Action Of Calcium Antagonists Research Articles

ChemInform Abstract: Condensation of Substituted 2-Aminopyridine with β-Ketocarboxylic Esters: 4H-Pyrido[1,2-a]pyrimidin-4-ones and Pyridin-2-ones.

We report the condensation of substituted 2-aminopyridines 5 with β-ketocarboxylic esters in polyphosphoric acid. In this reaction were obtained together with the target compounds, 4H-pyrido[1,2-a]pyrirnidin-4-ones 6 also the pyridin-2-ones 7. All the compounds 7 were tested for their calcium-antagonistic activity but failed to evoke any vasorelaxant response.

Novel Quinolizidinyl Derivatives as Antiarrhythmic Agents: 2. Further Investigation

Fifteen quinolizidine derivatives have been tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig (gp) heart tissues and to assess calcium antagonist activity. All compounds exhibited from moderate to high antiarrhythmic activity, and five of them (3, 4, 6, 13, and 15) were more active and potent than the reference drugs (amiodarone, lidocaine, procainamide, and quinidine). These compounds were studied on spontaneously beating Langendorff-perfuse gp heart; even at concentration 17-67 times higher than the corresponding EC(50) for antiarrhythmic activity, they prolonged the QT intervals only moderately, comparing favorably with amiodarone and quinidine. Compounds 3 and 15 deserve further investigation due to their interesting cardiovascular profiles.

Vascular-selective effect of lercanidipine and other 1,4-dihydropyridines in isolated rabbit tissues.

The aim of this study was to characterize the in-vitro vasoselectivity of lercanidipine (in comparison with lacidipine, amlodipine, nitrendipine and felodipine) by evaluating its functional calcium antagonistic activity on rabbit vascular (aorta) and cardiac tissues (heart ventricle). Although incubation with all the compounds tested elicited a concentration-dependent relaxant effect on vascular tissue precontracted with KCl (80 mM), 50% relaxation was reached at different times for each concentration and drug tested. At 10 nM concentration 50% relaxation was reached after 210 min with lercanidipine, 278 min with amlodipine, 135 min with lacidipine, 75 min with nitrendipine and 70 min with felodipine. The onset of the effect was, therefore, similar for lercanidipine, amlodipine and lacidipine, but faster for nitrendipine and felodipine. Similarly, all the compounds tested concentration-dependently reduced the force of cardiac contraction (negative inotropic activity). In this model, the time needed to reach 50% reduction in contractile force was also concentration-dependent, and the ranking order of the speed of onset of the effect (evaluated as the ratio of the IC50 values (the concentrations inhibiting contraction by 50%) calculated after 1 and 4 h incubation) was lacidipine (3.8) > amlodipine (9.6) > felodipine (39) > lercanidipine (68) = nitrendipine (89). The vasoselectivity, expressed as the ratio of the IC50 values obtained on cardiac and vascular tissue, were (for 4 h incubation) 730, 193, 95, 6 and 3 for lercanidipine, lacidipine, amlodipine, felodipine and nitrendipine, respectively, showing that lercanidipine is the most vasoselective of the calcium-antagonists tested. The results show that lercanidipine reduces the inotropic force of the rabbit heart to a lesser extent than do other calcium antagonists, and that this drug had the best heart/vessel selectivity index among the compounds tested at all the times tested.

