alpha 1 Receptors have been investigated using a variety of experimental approaches. alpha 1-Receptor stimulation of phosphoinositide (PI) hydrolysis shows differences in agonist efficacy. The potency series and antagonists clearly suggest that alpha 1 receptors are coupled to phosphoinositide hydrolysis. This coupling appears to be mediated by a guanine nucleotide protein coupling the agonist-receptor complex to the phosphoinositide phosphodiesterase. However, certain alpha 1-agonists stimulate phosphoinositide hydrolysis only at very high concentrations that are not sensitive to prazosin antagonism. Other studies on alpha 1-receptor desensitization note discrepancies in coupling to phosphoinositide hydrolysis that are also found when comparing hypertensive (SHR) and normotensive (WKY) rats. Furthermore, molecular studies indicate that the apparent molecular weight of the alpha 1 receptors varies among tissues. These studies suggest heterogeneity in alpha 1 receptors and alpha 1-receptor-mediated responses. This heterogeneity is supported by studies on alpha 1-adrenergic-receptor-mediated decreases in angiotensin II receptors. The response to alpha 1 stimulation is opposite to that found with phorbol esters, which mimic the second messenger response to PI hydrolysis. Thus, these studies suggest that alpha 1-adrenergic receptors are coupled to multiple second messenger responses, one of which is phosphoinositide hydrolysis.