Effects of inhibition of phosphodiesterase 3B in pancreatic islets on insulin secretion: a potential link with some stimulatory pathways.

OBJECTIVE: Elevated intracellular cAMP concentrations potentiate insulin secretion from pancreatic ß cells. Phosphodiesterase 3B (PDE3B) is highly expressed in these cells and plays a role in the regulation of insulin secretion. MATERIALS AND METHODS: In this study, effects of amrinone, an inhibitor of PDE3B on insulin release from isolated pancreatic islets, were determined. RESULTS: Exposure of islets to amrinone for 15, 30 and 90 min markedly increased secretion induced by 6.7 mM glucose. Amrinone enhanced also secretion stimulated by 6.7 mM glucose and DB-cAMP, an activator of PKA. It was also demonstrated that amrinone potentiated insulin secretion induced by 6.7 mM glucose in the combination with PMA (activator of PKC) or acetylcholine. However, the insulin-secretory response to glucose and glibenclamide was unchanged by amrinone. CONCLUSIONS: These results indicate that amrinone is capable of increasing insulin secretion; however, its action is restricted.

The evaluation of drug-induced changes in cardiac inotropy in dogs: Results from a HESI-sponsored consortium.

INTRODUCTION: Drug-induced effects on the cardiovascular system remain a major cause of drug attrition. While hemodynamic (blood pressure (BP) and heart rate (HR)) and electrophysiological methods have been used in testing drug safety for years, animal models for assessing myocardial contractility are used less frequently and their translation to humans has not been established. The goal of these studies was to determine whether assessment of contractility and hemodynamics, when measured across different laboratories using the same protocol, could consistently detect drug-induced changes in the inotropic state of the heart using drugs known to have clinically relevant positive and negative effects on myocardial contractility. METHODS: A 4×4 double Latin square design (n=8) design using Beagle dogs was developed. Drugs were administrated orally. Arterial blood pressure, left ventricular pressure (LVP) and the electrocardiogram were assessed. Each of the six laboratories studied at least 2 drugs (one positive inotrope (pimobendan or amrinone) and one negative inotrope) (itraconazole or atenolol) at 3 doses selected to match clinical exposure data and a vehicle control. Animals were instrumented with an ITS telemetry system, DSI's D70-PCTP system or DSI's Physiotel Digital system. Data acquisition and analysis systems were Ponemah, Notocord or EMKA. RESULTS: Derived parameters included: diastolic, systolic and mean arterial BP, peak systolic LVP, HR, end-diastolic LVP, and LVdP/dtmax as the primary contractility index. Blood samples were drawn to confirm drug exposures predicted from independent pharmacokinetic studies. Across the laboratories, a consistent change in LVdP/dtmax was captured despite some differences in the absolute values of some of the hemodynamic parameters prior to treatment. DISCUSSION: These findings indicate that this experimental model, using the chronically instrumented conscious dog, can accurately and consistently detect changes in cardiac contractility, across multiple sites and instrumentation systems, and that data obtained in this model may also translate to clinical outcomes.

ß2 adrenergic receptor activation governs cardiac repolarization and arrhythmogenesis in a guinea pig model of heart failure.

ß2-AR activation increases the risk of sudden cardiac death (SCD) in heart failure (HF) patients. Non-selective ß-AR blockers have greater benefits on survival than selective ß1-AR blockers in chronic HF patients, indicating that ß2-AR activation contributes to SCD in HF. This study investigated the role of ß2-AR activation on repolarization and ventricular arrhythmia (VA) in the experimental HF model. The guinea pig HF was induced by descending aortic banding. The effective refractoriness period (ERP), corrected QT (QTc) and the incidence of VA were examined using Langendorff and programmed electrical stimulation. Ikr and APD were recorded by the whole cell patch clamp. Selective ß2-AR agonist salbutamol significantly increased the incidence of VA, prolonged QTc and shortened ERP. These effects could be prevented by the selective ß2-AR antagonist, ICI118551. Salbutamol prolonged APD90 and reduced Ikr in guinea pig HF myocytes. The antagonists of cAMP (Rp-cAMP) and PKA (KT5720) attenuated Ikr inhibition and APD prolongation induced by salbutamol. However, the antagonists of Gi protein (PTX) and PDE III (amrinone) showed opposite effects. This study indicates that ß2-AR activation increases the incidence of VA in the experimental HF model via activation of Gs/cAMP/PKA and/or inhibition of Gi/PDE pathways.

