Effects of pinacidil on guinea‐pig isolated perfused heart with particular reference to the proarrhythmic effect

Padrini, Roberto; Bova, Sergio; Cargnelli, Gabriella; Piovan, Donatella; Ferrari, Mariano

doi:10.1111/j.1476-5381.1992.tb09044.x

Cited by 32 publications

(26 citation statements)

References 29 publications

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“…The finding of the current study showed that pinacidil induced VF in about 20% of the anesthetized rabbits. This is consistent with previous studies in which the use of ATP sensitive "openers" of potassium channel (I K-ATP ) has been shown to be associated with VF (Chi et al, 1990;Lu et al, 2008;Padrini et al, 1992). It is known that I K-ATP openers shorten action potential duration so that the effective refractory period is abbreviated (Milberg et al, 2007).…”

Section: Discussionsupporting

confidence: 80%

Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes

et al. 2017

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-The current regulatory guidelines recommend the use of QT interval to assess the risk of arrhythmogenic potential of new chemical entities. Recently, the electromechanical window (EMW), the difference in duration between electrical and mechanical systole, has been proposed as markers for druginduced torsades de pointes (TdP); however, data of EMW in short QT model are not available. This study aimed to characterize the EMW as a marker for drug-induced ventricular arrhythmias in anesthetized rabbit model of long QT syndrome type 2 (LQT2) and short QT syndrome (SQTS) infused with reference compounds known to lengthen or shorten QT intervals. After rabbits were anesthetized with isoflurane, body surface electrocardiograms and left ventricular pressure were recorded. The LQT2 was produced by intravenous infusion with dofetilide (n = 6), quinidine (n = 6) and sotalol (n = 6) whereas the SQTS was induced by intravenous escalating concentrations of nicorandil (n = 7), pinacidil (n = 5) and cromakalim (n = 5). The EMW in anesthetized rabbits ranged from 1.3 to 53.3 msec. All three drugs known to lengthen QT intervals prolonged QT and QTcF interval while the EMW was markedly decreased to negative values. Pinacidil significantly produced QT and QTcF shortening and significantly abbreviated the EMW (p < 0.05). This study demonstrated that the EMW is associated with QT intervals (p < 0.001). It is negative in the presence of QT-prolonging drugs while it is more positive in the presence of QT-shortening drugs. The results suggest that the EMW in anesthetized rabbits can be used in drug safety evaluation in addition to the QT interval.

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Section: Discussionsupporting

confidence: 80%

Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes

et al. 2017

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“…Since Kir6.2 serves as the pore-forming subunit in many other tissues including heart, brain and smooth muscle, mutations that lead to reduced ATPsensitivity and increased K ATP channel activity can be expected to have extra-pancreatic actions. These could have adverse effects, as exemplified by the high incidence of ventricular fibrillation observed when guinea-pig hearts are treated with the K + channel opener pinacidil [135].…”

Section: Diseases Of K Atp Channel Regulationmentioning

confidence: 99%

ATP-sensitive K + channels and insulin secretion: their role in health and disease

