AGE-DEPENDENT AND PATHOLOGY-DEPENDENT ALTERATIONS IN THE EFFICACY OF PHENYLEPHRINE-INDUCED AND 5-HYDROXYTRYPTAMINE-INDUCED CONTRACTIONS IN ISOLATED RAT AORTA

Male Fischer 344 rats were made diabetic for 8-9 weeks by a single intraperitoneal injection of streptozotocin. Steady-state contractile responses elicited by 5-hydroxytryptamine (5-HT) and phenylephrine (PE) activation of the 5-HT2- and alpha-1-adrenergic receptors, respectively, were studied in aortic rings from diabetic, age-matched control and 24-month-old (senescent) F-344 rats. Concentration-response curves (CRCs) for PE and 5-HT were analyzed by the Black and Leff operational model of pharmacological agonism to determine efficacy (tau) and slope factor values. Efficacy estimates obtained with the operational model were compared to two commonly used model-independent estimates of agonist efficacy; 1) Stephenson's efficacy estimate (e), and 2) the estimation of agonist receptor reserves. The estimated-tau for PE in aortic rings from age-matched control animals (12.38) was significantly reduced by both experimental diabetes (4.52) and senescence (7.12), and these findings were in agreement with results obtained using the model-independent efficacy estimates. However, with respect to 5-HT-induced contractions, the estimated-tau in age-matched control animals (2.46) was also significantly reduced by both diabetes (1.58) and senescence (1.69), but these alterations were not detected by the model-independent efficacy estimates. In all cases, a decrease in operational efficacy, tau, was associated with a decrease in the asymptote of the PE or 5-HT CRC (expressed as the agonist maximal effect (E(max))/tissue maximal effect (T(max)) and/or alterations in the fractional occupancy/response relationship. In addition, tau Was sensitive to small changes in agonist efficacy that occurred in the absence of any apparent alterations in the occupancy/response relationship. As such, these studies extend our previous observations in rat aorta to highlight the advantages of using the Black and Leff efficacy estimate, tau, rather than other commonly used model-independent estimates of agonist efficacy.