Inhibition of phosphodiesterase 3B in insulin-secreting cells of normal and streptozocin-nicotinamide-induced diabetic rats: implications for insulin secretion.

Cyclic adenosine monophosphate (cAMP) plays important role in the potentiation of insulin secretion in pancreatic B-cells. However, the relevance of cAMP-degrading enzymes in the regulation of insulin secretion is not fully elucidated. The present work was undertaken to determine effects of inhibition of phosphodiesterase 3B (PDE3B) by amrinone on insulin secretion from pancreatic islets and perfused pancreas of normal and mildly diabetic rats. Inhibition of this enzyme was demonstrated to substantially increase insulin-secretory response to 6.7 mM glucose in the isolated islets and perfused pancreas of non-diabetic rats. Increment in glucose-induced insulin secretion resulting from inhibition of PDE3B was accompanied by an increase in islet cAMP levels and was suppressed by inhibition of protein kinase A. It was also demonstrated that insulin secretion stimulated by glucose and 1 µM forskolin was only slightly elevated in the presence of amrinone. Moreover, insulin release induced by succinate instead of glucose was also augmented by inhibition of PDE3B in rat islets. However, exposure of the pancreatic islets of streptozotocin-nicotinamide-induced diabetic rats to amrinone appeared to be without any effect on glucose-induced insulin secretion. Similar lack of response was shown in the perfused pancreas of diabetic rats. These results indicate that inhibition of PDE3B by amrinone significantly augments insulinotropic action of physiological glucose in B-cells of normal rats. This effect is mediated via protein kinase A and may be also induced in the presence of metabolizable stimuli other than glucose. Effects generated by amrinone were demonstrated to be, however, insufficient to enhance glucose-induced insulin secretion in B-cells of streptozotocin-nicotinamide-induced diabetic rats.

Mechanisms of increased right and left ventricular oxygen uptake during inotropic stimulation.

AIMS: Few studies have investigated oxygen supply/demand relations in right ventricle (RV). The current study compared changes in myocardial oxygen uptake (MVO2) and its determinants, myocardial blood flow (MBF) and oxygen extraction (EO2), in RV and left ventricle (LV) during stimulation with inotropic drugs. MAIN METHODS: Twenty-one anesthetized dogs were studied. MBF was measured with radioactive microspheres. A-VO2 difference was determined separately for RV and LV, and used to calculate MVO2 (Fick equation) and EO2. Responses to iv. infusions of isoproterenol (0.1 µg/kg/min), dobutamine (5 µg/kg/min), and amrinone (1mg/kg+10 µg/kg/min) were assessed. KEY FINDINGS: Baseline MVO2 in RV was 50-60% of that in LV. The inotropes increased MVO2 in both RV and LV (range 32-63%; P<0.05). With isoproterenol, the increased MVO2 in the RV was due to increases in both MBF and EO2, whereas in LV it was due only to increases in MBF. With dobutamine and amrinone, the increased MVO2 in RV was due to increased MBF while EO2 was constant (dobutamine) or decreased (amrinone), and that in the LV was due to increased MBF while EO2 decreased. SIGNIFICANCE: RV possesses EO2 reserve that contributed to increased MVO2 during isoproterenol infusion, whereas LV depended on increased MBF alone. Because dobutamine and amrinone caused direct coronary vasodilation, i.e., "luxuriant perfusion," it was not necessary to recruit the EO2 reserve. Thus, it remained available to meet further increases in MVO2 or to maintain MVO2 in the face of reductions in MBF.

Myocardial cyclic AMP augmentation with high-dose PDEIII inhibitor in terminal warm blood cardioplegia.

