The role of sodium and potassium ions, and the possible involvement of the membrane sodium pump has been studied in the development of a contractile response to, and the development of tachyphylaxis to, angiotensin II. It is suggested that a membrane depolarization may have a role in the mechanism of the contractile response to angiotensin II, as responses of the rabbit aorta to angiotensin II were selectively inhibited in K-free medium. Acute or chronic increases in medium sodium, however, did not influence the response of the rabbit aorta to angiotensin II. On the rat aorta increased medium sodium concentrations potentiated the response to angiotensin II and inhibited the development of tachyphylaxis. Membrane depolarization or hyperpolarization does not appear to be part of the mechanism of development of tachyphylaxis to angiotensin II on the rat aorta, as response to both NE and angiotensin II were inhibited equally by exposure of the rat aorta to K-free medium, i.e., nonspecific desensitization occurred, as opposed to the specific desensitization which defines tachyphylaxis.