ABSTRACT
We tried to clarify the size and the common charge distribution of the inhibition or stimulation of human platelet aggregation by structure-activity relationship. Numerous inhibiting and stimulating agents were able to enter the receptors. Inhibitory receptor had recess of 14 x 12.5 A in diameter. Stimulatory receptor had recess of 11 x 12 A in diameter. In the recess, there were three charges, two negative and one positive in the inhibitory receptor, and one negative and two positive in the stimulatory receptor, respectively. Charge distributions and conformation of inhibiting or stimulating agents were similar for the inhibitory agents, prostaglandin I2 (PGI2), PGD2, PGE1 adenosine and isoproterenol and conformation of the stimulating agents, thromboxane A2 (TXA2), platelet activating factor (PAF), adenosine diphosphate (ADP) and adrenaline. Each molecule had 3-10 inhibiting and stimulating conformations. The ratio of the number of conformations for inhibition and stimulating of platelet aggregation was highest for PGI2 which showed the strongest inhibitory activity. TXA2 was opposite in both respects.
Subject(s)
Platelet Aggregation/physiology , Receptors, Cell Surface/physiology , Humans , In Vitro Techniques , Models, Biological , Molecular Conformation , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacology , Prostaglandins/chemistry , Prostaglandins/pharmacology , Receptors, Cell Surface/drug effects , Receptors, Prostaglandin/drug effects , Receptors, Prostaglandin/physiology , Structure-Activity RelationshipABSTRACT
31P MRS longitudinal relaxation times (T1) were determined for C3H murine fibrosarcomas (FSaII), and mammary carcinomas (MCaIV). Tumors were implanted in the foot dorsum, and were 100-300 mm3 in volume. T1s were repeated after the animal was allowed to breathe 100% oxygen for 30 min and then again 36-48 hr following 30 Gy. The spectrum were obtained using an 8.5 T spectrometer with a 8 cm bore and a 1.4 cm single turn antenna coil. The 31P relaxation times for untreated tumors in air breathing animals were: 3.78 sec for phosphomonoesters, 4.37 sec for inorganic phosphate (Pi), 2.73 sec for phosphocreatine, 1.37 sec for gamma ATP, 1.14 sec for alpha ATP, and 1.18 sec for beta ATP. The Pi T1s were 4.37 and 4.70 sec in control and irradiated tumors in air breathing animals. Respiration of oxygen for 30 min reduced the T1s to 3.02 and 2.62 sec in control and irradiated tumors respectively. The Pi T1 of an anoxic tumor, determined on an in situ tumor 60 min after death was 5.93 sec. The oxygen breathing induced decrease in the T1 of Pi is unlikely to have been caused by the paramagnetic properties of oxygen alone, and suggests a component of increased magnetization transfer secondary to the ATPase reaction. Oxygen breathing following 30 Gy, resulted in a decreased growth time (800 mm3 endpoint) and an increased proportion of cells in S-phase. These results support the hypothesis that the decrease in Pi T1 measured with oxygen breathing is a measure of tumor oxygen tension and metabolic rate, and suggests that T1 measurement may indirectly predict tumor growth rate and DNA synthesis.