PURPOSE: Phosphodiesterase (PDE) III inhibitors have been reported in various cellular protective activities via the cyclic adenosine monophosphate (cAMP) pathway. We investigated the effects of amrinone on ischemia/reperfusion injury and intracellular calcium (Ca2+) handling if utilized as a component of terminal warm blood cardioplegia (TWBCP). METHODS: Anesthetized pig hearts were subjected to 90-min global ischemia with single-dose crystalloid cardioplegia, followed by 30-min reperfusion under cardiopulmonary bypass. The animals were divided into three groups according to the contents of TWBCP (n = 5 each): Control, no TWBCP; TWBCP, no additive; Amrinone, TWBCP with amrinone. The time course of cardiac function and biochemical samples were measured. Further, coronary perfusion and ventricular arrhythmia were evaluated during reperfusion. RESULTS: Cardiac function improved with amrinone. Specifically, the amrinone group showed an increase of myocardial cAMP (p <0.05) and a suppression of creatine kinase, troponin-T, and lipid peroxide after reperfusion (p <0.05); many cases also showed much improvement of coronary perfusion and spontaneous resuscitation after global ischemia. CONCLUSION: Ischemia and/or reperfusion deplete myocardial cAMP, leading to impaired Ca2+ handling and further to cardiac dysfunction. High-dose PDEIII inhibitor in TWBCP may replenish myocardial cAMP and promote rapid and sustained cardiac functional recovery with various cellular protective effects after open-heart surgery.

The role of phosphodiesterase 3 in endotoxin-induced acute kidney injury.

BACKGROUND: Acute kidney injury frequently accompanies sepsis. Endotoxin is known to reduce tissue levels of cAMP and low levels of cAMP have been associated with renal injury. We, therefore, hypothesized that endotoxin induced renal injury by activating phosphodiesterase 3 (PDE3) which metabolizes cAMP and that amrinone an inhibitor of PDE3 would prevent the renal injury. METHODS: Animals were divided into three groups (n = 7/group): 1) Control (0.9% NaCl infusion without LPS); 2) LPS (0.9% NaCl infusion with LPS); 3) Amrinone+LPS (Amrinone infusion with LPS). Either lipopolysaccharide (LPS) or vehicle was injected via the jugular vein and the rats followed for 3 hours. We explored the expression of PDE3 isoenzymes and the concentrations of cAMP in the tissue. RESULTS: The PDE3B gene but not PDE3A was upregulated in the kidney of LPS group. Immunohistochemistry also showed that PDE3B was expressed in the distal tubule in the controls and LPS caused PDE3B expression in the proximal as well. However, PDE3A was not expressed in the kidney either in the control or LPS treated groups. Tissue level of cAMP was decreased after LPS and was associated with an increase in blood urea nitrogen, creatinine, ultrastructural proximal tubular changes, and expression of inducible nitric oxide synthase (iNOS) in the endotoxemic kidney. In septic animals the phosphodiesterase 3 inhibitor, amrinone, preserved the tissue cAMP level, renal structural changes, and attenuated the increased blood urea nitrogen, creatinine, and iNOS expression in the kidney. CONCLUSION: These findings suggest a significant role for PDE3B as an important mediator of LPS-induced acute kidney injury.

Drug effect unveils inter-head cooperativity and strain-dependent ADP release in fast skeletal actomyosin.

Amrinone is a bipyridine compound with characteristic effects on the force-velocity relationship of fast skeletal muscle, including a reduction in the maximum shortening velocity and increased maximum isometric force. Here we performed experiments to elucidate the molecular mechanisms for these effects, with the additional aim to gain insight into the molecular mechanisms underlying the force-velocity relationship. In vitro motility assays established that amrinone reduces the sliding velocity of heavy meromyosin-propelled actin filaments by 30% at different ionic strengths of the assay solution. Stopped-flow studies of myofibrils, heavy meromyosin and myosin subfragment 1, showed that the effects on sliding speed were not because of a reduced rate of ATP-induced actomyosin dissociation because the rate of this process was increased by amrinone. Moreover, optical tweezers studies could not detect any amrinone-induced changes in the working stroke length. In contrast, the ADP affinity of acto-heavy meromyosin was increased about 2-fold by 1 mm amrinone. Similar effects were not observed for acto-subfragment 1. Together with the other findings, this suggests that the amrinone-induced reduction in sliding velocity is attributed to inhibition of a strain-dependent ADP release step. Modeling results show that such an effect may account for the amrinone-induced changes of the force-velocity relationship. The data emphasize the importance of the rate of a strain-dependent ADP release step in influencing the maximum sliding velocity in fast skeletal muscle. The data also lead us to discuss the possible importance of cooperative interactions between the two myosin heads in muscle contraction.

