cardiovascular-agents and alinidine

Several clinical studies demonstrate the importance of the heart rate for the cardiovascular morbidity and mortality. Over the last 50 years, some thought has been given to those substances that selectively reduce the heart rate. It is now recognized that I(f) ion channels of the sinus node play a major role in the automatism and modulation of the heart rate. Substances that selectively reduce the heart rate should decrease myocardial oxygen consumption and increase oxygen delivery via the prolonged diastolic coronary perfusion. Direct inotropic effects, however, are unlikely. In principle, anti-anginal and anti-ischemic effects of specific bradycardic substances can be expected. The clinical experience with some of the former bradycardic substances has not been sufficiently convincing. The more recent ivabradine (Procoralan presents an exception to this, as it successfully completed a clinical program for the treatment of chronically stable angina pectoris. In this review article, specific bradycardic substances (= I(f) channel inhibitors) are presented together with the corresponding experimental and clinical studies. The studies were selected against the background of the efficacy of I(f) channel inhibitors in the therapy of cardiovascular disease. As only ivabradine has completed a study on 5,000 patients, the discussion on that particular I(f) channel inhibitor is somewhat extensive. In addition, prospective possibilities and limitations of bradycardic substances are presented.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzazepines; Cardiotonic Agents; Cardiovascular Agents; Clonidine; Coronary Artery Disease; Humans; Isoindoles; Ivabradine; Phthalimides; Practice Guidelines as Topic; Practice Patterns, Physicians'

First described over a quarter of a century ago, the cardiac pacemaker "funny" (I(f)) current has been extensively characterized since, and its role in cardiac pacemaking has been thoroughly demonstrated. A similar current, termed I(h), was later described in different types of neurons, where it has a variety of functions and contributes to the control of cell excitability and plasticity. I(f) is an inward current activated by both voltage hyperpolarization and intracellular cAMP. In the heart, as well as generating spontaneous activity, f-channels mediate autonomic-dependent modulation of heart rate: beta-adrenergic stimulation accelerates, and vagal stimulation slows, cardiac rate by increasing and decreasing, respectively, the intracellular cAMP concentration and, consequently, the f-channel degree of activation. Four isoforms of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels have been cloned more recently and shown to be the molecular correlates of native f-channels in the heart and h-channels in the brain. Individual HCN isoforms have kinetic and modulatory properties which differ quantitatively. A comparison of their biophysical properties with those of native pacemaker channels provides insight into the molecular basis of the pacemaker current properties and, together with immunolabelling and other detection techniques, gives information on the pattern of HCN isoform distribution in different tissues. Because of their relevance to cardiac pacemaker activity, f-channels are a natural target of drugs aimed at the pharmacological control of heart rate. Several agents developed for their ability to selectively reduce heart rate act by a specific inhibition of f-channel function; these substances have a potential for the treatment of diseases such as angina and heart failure. In the near future, devices based on the delivery of f-channels in situ, or of a cellular source of f-channels (biological pacemakers), will likely be developed for use in therapies for diseases of heart rhythm with the aim of replacing electronic pacemakers.

Topics: Amino Acid Sequence; Animals; Benzazepines; Cardiovascular Agents; Clonidine; Cyclic Nucleotide-Gated Cation Channels; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ion Channels; Ivabradine; Nerve Tissue Proteins; Potassium Channels; Pyrimidines; Sinoatrial Node; Structure-Activity Relationship

This study was conducted to explore mechanisms that could explain the possible clinical benefit of early administration of a beta 1-selective adrenoreceptor blocking agent or a bradycardiac drug as adjunct to thrombolysis in acute myocardial infarction.. The effects of beta-blockers given concomitantly with thrombolytic therapy in patients with acute myocardial infarction have not been fully examined. The potential role of specific bradycardiac agents lacking negative inotropism as an alternative to beta-blockers in this setting has never been studied in humans.. In a double-blind study, we examined the effects of early intravenous and continued oral administration of a beta-blocker (atenolol), a specific bradycardiac agent (alinidine) or placebo on left ventricular function, late coronary artery patency, infarct size, exercise capacity and incidence of arrhythmias.. A total of 292 patients with acute myocardial infarction of < or = 5 h duration and without contraindications to thrombolytic or beta-blocker therapy were studied. Of these, 100 were allocated to treatment with atenolol (5 to 10 mg intravenously followed by 25 to 50 mg orally every 12 h), 98 to alinidine (20 to 40 mg intravenously followed by 20 to 40 mg orally every 8 h) and 94 to placebo. All patients received 100 mg of alteplase over 3 h and full intravenous heparinization. No significant differences in coronary artery patency, global ejection fraction or regional wall motion were observed at 10 to 14 days among the three groups. Likewise, enzymatic and scintigraphic infarct size were also very similar. Neither atenolol nor alinidine was associated with a significant reduction in the incidence of arrhythmias during the 1st 24 h. No significant differences in clinical events were observed, with the exception of a greater incidence of nonfatal pulmonary edema in the atenolol group (6% vs. 1% in the alinidine group and 0% in the placebo group, p = 0.021).. In the absence of contraindications, the administration of a beta-blocker or a specific bradycardiac agent together with thrombolytic therapy was safe. In this limited number of patients, these agents did not appear to enhance myocardial salvage or preservation of left ventricular function or to reduce the incidence of major arrhythmias in the early phase of infarction.

Topics: Adult; Aged; Arrhythmias, Cardiac; Atenolol; Cardiovascular Agents; Clonidine; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Exercise Test; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome; Vascular Patency; Ventricular Function, Left

The present study has been performed to assess the effects of alinidine on diastolic duration during exercise in chronic coronary artery disease. Twelve male patients with stable effort angina and without previous myocardial infarction were studied. They received alinidine or placebo in a double-blind randomized crossover trial for 3 days after a wash-out period of 4 days. Alinidine was administered at a dosage of 30 mg 3 times a day. At the end of each treatment the patients underwent upright bicycle exercise. Left ventricular time intervals were obtained by means of carotid thermistor plethysmography. Diastolic duration was calculated by subtracting the electromechanical systole from the R-R interval and expressed as a percentage of the cardiac cycle (%D). Alinidine increased both total exercise duration from 246.7 +/- 120.7 to 346.6 +/- 114.1 s (p less than 0.05) and time to 0.1-mV ST segment depression from 98.3 +/- 53 to 187.2 +/- 105 s (p less than 0.05). Similarly the drug induced a reduction of the rate-pressure product and of the extent of ischemic ST segment depression during exercise. %D was increased by alinidine both at rest and during exercise. A direct linear regression between R-R and %D was found after both alinidine and placebo treatments either at rest or during exercise. Nevertheless, no difference was observed between both slopes and intercepts. Therefore, since the relationship between R-R interval and %D was unaffected by alinidine, it was possible to hypothesize that the changes in diastolic duration were due only to the bradycardic action of the drug.