A Case of Simultaneous Bilateral Putaminal Hemorrhage

Simultaneous occurrence of multiple intracerebral hemorrhages is a rare condition. Here we report a case of simultaneous bilateral putaminal hemorrhage. A 74–year–old woman suddenly collapsed on the street. She had been medicated for hypertension for thirty years. She was receiving an angiotensin receptor blocker, a long–acting calcium antagonist and aspirin. On admission, she was comatose (Glasgow Coma Scale E1V1M2). The size of her right pupil was 4.0 mm, the left pupil was 5.0 mm. Computed tomography of her brain identfied hematomas in bilateral putamen. The right putaminal hemorrhage was 7×4×7cm, and the left hemorrhage was 5×2×4cm. As the hematomas were large and her neurological condition was severe, no surgical intervention was attempted. She died on the sixth day after admission. An autopsy of her brain was performed with the permission of her family. However, her brain was severely autolytic; therefore, pathological findings were difficult to detect.We identified 27 cases of simultaneous bilateral putaminal hemorrhage in the literature. We summarized these cases and ours. The mean age was 56.75 years old. Nineteen cases had a history of hypertension. Twenty–five cases were comatose or semi–comatose at onset. Fifteen cases (55.6%) died. Many of surviving cases were severely disability. Multiple intracerebral hemorrhages occur in patients with hypertension, coagulation defects, neoplasm, multiple small aneurysms, or angiopathies. However, the underlying mechanism for simultaneous bilateral putaminal hemorrhages is not clear.

Cardiac and Electrophysiological Effects of Primary and Refined Extracts fromLeonurus cardiacaL. (Ph.Eur.)

Although several antiarrhythmic drugs of chemical origin are in clinical use since decades, their application is often limited by their adverse effects and especially by their inherited proarrhythmic risk, which can lead to a significantly increased mortality in patients receiving these compounds. On the other hand, aqueous extracts from the aerial parts of the European Lamiaceae Leonurus cardiaca (Ph.Eur.) have been used for centuries as a remedy against tachyarrhythmia and other cardiac disorders. Nevertheless, a scientific basis for the claim of direct cardiac electrophysiological, antiarrhythmic, or functional effects of Leonurus cardiacae herba (LCH) preparations has not been established until now. In order to enrich the active constituents from the primary extract which was tested as the most cardioactive, namely the aqueous Soxhlet extract, and to eliminate undesired substances such as the dichloromethanic fraction or potassium, a bioassay guided fractionation procedure was applied, resulting in the development of a Leonurus cardiaca refined extract (LCRE) which was characterised together with Leonurus crude extracts by a newly developed gradient elution HPLC fingerprint analysis for separation and quantification of six major phenolics as well as by qNMR for determining the stachydrine content. This refined extract was applied intracoronarily in isolated rabbit hearts perfused according to the Langendorff technique. Mapping experiments with 256 electrodes on the heart surface showed a reduction of left ventricular pressure and an increase of relative coronary flow at concentrations of 1.0 and 2.0 mg/mL LCRE. Furthermore, the PQ-interval was prolonged and both the basic cycle length and the activation recovery interval increased. In addition, voltage-clamp measurements were performed on the following cell models in order to characterise the electrophysiological profile of LCRE: neonatal rat ventricular cardiomyocytes to investigate the effect on I(Na) and I(Ca.L), sinoatrial node cells and ventricular myocytes isolated from adult guinea pigs to test effects on I(f) and action potential (AP) duration, as well as HERG-transfected HEK 293 cells to analyse the influence on the I (K.r). In these voltage clamp experiments LCRE exerted a calcium-antagonistic activity by I(Ca.L) blockade, reduced the repolarising current I(K.r), and prolonged the AP-duration, while I(Na) was not affected. Although LCRE displayed only weak effects on the I(f) amplitude and voltage dependence, it significantly prolonged the activation time constant of I(f). Thus, LCRE acts on multiple electrophysiological targets, specifically I(Ca.L), I(K.r), and I(f), observed both at whole organ and single cell level.

Management of benign prostatic hypertrophy-related urinary retention: current trends and perspectives.

The failure of prostate-directed treatment modalities to help all men or all symptoms has questioned the longstanding assumption that the prostate is at the root of all male urinary symptoms, and a correlation between urinary bladder function and prostate pathology has been recognized. Now, it is widely recognized that bladder dysfunction plays a role in some, if not most, of the benign prostatic hyperplasia-related symptoms and signs, and recent studies have suggested that pharmacotherapies that target the bladder, such as antimuscarinics, may improve storage urinary symptoms. Indeed, the current mainstays of overactive bladder syndrome pharmacotherapy are antimuscarinic agents with mixed actions, including musculotropic (calcium antagonistic) activity. Moreover, the combination therapy with alpha blocker and antimuscarinic agents is now suggested when bladder outlet obstruction related to benign prostatic hyperplasia coexists with overactive bladder symptoms. Combinational treatment, targeting to both decrease resistance to urine outflow through the prostatic urethra and increase bladder smooth muscle, may improve the bladder outlet surgery success rate, and perhaps it might reinforce the need to offer an additional trial without catheter in patients with benign prostatic hyperplasia who are likely to suffer from detrusor hypocontractivity. Currently, no clinical trial supporting the use of parasympathomimetic drugs in those with poor voiding and longstanding symptomatic benign prostatic hyperplasia exists in the literature; however, experimental studies present promising results.

