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 … Show more
“…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.…”
Section: Discussionmentioning
confidence: 95%
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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).…”
1 The report of the depression by indomethacin of vasoconstrictor responses to noradrenaline and their partial restoration by prostaglandin E2 (PGE2) and PGE1 in rat isolated perfused mesenteric blood vessels was investigated. The further suggestion that prostaglandins may be necessary for the combination of noradrenaline with the a-adrenoceptor in this tissue was also studied. 2 The reported depression by indomethacin was confirmed and was further shown to be in the form of a concentration-dependent flattening of the noradrenaline concentration-effect curve. 3 A concentration-dependent restorative effect was observed for all prostaglandins studied. The decreasing order of potency for the restoration towards normal of the indomethacin-depressed responses to noradrenaline was: PGE2, PGE1, PGA1, PGF2,, PGA2.4 The prostaglandins studied were not uniform in their restorative actions and could be separated into two groups. PGE2 and PGE1 restored responses towards the control level whereas PGA1, PGA2 and PGF2a increased responses to an above control level and did so over a smaller concentration range. The possibility of several prostaglandin receptors is discussed. 5 At concentrations equi-effective in restoring depressed responses to control levels PGA1 but not PGE2, caused a parallel shift of the noradrenaline concentration-effect curve to the left and a small, gradual rise in the basal perfusion pressure. 6 The reason for the differing effects remains obscure but does not seem to involve a change in the a-adrenoceptor as indicated by the pA2 of phentolamine. Furthermore, the restorative and potentiating effect of PGA1 is not mediated by blockade of neuronal uptake of noradrenaline. 7 It appears that prostaglandins are required for the vasoconstrictor action of noradrenaline in rat mesenteric blood vessels and that this effect is distal to the drug-receptor interaction. The possible involvement of prostaglandins with intracellular calcium ions is discussed.
“…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.…”
Section: Discussionmentioning
confidence: 95%
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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).…”
1 The report of the depression by indomethacin of vasoconstrictor responses to noradrenaline and their partial restoration by prostaglandin E2 (PGE2) and PGE1 in rat isolated perfused mesenteric blood vessels was investigated. The further suggestion that prostaglandins may be necessary for the combination of noradrenaline with the a-adrenoceptor in this tissue was also studied. 2 The reported depression by indomethacin was confirmed and was further shown to be in the form of a concentration-dependent flattening of the noradrenaline concentration-effect curve. 3 A concentration-dependent restorative effect was observed for all prostaglandins studied. The decreasing order of potency for the restoration towards normal of the indomethacin-depressed responses to noradrenaline was: PGE2, PGE1, PGA1, PGF2,, PGA2.4 The prostaglandins studied were not uniform in their restorative actions and could be separated into two groups. PGE2 and PGE1 restored responses towards the control level whereas PGA1, PGA2 and PGF2a increased responses to an above control level and did so over a smaller concentration range. The possibility of several prostaglandin receptors is discussed. 5 At concentrations equi-effective in restoring depressed responses to control levels PGA1 but not PGE2, caused a parallel shift of the noradrenaline concentration-effect curve to the left and a small, gradual rise in the basal perfusion pressure. 6 The reason for the differing effects remains obscure but does not seem to involve a change in the a-adrenoceptor as indicated by the pA2 of phentolamine. Furthermore, the restorative and potentiating effect of PGA1 is not mediated by blockade of neuronal uptake of noradrenaline. 7 It appears that prostaglandins are required for the vasoconstrictor action of noradrenaline in rat mesenteric blood vessels and that this effect is distal to the drug-receptor interaction. The possible involvement of prostaglandins with intracellular calcium ions is discussed.
“…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.…”
Summary
Isolated tissues of the guinea‐pig were bathed with Krebs solution at 37° C and subjected to 100 ms pulses of electrical stimulation for 30 min at a frequency of 0·1 or 1·0 Hz. The tissues were then dried, ashed, and the ash analysed for calcium, sodium, potassium and magnesium.
Gastric smooth muscle, cardiac and skeletal muscles and brain all showed a gain of sodium and calcium and a loss of potassium in response to electrical stimulation, but there was no significant change in the magnesium content of any of these tissues.
Indomethacin (0·5 mm) reduced the calcium content of unstimulated gastric smooth muscle and reduced the gain of calcium and sodium in response to electrical stimulation, but slightly increased the net loss of potassium in response to electrical stimulation.
Gastric smooth muscle which had gained calcium as a result of electrical stimulation, gradually lost it again when stimulation ceased. Indomethacin (0·5 mm) hastened the net loss of calcium from previously stimulated muscle.
Indomethacin (0·5 mm) failed to alter the calcium, sodium, potassium and magnesium contents of unstimulated cardiac muscle, skeletal muscle and brain. In these tissues indomethacin (0·5 mm) also failed to prevent the changes in the content of these minerals which occurred in response to electrical stimulation.
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