Topics: Angina Pectoris; Cardiovascular Agents; Chronic Disease; Clonidine; Diastole; Double-Blind Method; Exercise Test; Humans; Male

A hyperkinetic heart syndrome has been diagnosed in 10 patients by clinical investigation and right-heart catheterization at rest and during exercise. Subsequently, the patients received 3 X 40 mg alinidine, and 2 X 40 mg propranolol and placebo, each for 2 weeks in a double-blind crossover study. Heart rate at rest (P less than 0.05) and during exercise (P less than 0.001) decreased significantly under alinidine and propranolol to the same extent (control, 83/170; alinidine, 68/146; propranolol, 73/139; placebo, 83/162 beats per min). Lower limb flow at rest and after exercise, measured by plethysmography, as well as left-ventricular fractional shortening and mean velocity of circumferential fiber shortening, measured by echocardiography, decreased insignificantly. Sedation and a dry mouth occurred in six patients under alinidine, while fatigue and cold hands and/or feet were reported by five patients under propranolol. Thus, alinidine may be used as an alternative to beta-blocking in the treatment of the hyperkinetic heart syndrome.

Topics: Adult; Blood Pressure; Cardiovascular Agents; Clonidine; Echocardiography; Female; Heart Rate; Humans; Male; Middle Aged; Neurocirculatory Asthenia; Propranolol

Alinidine is a new bradycardic agent which has been shown to be beneficial in the treatment of coronary heart disease. Patients with both coronary heart disease and obstructive lung disease are difficult to treat, because the use of beta-blockers in them is greatly limited by their potential to provoke bronchospasm. Alinidine has no beta-blocking, muscarinic or quinidine-like properties. In a randomized double-blind cross-over study the heart rate reducing effect and safety of alinidine 40 mg p.o. has been examined in 12 symptom-free asthmatics. Alinidine significantly reduced mean heart rate from 81 +/- 10.5 beats/min to 65 +/- 9.7 beats/min two hours after administration. Forced expiratory volume in one second (FEV1), vital capacity (CV), airway resistance (Raw), functional residual capacity (FRC), and specific airway conductance (SGaw) were not affected. It is concluded that alinidine did not influence respiratory function in patients with bronchial hypersensitivity.

Topics: Adult; Asthma; Blood Pressure; Cardiovascular Agents; Clonidine; Double-Blind Method; Heart Rate; Humans; Male; Middle Aged; Random Allocation; Respiratory Function Tests

Topics: Adult; Blood Pressure; Cardiovascular Agents; Clonidine; Heart Rate; Humans; Hydralazine; Male; Posture; Propranolol

Topics: Aged; Angina Pectoris; Blood Pressure; Cardiovascular Agents; Clinical Trials as Topic; Clonidine; Double-Blind Method; Electrocardiography; Heart Rate; Humans; Male; Middle Aged; Physical Exertion

We tested the hypothesis that induction of chronic bradycardia would trigger an upregulation of key growth factors and receptors, which would then lead to angiogenesis and improve coronary reserve in the left ventricle after myocardial infarction.. Bradycardia was induced in rats by administering alinidine via osmotic pumps beginning 1 day after coronary artery ligation. Echocardiographic analysis was conducted before and after treatment. Morphometric analysis was used in perfusion-fixed hearts to document arteriolar and capillary growth. Western blots were used to evaluate growth factor and receptor changes. During the first week of treatment, vascular endothelial growth factor (VEGF), VEGF receptor 1 (Flt-1), and basic fibroblast growth factor proteins were higher in the treated group, whereas VEGF receptor 2 (Flk-1), angiopoietin-1, and angiopoietin-2 were not affected by treatment. After 3 weeks, VEGF protein remained elevated, and bradycardia was associated with a higher capillary length density in the border (40%) and remote (14%) regions and a higher arteriolar length density in the septum (62%), despite a greater increase in left ventricular mass. Although arteriolar length density increased in all size classes, the greatest increase occurred in the smallest (terminal) arterioles. This vascular growth was associated with a 23% greater coronary reserve. Echocardiography revealed a smaller increase in ventricular volume and a greater preservation of ejection fraction in rats treated with bradycardia.. Pharmacologic induction of bradycardia enhances vascularity and coronary reserve, preserves function of surviving myocardium, and therefore, is a noninvasive, therapeutic avenue that provides an alternative to gene therapy.

Topics: Angiopoietin-1; Angiopoietin-2; Animals; Bradycardia; Cardiovascular Agents; Clonidine; Coronary Vessels; Drug Evaluation, Preclinical; Extracellular Matrix Proteins; Fibroblast Growth Factor 2; Heart Ventricles; Hypertrophy, Left Ventricular; Ligation; Male; Models, Animal; Myocardial Infarction; Myocytes, Cardiac; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley; Stroke Volume; Ultrasonography; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

The antiischemic and antiarrhythmic effects of alinidine and a number of novel alinidine analogs were examined by using perfused rat-heart models. In the isolated working rat heart, the alinidine analog TH91:21 (10 microM; a butyl derivative) significantly increased the postischemic recovery of the heart in terms of both power and efficiency when compared with the control group. In the in situ perfused heart model, this same compound, along with TH91:22 (10 microM; a pentyl derivative) also significantly reduced the severity of both ischemia- and reperfusion-induced arrhythmias in both paced and unpaced hearts. Thus this study is the first to demonstrate the potent antiarrhythmic efficacy of two novel alinidine analogs TH91:21 and TH91:22, with TH91:21 also demonstrated to be a potent antiischemic agent in the isolated working rat heart. Although the mode of action of these compounds remains unclear, results from this study suggest that it is not simply a result of bradycardia or blockade of KATP channels, two actions these compounds possess. These compounds thus possess a novel and beneficial pharmacologic profile worthy of further study.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bradycardia; Cardiac Pacing, Artificial; Cardiovascular Agents; Clonidine; Heart; Male; Potassium Channel Blockers; Rats; Rats, Inbred WKY; Reperfusion Injury; Structure-Activity Relationship

We studied the cardiac electrophysiological effects of falipamil, a specific bradycardic agent, in conscious dogs, in comparison with those of alinidine. Sinus rate, corrected sinus recovery time, and Wenckebach point were measured in six intact dogs. Atrial rate, ventricular rate, and atrial effective refractory period were measured in six atrioventricular-blocked dogs. In both groups, blood pressure was also monitored. Each dog received, with at least a three-day interval, falipamil (hydrochloride) and alinidine (hydrobromide) in four successive intravenous injections, 30 min apart, at 0.5, 0.5, 1, and 2 mg kg-1. Falipamil increased sinus rate and atrial rate, but decreased ventricular rate, whereas alinidine decreased sinus rate and ventricular rate, but increased atrial rate. Falipamil shortened corrected sinus recovery time and increased Wenckebach point, whereas alinidine lengthened corrected sinus recovery time and decreased Wenckebach point. Falipamil and alinidine increased atrial effective refractory period. Neither falipamil nor alinidine modified mean blood pressure in either group. Overall, these results show that (a) falipamil exhibits effects on the electrical activity of the heart, reflecting the predominant direct vagolytic effect of this drug, (b) alinidine exhibits effects reflecting the marked antiarrhythmic potential of this agent, and (c) thus indicate that two drugs with almost identical specific bradycardic properties can produce quite different electrophysiological effects in the conscious dog.