Condensed 1,4-dihydropyridines with various esters and their calcium channel antagonist activities

New alkyl 2,6,6-(2,7,7)-trimethyl-4-(2-fluoro-3-chloro-5-trifluoromethylphenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates and 9-(3-chloro-2-fluoro-5-trifluoromethylphenyl)-6,6(7,7)-dimethyl-6,7-dihydrofuro[3,4- b]quinoline-1,8-diones have been synthesised and their calcium antagonistic activities on isolated rabbit sigmoid colon have been investigated and compared with Nifedipine. The investigation examined the influence of ester groups in the 3-position of the HHQ ring and the 2-methoxyethyl analogs were found to be the most active derivatives.

Vasorelaxant Effect of a Self-etch Adhesive System through Calcium Antagonistic Action

Etch-and-rinse adhesives can cause vasorelaxation via mechanisms occurring in the endothelium and smooth muscle, including the release of nitric oxide (NO). This effect might promote or aggravate bleeding if such adhesives are placed inadvertently on iatrogenic pulp microexposures. The present study assessed the vasoactive potential of a newer generation self-etch adhesive, Clearfil Protect Bond (CPB), on isolated rat aorta. Cumulative concentrations of the primer, bond, and mixture of CPB elicited concentration-dependent relaxation of phenylephrine-induced active tonus in the rat aorta, demonstrating that the tested self-etch adhesive can lead to vasorelaxation of pulp vessels that is mediated by Ca 2+ antagonistic effect. The vasorelaxant effect of CPB or its components was mediated neither via endothelium-dependent NO and prostanoid-dependent mechanisms nor by K + efflux through K + channels. Mechanical removal of the endothelium did not significantly alter the relaxation induced by CPB. Assuming these data can be extrapolated to the clinical situation, CPB, either in mixed form or by its components, can lead to vasorelaxation of pulp vessels that is mediated by a Ca 2+ antagonistic effect. If CPB is placed inadvertently on pulp microexposures during direct pulp capping, this effect might promote bleeding that might impair healing and, via plasma exatravasation, might compromise resin infiltration and polymerization.

The antiarrhythmic effects of Leonurus cardiaca on cardiac electrophysiology

Although several antiarrhythmic drugs of chemical origin are in clinical use since decades, their application is often limited by their adverse effects and especially by their inherited proarrhythmic risk, which can lead to a significantly increased mortality in patients receiving these compounds [1]. On the other hand, aqueous extracts from the central European Lamiaceae Leonurus cardiaca have been used for centuries as a remedy against tachyarrhythmia and other cardiac disorders. Nevertheless, a scientific basis for the claim of a direct cardiac electrophysiological or antiarrhythmic effect of Leonurus preparations has not been established up to now [2]. In order to concentrate the active compounds from the raw decoct and to eliminate undesired substances, a bioassay guided fractionation procedure was applied, resulting in a refined extract the reproducibility of which was controlled by TLC and HPLC. This refined extract was applied intracoronarily in isolated rabbit hearts perfused according to the Langendorff technique. Mapping experiments with 256 electrodes on the heart surface (HAL4) showed a reduction of left ventricular pressure and an increase of relative coronary flow at a concentration of 2.0mg refined extract per ml. Furthermore, the PQ-interval was prolonged and both the basic cycle length and the activation recovery interval were increased. In addition, patch-clamp-investigations were performed on several cell models demonstrating that the refined extract exerted calcium-antagonistic activity (ICa.L blockade) and prolonged the AP-duration, possibly explaining the old traditional use of Leonurus cardiaca, described in German herbals [3] as „fürtrefflich gut zu dem Zittern und Klopfen des Herzens“.

