Cardiovascular Research 34 1997.

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Review

Sulfonylurea derivatives in cardiovascular research and in cardiovascular patients

Carl E. Schotborgh a , Arthur A.M. Wilde
a

a,b, )

Department of Clinical and Experimental Cardiology, Academic Medical Center, Uniersity of Amsterdam, PO BOX 22700, 1100 DE Amsterdam, Netherlands b The Heart-Lung Institute, Uniersity of Utrecht, Utrecht, Netherlands Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on January 14, 2014 Received 28 October 1996; accepted 14 January 1997

Abstract Sulfonylurea derivatives are hypoglycemic drugs frequently used in the treatment of non-insulin-dependent diabetes mellitus NIDDM.. In the b-cell sulfonylureas act by blocking ATP-sensitive potassium channels K.ATP channels.. In several organ systems, including the cardiovascular system, sulfonylurea receptors and functional K.ATP channels have been identified. In the heart their role is not clear; an endogenous cardioprotective effect has been suggested. There is no doubt that K.ATP channels are effectively blocked by sulfonylureas. In the last decade sulfonylureas have been widely used as a pharmacological tool in experimental cardiac. research. Blockade of K.ATP channels is the proposed cellular mechanism of action for all sulfonylurea-related effects. However, other membrane currents are affected as well. In addition, myocardial metabolism is modified by sulfonylurea pretreatment. Hence, it should seriously be questioned whether these drugs are suitable in assessing involvement of cardiac K.ATP channels in, for example, ischemia-related events. The detrimental effects of sulfonylureas in experimental studies on myocardial ischemia have led to speculation whether the widespread use of these drugs in patients with NIDDM, most often suffering from accompanying ischemic heart disease, should be reconsidered. However, a review of the clinical literature reveals that the most consistent finding is a lower incidence of ventricular arrhythmias associated with the use of glibenclamide, while no excess mortality has been shown for this agent in NIDDM with ischemic heart disease. Despite some direct effects on systemic and coronary vasculature, there are, at present, no firm clinical data on the basis of which sulfonylurea derivatives should be withheld from the cardiac patient.
Keywords: Sulfonylureas; Diabetes; Potassium channel, ATP-sensitive; Arrhythmias; Myocardial infarction; Myocardial ischemia

1. Introduction Sulfonylurea derivatives are hypoglycemic drugs frequently used in the treatment of non-insulin-dependent diabetes mellitus NIDDM.. The mode of action of sulfonylureas on the b-cell has been elucidated and involves blockade of the ATP-sensitive potassium channels K.ATP channels.. The b-cell sulfonylurea receptor has been purified and cloned w1x. In itself the sulfonylurea receptor named SUR1. does not possess ion-conducting properties, but together with an inwardly rectifying Kq channel called Kir 6.2. it forms Kq channels with characteristics closely resembling functional pancreatic K.ATP channels w2x. Sul-

fonylurea receptors and functional K.ATP channels have been identified in several organ systems and their role and function in physiological and pathophysiological states has been described in many of them. In mitochondrial membranes of various tissues, including myocardium, K.ATP channels are also expressed w35x. On the molecular level a second type of sarcolemmal. sulfonylurea receptor, designated SUR2, has been identified, with the highest expression levels in cardiac and skeletal muscle w6,7x. A further subdivision has been described with the demonstration of a SUR2 subtype, designated SUR2A, exclusively expressed in heart and skeletal muscle and SUR2B, ubiquitously expressed in these and other extrapancreatic tissues