Topics: Animals; Atrioventricular Node; Blood Pressure; Bundle of His; Cardiovascular Agents; Clonidine; Dogs; Electroencephalography; Electrophysiology; Female; Heart; Heart Rate; Isoindoles; Male; Phthalimides; Sinoatrial Node

The goal of the present study was to further characterize the effects of the novel cardioprotective agent BMS-180448 on potassium fluxes in cardiac and vascular smooth muscle. Exposure of voltage-clamped guinea pig ventricular myocytes to BMS-180448 (300 microM) produced an inhibition of IK followed by the delayed (5.5 +/- 0.5 min) activation of a large time-independent potassium current. At 100 microM, BMS-180448 produced only inhibition of IK. The BMS-180448 activated current was refractory to block by 30 microM glyburide but was largely inhibited by 100 microM alinidine (84 +/- 6% inhibition at +40 mV). Cromakalim (100 microM)-activated currents were fully inhibited by 3 microM glyburide and 79 +/- 4% blocked by 100 microM alinidine. The current responses to BMS-180448 were unaffected by the inclusion of 10 mM UDP (100 microM ATP) in the pipette. BMS-180448 also produced a concentration-dependent increase in 86Rb efflux from aortic strips; efflux responses were increased in low calcium medium and fully antagonized by 3 microM glyburide. Thus, BMS-180448 activates a potassium conductance in both cardiac and smooth muscle. The glyburide sensitivity of the BMS-180448-induced increase in 86Rb efflux from the aortic preparations suggests that this drug activates IKATP in vascular smooth muscle. Moreover, the observation that BMS-180448 (100 microM) partially inhibits the effects of cromakalim in ventricular muscle cells suggests that these drugs interact, directly or indirectly, with a common site in cardiac muscle.

Topics: Animals; Aorta, Thoracic; Benzopyrans; Cardiotonic Agents; Cardiovascular Agents; Cells, Cultured; Clonidine; Glyburide; Guanidines; Guinea Pigs; Heart Ventricles; Male; Muscle, Smooth, Vascular; Myocardium; Patch-Clamp Techniques; Potassium Channels; Rabbits; Rubidium Radioisotopes

We studied the cardiac electrophysiologic effects of alinidine in conscious dogs. Sinus rate, corrected sinus recovery time (CSRT), and Wenckebach point (WP) were determined in 6 intact dogs. Atrial and ventricular rates, and atrial effective refractory period (AERP) were determined in 6 atrioventricular (AV)-blocked dogs. In both groups, we also measured blood pressure (BP) and plasma alinidine concentrations. Each dog received four intravenous (i.v.) injections of 0.5, 0.5, 1, and 2 mg/kg alinidine (hydrobromide) 30 min apart. At all doses, alinidine decreased sinus rate (< or = 43%) and ventricular rate (< or = 44%), but increased atrial rate (< or = 31%). It lengthened CSRT (< or = 71%) at the two highest doses and increased AERP (< or = 33%) and decreased WP (< or = 33%) at all doses. Alinidine did not modify mean BP at any dose in either group. Overall, these results indicate that alinidine exhibits electrophysiologic effects in conscious dogs that reflect antiarrhythmic potentials of this drug apart from its assumed antiischemic properties.

Topics: Animals; Anti-Arrhythmia Agents; Atrioventricular Node; Blood Pressure; Bundle of His; Cardiovascular Agents; Clonidine; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Electrophysiology; Female; Heart Rate; Injections, Intravenous; Male; Sinoatrial Node

ZENECA ZD7288 (4-(N-ethyl-N-phenyl-amino)-1,2-dimethyl-6-(methylamino) pyrimidium chloride) is a novel compound which we compared with alinidine and UL-FS 49 (zatebradine) in guinea pig sinoatrial node (SAN) and papillary muscle preparations, using conventional microelectrode techniques. At low concentrations (1 x 10(-8)-1 x 10(-6) M), ZD7288 caused slowing of the diastolic depolarisation rate of SAN pacemaker cells, thus prolonging the diastolic interval and slowing the beating rate. Alinidine and UL-FS 49 also had qualitatively similar effects on diastolic depolarisation rate, but ZD7288 caused least prolongation of the action potential duration (APD) of SAN cells at the concentrations that had "selective bradycardic actions." ZD7288 affected the APs of ventricular cells in guinea pig papillary muscle only at relatively high concentrations (3 x 10(-6)M-1 x 10(-4) M), which reduced plateau potential duration, although total APD was less affected. Reduced force of contraction (FOC) was also observed at these high concentrations; significant effects on AP Vmax were noted only at concentrations > or = 3 x 10(-5)M. Alinidine also had negative inotropic effects on papillary muscle, but its effects were noted at concentrations similar to those with bradycardic actions; in contrast, UL-FS 49 had marked positive inotropic actions and also increased ventricular APD within the bradycardic concentration range. These data provide a basis for the selective actions of ZD7288 on heart rate (HR).

Topics: Action Potentials; Animals; Benzazepines; Cardiovascular Agents; Clonidine; Dose-Response Relationship, Drug; Electrophysiology; Guinea Pigs; Heart Rate; Heart Ventricles; In Vitro Techniques; Male; Microelectrodes; Myocardial Contraction; Papillary Muscles; Pyrimidines; Sinoatrial Node

1. The effect of alinidine on transmural flow redistribution during hypoperfusion was studied in the isolated rat heart. 2. Low flow perfusion of paced (5 Hz) rat Langendorff preparations with Tyrode's solution for 60 min resulted in loss of left ventricular pressure amplitude and contracture. 3. In the presence of 45.6 mumol/L alinidine in the hypoperfusion medium contractility was maintained and contracture was missing. 4. Myocardial sphere densities were assessed by infusion of fluorescent microspheres after 60 min of hypoperfusion. Histomorphometric evaluation of the left ventricular wall indicated marked redistribution of myocardial flow to the epicardium. Endo/epicardial quotients of sphere densities were significantly greater in alinidine-treated hearts. 5. Perfusion of hearts with 45.6 mumol/L alinidine for 30 min at a pressure of 80 cmH2O decreased coronary flow and contractility, but did not change the transmural quotient of sphere densities. 6. These results show that in isolated rat hearts with a ventricular wall of only 3-4 mm thickness severe hypoperfusion induces a shift in transmural flow distribution which is prevented by alinidine.

Topics: Animals; Blood Pressure; Cardiac Pacing, Artificial; Cardiovascular Agents; Clonidine; Coronary Circulation; Heart; In Vitro Techniques; Male; Microspheres; Myocardial Contraction; Rats; Rats, Inbred Strains; Ventricular Pressure

Alinidine, and eight derivatives, were synthesized and tested for their ability to antagonise the actions of the K+ channel opener cromakalim in rat thoracic aorta, and for their ability to induce bradycardia in rat isolated spontaneously beating right atria. Ring segments of rat thoracic aorta were suspended in organ baths to record isometric tension. Tissues were precontracted with K+ (20 mM), and full concentration-relaxation curves constructed to cromakalim (0.01-30 microM) in the absence and presence of increasing concentrations of alinidine/derivative. The majority of the compounds tested caused rightward shifts in the cromakalim concentration-effect curves. Rat spontaneously beating right atria were suspended in organ baths to record rate of contraction. Addition of alinidine/derivative caused a concentration-dependent negative chronotropic response. In terms of structure-activity relationships, increasing the length of the N-allyl side-chain on the alinidine molecule (from 3 carbon (3C), to 5C) resulted in a significant increase in the activity of the compounds as both bradycardic agents and cromakalim antagonists. The most potent compounds in both cases (bradycardic agent and cromakalim antagonist) had no double bond in the side chain. The results suggest that the carbon side-chain influences the activity of alinidine-related compounds both as cromakalim antagonists and as bradycardic agents. However, while similar structure-activity relationships appear to apply for both effects in some instances, there was no significant correlation between the two actions of the alinidine analogues. The results suggest that the ability of alinidine-derivatives to induce bradycardia or to block K+ channels opened by cromakalim can be differentiated on the basis of structure.