Design, synthesis and pharmacological evaluation of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives as inotropic agents.

Selective PDE3 inhibitors improve cardiac contractility and may be used in congestive heart failure. However, their proarrhythmic potential is the most important side effect. In this research we designed, synthesized and evaluated the potential cardiotonic activity of thirteen PDE3 inhibitors (4-[(4-methyl-2-oxo-1,2-dihydro-6-quinolinyl)oxy]butanamide analogs) using the spontaneously beating atria model. The design strategy was based on the structure of cilostamide, a selective PDE3 inhibitor. In each experiment, atrium of reserpine-treated rat was isolated and the contractile and chronotropic effects of a synthetic compounds were assessed. All experiments were carried out in comparison with IBMX, amrinone and cilostamide as standard compounds. The results showed that, among the new compounds, the best pharmacological profile was obtained with the compound 6-[4-(4-methylpiperazine-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1H)-one, 4j, which displayed selectivity for increasing the force of contraction (165 +/- 4% change over the control) rather than the frequency rate (115 +/- 7% change over the control) at 100 microM and potent inhibitory activity of PDE3 with IC(50) = 0.20 microM.

Effect of nitric oxide/cyclic guanosine mono-phosphate pathway on gallbladder relaxant response in bile duct-ligated guinea pigs.

BACKGROUND/AIMS: Common bile duct ligation (CBDL) in the guinea pig is a well-defined model of acalculous cholecystitis. Nitric oxide (NO) mediates smooth muscle relaxation by stimulating the activity of soluble guanylate cyclase. The aim of this study was to determine whether the NO/cyclic guanosine monophosphate pathway plays a role in gallbladder relaxant response after CBDL. METHODS: Relaxant response of gallbladder muscle strips from CBDL and sham-operated guinea pigs was studied in vitro. Animals were treated with saline, aminoguanidine or an aminoguanidine + L-arginine combination in vivo. Concentration-response curves of papaverine, diethylamine/NO, YC-1, sildenafil and amrinone were obtained and relaxations in each group were calculated as the percent of the contractions induced by carbachol (10(-6) M). RESULTS: There was a significant decrease in the gallbladder muscle relaxant responses to these substances in CBDL and aminoguanidine groups compared with sham surgical controls. The decreased relaxant response was reversed by aminoguanidine + L-arginine but not by aminoguanidine alone. CONCLUSION: Decreased relaxant responses might be due to the reduced guanylate cyclase enzyme activity, but further studies are required.

Effects of amrinone in an experimental model of hepatic ischemia-reperfusion injury.

BACKGROUND: During some surgical interventions, temporary occlusion of the hepatic blood supply may cause ischemia-reperfusion (IR) injury. Recent studies suggest that type 3 phosphodiesterase inhibitors may have a beneficial effect on liver IR injury. The aim of this study was to investigate whether amrinone, a type 3 phosphodiesterase inhibitor, could have a protective effect on liver having experimental liver IR injury. MATERIALS AND METHODS: Sixty Wistar albino rats were randomly divided into three groups. The IR and amrinone groups were subjected to 1 h total hepatic ischemia, followed by 2 h of reperfusion. The sham group underwent midline laparotomy only. Amrinone 10 microg/kg/min was infused to the amrinone group during the 3 h of the IR period. Histopathological examination, biochemical liver function, and liver adenosine triphosphate concentration after reperfusion and survival rate on the seventh day after the IR insult were recorded. RESULTS: Serum aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase levels, and histological damage scores in the amrinone and IR groups were significantly higher compared with the sham group (P < 0.01). However, all of these values were significantly lower in the amrinone group than in the IR group (P < 0.05). Liver adenosine triphosphate levels and the rat survival rate in the amrinone and IR groups were significantly lower than those in the sham group (P < 0.01). However, these values were significantly higher in the amrinone group compared to those in the IR group (P < 0.01). CONCLUSIONS: These results suggest that amrinone plays a significant role in the protection of liver against IR injury and that this treatment may be a novel pharmacological agent for safe and efficient liver surgery.

