Rings of isolated epicardial coronary arteries made to contract with prostaglandin F2 alpha relax when their sympathetic nerves are stimulated. This response, which is the opposite of that seen in other systemic blood vessels, results from activation by norepinephrine (NE) of beta 1 adrenoceptors, which predominate over alpha 1 adrenoceptors in the main coronary arteries. A modest contraction occurs only when the beta 1 adrenoceptors are blocked. As each branch leaves the main artery, only beta 1 adrenoceptors are present, so that the sole effect of NE is to cause relaxation. Like the terminations of other sympathetic nerves, those to the main coronary arteries or their branch vessels contain alpha 2 adrenoceptors that when activated reduce the output of neurotransmitter. When these prejunctional receptors are inhibited with phentolamine, there is a greater relaxation in response to activation of the sympathetic nerves, which is caused by increased release of NE. Thus, the in vivo observation that phentolamine increases coronary blood flow may be explained by the action of this drug on prejunctional alpha 2 adrenoceptors rather than on alpha 1 adrenoceptors on the smooth muscle cells themselves.