The blood pressure and heart rate effects of a synthetic alkyl ether phospholipid and similar lipids derived from beef heart and egg yolk were studied in normotensive, renal, and spontaneously hypertensive rats. Each agent (1.25 to 10 micrograms/kg) produced a dose-related decrease in blood pressure and increase in heart rate in each model after rapid IV injection. The degree of blood pressure lowering was dependent upon the pretreatment blood pressure. Alkyl ether phospholipid was infused at 10 to 30 micrograms/kg/min to SHR and to platelet depleted SHR; comparable effects (blood pressure decreases and heart rate increases) were noted in both models. Reversal of the epinephrine pressor response was seen in all rats. When administered orally in ascending doses on three consecutive days, 50 and 150 micrograms/kg b.i.d. doses (Day 1 and 2) were inactive whereas 500 micrograms/kg b.i.d. (Day 3) decreased blood pressure by 25 +/- 8 and 21 +/- 8 mm Hg in renal and spontaneously hypertensive rats, respectively. Side effects (by all routes) included limp, cyanotic hind limbs and sedation and were similar in SHR and platelet depleted SHR. Significant, sustained blood pressure lowering was not achieved by any of the alkyl ether phospholipids in the conscious rat models at doses devoid of limiting side effects. The results of these studies show: 1) the BP, HR, and toxic profiles of all three alkyl ether phospholipids were qualitatively similar, 2) at doses causing significant BP lowering there was epinephrine reversal suggesting an alpha-adrenergic blocking component of action, 3) the BP, HR, and toxic effect profiles of alkyl ether phospholipid were comparable in normal and platelet depleted SHR and apparently not platelet-dependent, 4) sustained antihypertensive activity could be achieved by the oral route; however the effects were modest (12 +/- 4% decrease) and associated with limiting side effects.