Synthesis and cardiovascular activity of difluro-substituted hexahydroquinoline

Twenty-two new methyl (ethyl) 2,6,6- or 2,7,7-trimethyl-5-oxo-4-(disubstituted phenyl)-1,4,5,6,7,8-hexahydro-quinoline-3-carbohydrates and 12 new N-N-diethyl 2,6,6 or 2,7,7-trimethyl-5-oxo-4-(disubstituted phenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide derivatives are synthesized and their activity on calcium channel antagonists was observed. Synthesis was done by the Hantzsch reaction. Calcium antagonistic activity was determined by tests performed on isolated rat ileum and thoracic arteries.

Does ivabradine exhibit a role in the reduction of bladder overactivity?

Dear Editor, Ivabradine is a novel selective and specific inhibitor of the sinus node If current that induces heart rate reduction in a dose-dependent manner, with no direct hemodynamic effects [1, 2]. Moreover, it has been proved that it improves LV systolic function, reduces collagen density in the non-infarcted myocardium, and improves myocardial perfusion and the coronary reserve [3, 4]. It is less than a decade since it was first used for the treatment of chronic stable angina. Our anecdotal experience, however, suggests that it could possibly play a role in the reduction of bladder overactivity. Three months ago, a patient with lower urinary tract symptoms (LUTS), suggestive for benign prostatic hyperplasia treated with an a-blocker (AB), reported a significant reduction of storage symptoms after the introduction of ivabradine therapy for the treatment of co-morbitant chronic stable angina. In order to verify if the above-mentioned observation is a correlation or a coincidence, we asked five more patients with diagnosed benign prostatic hyperplasia suffering from storage LUTS (daytime urinary frequency, nocturia and urgency) and chronic stable angina to complete the International Prostate Symptom Score (IPSS) questionnaire prior and after ivabradine treatment. Surprisingly four out of five patients reported a significant reduction of storage LUTS (especially nocturia), resulting in an overall reduction of symptom bothersomeness (from moderately symptomatic to mildly symptomatic). In contrast, the IPSS of the remaining patient remained unchanged. Current knowledge on bladder patho-physiology does not allow for the evaluation of the abovementioned observation. However, the failure of prostate-directed treatments to help all men or all symptoms has led investigators to question the longstanding assumption that the prostate is at the root of all male urinary symptoms [5]. It is now widely recognized that bladder dysfunction plays a role in some, if not most, cases, and recent prospective studies and post-hoc analyses have suggested that pharmacotherapies that target the bladder, such as antimuscarinics, may improve storage urinary symptoms [6]. Indeed, the current mainstays of overactive bladder (OAB) pharmacotherapy are antimuscarinic agents, with mixed actions, including musculotropic (calcium antagonistic) activity [7, 8]. Although the exact mechanism is not clearly understood it could be assumed that it involves interplay between several ionic currents: whole-cell patch clamp studies showed that acetylcholine causes an outward K + current, presumably mediated through Ca 2+ -activated K + channels. Muscarinic M3 receptors are thought to act through increased polyphosphoinositide hydrolysis, inositol 1,4,5-triphosphate (IP 3) K. Stamatiou (&) I. Heretis Faculty of Medicine, Urology Department, University of Crete, Voutes Point, Iraklio, Crete 71110, Greece e-mail: stamatiouk@yahoo.com; stamatiouk@gmail.com

Pharmacological effects of propiverine and its active metabolite, M‐1, on isolated human urinary bladder smooth muscle, and on bladder contraction in rats