Topics: Animals; Benzopyrans; Cardiovascular Agents; Clonidine; Cromakalim; Heart Rate; In Vitro Techniques; Male; Potassium Channels; Pyrroles; Rats; Structure-Activity Relationship

1. ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyridinium chloride) is a sinoatrial node (SAN) modulating agent which produces a selective slowing of the heart rate. Its effects have been studied in single, freshly dissociated guinea-pig SAN cells, by standard patch clamp procedures. 2. Whole-cell inward currents were evoked by hyperpolarizing voltage clamp steps from a holding potential of -40 mV. ZD7288 inhibited the hyperpolarization activated cationic current (If) in a concentration-dependent manner. The 'selective bradycardic agents' alinidine and UL-FS 49 (zatebradine) both also inhibited If. 3. The activation of If was investigated by measuring tail current amplitudes at +20 mV after hyperpolarizing steps to different potentials to activate the current. The reduction in If resulted from both a shift in the If current activation curve in the negative direction on the voltage axis, and also a reduction in the activation curve amplitude. 4. ZD7288 did not affect the ion selectivity of the If channel, since the tail current reversal potential was unchanged in the presence of the drug. 5. With ZD7288 the inhibition of If was not use-dependent, whereas UL-FS 49 displayed use-dependence in the block of the If current. 6. Whereas ZD7288 had no significant effect on the delayed rectifier current (Ik) in these cells, both alinidine and UL-FS 49 significantly reduced Ik at the same concentrations which reduced If. 7. The data show that ZD7288 reduces If by affecting the activation characteristics of the If current; this inhibition may account for this agent's selective bradycardiac properties.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Benzazepines; Cardiovascular Agents; Clonidine; Electrophysiology; Guinea Pigs; In Vitro Techniques; Ion Channels; Membrane Potentials; Pyrimidines; Sinoatrial Node

We compared the antianginal effect of E4080, a novel bradycardiac agent with coronary vasodilating properties, with those of a bradycardiac agent and some coronary vasodilators in vasopressin-induced anginal model of guinea pigs. An i.v.-administration of vasopressin (0.2 IU/kg) produced an ST segment elevation on electrocardiograms (ECG) of 0.30 +/- 0.05 mV from the baseline within 30 sec in anesthetized guinea pigs. The ST segment elevation on ECG was used as an index of myocardial ischemia. E4080 and other drugs were injected i.v. 5 min before the administration of vasopressin. E4080 at 5 mg/kg depressed the ST segment elevation induced by vasopressin to 0.06 +/- 0.01 mV (20% of control, n = 6, P < 0.001). However, alinidine (5 mg/kg), which produced the same bradycardic action (reduction of heart rate by 50%) as that of E4080, tended to inhibit the ST segment elevation, but this was not statistically significant. On the other hand, other vasodilators such as isosorbide dinitrate (0.3 mg/kg), nifedipine (0.1 mg/kg) and lemakalim (1 mg/kg) also significantly reduced the ST segment elevation to 0.16 +/- 0.03, 0.08 +/- 0.04 and 0.09 +/- 0.03 mV, respectively. These results suggest that the inhibitory effect of E4080 on the ST segment elevation induced by vasopressin is due to the coronary vasodilating effect rather than the bradycardiac effect, and that E4080 would be useful as an antianginal agent.

Topics: Anesthesia; Animals; Benzopyrans; Cardiovascular Agents; Catechols; Clonidine; Coronary Vessels; Cromakalim; Electrocardiography; Guinea Pigs; Heart Rate; Imidazoles; In Vitro Techniques; Isosorbide Dinitrate; Male; Nifedipine; Pyrroles; Vasodilator Agents; Vasopressins

In patients with coronary artery disease, the reduction of heart rate (HR) by beta-blockers can further impair myocardial function by reducing the contractility and coronary perfusion. This is possibly not the case for "specific bradycardic agents" like alinidine (ALI). The effect of ALI on ischemic myocardium, therefore, was studied in anesthetized open-chest dogs measuring left ventricular end-diastolic pressure (LVedP), dP/dt, aortic pressure (AoP) by catheter tip manometers, coronary blood flow (Q) electromagnetically, end-diastolic length (edL) and systolic shortening (sdL in %edL) of ischemic (RISC) and non-ischemic (NISC) wall segments by sonomicrometry. Group A (n = 11): Left coronary artery constriction to reduce Q (-53%) and poststenotic sdL (-54%), then i.v. injection of ALI (0.25 + 0.25 + 0.5 + 1.0 mg/kg), thereafter atrial pacing at HR before ALI. Group B (n = 9): Installation of an aorto-coronary bypass, pump-perfused at 50% of free flow, infusion of ALI into the bypass. The results showed that ALI iv dose-dependently reduced HR from 135/min to 90/min, LVedP rose from 8.6 to 10.0 mmHg and NISC-edL from 14.1 to 14.6 mm indicating increased ventricular filling. Non-ischemic systolic shortening did not change. Ischemic systolic shortening was improved from 9.2% to 17.5%, which was not due to an increase in RISC-edL (14.8 versus 14.7 mm), enhanced RISC-Q (13 versus 12 ml/min), reduced AoP (86 versus 84 mmHg) or change in inotropy (dP/dtmax: 2290 versus 2240 mmhg/s), but the increase in RISC-sdl correlated closely (r greater than 0.85) to the reduction in HR (oxygen-demand).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Cardiovascular Agents; Clonidine; Coronary Circulation; Coronary Disease; Dogs; Female; Heart; Heart Rate; Hemodynamics; Male

Alinidine is a new bradycardic agent that interferes with ion channels and the if pacemaker current. To determine if alinidine had antiischemic effects unrelated to its bradycardic action, myocardial metabolism was studied during a pacing-stress test in 20 patients with coronary artery disease and angina pectoris, before and after intravenous infusion of alinidine (10 mg, n = 10; 50 mg, n = 10). When compared to the control pacing-stress test, the low dose of alinidine had no significant effect on aortic pressure, coronary sinus flow (-3%, NS), myocardial oxygen extraction, or myocardial lactate uptake. After the high dose of alinidine, aortic pressure and coronary sinus flow remained unchanged but the arteriocoronary sinus difference in oxygen content increased (12.2 +/- 1.3 to 12.7 +/- 1.4 ml/100 ml; p less than 0.0002) above the values observed during the control pacing-stress test, while both the chemical lactate extraction fraction (-19 +/- 30 to 15 +/- 21%; p less than 0.025) and the L-[1-14C]lactate extraction fraction increased. Accordingly, the net myocardial lactate uptake (corrected for production) had increased from 14 +/- 32 during the control pacing-stress test to 29 +/- 24 mumol/min during the pacing repeated after the high dose of alinidine (p less than 0.05). After the high dose of alinidine, the free fatty acid uptake also rose slightly (+23%; NS) and the alanine production was reduced in 7 of 10 patients (-3.6 +/- 1.7 to -1.4 +/- 0.6 mumol/min; NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Cardiovascular Agents; Clonidine; Coronary Disease; Dose-Response Relationship, Drug; Female; Heart Rate; Hemodynamics; Humans; Injections, Intravenous; Lactates; Male; Middle Aged; Oxygen Consumption

