Limitations of Schild plots in a two-receptor system: alpha adrenoceptors of vascular smooth muscle.

The contractile response of vascular smooth muscle to l-norepinephrine is mediated almost exclusively by alpha-1 adrenoceptors in some blood vessels, and by a mixture of alpha-1 and postsynaptic alpha-2 receptors in others. To learn the sensitivity of the Schild plot as a test for the presence of more than one receptor type in such tissues, we constructed the plots to be expected from the dissociation constants of l-norepinephrine and prazosin for alpha-1 and alpha-2 adrenoceptors, using values determined by radioligand methods, and examining the effects of varying the proportions of the two types. The principles involved can be applied to other drugs and other two-receptor systems. Two occupation-response models were tested, one perfectly linear and the other convex toward the response axis. No receptor reserve was assumed, in accordance with experimental observations on vascular adrenoceptors. Schild plots over the range of antagonist concentrations customarily used did not deviate significantly from a straight line with a slope between 0.95 and 1.05 unless the second type amounted to more than 35% of the total receptors in the linear model, or more than 15% in the nonlinear model. Inasmuch as 95% CL of +/- 20% are often reported for experimental estimates of the slope, it may be difficult in practice to recognize from Schild plots the presence of a second receptor type unless it amounts to at least one-third of the total receptor pool.