To investigate the effects of M-1, a major active metabolite of propiverine on the bladder. We have evaluated the effects of M-1 on the contractions induced by carbachol, KCl, CaCl(2), and electrical field stimulation (EFS) in human detrusor smooth muscles, and pelvic nerve stimulation-induced bladder contractions in rats. The effects of M-1 were also compared with the effects of propiverine and tolterodine. Pretreatment with propiverine and tolterodine caused parallel shifts to the right of the concentration-response curves to carbachol. M-1 caused concentration-dependent reduction in the maximum contractile responses induced by carbachol. Although tolterodine did not inhibit the KCl- and CaCl(2)-induced contractions, M-1 and propiverine significantly inhibited these contractions. In the presence of atropine, M-1 and propiverine significantly inhibited the atropine resistant part of the contraction induced by EFS. On the other hand, tolterodine did not have significant inhibitory effects on atropine resistant contractions. Pelvic nerve stimulation induced bimodal phasic and tonic contractions in the rat bladder. M-1 mainly inhibited the phasic contraction. Tolterodine caused a significant inhibition in the tonic contraction, and propiverine had inhibitory effects on both contractions. The present results suggest that M-1 has inhibitory effects on the bladder smooth muscles through calcium antagonistic action. It is possible that the clinical effects of propiverine on the human bladder are based not only on the action of propiverine itself but also on one of its active metabolites, M-1.

A double-blind comparative study of clinical efficacy of verapamil versus lithium in acute mania

Objectives. The importance of intracellular calcium ions to processes that may be involved in mania and the calcium antagonist action of mood stabilizers suggest a role of verapamil in the treatment of mania. This study was undertaken to compare the clinical efficacy and tolerability of verapamil versus lithium in manic patients. Methods. Patients with acute mania were randomized to receive lithium (N =25) or verapamil (N =25) in a 4-week double-blind comparative study. Both groups were homogeneous with regard to demographic and disease variables. The primary efficacy measures were the mean change from the baseline to the last assessment in BRMS (Bech–Raefelson Mania Rating Scale) and YMRS (Young-Mania Rating scale) total score. The rating scales were administered to the patients on day 1, 3, 5, 7, 11, 13, 17, 21, 28 of the study. Attendant's assessment of relief and adverse events were recorded during the study. Results. Both treatment groups showed significant decrease in mean BRMS and YMRS score assessed at different points of time. The study showed an equal efficacy of verapamil compared with lithium in the treatment of mania. The findings were supported by good tolerability of verapamil treatment. Conclusion. This study found equal benefit of verapamil over lithium in treating acute mania.

Synthesis and Calcium Modulatory Activity of 3‐Alkyloxy‐ carbonyl‐4‐(disubstituted)aryl‐5‐oxo‐1,4,5,6,7,8‐hexa‐hydroquinoline Derivatives

In this study, twelve hexahydroquinoline derivatives which are condensed analogs of the 1,4-DHP molecule were synthesized and evaluated for their calcium-antagonistic activity. The results indicated that all compounds and nifedipine produced concentration-dependent relaxation in rabbit gastric fundus smooth muscle strips. The relaxant effects of the compounds on the tissues were expressed as percentage of the precontraction using Ca(2+). The maximum response (E(max)) and pD(2)values (the negative logarithm of the concentration for the half-maximal response (EC(50))) were calculated. It is generally believed that introduction of a second electron-withdrawing substituent into the phenyl ring increases the mentioned activity. Methyl-2,7,7-trimethyl-4-(2-nitro-5-chlorophenyl)-5-oxo-l,4,5,6,7,8-hexahydroquinoline-3-carboxylate 2a has been found to be the most active compound in this serie.

Synthesis, QSAR and Calcium Channel Modulator Activity of New Hexahydroquinoline Derivatives Containing Nitroimidazole

The discovery that 1,4-dihydropyridine class of calcium channel antagonists inhibit Ca2+ influx represented a major therapeutic advance in the treatment of cardiovascular disease. In contrast to the effects of known calcium channel blockers of the Nifedipine-type, the so-called calcium channel agonists, such as Bay K8644 and CGP 28392, increase calcium influx by binding at the same receptor regions. Our goal was to discover a dual cardioselective Ca2+-channel agonist/vascular selective smooth muscle Ca2+ channel antagonist third-generation 1,4-dihydropyridine drug which would have a suitable therapeutic profile for treating congestive heart failure (CHF) patients. A series of unsymmetrical alkyl, cycloalkyl and aryl ester analogues of 2-methyl-4-(1-methyl)-5-nitro-2-imidazolyl-5-oxo-1,4,5,6,7, 8-hexahydroquinolin-3-arboxylate were synthesized using modified Hantzsch reaction. All compounds show calcium antagonist activity on guinea-pig ileum longitudinal smooth muscle and some of them show agonist effect activity on guinea-pig auricle. Effect of structural parameters on the Ca2+ channel agonist/antagonist was evaluated by quantitative structure-activity relationship analysis. These compounds could be considered as a synthon for developing a suitable drug for treating CHF patients.

