Abstract
Phenoxybenzamine induced a slowly developing and concentration dependent positive chronotropic effect in isolated spontaneously beating guinea-pig atria. The rate-accelerating effect was blocked by propranolol or by reserpine pretreatment and, therefore, appears to be mediated through endogenous norepinephrine. Pargyline pretreatment increased the rate accelerating effects of phenoxybenzamine. Supersensitivity to norepinephrine was obtained in the presence of phenoxybenzamine except for the concentration of 10 µ/ml which induced a shift to the right and a depression of the maximum. The latter was related to the decelerating effects of large concentrations of phenoxybenzamine. In atria, in which the norepinephrine stores were labeled with 3H-norepinephrine, phenoxybenzamine (3 µ/ml) produced an increased release of 3H-norepinephrine and of 3H-3,4-dihydroxyphenylglycol (DOPEG). The metabolic pattern of transmitter released by phenoxybenzamine was similar to that obtained in the presence of a reserpinelike agent, Ro 4-1284. Inhibition of presynaptic monoamine oxidase with bretylium resulted in a selective decrease in the spontaneous outflow of the deaminated glycol, DOPEG. These results support the view that DOPEG is formed predominantly as a result of presynaptic monoamine oxidase activity. In the presence of cocaine, the small increase in spontaneous release of tritiated compounds was accounted for entirely by norepinephrine. Phenoxybenzamine can be described as reserpine-like as far as the presynaptic metabolism of the released norepinephrine and as tyramine-like with regard to its ability to release the transmitter and to sensitize to norepinephrine.
Footnotes
- Received June 29, 1971.
- Accepted September 23, 1971.
- © 1972 by The Williams & Wilkins Co.
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