Blockade of vascular ATP-sensitive potassium channels reduces the vasodilator response to ischaemia in humans

Abstract

In 1983, Noma [1] was the first to describe that an outward potassium current increased significantly when guinea pig or rabbit cardiac muscle cells were subjected to hypoxia. This current was caused by the activation of potassium channels, which was independent of the intracellular Ca 2+ concentration, but dependent on the intracellular concentration of adenosine-5 ′-triphosphate ([ATP] i ). These so-called ATPsensitive potassium (K ATP ) channels were suggested to play a cardioprotective role during ischaemia. Later, K ATP channels were also found in skeletal muscle [2], smooth muscle [3] and pancreatic beta cells [4] from animals. In pancreatic beta cells the K ATP channels mediate insulin secretion [5] and are a target for sulphonylurea derivatives in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) [6]. Sulphonylurea derivatives are highly specific in blocking pancreatic and cardiovascular K ATP channels, and Diabetologia (1996Diabetologia ( ) 39: 1562Diabetologia ( -1568 Blockade of vascular ATP-sensitive potassium channels reduces the vasodilator response to ischaemia in humans Summary Experimental data show that ATP-sensitive potassium (K ATP ) channels not only occur in pancreatic beta cells, but also in the cardiovascular system, where they mediate important cardioprotective mechanisms. Sulphonylurea derivatives can block the cardiovascular K ATP channels and may therefore interfere with these cardioprotective mechanisms. Therefore, it is of clinical importance to investigate whether sulphonylurea derivatives interact with vascular K ATP channels in humans. Using venous-occlusion strain-gauge plethysmography, we investigated whether ischaemia-induced reactive hyperaemia is reduced by the sulphonylurea derivative glibenclamide in 12 healthy male non-smoking volunteers. Forearm vasodilator responses to three periods of arterial occlusion (2, 5 and 13 min) during concomitant infusion of placebo into the brachial artery were compared with responses during concomitant intra-arterial infusion of glibenclamide (0.33A control study (n = 6) showed that time itself did not change the vasodilator response to ischaemia.Glibenclamide significantly increased minimal vascular resistance (from 2.1 ± 0.1 to 2.3 ± 0.2 arbitrary units, Student's t-test: p = 0.01), and reduced mean forearm blood flow (from 37.5 ± 2.0 to 35.4 ± 2.0 ml ⋅ min -1 ⋅ dl -1 after 13 min occlusion, ANOVA with repeated measures: p = 0.006) and flow debt repayment during the first reperfusion minute (ANOVA with repeated measures: p = 0.04). In contrast, total flow debt repayment was not affected. Infusion of glibenclamide into the brachial artery resulted in local concentrations in the clinically relevant range, whereas the systemic concentration remained too low to elicit hypoglycaemic effects. Our results suggest that therapeutic concentrations of glibenclamide induce a slight but significant reduction in the early and peak vasodilation during reactive hyperaemia.

Characteristic Features of in vivo Skin Microvascular Reactivity in CADASIL

“…Previous In vivo skin vasoreactivity in CADASIL C Gobron et al studies have shown that a selective blockade of the metabolic response or of shear stress molecules can alter the amplitude but do not modify the kinetics of the hyperemic response (Bijlstra et al, 1996;Joannides et al, 1995). Modifications of the myogenic response are presumably responsible for the characteristic profile of the hyperemic response observed in CADASIL.…”

KATP Channels and Pancreatic Islet Blood Flow in Anesthetized Rats

“…However, in view of previous findings when applying sulfonylureas, we consider a decrease in islet blood flow to be a logical consequence of administering these substances. Thus, depending on the dose, glibenclamide is known to reduce early and peak vasodilatation following reactive hyperemia in humans (39). Furthermore, glibenclamide (20 mg/kg) to rats increased vascular resistance and caused a systemic vasoconstriction (40).…”

Sulfonylurea Treatment of Type 2 Diabetic Patients Does Not Reduce the Vasodilator Response to Ischemia

“…The fourth possible reason for the discrepancies among previous findings and our results is that previous studies were performed on healthy volunteers with high vascular response to ischemia. Interestingly, the effects of glibenclamide on healthy subjects was slight, although statistically significant (14). The present study involves an elderly population with impaired vascular response to acute ischemia.…”

“…Glimepiride is a new sulfonylurea compound that interacts more selectively with the ␤-cell K ATP channels (12). In agreement with experimental evidence, studies in humans have shown that acute administration of glibenclamide, but not of the pancreasspecific glimepiride, induces potentially harmful cardiovascular effects in both nondiabetic patients with coronary artery disease and healthy volunteers (13)(14)(15)(16)(17).…”

“…Evidence shows that though glibenclamide and other sulfonylureas promote insulin secretion by the blockade of pancreatic K ATP channels, they also neutralize the vascular protective mechanism that is triggered during ischemia (8, 13,14). By contrast, the new-generation sulfonylurea, glimepiride, is more pancreasspecific and does not interfere with vascular K ATP channel activation (12,16).…”