Evidence for differential roles of nitric oxide (NO) and hyperpolarization in endothelium‐dependent relaxation of pig isolated coronary artery

Abstract

1 The possible roles of endothelial and smooth muscle cell hyperpolarization and nitric oxide (NO) in endothelium-dependent relaxation were examined in isolated rings of pig right coronary artery. 2 The effects of hyperpolarization were prevented with high K+ (30-125 mM), isotonic Krebs solutions. Functional antagonism due to high K+-induced smooth muscle contraction was prevented with 0.3 gM nifedipine (in all treatments, for consistency). All rings were contracted with the thromboxanemimetic U46619, (1-100 nM) to bring them to an initial active force of within 30-50% of maximum contraction.3 High K+ had no effects on the sensitivity (EC") or time course of endothelium-dependent (substance P, SP; bradykinin, BK; calcimycin, A23187) and -independent (sodium nitroprusside, SNP) agents.Maximum relaxations (R.,) to SP, BK and A23187 were reduced significantly by approximately 20% but only with 125 mM K+.

Enhanced role for the opening of potassium channels in relaxant responses to acetylcholine after myocardial ischaemia and reperfusion in dog coronary arteries

“…In this study however we did not observe any e ect of K + on ACh-induced relaxation in the absence or presence of NO synthase inhibition in nonischaemic arteries. The reason for the di erence between the present observation and those of Cocks and colleagues (Kilpatrick & Cocks 1994;Drummond & Cocks 1996) is not known but may involve the use of di erent agonists (ACh versus bradykinin) or species (dog versus pig and cow).…”

“…Several previous studies have reported that endotheliumdependent relaxation of coronary arteries in normal circumstances does not involve K + channel opening but if NO synthesis is inhibited, a K + sensitive component of the relaxation is revealed (Kilpatrick & Cocks 1994;Drummond & Cocks, 1996). Thus it was proposed that an endotheliumderived K + channel opener, possibly EDHF, acted as a reserve to NO to maintain vasodilatation.…”

“…To determine whether the opening of K + channels might be contributing to the endothelium-dependent relaxation we examined the responses to ACh in the presence of a depolarizing concentration of K + (67 mM). To prevent K + -induced contraction we also added the L-type Ca 2+ channel blocker nifedipine (Kilpatrick & Cocks, 1994). The rings were then precontracted with the thromboxane mimetic U46619 to the same level as in previous treatment groups so that the relaxant responses were not a ected by di erences in active tension.…”

“…Control relaxant responses to ACh were determined in artery rings from all dogs and control responses to sodium nitroprusside (SNP) in artery rings from four ischaemic/ reperfused dogs. In artery segments isolated from ischaemic/ reperfused dogs relaxant responses were also examined in the presence of the following treatments: Concentrations of K + higher than 25 mM inhibit the activity of K + channels (Chen & Suzuki, 1989) and concentrations of 60 ± 80 mM K + have previously been used to investigate the role of EDHF in coronary artery relaxation (Kilpatrick & Cocks, 1994;Drummond & Cocks, 1996). The L-type Ca 2+ channel blocker, nifedipine, was included to prevent contraction in response to the K + -induced hyperpolarization (Kilpatrick & Cocks, 1994); (v) Tetraethylammonium (TEA, 10 73 M, ACh n=5, SNP n=4) to inhibit large conductance calcium activated potassium (BK Ca ) channels; (vi) Glibenclamide (10 76 M, ACh n=4) to inhibit ATP-sensitive potassium (K ATP ) channels; or (vii) TEA (10 73 M) plus L-NOARG (10 74 M, ACh n=5).…”

“…Even though EDHF can cause relaxation, its e ect is transient (Komori & Vanhoutte, 1990) and in some studies it contributes to relaxation only when the NO system is blocked (Kilpatrick & Cocks, 1994;Drummond & Cocks, 1996). This suggests that EDHF may operate as a reserve system when the NO system is impaired which, for example, can occur in artery diseases (Garland et al, 1995).…”