Effect of 45nm silver nanoparticles (AgNPs) upon the smooth muscle of rat trachea: Role of nitric oxide

Background A class Ib antiarrhythmic drug, mexiletine, augments relaxations produced by adenosine triphosphate (ATP) sensitive K+ channel openers in isolated rat aortas, suggesting that it produces changes in the vasodilation mediated by ATP-sensitive K+ channels. Nitric oxide can induce its vasodilator effect via K+ channels, including ATP-sensitive K+ channels, in smooth muscle cells. Effects of mexiletine on arterial relaxations to nitric oxide donors, have not been studied. Therefore, the current study in isolated rat aortas was designed to (1) evaluate whether mexiletine augments relaxation in response to nitric oxide donors, including sodium nitroprusside, and (2) determine the role of K+ channels in mediating effects of mexiletine on such nitric oxide-mediated relaxation. Methods Rings of rat aortas without endothelia were suspended for isometric force recording. Concentration-response curves of sodium nitroprusside (10(-10) to 10(-5) M) and 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7; 10(-9) to 10(-5) M) were obtained in the absence and in the presence of mexiletine, in combination with a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo [4,3,-a]quinoxaline-1-one (ODQ), or inhibitors for ATP-sensitive K+ channels (glibenclamide), inward rectifier K+ channels (BaCl2), delayed rectifier K+ channels (4-aminopyridine), large conductance Ca2+-dependent K+ channels (iberiotoxin), or small conductance Ca2+-dependent K+ channels (apamin). Results Mexiletine (10(-5) or 3 x 10(-5) M) augmented relaxations to sodium nitroprusside and NOC-7. In arteries treated with glibenclamide (10(-5) M), mexiletine (3 x 10(-5) M) did not affect relaxations to nitric oxide donors, whereas mexiletine augmented relaxations to sodium nitroprusside despite the presence of BaCl2 (10(-5) M), 4-aminopyridine (10(-3) M), iberiotoxin (5 x 10(-8) M) and apamin (5 x 10(-8) M). Relaxations to sodium nitroprusside were abolished by ODQ (5 x 10(-6) M), whereas these relaxations were augmented by mexiletine (3 x 10(-5) M) in arteries treated with ODQ (5 x 10(-6) M). Conclusions These results suggest that ATP-sensitive K+ channels in vascular smooth muscle, contribute to the augmented vasodilator effect of a nitric oxide donor, sodium nitroprusside induced by mexiletine, and that the vasodilator effect is produced, at least in part, via the guanylate cyclase-independent mechanism.

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Hyperglycemia increases endothelial superoxide that impairs smooth muscle cell Na+-K+-ATPase activity

AJP Cell Physiology ◽

10.1152/ajpcell.00343.2001 ◽

2002 ◽

Vol 282 (3) ◽

pp. C560-C566 ◽

Cited By ~ 59

Author(s):

Sandeep Gupta ◽

Eugene Chough ◽

Jennifer Daley ◽

Peter Oates ◽

Keith Tornheim ◽

...

Keyword(s):

Nitric Oxide ◽

Superoxide Dismutase ◽

Smooth Muscle ◽

Steady State ◽

Atpase Activity ◽

Rabbit Aorta ◽

Enhanced Chemiluminescence ◽

Arterial Tissue ◽

Reciprocal Change

Nitric oxide (NO) plays an important role in the control of numerous vascular functions including basal Na+-K+-ATPase activity in arterial tissue. Hyperglycemia inhibits Na+-K+-ATPase activity in rabbit aorta, in part, through diminished bioactivity of NO. The precise mechanism(s) for such observations, however, are not yet clear. The purpose of this study was to examine the role of superoxide in modulating NO-mediated control of Na+-K+-ATPase in response to hyperglycemia. Rabbit aorta incubated with hyperglycemic glucose concentrations (44 mM) demonstrated a 50% reduction in Na+-K+-ATPase activity that was abrogated by superoxide dismutase. Hyperglycemia also produced a 50% increase in steady-state vascular superoxide measured by lucigenin-enhanced chemiluminescence that was closely associated with reduced Na+-K+-ATPase activity. Specifically, the hyperglycemia-induced increase in vascular superoxide was endothelium dependent, inhibited by l-arginine, and stimulated by N ω-nitro-l-arginine. Aldose reductase inhibition with zopolrestat also inhibited the hyperglycemia-induced increase in vascular superoxide. In each manipulation of vascular superoxide, a reciprocal change in Na+-K+-ATPase activity was observed. Finally, a commercially available preparation of Na+-K+-ATPase was inhibited by pyrogallol, a superoxide generator. These data suggest that hyperglycemia induces an increase in endothelial superoxide that inhibits the stimulatory effect of NO on vascular Na+-K+-ATPase activity.

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