Cross-perfused canine atrial preparations were used to investigate the direct and indirect cardiac actions of clonidine and alinidine. Intravenous injections of clonidine (0.1-3 micrograms/kg) produced an initial brief pressor response and bradycardia followed by hypotension in the intact dog. Chronotropic and inotropic responses were absent in the isolated atrium perfused with the intact dog's blood. Intravenous clonidine (10-300 micrograms) also induced negative chronotropic and inotropic effects in isolated atria. On the other hand, alinidine, at doses which caused a depressor action and bradycardia in the intact dog, consistently produced negative chronotropic and inotropic effects in the isolated atrium. Therefore, it was confirmed that a relatively small dose of clonidine has a selective vascular action, while alinidine has direct cardiac depressant properties at all effective doses. Negative chronotropic and inotropic effects of peripheral vagal stimulation, carbachol and adenosine were not significantly modified by 100 or 300 micrograms doses of intraarterial clonidine. On the other hand, the effects of vagal stimulation and carbachol were significantly inhibited by 100 and 300 micrograms of alinidine, without affecting adenosine-induced cardiac actions. Therefore, it was demonstrated that alinidine has anti-muscarinic properties.

Topics: Animals; Cardiovascular Agents; Clonidine; Cross Circulation; Dogs; Heart; Heart Rate; Myocardial Contraction; Parasympatholytics

The bradycardiac drug alinidine (2.8-182.3 microM) antagonized the negative inotropic effect of adenosine in isolated left rat atria in a non-competitive fashion. A 50% reduction of the maximal adenosine effect was achieved with 64.6 microM alinidine. The shortening of the action potential duration and the suppression of slow action potentials in guinea pig atria by 1-10 microM adenosine could be abolished by 5.7 microM alinidine. Adenosine (1 mM) exerted a negative inotropic effect on isolated strips from the right ventricle of rat heart exposed to 0.36 microM isoproterenol, an effect which was fully antagonized by 91.1 microM alinidine. Addition of 1 mM adenosine to spontaneously beating isolated rat atria induced pronounced bradycardia. Under these conditions, the bradycardiac agent alinidine increased the contractile rate concentration dependently (11.4-182.3 microM), while the chemically unrelated bradycardiac compound UL-FS 49 did not accelerate the beat frequency. As alinidine antagonized all the cardiac actions of adenosine that we tested, it may be concluded that the drug interferes with A1-receptor-mediated effects.

Topics: Action Potentials; Adenosine; Animals; Atropine; Cardiovascular Agents; Clonidine; Electric Stimulation; Electrophysiology; Guinea Pigs; Heart; In Vitro Techniques; Male; Membrane Potentials; Myocardial Contraction; Rats

The mechanism of action of the two "specific bradycardic agents" alinidine and AQ-A 39 (falipamil) is still a matter of controversy. Their binding properties to atrial and ventricular myocardium of the guinea pig and rat were, therefore, investigated by the radioligand binding technique. In competition studies against the nonselective antagonists [125I]3-quinuclidinyl 4-iodobenzilate [( 125I]QNB) and 1-N-methyl-[3H]scopolamine methylchloride [( 3H]NMS), both alinidine and AQ-A 39 competitively displaced the radioligands with I50 values (corrected for radioligand concentration) of 1-2 microM (alinidine/[125I]QNB) and 4 microM (alinidine/[3H]NMS), respectively. The I50 values for AQ-A 39 were lower by a factor of two. Slope factors (pseudo Hill coefficients) were 0.7-0.8 (AQ-A 39) and 0.8-0.9 (alinidine), and significantly lower than unity in both atria and ventricle. The guanosine triphosphate (GTP) (100 microM) and 5'-guanylimido-di-phosphate [Gpp(NH)p] (100 microM) slightly creased [3H]QNB binding and produced no or only a small (factor 2-3) rightward shift of alinidine and AQ-A 39 competition curves. At high concentration (1 mM), AQ-A 39 drastically decreased [125I]QNB dissociation rate from both atrial and ventricular receptors (t1/2 control, 19 min; plus AQ-A 39, 75 min) while alinidine (1 mM) decreased dissociation half-life in ventricle with no change in atria. It is concluded that both bradycardic agents possess some but not all characteristics of weak agonists in binding studies, and that they also bind to an allosteric site of the muscarinic receptors. Association with this site could possibly activate a mixed Na+/K+ inward pacemaker current (if) resulting in bradycardia.

Topics: Animals; Binding, Competitive; Cardiovascular Agents; Clonidine; Guanosine Triphosphate; Guinea Pigs; In Vitro Techniques; Isoindoles; Myocardium; Phthalimides; Quinuclidines; Quinuclidinyl Benzilate; Radioligand Assay; Rats; Receptors, Muscarinic

Topics: Adult; Aged; Cardiovascular Agents; Clonidine; Female; Heart Diseases; Hemodynamics; Humans; Male; Middle Aged; Postoperative Period; Time Factors

The cardiovascular effects of a specific bradycardic agent, AQ-A 39, were investigated in intact donor dogs and isolated and cross-perfused dog heart preparations. Intravenous administration of AQ-A 39 (10-1000 micrograms/kg) to the donor dog caused a dose-dependent heart rate decrease in the donor dog and a decreased atrial rate in the isolated atrium perfused by the donor's blood. The arterial blood pressure of the donor dog and contractile force of the atrial preparation were unchanged or slightly decreased. The direct injection of AQ-A (1-300 micrograms) into the sinus node artery of the isolated atrium caused dose-dependent negative chronotropic and slight, transient positive inotropic responses. Alinidine and verapamil caused marked negative chronotropic and inotropic responses. The negative chronotropic effect of AQ-A 39 was not modified by atropine. However, it was enhanced slightly but significantly by propranolol, indicating that AQ-A 39-induced bradycardia was antagonized partly by beta-adrenoceptor function. These results confirmed that AQ-A 39 selectively reduced sinus rate by a direct action on the sinus node. Furthermore, the potency of the bradycardiac action, compared with the decrease in contractility, was greater than for alinidine or verapamil. AQ-A 39 (300 micrograms) tended to depress norepinephrine (NE)-induced positive chronotropic but not inotropic effects in isolated atria. By contrast, verapamil (3-10 micrograms) significantly depressed the NE-induced positive inotropic but not the chronotropic effect, and propranolol (10 micrograms) suppressed both cardiac effects of NE. These data suggest that the AQ-A 39-induced, selective attenuation of the NE-induced chronotropic effect is not due to either calcium channel blockade or beta-adrenoceptor antagonism.