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w7,8x. In situ hybridization of the latter subtype shows specific staining in the vascular structures of these tissues and for example in the muscularis layer of intestine w7x. In analogy with SUR1, co-expression of SUR2A and SUR2B with Kir 6.2 reconstitutes functional K.ATP channels of respectively the cardiac and skeletal type w6x and the smooth muscle type w8x. In general, K.ATP channels couple the metabolic state of the cell to its electrical activity. Thus, in the b-cell a regulatory role in determining insulin secretion has been established. In systemic and coronary vasculature, K.ATP channels are involved in the regulation of vascular tone w9x. In neurons, K.ATP channels can modify neurotransmitter release. However, in myocardial tissue the role is not clear; an endogenous protective role has been suggested. K.ATP channels are effectively blocked by sulfonylureas. This property has prompted many basic scientists to use representatives of this group, most often glibenclamide, as a pharmacological tool in experimental research. Blockade of K.ATP channels is the proposed cellular mechanism of action for all sulfonylurea-related effects. Other effects of sulfonylurea derivatives have been described as well but are seldom considered to play a role. This review aims, in the first place, to address whether all sulfonylurea effects are indeed to be explained by blockade of K.ATP channels. Opening of myocardial K.ATP channels is cardioprotective, as is expressed in different functional and metabolic variables w10x. Sulfonylureas consistently counteract the beneficial effects of K.ATP channel openers see Ref. w10x for review.. In the absence of openers of K.ATP channels sulfonylureas may even exert deleterious effects on ischemic hearts: for example, in terms of reduced time before ischemic contracture develops w11,12x, increased infarct size w13x, more stunning w11,14x, or prevention of preconditioning w15x. However, ischemia-related arrhythmias might be prevented by sulfonylurea pretreatment w16x. The deleterious effects of sulfonylureas have led to speculation whether the widespread use of these drugs in patients with NIDDM, most often suffering from accompanying ischemic heart disease as well, should be reconsidered w1517x. In addition to the critical assessment of their mechanism of action, relevant clinical data with respect to these postulated deleterious effects will be discussed.

2. Effects on membrane currents There can be no doubt that sulfonylurea derivatives effectively block myocardial K.ATP channels. The most widely used representative glibenclamide glyburide. is one of the most potent sulfonylureas w18x. Clinically, in patients on glibenclamide a wide concentration range is encountered 01.5 m Mrl; mean 0.5 m Mrl. w19x. In vitro experiments on isolated guinea-pig and rat ventricular

myocytes revealed that the efficacy of glibenclamide-induced inhibition of myocardial K.ATP channels is, compared to pancreatic b-cells, relatively low with a half-maximal inhibition concentration IC 50 . in the order of 510 m M w20,21x. Although lower values for cardiac K.ATP channels have been reported as well w22x, the affinity for pancreatic K.ATP channels is presumably 3 orders of magnitude higher w15,18,23,24x. In line with these findings are the functional characteristics, including a higher affinity for glibenclamide in the same order of magnitude of SUR1 as of SUR2 w6x. Of particular relevance to the question whether myocardial K.ATP channel block is involved in the sulfonylurea-related deleterious effects is the observation that its efficacy to block the channel is increased by a reduction in pH w25x and is reduced after prolonged metabolic stress w20,26x. K.ATP channels are not the only cardiac ionic channels inhibited by sulfonylureas. Recently, glibenclamide has been demonstrated to block the cAMP-activated chloride conductance ICl, cAMP . w27x. The Hill coefficient for the effect on ICl, cAMP and on K.ATP channels is roughly similar, but the effective concentration range is considerably higher half-maximal inhibition of ICl, cAMP "30 m M w27x compared to 510 m M for half-maximal inhibition of K.ATP channels. see above.. Glibenclamide also blocks the cystic fibrosis transmembrane conductance regulator, another chloride channel, expressed in the heart with unknown function. The blocking action was irreversible with half-maximal inhibition in a concentration range comparable to affect ICl, cAMP w28x. It is not known whether factors pertinent to ischemia modify the glibenclamide sensitivity of these currents. In non-cardiac tissue effects on other ion channelsrcurrents have been described. Whereas in pancreatic b-cells sulfonylureas seem to be rather specific, with no effects at relevant dosages on other Kq channels w29x, glibenclamide has been shown to inhibit a voltage-gated, Ca2q- and ATP-independent Kq current in the human neuroblastoma cell line SH-SY5Y cells expressing several properties of noradrenergic neurons. w30x. In vascular smooth muscle cells glibenclamide 10 m M. has been shown to modulate the L-type Ca2q channel current both an increase and a decrease have been described, depending on the presence of the agonist BAY k-8644. w31x and to abolish, at the single channel level, the potassium channel opener-induced increase in the Ca2q-activated Kq channel w32x. In contrast, in isolated smooth muscle cells from rabbit portal vein glibenclamide did not affect the Ca2q-activated Kq channel w33x. In the same preparation glibenclamide inhibited the potassium channel opener-induced block of the oscillatory outward current w33x. This current is believed to be elicited by Ca2q release from an intracellular store. The modulating effects of both the potassium channel opener pinacidil and glibenclamide suggest an effect on the kinetics of calcium release from these stores, which putatively represent the sarcoplasmic reticulum SR.. A similar con-