Inotropic and chronotropic effects of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives in isolated rat atria.

BACKGROUND: Selective phosphodiesterase (PDE3) inhibitors improve cardiac contractility and may use in congestive heart failure. However, their proarrhythmic potential is the most important side effect. METHODS: In this research, we evaluated the potential cardiotonic activity of six new synthesized selective PDE3 inhibitors (6-hydroxy-4-methylquinolin-2(1H)-one derivatives) using the spontaneously beating atria model. In each experiment, atrium of reserpine-treated rat was isolated and the contractile and chronotropic effects of a synthesized compound were assessed. The 3-isobutyl-1-methylxanthine, a non-selective PDE inhibitor, was used for comparison. RESULTS: The results showed that, among new compounds, the best pharmacological profile was obtained with the compound 6-[4-(4-methylpiperazine-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1H)-one, C6, which displayed selectivity for increasing the force of contraction (168 +/- 5% change over the control) rather than the frequency rate (138 +/- 5% change over the control) at 300 microM. However, C6 at concentrations of 10 and 100 microM produced left and upward shift in the positive inotropic concentration-response curve of isoprenaline. The -log EC50 of isoprenaline was 8.843 +/- 0.171 in the absence, 9.448 +/- 0.138 and 9.456 +/- 0.107 in the presence of 10, 100 microM of C6, respectively (P<0.001, n = 6). Also, amrinone, a selective PDE3 inhibitor, shifted the isoprenaline concentration-response curve to the left and upward. The concentration of 10 and 100 microM amrinone decreased -log EC50 of isoprenaline to 9.527 +/- 0.287 and 9.423 +/- 0.243, respectively (P<0.001, n = 6). Moreover, the positive chronotropic effect of isoprenaline was not affected by amrinone or C6. CONCLUSION: This study provides functional evidence for the positive inotropic effect of C6. Considering the augmentation of isoprenaline positive inotropic concentration-response with C6 and amrinone, we conclude that C6 produces its effect via potentiation of cAMP-dependent signaling system and possibly by inhibition of PDE3 activity.

Effects of phosphodiesterase (PDE) inhibitors on human ether-a-go-go related gene (hERG) channel activity.

It is presumed that phosphodiesterase (PDE) inhibitors have two mechanisms for inhibition of hERG currents in the acute applications to cells: direct channel block, and downregulation of human ether-a-go-go related gene (hERG) activities by PKA-dependent pathway mediated phosphorylation through their inhibitory effects against PDE enzymes. However, it is unknown whether PDE inhibition contributes to the inhibitory effects of PDE inhibitors on hERG currents. This study examined the effects of various PDE inhibitors on hERG currents using both the whole-cell and perforated patch-clamp techniques in hERG transfected CHO-K1 cells. The study also investigated the contribution of the PKA-dependent pathway to the inhibitory effects of PDE inhibitors on hERG currents. Of the PDE inhibitors tested, vinpocetine, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), vesnarinone, rolipram and dipyridamole decreased hERG currents in a concentration-dependent manner. Vinpocetine and vesnarinone markedly decreased the hERG current with an IC (50)of 0.13 and 20.6 microm, respectively, at comparatively low concentrations. Furthermore, vinpocetine caused a cumulative block of hERG currents. Milrinone, amrinone and zaprinast had no effect on the hERG current up to 100 microm. Of the PDE3 inhibitors (vesnarinone, amrinone and milrinone), only vesnarinone showed an hERG inhibitory effect. The inhibitory effects of vinpocetine and vesnarinone were not significantly affected by the co-application of protein kinase inhibitors. Furthermore, the protein kinase activators had no effect on hERG currents. It is concluded that vinpocetine and vesnarinone block the hERG channel directly, and that the inhibitory effect on intracellular PDE in the PKA-dependent pathway may not be involved in the inhibition of hERG currents in hERG transfected CHO-K1 cells.