Topics: Animals; Cardiovascular Agents; Clonidine; Dogs; Dose-Response Relationship, Drug; Heart; Heart Atria; Heart Rate; Isoindoles; Myocardial Contraction; Phthalimides; Verapamil

(1) The "specific bradycardic agent" alinidine reduces the slope of the diastolic depolarization in sinoatrial tissue and Purkinje fibers. In short Purkinje fibers of sheep, alinidine (28 microM) decreased the pacemaker current by a dual action. The voltage dependence of if activation was shifted in the hyperpolarizing direction by 7.8 +/- 0.6 mV (n = 18, p less than 0.001) and the conductance of the fully activated if current was reduced to 73 +/- 2% (n = 18, p less than 0.001) of its control value. These effects were reversible and dose-dependent. (2) Ionophoretic injections of alinidine caused reversible reductions of the diastolic depolarization rate and simultaneous transient hyperpolarizing shifts of the if activation range. (3) Some prolongation of the action potential duration was observed at 28 microM and more pronounced at higher concentration. This was presumably the consequence of a reduction by alinidine of outward repolarizing current carried by the background inward rectifier and plateau current ix. (4) The action of alinidine on if resulted in a slower activation of a reduced fraction of the pacemaker current at the maximal diastolic potential level. This explains the decrease of the diastolic depolarization rate observed in Purkinje fibers.

Topics: Action Potentials; Animals; Biological Clocks; Cardiovascular Agents; Clonidine; Heart Conduction System; In Vitro Techniques; Iontophoresis; Kinetics; Membrane Potentials; Purkinje Fibers; Sheep

The effects of alinidine on negative chrono- and inotropic responses to cholinergic interventions, i.e., intramural vagal nerve stimulation and an injection of acetylcholine (ACh) or carbachol, were investigated in isolated, blood-perfused canine atrial preparations perfused by arterial blood from donor dogs. Vagal nerve stimulation (5, 10 or 30 Hz) and an injection of ACh (0.17-1.65 nmol) or carbachol (0.05-0.55 nmol) induced frequency-dependent and dose-dependent negative chrono- and inotropic responses, respectively. These responses were reproducible in the same preparation. During the negative chrono- and inotropic responses to alinidine (85-854 nmol), cardiac responses to cholinergic interventions were depressed dose-dependently. The depressive effects of alinidine on the negative chronotropic responses were significantly (P less than .05) greater than those on the negative inotropic ones. However, alinidine did not affect adenosine-induced negative cardiac responses. Atropine (0.43-4.32 nmol) uniformly blocked responses to cholinergic intervention dose-dependently. The potency of the antimuscarinic effect of alinidine was approximately 1/200 to 1/500 of the potency of atropine at the 50% inhibition dose for responses to vagal stimulation, carbachol and ACh. Intravenous administration of alinidine (1 mg/kg) to the donor dog also suppressed cardiac responses to choline esters and vagal stimulation in the isolated atrium perfused by the donor's blood. These results suggest that alinidine has suppressive effects on the negative chrono- and inotropic responses to exogenous choline esters and endogenous ACh from parasympathetic nerve terminals at the post-junctional cholinergic muscarinic receptors in the dog heart.

Topics: Acetylcholine; Adenosine; Animals; Atropine; Carbachol; Cardiovascular Agents; Clonidine; Depression, Chemical; Dogs; Electric Stimulation; Heart Rate; Myocardial Contraction; Vagus Nerve

Electrophysiological effects of alinidine on rabbit sino-atrial node cells were examined. Alinidine was applied in concentrations between 0.3 and 100 micrograms/ml and decreased the spontaneous frequency in a dose-dependent manner. The maximum rate of rise and the amplitude of action potentials of the spontaneously beating rabbit sino-atrial node were decreased in the presence of alinidine concentrations higher than 10 and 100 micrograms/ml, respectively. The maximum diastolic potential was depolarized by alinidine at 100 micrograms/ml. The main effect of alinidine was a dose-dependent decrease in slope of diastolic depolarization (a prolongation of the cycle length) and a delayed repolarization of the action potential. In voltage clamp experiments, alinidine suppressed the slow inward current (Is) and the outward current (Ik) dose dependently, without altering steady-state inactivation of Is (f infinity) and the activation of Ik (p infinity). The hyperpolarization-activated inward current (Ih) was also reduced. These results suggested that alinidine decreased Is, Ik and Ih due to reduction in the conductance of these current systems. The changes in the ionic currents in the presence of alinidine can explain the changes in configuration of the action potential and must contribute to the negative chronotropic action of alinidine.

Topics: Action Potentials; Animals; Cardiovascular Agents; Clonidine; Depression, Chemical; Diastole; Dose-Response Relationship, Drug; Electrophysiology; Female; In Vitro Techniques; Male; Membrane Potentials; Rabbits; Sinoatrial Node

The effects of the bradycardiac agent alinidine on hemodynamic parameters and regional contractile function were investigated in 6 chronically instrumented dogs trained to submit to 5 consecutive treadmill exercise runs. The experiments were performed during stenosis of the circumflex branch of the left coronary artery (LCX). After 2 control runs which had induced regional contractile dysfunction of comparable intensity, alinidine was infused intravenously at a dosage of 1 mg/kg per 5 min. The drug significantly reduced the resting function of both the LCX area (-16%) and the area perfused by the unstenosed anterior descending branch of the left coronary artery (LAD, -3%). However, the exercise-induced dysfunction of the LCX area was markedly improved in the 1st post-drug run and completely abolished during the 2nd and 3rd post-drug runs. As indicated by the reduction of heart rate (-18%) and positive dp/dtmax (-24%) during peak exercise, this improvement may be attributed to a bradycardiac and a negative inotropic effect of this drug. Further benefit may be ascribed to a decreased in arterial blood pressure after alinidine.

Topics: Animals; Cardiovascular Agents; Clonidine; Dogs; Female; Heart Rate; Hemodynamics; Male; Myocardial Contraction; Physical Exertion; Time Factors

Propranolol (0.5 mg X kg-1 X 5 min-1), alinidine (1 mg X kg-1 X 5 min-1) and the benzazepinon UL-FS 49 (0.5 mg X kg-1 X 5 min-1) were investigated in a canine model of exercise-induced transient myocardial dysfunction, mimicking exercise-induced functional impairment during angina pectoris in man. Each drug was infused intravenously, after two control treadmill exercise runs had shown comparable, ultrasonically assessed regional contractile dysfunction in an area supplied by a partly stenosed branch of the left coronary artery. All three drugs abolished exercise-induced regional contractile dysfunction. Propranolol and alinidine comparably decreased heart rate and positive dp/dtmax during exercise. UL-FS 49 showed a marked negative chronotropic effect without affecting positive dp/dtmax. Thus, prevention of exercise-induced regional contractile dysfunction has been shown for the first time using a selective bradycardic agent.

Topics: Animals; Arrhythmias, Cardiac; Benzazepines; Cardiovascular Agents; Clonidine; Dogs; Hemodynamics; Male; Myocardial Contraction; Physical Exertion; Propranolol

The direct effects of alinidine (N-allyl-clonidine) on the sinus node and atrioventricular (AV) junction were studied in 18 anesthetized dogs. Stimulus frequency-response curves to right stellate ganglion and right cervical vagus stimulations as well as responses to norepinephrine or acetylcholine were determined before and after selective perfusion of alinidine into the sinus node artery. Alinidine (1 microgram/ml) had no effect on spontaneous sinus rate [148 +/- 5 (SE) beats/min]. However, alinidine concentrations of 5, 10, and 25 micrograms/ml produced significant (P less than 0.05) sinus slowing to 138, 127, and 121 beats/min, respectively. Recovery to control rate was dose dependent and took from 4 to 33 min. Sinus rate increases with right stellate stimulations were not affected by alinidine. However, sinus rate decreases with right vagal stimulations were significantly (P less than 0.01) attenuated by alinidine. The negative chronotropic effects of acetylcholine were not influenced by alinidine. Alinidine (1-100 micrograms/ml into AV node artery) had no effect on the A-H interval of the His bundle electrogram. However, alinidine (10 and 25 micrograms/ml) diminished the AV block produced by stimulation of the left vagus in electrically paced hearts but not the negative dromotropic actions of directly administered acetylcholine. Thus alinidine has direct negative chronotropic effects, no effect on sinus node responses to sympathetic stimulation, ability to diminish sinus node and AV junctional responses to vagal stimulations without interference at the cholinergic muscarinic receptor, and 4) no effect on AV nodal conduction.