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clusion has been reached by Chopra et al. who described a direct action of K.ATP channel modulators including glibenclamide in concentrations ) 1 m M. on intracellular calcium stores in cultured airway smooth muscle of the rabbit w34x. Indeed, in skeletal muscle Ca2q transport across the SR membrane is influenced by the state of Kq channels in the SR membrane w35x. K.ATP channels may be involved in this process.

3. Effects on myocardial energy metabolism Sulfonylureas affect myocardial energy metabolism. In aerobic rat hearts tolbutamide in clinically relevant dosages. markedly stimulated glycogenolysis, glucose uptake and utilization and at the same time decreased fatty acid metabolism w36,37x. The latter effect is due to direct inhibition of mitochondrial carnitine palmitoyltransferase, which is the key regulatory enzyme in fatty acid oxidation w38x. Alternatively, it may be speculated that blockade of mitochondrial K.ATP channels, with, compared to the sarcolemmal K.ATP channel, roughly similar affinity for sulfonylureas w4x, is involved. As a result of stimulation of anaerobic glycolysis lactate production is increased, prior to any metabolic challenge w39,40x, and within 30 min glycogen levels may decrease by 30% w36,37x. Due to these effects the contribution of glucose metabolism to ATP synthesis is greatly enhanced by tolbutamide w36,37x. These effects, which are independent of insulin, are even more pronounced in diabetic hearts w37x. Observations that lactate production is inhibited during myocardial hypoxia w20x and myocardial ischemia w41x may reflect the reduced glycogen content prior to the experimental event.

4. Impact on sulfonylurea action during metabolic inhibition Glibenclamide-sensitive effects during metabolic inhibition include hypoxia- and ischemia-related action potential shortening, a rise in the extracellular potassium concentration wKqx o ., a decrease in incidence of arrhythmias and the occurrence of preconditioning. The question now to address is whether it is possible that the sulfonylurea-induced effects on membrane currents other than the K.ATP channel or on myocardial glucose and free fatty acid metabolism are of any relevance to these effects. It may be argued that the relatively high concentrations needed to affect other currents preclude any non-K.ATP channel mediated effect. However, as mentioned before, with regard to the blocking efficacy of glibenclamide, it has been shown that intracellular pH sensitizes the channel to

glibenclamide w25x. Similar effects might be present for any other sulfonylurea-mediated effect. Particularly the shortening of the action potential and the increased Kq efflux are widely believed to result from hypoxiarischemia-induced activation of K.ATP channels. This belief is almost exclusively based on the sulfonylurea sensitivity of these phenomena see Refs. w16x and w42x.. However, for example, with regard to the hypoxia-induced action potential shortening a variety of other currents might be involved, including ICl, cAMP as has been suggested previously w43x. Indeed, modulation of the extracellular chloride concentration and addition of chloride channel blockers which are devoid of any effect on the K.ATP channel current. attenuate the early hypoxia-induced shortening of the action potential w44x. Hence, potentially the glibenclamide-induced blockade of ICl, cAMP may be involved in the attenuation of the hypoxia-related action potential shortening. The observation that the forskolin-induced shortening of the action potential is reversed by glibenclamide w27x corroborates this suggestion. The 36fold difference in effective blocking concentration would preclude glibenclamide-induced block of ICl, cAMP being involved, but these values have been obtained in normoxic conditions. Although in later stages of metabolic deprivation the glibenclamide K.ATP channel block becomes less efficient w20,26x, no information is available on the blocking efficacy of other currents in similar conditions. We have previously noted that the observed time-delay for the channel to open in response to hypoxia w45x, ischemia w46x or metabolic inhibition w47x is indeed difficult to reconcile with involvement of K.ATP channels in early action potential shortening w42x. In addition to theoretical considerations precluding a causative role for any Kq channel in determining increased Kq efflux, the latter arguments also hold for a potential role of K.ATP channels in explaining increased Kq efflux w42x. Further, the observation that glibenclamide might prevent hypoxia-induced Kq efflux by "50%, which occurred in the absence of any change in action potential duration, also suggests that the sulfonylurea effect on Kq efflux is not related to K.ATP channels w48x. Pivotal to an alternative explanation for the sulfonylurea-induced effects on Kq accumulation might be the reduced levels of glycogen after pretreatment with sulfonylurea derivatives see above.. Such an effect will reduce glycolytic activity during the subsequent ischemic episode. This may result in less lactate production and in less intracellular acidification. Attenuation of intracellular acidification has been shown to be associated with less Kq accumulation w49x. Indeed, ischemia-induced w41x and hypoxia-induced lactate efflux w20x has been reported to be attenuated after glibenclamide pretreatment and we have observed an inverse linear relationship between the pre-ischemic lactate production by glibenclamide and the effect on extracellular potassium wWilde et al., unpublished observationsx. In addition, 3 P-nuclear magnetic resonance spectroscopy during

