STUDIES ON THE MECHANISM OF THE INHIBITORY EFFECT OF DESIPRAMINE (DMI) ON VASCULAR SMOOTH MUSCLE CONTRACTION

¹ Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

The inhibitory effect of desipramine (DMI) on the constrictor response of vascular smooth muscle to different types of stimulants was studied in the isolated perfused renal artery of the rat. DMI in concentrations of 5 x 10^-7, 10^-6 and 5 x 10^-6 M progressively inhibited norepinephrine (NE)-induced contractions, decreasing both the maximum and the slope of the log dose-response curve. The antagonism between DMI and NE was not competitive. Increasing the Ca⁺⁺ concentration in the perfusate (to 13 mM) partially antagonized the inhibitory effect of DMI (6.6 x 10^-6 M) on arteries previously caused to contract by perfusion with NE (3 x 10^-6 M). On the other hand, in a low Ca⁺⁺ medium (0.26 mM) the inhibitory effect of DMI (6.6 x 1O^-7 M) on the response to injected NE was more pronounced. The barium-induced contraction of the artery (BaCl², 10^-3 M) also was antagonized by DMI in a dose-dependent manner, but was not inhibited by equimolar concentrations of phentolamine or phenoxybenzamine. These findings suggest that DMI exerted its inhibitory action at a site along the "excitation-contraction coupling" pathway which was common to adrenergic and nonadrenergic stimulants. Two possible mechanisms were suggested: 1) decrease in permeability of smooth muscle cell membrane to extracellular Ca⁺⁺ and/or an interference with the inward release of membrane bound Ca⁺⁺ and 2) competition with Ca⁺⁺ at the hypothetical receptor site inside the cell.