Neuropeptide Y (NPY) is a vasoconstrictor peptide known to be present in the adrenal medulla, the terminal nerve endings, and in plasma. This study was designed to test whether NPY could prevent the acute blood pressure fall induced by endotoxin administration. Normotensive rats were subjected to adrenal demedullation on the right side and were either adrenalectomized or sham-operated on the left side. Eight to ten days later, NPY (0.07 microgram/min i.v.) or its vehicle were infused for 95 minutes into these conscious, semirestrained rats. The same experiments were performed with rats that received an infusion of epinephrine (0.1 microgram/min). These doses of NPY and epinephrine when given alone had no blood pressure effect. During the last 75 minutes of the 95-minute infusion, endotoxin (lipopolysaccharide Escherichia coli 0.111:B4, 10 micrograms/min i.v.) or its vehicle were administered. In rats with an intact adrenal gland, endotoxin failed to induce hypotension. In rats lacking a functioning adrenal medulla, however, endotoxin induced a pronounced mean blood pressure fall of 55 +/- 11.6 mm Hg (mean +/- SEM). This blood pressure drop could be prevented equally well with NPY and with epinephrine infusion and averaged 11 +/- 2.3 and 16 +/- 2.4 mm Hg, respectively, at the end of the experiment. Additional rats were biadrenalectomized and supplemented with an excess of glucocorticoids and mineralocorticoids. In these rats also, NPY markedly attenuated the blood pressure fall resulting from endotoxemia. These data taken together indicate that in conscious rats with no adrenal medulla, the acute blood pressure fall induced by endotoxin administration is greatly enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)