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global ischemia in glycogen-depleted hearts by other means, including which preconditioning. revealed less intracellular acidification than in control hearts w50,51x. Extracellular acidification is not affected by glibenclamide in a variety of species where it does attenuate the ischemiainduced early rise in extracellular potassium w40x, but this might well be a too crude measure for anaerobic. glycolytic activity. Lactate has been shown to reduce action potential duration w52x, which in itself may involve K.ATP channel activation w53x. Hence, the sulfonylurea-induced decrease in lactate efflux may serve as an alternative explanation for the related attenuation of action potential shortening. The favorable effects of sulfonylureas on the arrhythmias during acute ischemia may relate to attenuation of the action potential shortening and the attenuation of the rise in wKqx o . Particularly slowing of conduction, which is closely related to wKqx o , is considered to play a key role in arrhythmogenesis in early ischemia. With regard to preconditioning, two sulfonylurea-induced effects can be regarded as seriously confounding factors in explaining the modulatory effects of preconditioning: 1. the effects on metabolism discussed above and 2. the possible modulation of adenosine release, which seems to be a critical mediator of preconditioning. In general, preconditioning, which also leads to reduced glycogen content prior to the index ischemic period, is abolished by sulfonylureas see Ref. w10x.. Pre-ischemic reduction in glycogen content protects the heart from subsequent prolonged ischemia, in terms of myocardial injury i.e., preconditioning. w54x. However, the concomitant sulfonylurea-induced prolonged action potential during ischemia may outweigh this effect and therefore not lead to attenuation of ischemic damage. Finally, glibenclamide has been shown to influence adenosine release. Experimental results are controversial; ischemia-related adenosine release in rabbits was not influenced by glibenclamide w55x, but in rats the 5X-nucleotidase-mediated adenosine release was reduced by glibenclamide in a concentration-dependent manner; EC 50 10 m M. w56x. Because the adenosine release during ischemia invoked in the occurrence of preconditioning is mediated by the enzyme 5X-nucleotidase w57x, any sulfonylurea effect on this pathway will have an impact on preconditioning. In summary, in addition to blocking K.ATP channels there are many other effects of sulphonylureas. Since these effects might have impact on, probably all, ischemia-related events, the suitability of these drugs for assessment of involvement of cardiac K.ATP channels has been seriously questioned. Careful selection of the concentration might provide useful information. However, in the absence of relevant data on, for example, the blocking efficacy of glibenclamide on other currents in pathophysiological conditions, the statement that sulfonylureas cannot be used at all to serve this purpose might even be correct. Likewise, the use of glibenclamide to prove involvement of K.ATP

channels in vascular smooth muscle has been questioned w58x.

