Evidence that pinacidil may promote the opening of ATP‐sensitive K+ channels yet inhibit the opening of Ca²⁺‐activated K+ channels in K⁺ ‐contracted canine mesenteric artery

May 1, 1990British journal of pharmacology

Pinacidil may open energy-sensitive potassium channels but block calcium-activated potassium channels in contracted dog intestinal arteries

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Abstract

Cromakalim and pinacidil relaxed arterial strips precontracted with 20.9 mM K+ with pD2 values of 6.56 and 5.88, respectively.

High concentrations of pinacidil relaxed arterial strips bathed in 65.9 mM K+ and inhibited calcium-induced contractions.
Both cromakalim and pinacidil increased the basal 86Rb efflux in arterial strips preloaded with 86Rb.
Pinacidil induced a smaller increase in 86Rb efflux compared to cromakalim when arterial strips were contracted with 65.9 mM K+.
Addition of nifedipine to contracted arterial strips enhanced the effect of pinacidil on 86Rb efflux, while leaving cromakalim's effect unchanged.
Pinacidil's effect on 86Rb efflux may result from opposing actions on potassium channels, influenced by calcium influx inhibition.

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1. The effects of cromakalim and pinacidil on contraction and 86Rb efflux were investigated in strips of canine mesenteric artery. 2. Cromakalim and pinacidil relaxed arterial strips precontracted with 20.9 mM K+ with pD2 values of 6.56 and 5.88, respectively. 3. High (above 10 microM) concentrations of pinacidil, but not cromakalim, relaxed arterial strips bathed by a medium containing 65.9 mM K+, and inhibited Ca2(+)-induced contractions in strips bathed by a medium containing 80 mM K+. These findings suggested that pinacidil may act as an inhibitor of Ca2+ influx. 4. In arterial strips preloaded with 86Rb, cromakalim and pinacidil increased the basal 86Rb efflux. 5. When the effects of cromakalim and pinacidil on 86Rb efflux were determined in arterial strips contracted with 65.9 mM K+, both drugs increased 86Rb efflux. The increase in 86Rb efflux induced by pinacidil was much smaller than that induced by cromakalim. Under the same conditions, nifedipine decreased 86Rb efflux. 6. After the addition of nifedipine to arterial strips contracted with 65.9 mM K+, pinacidil produced a greater increase in 86Rb efflux than in the absence of nifedipine, whereas the effects of cromakalim were the same for the two conditions. Therefore, the effects of pinacidil on 86Rb efflux may be the resultant of two opposing effects: an increased 86Rb efflux due to the opening of ATP-sensitive K+ channels, and a decreased efflux due to the closing of Ca2(+)-activated K+ channels. 7. In causing relaxation, cromakalim was competitively antagonized by glibenclamide with a pA2 value of 7.16. However, glibenclamide antagonism of pinacidil was not of the simple competitive type, suggesting that inhibition of Ca2 + influx may contribute to the relaxant action of pinacidil. 8. It may be concluded that although the ability of pinacidil to increase 86Rb efflux via ATP-sensitive K+ channel opening was similar to that of cromakalim, the inhibition of Ca2 + influx by pinacidil may reduce the opening of Ca2 +-activated K+ channels in K+-contracted arterial strips.

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Evidence that pinacidil may promote the opening of ATP‐sensitive K+ channels yet inhibit the opening of Ca²⁺‐activated K+ channels in K⁺ ‐contracted canine mesenteric artery

Abstract

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