Abstract
Calcium antagonists have routinely been assumed to inhibit the contractions of arterial smooth muscle through block of membrane channels. The effects of nifedipine and diltiazem on contractions were examined in in vitro preparations of cattle coronary artery, one of the key therapeutic targets of calcium antagonists, to determine if alternate mechanisms of action are involved. Contractions elicited in calcium-free Krebs, in the presence of U 46619, to potassium channel inhibitors (4-aminopyridine and tetraethylammonium) and to a Na+-K+-ATPase inhibitor (ouabain), were antagonized by low concentrations of nifedipine (3 × 10− 9 - 3 × 10− 8M) and by diltiazem (3 × 10− 8 and 1 × 10− 7 M). Contractions produced in calcium-free Krebs to KCl (50 mM) were antagonized similarly by calcium antagonists. Contractions to depolarizing agents in calcium-free Krebs were antagonized at lower concentrations of nifedipine than comparably elicited responses in Krebs containing 2.3 mM calcium. In addition, higher concentrations of nifedipine were required to antagonize contractions to extracellular calcium, produced in preparations maintained in calcium-free Krebs in the presence of KCl (50 mM), than were needed to block contractions to KCl or to potassium channel inhibitors elicited in calcium-free Krebs. Pretreatment of preparations in calcium-free Krebs with ryanodine (30 μM) did not reduce the nifedipine-sensitive contractions elicited in calcium-free Krebs. It is concluded that at least some of the therapeutic effects of calcium antagonists on arterial tone may be the consequence of antagonism at vascular smooth muscle cell site(s) at which calcium is released or interacts, rather than of block of calcium entry through membrane L channels.
Footnotes
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Send reprint requests to: Dr. Stanley Kalsner, Professor and Chair, Department of Physiology and Pharmacology, The City University of New York Medical School, The Sophie Davis School of Biomedical Education, 138th Street and Convent Avenue, New York, NY 10031.
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↵1 This research was supported, in part, by a grant from PSC/CUNY.
- Abbreviations:
- TEA
- tetraethylammonium chloride
- 4-AP
- 4-aminopyridine
- SKF 525A
- diethylaminoethyl-diphenylpropylacetate
- g/t
- grams of tension
- Received September 9, 1996.
- Accepted January 17, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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