5. NIDDM, sulfonylurea derivatives and cardiac disease NIDDM patients are at increased risk of cardiovascular morbidity and mortality w59,60x. In these patients sulfonylureas have always been the cornerstone of oral therapy w61x, despite the early report of the University Group Diabetes Program which suggested an association between tolbutamide therapy and an increased risk of cardiovascular mortality w62x. However, shortly after its appearance this report became extensively criticized for methodological and statistical reasons w6365x. The results of 7 other epidemiological studies performed in the 1970s were contradictory and not conclusive either w66x. Later Rytter et al. retrospectively compared patients with IDDM to those with NIDDM with respect to the prevalence and mortality of acute myocardial infarction w60x. They found a significantly higher mortality rate from acute myocardial infarction in NIDDM patients treated with oral hypoglycemic agents than in NIDDM patients treated with insulin 50 vs 9.1%; distribution of hypoglycemic agents not specified.. This difference could not be explained by better in-hospital metabolic control in the insulin-treated patients. However, the pre-hospital metabolic state, a determinant of outcome in this study, was not reported for the two groups w60x. In another analysis of diabetic patients presenting with myocardial infarction, sulfonylurea treatment did not influence hospital outcome in terms of morbidity pump failure. and mortality w67x. In this study prior metabolic control, assessed by glycosylated glucose, did not predict outcome either. Finally, Ulvenstam et al. reported on the long-term follow-up of diabetic men who survived a first myocardial infarction w68x. Only a trend towards a higher mortality among patients treated with sulfonylureas compared to those on insulin IDDM an NIDDM. was found w68x. The interpretation of the results concerning the subgroups mentioned above is hampered by the small number of patients and the lack of sufficient data on clinical variables, such as metabolic control, infarction size and concomitant treatment. The discovery of the mode of action of sulfonylureas blockade of pancreatic B-cell K.ATP channel. and of the presence of K.ATP channels in the heart and vascular tissue eventually gave rise to new discussions on the clinical implications of the use of these agents in cardiovascular patients w1517x. These discussions were largely based on experimental data showing significant interaction of sulfonylureas with the cardiovascular system. Most of these, predominantly negative, data have been reviewed by Smits and Thien w17x and by Leibowitz and Cerasi w15x and will not be repeated here. We will focus on studies evaluating the direct. cardiovascular effects of sulfonylureas in man. In reviewing these data the principle interest is not

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whether the sulfonylurea-related effects are mediated by K.ATP channel block or not. As argued by Smits and Thien w17x, plasma sulfonylurea concentrations in man on chronic treatment may well be sufficient to block vascular and cardiac K.ATP channels.

clamide induced an increase of the relative changes in systemic vascular resistance index also after 4 weeks of treatment whereas metformin, a biguanide, unrelated to sulfonylureas, had no effect w75x. 6.2. Myocardial ischemia and preconditioning

6. Direct cardiovascular effects of sulphonylureas in man 6.1. Vascular tone Whereas in different experimental models sulfonylureas have been shown to interfere with coronary vascular smooth muscle relaxation, there are no such data in man. In a study by Nahser el al. w69x, evaluating maximal coronary flow reserve and metabolic coronary vasodilation in diabetic and non-diabetic patients, no difference was found between diabetic patients on insulin treatment and those on sulfonylurea derivatives. This study, however, was not designed to investigate the effects of these agents on coronary flow characteristics. Furthermore, on the day of the experiment oral hypoglycemic agents were withheld, probably resulting in serum levels too low to elicit any effect. More data are available on the peripheral vascular effects of sulfonylureas in man. The acute effects of glibenclamide on baseline flow and hyperemic response to arterial occlusion in the human calf were studied recently w70x. After oral ingestion of 7.5 mg glibenclamide there was a significant decline in baseline flow 30 and 42% of control value after 1 and 2 h. and in peak reactive flow 22, 30 and 28% of control value after 1, 2 and 3 h., and an increase in the duration of the hyperemic response after 2 and 3 h. Total reactive hyperemic volume was not significantly influenced by glibenclamide. Placebo did not cause significant changes in any of these parameters w70x. In another study it was demonstrated that the vasodilator effect of diazoxide was significantly reduced by concomitant infusion of glibenclamide w71x. An important finding in these two studies is the fact that glibenclamide is able to elicit measurable vascular effects at therapeutic serum levels 250 ngrml s 0.5 m M. w19,72x. Taking into account the high degree of binding to serum albumin ) 99%. w73x, the serum levels of free glibenclamide in these studies were lower than the threshold value for inhibition of the effect of potassium channel openers on vascular activity 25 ngrml s 0.05 m M. in the experimental model w74x. These findings w70,71x might have clinical implications for NIDDM patients with coronary disease treated with sulfonylureas. However, it should be emphasized that these studies dealt with healthy volunteers and that there might be different sensitivities for glibenclamide in coronary and peripheral smooth muscle K-ATP channel receptors. In addition, by design only the acute effects of the drugs were investigated, but it has been demonstrated that gliben-