Ashcroft

Gribble²

1999

Diabetologia

410

279

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IntroductionSulphonylureas have been used for over 50 years to enhance insulin secretion in patients with Type II (non-insulin-dependent) diabetes mellitus but their therapeutic target was not discovered until 1985 and we are only just beginning to address their molecular mechanism of action. The sulphonylurea drugs were discovered serendipitously by Marcel Janbon in 1942, when he observed a high incidence of hypoglycaemic symptoms in typhoid patients treated with the bacteriostatic agent p-aminobenzenesulphamidoisopropylthiodiazole (2254RP) [1]. This observation was extended by Auguste Loubatires, who showed that 2254RP induced hypoglycaemia in dogs by stimulating insulin secretion [2]. Subsequently, it was discovered that another sulphonamide drug being tested for bacteriostatic effects, carbutamide, also caused hypoglycaemia in man [3]. Clinical studies followed and led to the development of tolbutamide for the treatment of Type II diabetes. The full story of these pioneering experiments has been vividly recounted in an earlier review by Henquin [4]. Numerous sulphonylureas and related compounds have now been synthesized, with different potencies and time-courses of action and many millions of Type II diabetic patients are now routinely treated with these drugs.The first clues to the mechanism of action of sulphonylureas on insulin secretion came with the discovery that these drugs depolarize the pancreatic beta cell and stimulate electrical activity [5] and the finding that this depolarization was due to a decrease in the potassium permeability of the beta-cell membrane [6]. Patch-clamp studies subsequently showed that sulphonylureas interact specifically with the ATP-sensitive potassium (K ATP ) channel in the betacell membrane and bring about its closure [7]. The activity of the K ATP channel sets the resting membrane potential of the unstimulated beta cell and its closure decreases the membrane K + permeability, producing membrane depolarization and insulin secretion [8]. Radioligand binding studies established the presence of both low-affinity and high-affinity sulphonylurea binding sites in the beta-cell membrane [9, 10] and led to considerable speculation about whether the high-affinity sulphonylurea receptor and the K ATP channel were the same or different proteins. The purification and subsequent cloning of a high-affinity sulphonylurea receptor from insulinoma cells [11] resolved this issue by showing that this receptor is an integral component of the K ATP channel [12,13].In this article, we review the role of the K ATP channel in insulin secretion in health and disease. We also summarise current knowledge of how sulphonylureas act on the different types of K ATP channel found in beta cells and in extra-pancreatic tissues, and discuss the implications of these findings for the use of sulphonylureas as therapeutic agents to stimulate insulin secretion in humans. Finally, we consider the evidence for additional targets for sulphonylureas, both within the beta cell and in extra-pancreatic tissues.Funct...

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“…The heterogeneous response to pinacidil observed in our experimental series is inconsistent with a greater role for I K-ATP in epicardium versus endocardium, as has been suggested for the feline heart. 19 Although previous studies have shown that pinacidil facilitates the induction of VF under both normoxic conditions and conditions of ischemia/reperfusion, 20,21 relatively little information regarding the mechanism of its arrhythmogenesis has been provided. Abbreviation of the effective refractory period by I K-ATP openers has been shown to increase ventricular vulnerability to reentry and to accelerate its rate in a model of VF in superfused canine right ventricular epicardial slices.…”

Section: Circulation December 14 2004mentioning

confidence: 99%

Amplified Transmural Dispersion of Repolarization as the Basis for Arrhythmogenesis in a Canine Ventricular-Wedge Model of Short-QT Syndrome

2004

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Background-The short-QT syndrome is a new clinical entity characterized by corrected QT intervals Ͻ300 ms and a high incidence of ventricular tachycardia (VT) and fibrillation (VF). Gain-of-function mutations in the gene for outward potassium currents have been shown to underlie the congenital syndrome. The present study examined the cellular basis of VT/VF in an experimental model associated with short QT intervals created with a potassium channel activator. Methods and Results-Transmembrane action potentials from epicardial and M regions, 4 transmural unipolar electrograms, and a pseudo-ECG were simultaneously recorded in canine arterially perfused left ventricular wedge preparations. At a basic cycle length of 2000 ms, pinacidil (2 to 3 mol/L) abbreviated the QT interval from 303.7Ϯ5.4 to 247.3Ϯ6.9 ms (meanϮSEM, PϽ0.0001). The maximal transmural dispersion of repolarization (TDR max ) increased from 27.0Ϯ3.8 to 64.9Ϯ9.2 ms (PϽ0.01), and an S2 applied to the endocardium induced a polymorphic VT (pVT) in 9 of 12 wedge preparations (PϽ0.01). Addition of isoproterenol (100 nmol/L, nϭ5) led to greater abbreviation of the QT interval, a further increase in TDR max (from 55.4Ϯ13.7 to 69.7Ϯ8.3 ms), and more enduring pVT. TDR max was correlated significantly with the T peak -T end interval under all conditions. The effects of pinacidil were completely reversed by glybenclamide (10 mol/L, nϭ4) and partially reversed by E4031 (5 mol/L, nϭ5), which prevented induction of pVT in 3 of 5 preparations. Conclusions-Our

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Effects of pinacidil on guinea‐pig isolated perfused heart with particular reference to the proarrhythmic effect

Cited by 32 publications

References 29 publications

Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes

Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes

ATP-sensitive K + channels and insulin secretion: their role in health and disease

Amplified Transmural Dispersion of Repolarization as the Basis for Arrhythmogenesis in a Canine Ventricular-Wedge Model of Short-QT Syndrome

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