Potentiation of isoproterenol-induced relaxation of isolated trachea by aminophylline: modulation by desensitization.

Continued exposure of many beta-adrenoceptor-coupled adenylate cyclase systems to high doses of agonist causes diminished responsiveness, a phenomenon called desensitization. After exposure of isolated guinea pig tracheae to a high concentration of isoproterenol for 30 min, relaxation produced by subsequent challenge by a lower concentration was attenuated, as expected. However, potentiation of isoproterenol-induced relaxation by aminophylline was greater after desensitization as compared to that prior to desensitization. This observation was further investigated using a graphical method that allows quantitative and statistical evaluation of combinations of synergistically acting drugs. Concentration-relaxation curves (CRC) for isoproterenol alone and in the presence of a fixed concentration of aminophylline were determined in isolated rat trachea. A theoretical additive curve was constructed from the data obtained, and the displacement of the isoproterenol CRC from the theoretical additive curve caused by aminophylline in tracheae desensitized by 2.5 hr of exposure to 2 X 10(-5) M isoproterenol (DESN) was compared to that in tracheae equilibrated for a similar period in physiologic salt solution (CON). Desensitization had no significant effect on aminophylline-induced relaxation but caused a marked depression and right-shift of the isoproterenol CRC. In the CON group aminophylline shifted the isoproterenol CRC upward and to the left indicating that the synergistic interaction between the two agents was greater than additive. The left-shift and elevation of the ceiling effect of the isoproterenol CRC caused by aminophylline were significantly greater in the DESN group vs the CON group. These observations from intact tissue are compared with published data from biochemical and broken cell studies. The possibility of increased phosphodiesterase activity as an explanation for the observations reported is discussed.