A comparison of three phosphodiesterase type III inhibitors on mechanical and metabolic function in guinea pig isolated hearts.

Little is known about of the comparative cardiac lusitropic and coronary vasoactive effects of type III phosphodiesterase inhibitors independent of their systemic circulatory effects. We hypothesized that phosphodiesterase inhibitors have dissimilar concentration-dependent effects on cardiac function and metabolism and that their coronary vasodilatory effects are solely dependent on flow autoregulation secondary to positive inotropic effects. Our aim was to compare the dose-response electrophysiologic, mechanical, vasodilatory, and metabolic properties of three clinically available phosphodiesterase inhibitors in isolated Langendorff perfused guinea pig hearts. We found that, over a range from 10(-7) to 10(-4) M, amrinone, enoximone, and milrinone each produced maximal concentration-dependent positive chronotropic (12%, 18%, 26%), inotropic (16%, 26%, 26%), and lusitropic (14%, 21%, 19%) effects. At clinical concentrations, all phosphodiesterase inhibitors increased heart rate, but only milrinone significantly enhanced contractility and relaxation (11%). Each phosphodiesterase inhibitor similarly increased contractility at its highest concentration; this was accompanied by an increase in oxygen consumption, which was matched by comparable increases in coronary flow and oxygen delivery. Coronary flow reserve was preserved at the highest concentration of each drug, indicating that an increased metabolic rate was responsible for the increase in coronary flow by each drug at each concentration. Over the concentrations examined, we conclude that each of the phosphodiesterase inhibitors does not directly promote coronary vasodilation and that milrinone has the most prominent effects on contractility and relaxation at clinically relevant concentrations.

The effect of amrinone on liver regeneration in experimental hepatic resection model.

BACKGROUND: The phosphodiesterase inhibitors (PDEIs) have been proposed to improve hepatic reperfusion injury and hepatosplanchnic circulation, but the effects of these agents on liver regeneration have not been investigated thoroughly. The aim of this study was to investigate the effect of amrinone, a PDEI, on liver regeneration in rats. MATERIALS AND METHODS: Sixty rats were divided into two groups, control and amrinone. Each group was then divided into three groups (n=10). An infusion of amrinone to the study group and of 0.9% NaCl to the control group was performed. Seventy percent liver resection was performed to the rats during the first hour of infusion. The infusion was maintained for 17 h after resection. A total of 18 h infusion was performed. Rats were allowed to survive for 24, 48, and 72 h, and then they were sacrificed. Biochemical, morphological, hematological, and histopathologic measurements and assessments were performed. RESULTS: There were statistically significant differences between the amrinone and control groups in alkaline phosphatase and relative liver weights at 24, 48, and 72 h (P<0.05). There also were statistically significant differences between the groups in AST, bilirubin, and albumine levels at 24 h, ALT and prothrombine time levels at 48 h, and aspartate aminotransferase and alanine aminotransferase levels at 72 h (P<0.05). Hepatic ATP levels, mitotic index, and proliferating cell nuclear antigen labeling index were significantly higher in amrinone group compared with control group at all three time intervals (P<0.05). CONCLUSIONS: Amrinone improves both morphological and functional liver regeneration after liver resection.

Effects of a phosphodiesterase 3 inhibitor, olprinone, on rhythmical change in tension of human gastroepiploic artery.