Although the effect of sulfonylureas at therapeutic levels on the human coronary vasculature remains to be determined, some evidence that human myocardium is sensitive to such levels of glibenclamide already exists. The oral administration of 10 mg glibenclamide, prior to the procedure, abolished the attenuation of ST-segment shift at a second balloon inflation during coronary angioplasty w76x. Inhibition of collateral circulation recruitment by glibenclamide as a possible explanation for this finding was very unlikely based on angiographic assessment., suggesting a direct myocardial effect of glibenclamide on ischemic preconditioning. Also in an in vitro model using right atrial trabeculae glibenclamide prevented ischemic preconditioning w77x. Since preconditioning is thought to protect the myocardium against subsequent ischemic events, resulting in less extensive myocardial infarction and better clinical outcome w78,79x, the use of glibenclamide might have deleterious effects in patients with repetitive myocardial ischemia treated with this agent. 6.3. Arrhythmias In various experimental models of acute ischemia pretreatment with sulfonylureas proved antiarrhythmic during myocardial ischemia w16x. Clinical data seem to corroborate these results. In a randomized crossover study in NIDDM glibenclamide versus metformin., glibenclamide significantly reduced the incidence of ventricular premature complexes and ventricular tachycardia during spontaneous. transient myocardial ischemia w80x. Glibenclamide did not alter the ischemic burden nor did it interfere with non-ischemia-related arrhythmias w80x. In a study on NIDDM patients suffering from acute myocardial infarction, ventricular fibrillation VF. occurred significantly less frequently in the glibenclamide-treated group than in NIDDM patients treated otherwise and than in non-diabetics 1.7 vs 7.9 and 9.9%, respectively. w81x. Although demographic, clinical and treatment parameters were comparable in the three groups, there was a much higher mortality rate in the non-glibenclamide treated diabetic patients, which was related to the higher incidence of heart failure in this group w81x. This finding suggests the presence of an unknown confounder, prompting cautious interpretation of the data from this study. On the other hand, recently presented data from a large retrospective study on patients with acute myocardial infarction, similarly showed that the rate of VF in patients on glibenclamide was lower than that for diabetics on gliclazide or insulin w82x. In this study, in contrast to the former study w81x, VF rate was the same as that of non-diabetics w82x.