Topics: Acetylcholine; Animals; Atrioventricular Node; Atropine; Cardiac Pacing, Artificial; Cardiovascular Agents; Clonidine; Depression, Chemical; Dogs; Electric Stimulation; Electrocardiography; Female; Heart Conduction System; Heart Rate; Male; Norepinephrine; Parasympathetic Nervous System; Parasympatholytics; Premedication; Propranolol; Sinoatrial Node; Stellate Ganglion; Time Factors; Vagus Nerve

Ligation of the left anterior descending coronary artery was performed in open-chest anaesthetized rats and mortality as well as changes in ECG were evaluated for 30 min thereafter. Saline or drugs were administered 15 min prior to ligation. In the control group, following a 4 min lag period ventricular arrhythmias as single ectopic beats, ventricular tachycardia and ventricular fibrillation (VF) appeared, reaching a maximum between 10 and 20 min and disappearing after 30 min. Mortality (40% in the control group) coincided with the period of maximal arrhythmias, with VF more common in animals that died than in those surviving. Alinidine, a drug which reduces sino-atrial rate specifically but has no conventional antiarrhythmic properties, reduced mortality and VF. By means of order statistics the quantity 'risk of death' was used for evaluation of drug effects, considering incidence of death and VF as well as duration of VF. This quantity was reduced in correlation with the dose of alinidine (1-6 mg/kg i.v.) and in correlation with the reduction of heart rate. Mexiletine, an antiarrhythmic drug with membrane-depressant properties, also reduced the 'risk of death' dose dependently (1-10 mg/kg i.v.), but there was no correlation with a decrease in heart rate. It is suggested that alinidine reduced 'risk of death' by means of a reduced oxygen demand due to a decrease in heart rate.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiovascular Agents; Clonidine; Coronary Disease; Electrocardiography; Heart Rate; Hemodynamics; Male; Mexiletine; Rats; Rats, Inbred Strains; Risk; Ventricular Fibrillation

Selectivity of alinidine for SA nodal automaticity vs. other cardiac activities was investigated using isolated, blood-perfused SA node, AV node and papillary muscle preparations of the dog. The drug was administered intra-arterially. In SA node preparations alinidine (1 microgram-1 mg) produced a dose-dependent decrease of sinus rate down to about 74% of the basal value at 1 mg, but no atrial standstill. In AV node preparations alinidine, injected into the posterior septal artery (PSA) which supplies the AV node, prolonged AV conduction time up to about 124% of the basal value but only in large doses (30 micrograms-1 mg). In the same preparations, when injected into the anterior septal artery, which supplies structures from the His bundle down to the ventricular septum (the intraventricular conduction system), alinidine in large doses (300 micrograms-1 mg) also prolonged AV conduction time nearly to the same extent as when injected into the PSA. In both cases neither second- nor third-degree AV block occurred. In paced papillary muscle preparations alinidine reduced the force of contraction down to about 64% of the basal value but in large doses (100 micrograms-1 mg). In spontaneously beating papillary muscle preparations alinidine reduced the rate of ventricular automaticity down to about 78% of the basal value but in large doses (100 micrograms-1 mg). Alinidine (100 micrograms-1 mg) produced a transient increase in blood flow in these preparations but not in SA node preparations. The cardiac effects of alinidine were longer-lasting than its vascular effect and the reduction of sinus rate was particularly long-lasting. The order of selectivity of alinidine determined from the above results is as follows: SA nodal automaticity much greater than ventricular automaticity greater than intraventricular conduction divided by AV nodal conduction divided by cardiac muscle contraction divided by coronary blood flow. Such a cardiovascular profile of alinidine is different from that of AQ-A 39, another bradycardic agent, which is nearly equi-effective on both SA nodal and ventricular automaticity.

Topics: Animals; Atrioventricular Node; Cardiovascular Agents; Clonidine; Coronary Circulation; Dogs; Female; Heart; Heart Rate; In Vitro Techniques; Male; Myocardial Contraction; Sinoatrial Node

The effect of alinidine on transmembrane electrical activity of nodal and atrial fibers was studied in the isolated right auricle of the guinea-pig. Alinidine was applied in concentrations between 0.72 and 28.5 X 10(-5) M. In nodal fibers the main effect was a dose-dependent decrease in rate of diastolic depolarization and a delayed repolarization of especially the terminal part of the action potential. In both fiber types alinidine causes a marked delay of the terminal part of repolarization; the increase of the duration of the action potential was related to the alinidine concentration over the whole concentration range used. In addition the amplitude of the action potential and the maximal diastolic potential are increased dose dependently up to a concentration of 2.8 x 10(-5) M. Application of higher concentrations does not increase these parameters. In nodal fibers diastolic depolarization is already depressed considerably at a relatively low concentration. This is particularly so in fibers that normally have a high rate of diastolic depolarization, i.e., the dominant pacemaker fibers. A shifting of the pacemaker seems only to occur at high concentrations (11.4 X 10(-5) M or higher). The strong negative chronotropic effect of alinidine can be attributed to both the depression of diastolic depolarization and the increase in duration of the action potential. At low concentrations the increase of the maximum diastolic potential can also contribute to the slowing of the heart rate.

Topics: Action Potentials; Animals; Cardiovascular Agents; Clonidine; Diastole; Female; Guinea Pigs; Heart; Heart Atria; In Vitro Techniques; Sinoatrial Node

Alinidine is a new sinus node inhibitor which does not interact with the beta adrenergic receptors. Its haemodynamic effects were studied in 57 patients; 24 with unstable angina, 9 with myocardial infarction and heart rate greater than 100 bpm but without heart failure. 10 with myocardial infarction treated with vasodilators and 14 with severe heart failure or shock. After dosages up to 40 mg alinidine, heart rate decreased by 14 +/- 7 bpm, mean arterial pressure was reduced by 3 +/- 6 mmHg, stroke volume remained unchanged while cardiac output decreased 0.5 +/- 0.61 min-1 and systemic vascular resistance increased. Signs of heart failure developed in 3 patients, although overall left ventricular filling pressure remained unchanged. The haemodynamic response to alinidine warrants further studies of its efficacy in patients with angina or sinus tachycardia.