The gastroepiploic artery, used widely as a conduit in coronary artery bypass grafting, has high vasospasticity. The aims of this study were to examine the vasorelaxant effects of three phosphodiesterase 3 (PDE3) inhibitors, olprinone, milrinone and amrinone, on isolated gastroepiploic arterial preparations in comparison with a calcium channel blocker diltiazem, and to confirm the mRNA expression of PDE3A isoenzyme using reverse transcription-polymerase chain reaction (RT-PCR) in the human gastroepiploic artery isolated from stomach removed in cancer surgery. In endothelium-denuded gastroepiploic arterial preparations, phenylephrine (100 microM) produced spontaneous, rhythmical changes in tension consisting of repeated contraction and relaxation. Olprinone at a concentration of 10 microM (n=6) significantly inhibited the frequency (2.7+/-1.1 times/30 min vs. 6.2+/-0.7 times/30 min in the vehicle group), maximum tension (1.7+/-0.6 g vs. 3.6+/-0.6 g in the vehicle group) and minimum tension (0.6+/-0.2 g vs. 1.7+/-0.3 g in the vehicle group) of rhythmical changes. Such potency is comparable to that of diltiazem, but is stronger than milrinone and amrinone. RT-PCR using PDE3A- or PDE3B-specific oligonucleotide primer demonstrated the existence of PDE3A sequence in the gastroepiploic artery. These results suggest that olprinone, a potent PDE3A inhibitor, would be suitable for protecting against perioperative spasm during coronary artery bypass graft surgery.

Protective effects of different antioxidants and amrinone on vancomycin-induced nephrotoxicity.

We have studied the effects of three antioxidants and amrinone, an inotropic agent, against vancomycin-induced nephrotoxicity in rats by investigating renal function and morphology. Thirty adult female Sprague Dawley rats (168-234 g) were divided into six groups. A saline-treated group served as control. The other five groups were treated for 7 days with vancomycin alone or in combination with alpha-lipoic acid, Ginkgo biloba extract 761, melatonin or amrinone. On day 8, all the rats were sacrificed by decapitation, kidney tissues were excised immediately and blood and kidney samples were collected. Blood urea and creatinine, kidney tissue malondialdehyde levels, and kidney superoxide dismutase and glutathione (GSH) peroxidase activities were measured. The kidneys were also examined for histological changes. Vancomycin administration led to increased urea, creatinine and malondialdehyde levels and decreased superoxide dismutase and GSH peroxidase activities. Co-administration of alpha-lipoic acid, Ginkgo biloba extract, melatonin or amrinone with vancomycin prevented the increases in the urea, creatinine and melondialdehyde levels and also resulted in higher superoxide dismutase and GSH peroxidase activities. The antioxidants and AMR improved the renal pathology compared to rats treated with vancomycin alone (P<0.05). These results indicate that the three antioxidants and amrinone have potential protective effects against vancomycin-induced nephrotoxicity, which might in part be due to inhibition of free oxygen radical production. Amrinone was the most effective drug as judged on the basis of the pathological findings.

Differential pharmacologic sensitivities of phosphodiesterase-3 inhibitors among human isolated gastroepiploic, internal mammary, and radial arteries.

UNLABELLED: Systematic investigations of the actions of phosphodiesterase (PDE)-3 inhibitors on different human vascular tissues have not been performed. We investigated the effects of specific PDE-3 inhibitors (olprinone, milrinone, and amrinone) on contracted human gastroepiploic arteries (n = 70), internal mammary arteries (n = 72), and radial arteries (n = 70) harvested from a total of 134 patients, all of whom were undergoing coronary artery bypass surgery. Each of these PDE-3 inhibitors dose-dependently diminished the contractile responses to 10(-6) mol/L norepinephrine and to either 10(-9) or 10(-8) mol/L of the thromboxane A2 analog U46619. In inducing vasorelaxations, these inhibitors were significantly more potent in norepinephrine-contracted rings than in those contracted with U46619. Further, at concentrations similar to the maximum therapeutic plasma concentrations (10(-7) mol/L olprinone; 10(-6) mol/L milrinone; 10(-5) mol/L amrinone) olprinone and milrinone were more potent at inducing relaxations than amrinone in gastroepiploic arteries and radial arteries, whereas in internal mammary arteries milrinone was more potent than the others. These results suggest different activities for the three PDE-3 inhibitors among human arteries located in different regions and may be informative about the effectiveness of these inhibitors in preventing spasms in the various arterial grafts used in revascularization. IMPLICATIONS: Because three phosphodiesterase-3 inhibitors (milrinone, olprinone, and amrinone) differed in their vasodilator potencies (against the contractile response to either norepinephrine or a thromboxane A2 analog) among human arteries removed from different parts of the body, their vascular relaxation profiles should be considered before they are used clinically.