Insulin hypoglycemia or epinephrine release may lead to adverse increases in blood pressure in the presence of non-cardioselective beta-blockers. However, increases in blood pressure have not been observed in beta-blocker treated patients during physical exercise, handgrip tests, or during infusions with the alpha-adrenergic agonist, phenylephrine. In this study we have further evaluated the role of adrenergic stimuli in the etiology of these responses of blood pressure during beta-blocker therapy. These data do not support a direct role for beta 2 receptors or norepinephrine in pressor responses observed during beta-blocker therapy. Blockade of beta 1 receptors or, more likely, a facilitating effect of propranolol upon the alpha-adrenergic receptors might explain the enhanced pressor responses found after administration of the alpha-adrenergic agonist, phenylephrine. However, high doses of phenylephrine seem needed to elicit such pressor responses.