The effect of drugs on the constriction of isolated depolarized blood vessels in response to calcium or barium

Abstract

1. The rat isolated anterior mesenteric artery was perfused at a constant rate with a calcium-free depolarizing solution. Injection close to the cannula of 0.05-0.1 ml. of solutions of CaCI2 (117 mM) or BaCl2 (100 mM) caused a rise in perfusion pressure.2. The responses to injected CaClI solution could be obtained repeatedly but those to successive injections of BaCl2 solution slowly declined. When the responsiveness to barium had almost disappeared, it could be restored by the addition to the perfusing fluid of a small amount of calcium (0.05 mM).3. The contractile effects of calcium or barium were antagonized by the addition to the perfusing fluid of several anti-inflammatory substances, certain local anaesthetics and certain spasmolytic drugs. 4. Perfusion of the mesenteric artery with a depolarizing solution containing 0.2 mM-CaCl2 caused a persistent rise of the perfusion pressure. This was rapidly and completely reversed by the addition of indomethacin (4 mg/100 ml.) or cinchocaine hydrochloride (2 mgf 00 ml.) to the perfusing fluid.5. The uptake of 45Ca by rat aorta depleted of calcium was reduced by amethocaine hydrochloride (10 mg/ 100 ml.) or cinchocaine hydrochloride (2 mg/100 ml.) but not by indomethacin (10 mg/100 ml.) or desipramine hydrochloride (1 mg/100 ml.).Ringer (1883) first showed that cardiac muscle requires calcium ions for contraction. Since then it has been shown that almost all types of muscle require calcium for contraction. It is now generally agreed that calcium ions are the link between excitation of the muscle cell surface and shortening of the contractile proteins within the cell. The very extensive literature on this subject has been reviewed by Shanes

The Influence of Prostaglandins on Noradrenaline‐induced Vasoconstriction in Isolated Perfused Mesenteric Blood Vessels of the Rat

“…The evidence of Northover (1968) coupled with the restorative action of prostaglandins is suggestive of prostaglandin participation in calcium activation of vascular smooth muscle contraction in rat mesenteric blood vessels. Any interpretation should however, be regarded with caution in view of the multiple effects of indomethacin and other NSAIDs.…”

“…Apart from the non-specific actions of indometha-cin already mentioned, Northover (1968; demonstrated that vasoconstrictor responses of the rat isolated perfused anterior mesenteric artery to adrenaline and to calcium ions were prevented or abolished by indomethacin and other NSAIDs. Continued perfusion of the tissue with calcium-containing depolarizing solution (high K+) caused a persistent rise in perfusion pressure which was rapidly reversed by these agents.…”

“…It is likely, therefore, that a calcium-dependent ATP-ase exists in vascular smooth muscle which may represent another target for indomethacin inhibition of vasoconstrictor responses. It is interesting to note, that the order of potency of NSAIDs for the abolition of responses to calcium (Northover, 1968) and for the inhibition of prostaglandin synthetase (Flower, 1974) appears to be the same. This evidence suggests at least two possibilities.…”

“…The EC50 of indomethacin for reduction of vasoconstrictor responses to adrenaline and Ca2+ was 35 ig/ml, a value similar to that found in this study (about 20 jug/ml) for 50% depression of the responses to noradrenaline. Northover (1968) concluded that indomethacin did not prevent calcium ions from being made available to the contractile proteins, but rather, prevented the calcium ions from causing the contractile proteins to shorten. A contractile protein has been extracted from vascular smooth muscle which resembles actomyosin from skeletal muscle in that it develops adenosine triphosphatase (ATP-ase) activity and contracts under the influence of calcium ions (Bohr, Filo & Guthe, 1962).…”

The effects of indomethacin on calcium, sodium, potassium and magnesium fluxes in various tissues of the guinea‐pig

“…Moreover, the accumulation of small amounts of ionic calcium within the cytoplasm of muscle cells is required to trigger the shortening of the contractile proteins (Somlyo & Somlyo, 1968. It may be significant, therefore, that indomethacin and a group of pharmacologically related drugs which are used clinically to treat various forms of tissue injury also inhibit contraction of smooth muscle in response to a variety of spasmogenic agents (Northover, 1967a(Northover, , b, 1968 and this inhibitory action can be attributed to the prevention of the net gain of calcium by the muscle cells (Northover, 1971). The experiments to be reported here were designed to investigate whether, in electrically stimulated smooth muscle, indomethacin prevents the net fluxes of other cations besides calcium, and were extended to include similar observations on certain other tissues.…”