Metabolism and Calcium Antagonism of Sodium Alginate Oligosaccharides

Sodium alginate oligosaccharides (NaAOs) consisting of a mixture of eight oligosaccharides have previously been reported to lower blood pressure. We investigated in this study the excretion of NaAOs into the urine or feces, and attempted to elucidate the mechanism for lowering blood pressure by using isolated mesenteric arteries from the rabbit. The recovery rate of P8, which is the main component of NaAOs, was 5.2% and 58.9% over 48 hours in the urine and feces, respectively. The mechanism for lowering blood pressure appeared to be NaAOs having calcium antagonist activity, especially voltage-operated calcium channels. Our results suggest that NaAOs are substantially excreted into the feces, although some of them may be absorbed internally, exerting antagonist activity towards the calcium channels, especially voltage-operated calcium channels.

N-Hydroxy-pyrroline Modification of Verapamil Exhibits Antioxidant Protection of the Heart against Ischemia/Reperfusion-Induced Cardiac Dysfunction without Compromising Its Calcium Antagonistic Activity

Any clinical intervention (e.g., coronary angioplasty, thrombolysis) used to reintroduce blood flow to an ischemic region of the myocardium is accompanied by a complex enzymatic cascade of reactions resulting in severe injury to the heart, termed myocardial ischemia/reperfusion (I/R) injury. In this study, we evaluated the ability of H-3010 (1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (2-(3,4-dimethoxyphenyl)-5-([2-(3,4-dimethoxyphenyl)ethyl]-methylamino)-2-isopropylpentyl)-amide), a pyrroline modification of verapamil (2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethylmethyl-amino]-2-(1-methylethyl)pentanenitrile), to protect the heart against I/R-mediated injury. Isolated perfused rat hearts pretreated with verapamil and H-3010 were subjected to 30 min of global no-flow ischemia followed by 45 min of reperfusion. The recovery (expressed as a percentage of preischemic baseline) in contractile function (left ventricular developed pressure) of hearts subjected to I/R was significantly higher in hearts treated with H-3010 at 5 microM (51.0 +/- 6.4%) as well as at 50 microM (75.1 +/- 7.4%) as compared with verapamil at 5 microM (32.2 +/- 3.7%) or untreated control hearts (18.1 +/- 2.8%). Creatine kinase release was significantly attenuated in hearts treated with H-3010 (45.7 +/- 4.5 U/liter) as compared with untreated controls (131.5 +/- 6.4 U/liter). Similar trends were also observed for lactate dehydrogenase release as well. A marked reduction in percent area of infarction was observed in the H-3010 group (11.7 +/- 1.6%) compared with verapamil (25.1 +/- 2.9%) and control (41.3 +/- 1.9%) groups. Additional in vitro studies showed a marked decrease in reactive oxygen species generation with H-3010. In conclusion, our data clearly demonstrated that the verapamil derivative, H-3010, significantly decreased I/R-induced cardiac dysfunction. This can be attributed to the combined benefits of the pyrroline moiety (antioxidant) and the parent verapamil component (antiarrhythmic) in the protection of the heart from I/R-induced injury.

