myocardial disease, and three with normal coronaries but with left ventricular failure. The results indicate that human hearts release significant amounts of adenosine during severe regional myocardial ischemia and anaerobic metabolism. Adenosine release might provide a useful supplementary index of the early effects of ischemia on myocardial metabolism, and might influence regional coronary flow during or after angina pectoris.

Cyanate, which is in equilibrium with urea, combines with the alpha-amino group of the aminoterminal valine of hemoglobin in an irreversible, specific carbamylation reaction. Partial carbamylation (0.72 residues/hemoglobin tetramer) as determined by cyanate-(14)C incorporation or hydantoin analysis diminishes the in vitro sickling phenomenon. Since cyanate may react not only with hemoglobin but also with functional groups of other red blood cell proteins, the in vitro effect of cyanate was studied on sickle cells. Cells were incubated with 10 mM KCl (control) or 10 mM KNCO (carbamylated) for 1 hr, washed, and resuspended in autologous plasma. Glycolysis, ATP and 2,3-diphosphoglyceric acid (DPG) stability, autohemolysis, and osmotic fragility were not affected by carbamylation. Potassium loss in carbamylated cells (2.8 mmol/liter) was less than in control cells (9.0 mmol/liter). Pyruvate kinase activity of carbamylated cells was decreased ( approximately 25%) but the activities of other glycolytic enzymes were similar to those of control cells. Oxygen affinity of carbamylated sickle, normal, and DPG-depleted normal cells increased, and was a sensitive index of the degree and duration of reaction with cyanate. The reactivity of carbamylated cells to DPG was similar to control cells. DPG-depleted carbamylated cells regenerated DPG and increased the P(50) when incubated with pyruvate, inosine, and phosphate. The Bohr effect of normal and of sickle cells was not affected (Deltalog P(50)/Delta pH=-0.48 and -0.53, respectively) after carbamylation. The reserve buffering capacity of plasma offset the slightly diminished ( approximately 15%) CO(2) capacity of carbamylated cells so that whole blood CO(2) capacity, pH, and P(CO2) were normal. These studies provide further support for the potential clinical use of cyanate in treating and preventing the anemia and painful crises of sickle cell disease.