Isoproterenol (4 mug/kg, i.m.) decreased mortality of conscious guinea pigs to histamine, when histamine was injected 8 min after a single dose. But, when guinea pigs were injected with isoproterenol or saline every 20 min for 5 hr, followed by a histamine challenge 8 (or 120) min later, there was no difference in mortality between the two groups. This failure of repeated doses of isoproterenol to protect guinea pigs (from effects of histamine) may be related to its cardiovascular effects, since control blood pressure decreased significantly more in the isoproterenol group than in the saline group. This hypothesis was supported by the observation that histamine-induced mortality was significantly increased in guinea pigs treated with a vasodilator (minoxidil), whose blood pressure decreased to the same level (54 +/- 5 mm Hg) as that observed after repeated doses of isoproterenol. Tachyphylaxis to heart rate or blood pressure responses of isoproterenol was not observed. 10 repeated additions of isoproterenol to spontaneously beating atria or tracheal strips did not show any tachyphylaxis, nor did 15-20 additions of isoproterenol to perfused lungs.