Synthesis and calcium channel antagonist activities of new derivatives of dialkyl 1,4-dihydro-2,6-dimethyl-4-(5-phenylisoxazol-3-yl)pyridine-3,5-dicarboxylates

The new analogues of nifedipine, in which 2-nitrophenyl group at position 4 is replaced by phenylisoxazolyl substituent, were synthesized. The symmetrical dialkyl 1,4-dihydro-2,6-dimethyl-4-(5-phenylisoxazol-3-yl)pyridine-3,5-dicarboxylates were prepared by classical Hantzsch condensation, and the asymmetrical analogues were synthesized using a procedure reported by Dagnino that involved the condensation of alkyl acetoacetate with alkyl 3-aminocrotonate and 5-phenylisoxazole-3-carboxaldehyde. The structure of all compounds was confirmed by IR, 1H NMR and Mass spectra. In vitro calcium channel antagonist activities were evaluated as calcium channel antagonists using the high K+ concentration of guinea-pig ileum longitudinal smooth muscle (GPILSM) assay. These compounds exhibited moderate calcium antagonist activity (IC50 = 10−7 to 10− 5 M range) relative to the reference drug nifedipine (IC50 = 1.10 ± 0.40 × 10−8 M).

Novel Quinolizidinyl Derivatives as Antiarrhythmic Agents

Eighteen analogues of lidocaine, mexiletine, and procainamide were synthesized, replacing their aminoalkyl chains with the rigid and cumbersome quinolizidine nucleus. The target compounds were tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig (gp) heart tissues and to assess calcium antagonist activity. Most compounds exhibited from moderate to high antiarrhythmic activity, and compounds 7, 9, and 19 were more active and potent than quinidine and lidocaine, while producing only modest inotropic, chronotropic, and vasorelaxant effects. These compounds were studied on spontaneously beating Langendorff-perfused gp heart. While quinidine and amiodarone produced a dose-dependent prolongation of all the ECG intervals, compounds 7, 9, and 19, even at concentrations 10-20 times higher than EC50 for the antiarrhythmic activity, only moderately prolonged the PR and QT intervals, leaving unchanged the QRS complex. Ether 7 deserves further investigations due to its interesting cardiovascular profile.

EFFECTS OF LANDIOLOL ON MECHANICAL AND METABOLIC CHANGES IN RAT REPERFUSED ISCHAEMIC HEARTS

1. The aim of the present study was to clarify the effects of landiolol, a short-acting selective beta(1)-adrenoceptor blocking agent, on mechanical and metabolic changes in postischaemic perfused hearts. 2. Rat isolated hearts (n = 30) were randomly separated into non-ischaemic or ischaemic groups. The latter group was further divided into Krebs'-Henseleit solution (KHS)- and landiolol (30, 100 or 300 micromol/L)-treated groups. Ischaemic hearts were subjected to 25 min global ischaemia and 20 min reperfusion under atrial pacing. Time-course changes in left ventricular (LV) end-diastolic pressure (LVEDP), LV developed pressure (LVDP), peak positive velocity of change of LV pressure (LVdP/dt(max)) and coronary flow were observed along with tissue contents of adenosine triphosphate (ATP), creatine phosphate, inorganic phosphate (Pi), malondialdehyde (MDA) and lactate dehydrogenase (LDH) release in coronary effluent. The effects of landiolol on rat isolated aortic preparations under KCl contraction were also investigated. 3. Ischaemia-reperfusion significantly impaired cardiodynamics, such as LVEDP, LVDP and LVdP/dt(max), decreased myocardial ATP content and increased Pi and LDH release. In the 30 micromol/L landiolol-treated group, cardiovascular parameters impaired by ischaemia-reperfusion and increased LDH release were further exacerbated and myocardial MDA content was significantly increased. In the 300 micromol/L landiolol-treated group, cardiac contractile dysfunction was improved and myocardial MDA, ATP and Pi contents were preserved. All measurements in the 100 micromol/L landiolol-treated group were similar to those in the ischaemic KHS group. Furthermore, significant relaxations of isolated aortic preparations were obtained with landiolol 30-1000 micromol/L, suggesting a possible calcium antagonism with landiolol. 4. In conclusion, landiolol, at low concentrations, aggravated myocardial ischaemia-reperfusion injuries, whereas at high concentrations it ameliorated them. The former effect may be mediated by the production of reactive oxygen species, whereas the latter may involve calcium antagonist activity.