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C.E. Schotborgh, A.A.M. Wilde r Cardioascular Research 34 (1997) 7380 w3x Inoue I, Nagase H, Kishi K, Higuti T. ATP-sensitive Kq channel in the mitochondrial inner membrane. Nature 1991;352:244247. w4x Paucek P, Miranova G, Mahdi F, Beavis AD, Woldegiorgis G, Garlid KD. Reconstitution and partial purification of the glibenclamide-sensitive, ATP-dependent Kq channel from rat liver and beef heart mitochondria. J Biol Chem 1992;267:2606226069. w5x Garlid KD, Paucek P, Yarov-Yarovoy V, Sun X, Schindler PA. The mitochondrial K AT P channel as a receptor for potassium channel openers. J Biol Chem 1996;271:87968799. w6x Inagaki N, Gonoi T, Clement IV JP, et al. A family of sulphonylurea receptors determines the pharmacological properties of ATP-sensitive Kq channels. Neuron 1996;16:10111017. w7x Chutkow WA, Simon C, Le Beau M, Burant CF. Cloning, tissue expression, and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular KATP channels. Diabetes 1996;45:14391445. w8x Isomoto S, Kondo C, Yamada M, et al. A novel sulphonylurea receptor form with BIR Kir 6.2. a smooth muscle type ATP-sensitive Kq channel. J Biol Chem 1996;271:2432124324. w9x Quayle JM, Standen NB. K.ATP channels in vascular smooth muscle. Cardiovasc Res 1994;28:797804. w10x Hearse DJ. Activation of ATP-sensitive potassium channels: a novel pharmacological approach to myocardial protection? Cardiovasc Res 1995;30:117. w11x Cole WC, McPherson CD, Sontag D. ATP regulated Kq channels protect the myocardium against ischemiarreperfusion damage. Circ Res 1991;69:571581. w12x Mitani A, Kinoshita K, Fukamachi K, et al. Effects of glibenclamide and nicorandil on cardiac function during ischemia and reperfusion. Am J Physiol 1991;261:H1864H1871. w13x Auchampach JA, Maruyama M, Cavero I, Gross GJ. The new Kq channel opener aprikalim RP 52891. reduces experimental infarct size in dogs in the absence of hemodynamic changes. J Pharmacol Exp Ther 1991;259:961967. w14x Auchampach JA, Maruyama M, Cavero I, Gross GJ. Pharmacological evidence for a role of ATP-dependent potassium channels in myocardial stunning. Circulation 1992;86:311319. w15x Leibowitz G, Cerasi E. Sulphonylurea treatment in NIDDM patients with cardiovascular disease: a mixed blessing. Diabetologica 1996;39:503514. w16x Wilde AAM, Janse MJ. Electrophysiological effects of ATP-sensitive potassium channel modulation: implications for arrhythmogenesis. Cardiovasc Res 1994;28:1624. w17x Smits P, Thien T. Cardiovascular effects of sulphonylurea derivatives. Implications for the treatment of NIDDM. Diabetologica 1995;38:116121. w18x Zunckler BJ, Lenzen S, Manner K, et al. Concentration-dependent effects of tolbutamide, meglitinide, glipizide, glibenclamide, and diazoxide on ATP-regulated Kq currents in pancreatic b-cells. Naunyn-Schmiedebergs Arch Pharmacol 1988;337:225230. w19x Sartor G, Melander A, Schersten E. Serum gliben B, Wahlin-Boll clamide in diabetic patients, and influence of food on the kinetics and effects of glibenclamide. Diabetologia 1980;18:1722. w20x Venkatesh N, Lamp ST, Weiss JN. Sulphonylureas, ATP-sensitive Kq channels, and cellular Kq loss during hypoxia, ischemia, and metabolic inhibition in mammalian ventricle. Circ Res 1991;69:623 637. w21x Ripoll C, Lederer J, Nichols CG. On the mechanism of inhibition of K AT P channels by glibenclamide in rat ventricular myocytes. J Cardiovasc Electrophysiol 1993;438447. w22x Findlay I. Inhibition of ATP-sensitive Kq channels in cardiac muscle by the sulphonylurea drug glibenclamide. J Pharmacol Exp Ther 1992;261:540545. w23x Schmid-Antomarchi H, De Weille J, Fosset M, Lazdunski M. The receptor for antidiabetic sulfonylureas controls the activity of the ATP-modulated Kq channel in insulin-secreting cells. J Biol Chem 1987;262:1584015844.

Studies involving first-generation sulfonylureas in diabetics with an acute myocardial infarction provided variable results. A trend towards a higher incidence of early VF was shown in diabetics on oral treatment mainly sulfonylureas., as compared to those treated with insulin or diet alone 12 vs 3 and 7%, respectively. w83x. In a similar study comparing these three groups no difference in primary VF incidence was observed at all w84x. In both studies time from onset of symptoms to hospital admission, a critical factor when it comes to the incidence of primary VF, was however not reported. 6.4. Other effects Some investigators reported a positive inotropic effect of sulfonylureas w85,86x, whereas others failed to confirm this finding w87,88x. In vitro studies showed evidence for beneficial effects of certain sulfonylurea derivatives on cardiovascular risk factors such as platelet aggregation and fibrinolysis w15,66x. However, the clinical relevance of these effects is unclear.

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7. Summary In summary, the most consistent finding concerning the cardiac effects of sulfonylurea derivatives in NIDDM with ischemic heart disease is the lower incidence of ventricular arrhythmia associated with the use of glibenclamide, while no excess mortality has been shown for this agent. The effect of blockade of myocardial preconditioning by this agent has still to be evaluated with respect to clinical end-points. It should be noted that in the older studies an excess of cardiovascular mortality in diabetics using sulfonylureas was an inconsistent finding and that in those studies virtually only first-generation agents were used. Furthermore, the findings of those studies might not be applicable to current clinical practice. Based on the direct effects described above there are, at present, no firm clinical data on the basis of which sulfonylurea derivatives should be withheld from the cardiac patient.

Acknowledgements Dr. A.A.M. Wilde is a clinical investigator for the Dutch Heart Foundation NHS grant D95r014..

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