Vascular Pharmacology of ATP-Sensitive K⁺ Channels: Interactions between Glyburide and K⁺ Channel Openers

Abstract

This study in isolated rabbit superior artery (RMA) investigated the interactions between glyburide, a known blocker of vascular ATP-sensitive K⁺ channels (K_atp), and several chemically diverse potassium channel openers (PCOs): minoxidil sulfate (MNXS; 5 µM), pinacidil (1 µM), cromakalim (0.5 µM)and RP-49356 (1 µM;a PCO from Rhône Poulenc). Relaxation time courses for these PCOs were obtained in norepinephrine (NE; 5 µM)-precontracted RMA, and the concentrations of PCOs found to be equipotent to each other in terms of the degree of maximum relaxation (about 80%) and the time course of relaxation (within 15 min) were chosen for further study. This was taken as a functional indicator of a similar degree as well as similar kinetics of K+ channel opening by these PCOs. Pretreatment with glyburide (10-500 nM)produced a dose-dependent inhibition of the PCO relaxation time course. The glyburide IC₅₀S against pinacidil, MNXS and RP-49356 were statistically similar and ranged from 72-79 nM. The glyburide IC50 against cromakalim was a modest 2-fold higher, at 148 nM. In contrast, pretreatment with charybdotoxin (200 nM) produced no significant inhibition of the maximum relaxation produced by these PCOs. Furthermore, glipizide, a sulfonylurea that is 10- to 25-fold less potent than glyburide for insulin secretion, was found to be 20- to 30-fold less potent than glyburide as a vascular K_ATP antagonist. These data suggest a mechanistic model in which these structurally diverse PCOs share a common critical step in the sequence of events leading to the K_ATP opening, and that glyburide interferes with this common critical step to produce a similar type of blockade against all four PCOs. Interaction studies with glyburide and pinacidil demonstrated 15 min to be the optimal pretreatment time for glyburide to produce maximal inhibition. Glyburide also reversed existing pinacidil relaxation regardless of the degree of pre-existing relaxation. These data suggest that glyburide is able to produce its blockade regardless of the state of K⁺ channel activation. Studies on the effect of pH (6.4 vs.7.3) showed that at acidic pH, pinacidil became less effective and the effectiveness of glyburide was significantly enhanced, whereas the actions of D600 remained unchanged. These data suggest the effects of both openers and blockers of the K_ATP are strongly pH dependent.

Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

“…Most fibrates are fairly lipid soluble (Miller and Spence, 1998;Mahley and Bersot, 2006) and thus should reach any potential intracellular cytosolic sites of action rather quickly. However, if like certain other lipophilic agents, fibrates must enter the space between bilayers of cellular membranes and then move laterally to reach delayed sites of action (Meisheri et al, 1993), a delay in their action seems reasonable. A more likely possibility is that, within a matter of hours, gemfibrozil is able to accumulate in arterial tissue up to concentrations that exceed its extracellular level.…”

Inhibitory Effect of High Concentration of Glucose on Relaxations to Activation of ATP-Sensitive K + Channels in Human Omental Artery

“…13,14 However, glibenclamide did not affect the basal tension as well as membrane potential of the omental artery, indicating that ATP-sensitive K ϩ channels may not play a role in the resting tone of visceral circulation in humans. In contrast to this finding, a recent human study has documented that direct administration of glibenclamide to the large coronary artery provokes reduction of resting vessel diameter, suggesting that these channels may modulate resting tone of the large coronary artery in humans.…”

Cardiovascular effects of sulphonylurea derivatives Implications for the treatment of NIDDM?

“…In vascular smooth muscle cells, this has been extensively stud ied by investigating the interaction between sulpho nylurea derivatives and K vn,-channel-opening drugs [19]. Potassium-channel-opening drugs comprise a group of vasodilator substances, including experi mental therapeutics such as cromakalini.…”

“…First, the glibenclamide concentrations as mentioned above concern peak levels, which of course will persist only for short periods after drug administration. Moreover, the con centrations which were shown to be effective in blocking vascular K ATP-channels [19] are not neces sarily high enough to interact with the more impor tant myocardial KAXP-channels. In this respect it has to be emphasized that differences in the pharmacoki netics between the several sulphonylurea derivatives have to be taken into account since agents with a rel atively short half-life are expected to show shorter periods of high plasma levels as compared with agents which have much longer half- In contrast to the aforem entioned observations, several investigators have shown beneficial effects of glibenclamide during myocardial ischaemia as far as the occurrence of ventricular fibrillation is con cerned.…”

“…The clinical implications may be two-jointed: first, sulphonylurea derivatives are thought to worsen the clinical outcome concern ing the recovery of the contractile function and contions as low as 0.01 (.imol/1 (~ 5 ng/ml) were able to recerning the ultimate infarct size in patients with duce the vascular relaxation induced by the KATPchannel-opening drug pinacidil [19]. In patients with N ID D M , treated by glibenclamide, plasma concen-N ID D M suffering from a myocardial infarction.…”