Topics: Adult; Aged; Angina Pectoris; Angina, Unstable; Cardiac Output; Cardiovascular Agents; Clonidine; Female; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction

Intracellular recordings were made from identified neurones in the brain of the snail, Helix aspersa. The effect of alinidine on the excitatory and inhibitory responses to acetylcholine and dopamine and on the excitatory response to 5-hydroxytryptamine (5-HT) was investigated. Alinidine was found to reduce the responses to acetylcholine and 5-HT and the excitatory response to dopamine but had no effect on the dopamine inhibitory response. pA2 values were determined for alinidine antagonism to indicate relative potency. The pA2 values against the excitatory responses of acetylcholine, dopamine and 5-HT were 5.8, 5.6 and 5.5 respectively. The pA2 value against acetylcholine inhibition was 3.5. From these studies it is suggested that alinidine interacts preferentially with the sodium inonophore, to a lesser degree with the chloride ionophore and not at all with the potassium ionophore on Helix central neurones.

Topics: Acetylcholine; Action Potentials; Animals; Brain; Cardiovascular Agents; Clonidine; Dopamine; Helix, Snails; Neurons; Serotonin; Sodium

The effects of N-allyl clonidine (St 567, alinidine), (0.5 mg/kg i.v.) a substance with specific bradycardic action at the sinus node, were studied on a total of thirteen patients in neuroleptanaesthesia and during controlled hypotension with sodium nitroprusside (SNP). Invariably, the fall in blood pressure was associated with an increase in heart rate (20.0 +/- 4.3+; P less than 0.01), presumably due to an activation of the arterial baroreceptor reflex. Alinidine decreased heart rate to the original level but no fall in cardiac output occurred a ventricular stroke volume and the calculated left ventricular stroke work were increased compensatorily (35.9 +/- 7.2% and 35.9 +/- 6.7%, P less than 0.01, respectively). In patients who received alinidine before the onset of controlled hypotension (n = 5) SNP failed to elicit an increase in heart rate. It is concluded that in patients under neuroleptanaesthesia tachycardiac does not play an important role for the maintenance of an adequate cardiac output during controlled hypotension with SNP.

Topics: Adult; Aged; Blood Pressure; Cardiac Output; Cardiovascular Agents; Clonidine; Ferricyanides; Heart Rate; Humans; Hypotension, Controlled; Middle Aged; Nitroprusside; Stroke Volume

The cardiovascular effects of dobutamine ( 7 micrograms/kg . min iv) and of additional N-allyl-clonidine (St 567, alinidine; 0.3 mg/kg iv), a compound which selectively inhibits the chronotropic effects of various stimulants, were studied in 9 patients scheduled for major abdominal surgery. Dobutamine increased cardiac index (CI), mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), and heart rate, but failed to change the left ventricular stroke volume (LVSV) significantly. Alinidine decreased cardiac rate and increased LVSV index and left ventricular stroke work index (LVSWI), whereas CI, MAP, and MPAP remained virtually unaffected. Similar results were obtained when the combination of dobutamine and alinidine was given to 4 patients in neuroleptanesthesia. Thus, the decrease in preload which is associated wit tachycardia seems to modify the increase in LVSV in response to inotropic stimulation with dobutamine.

Topics: Adult; Aged; Blood Pressure; Cardiac Output; Cardiovascular Agents; Catecholamines; Clonidine; Dobutamine; Drug Interactions; Heart Rate; Humans; Middle Aged; Stroke Volume; Surgical Procedures, Operative

The cardiocirculatory effects of N-allyl clonidine (ST 567, alinidine), a substance with specific bradycardiac action at the sinus node [Kobinger et al. 1979], were studied in 30 patients undergoing noncardiac surgery in neuroleptanesthesia. Alinidine (0.5 mg/kg i.v.) alleviated both spontaneous and reactive tachycardia, i.e., in response to deliberate hypotension with sodium nitroprusside (3.0 +/- 1.8 micrograms/kg i.v.), (decrease in heart rate from control: 20.7 +/- 5.7% and 25.4 +/- 3.2%, respectively), without affecting mean arterial blood pressure substantially. The slight but significant reduction in cardiac output can be explained, at least in part, by the decrease in heart rate, since the left ventricular stroke volume showed a tendency to increase and the mean pulmonary artery pressure failed to change significantly. Thus, alinidine may be useful for reducing heart rate and myocardial oxygen consumption in patients under neuroleptanesthesia.

Topics: Adult; Aged; Blood Pressure; Cardiovascular Agents; Clonidine; Heart Rate; Hemodynamics; Humans; Middle Aged; Neuroleptanalgesia; Nitroprusside

Topics: Animals; Cardiovascular Agents; Cats; Clonidine; In Vitro Techniques; Muscle Relaxation; Myocardial Contraction; Papillary Muscles; Sarcoplasmic Reticulum

Alinidine (ST 567, N-Allyl-Clonidine) exerted concentration-dependent negative chronotropic effects in isolated, spontaneously-beating sinus node cells and Purkinje fibres of guinea pigs and in ventricular strips of chick embryonic myocardium. Reduction of beat frequency by 30% was found after addition of 8.6 mumol/l alinidine in the former. A chronotropic effect was not seen during Ba2+-induced automaticity or triggered activity in guinea-pig papillary muscles and in enzymatically disaggregated cells of embryonic chick myocardium, which lose the beta-adrenoceptor responsiveness of the intact embryonic ventricle. In contrast to alinidine, D600 showed very pronounced and quinidine minor negative chronotropic effects in these latter experiments. Reduction of excitability, rate of rise of the action potential and velocity of repolarization as well as prolongation of the refractory period were seen after applications of very high concentrations of alinidine (285 mumol/l). In electrically-driven atria isometric peak tension was only slightly changed (increased by 85.5 mumol/l, decreased by 285 mumol/l) but it was reduced (to 36.8%) by alinidine (85.5 mumol/l) in papillary muscles. Both in atria and in papillary muscles, the maximum rate of rise of the action potential was unchanged by alinidine up to 85.5 mumol/l and the slight reduction following 285 mumol/l alinidine application was independent of the rate of stimulation. The present findings confirm the selectivity of the bradycardic effects of alinidine which has a main mode of action different to that of membrane stabilizing compounds or inhibitors of the slow inward current.

Topics: Action Potentials; Animals; Barium; Bradycardia; Calcium; Cardiovascular Agents; Chick Embryo; Clonidine; Guinea Pigs; Heart; Heart Conduction System; In Vitro Techniques; Muscle Tonus; Papillary Muscles

Alinidine, a new compound which reduces heart rate in man and animals, has a selective action on the sinus node. The dose-response relation between alinidine and frequency is not altered by atropine, and alinidine does not block the positive chronotropic action of isoprenaline. Alinidine has no negative inotropic action and has no effect on the linear relation between extracellular Ca and force of myocardial contraction. Alinidine did not alter the slope of the relation between frequency and external calcium concentration. Intracellular recordings showed that alinidine had no effect on the maximum rate of depolarisation or overshoot potential of rabbit atrial muscle, nor was conduction velocity, electrical threshold or maximum follow frequency affected. It was concluded that alinidine did not restrict current through fast inward channels. Alinidine did not increase resting potential or accelerate repolarisation, suggesting that potassium conductance was not increased. The effect of alinidine on frequency was not increased in 14 mmol . litre-1 KCl, or decreased in 2.24 mmol . litre-1 KCl, suggesting that the attachment of alinidine to receptors was not voltage-dependent. Spontaneous frequency was higher when NaCl was replaced by NaBr, and the bradycardic effect of alinidine was increased. Conversely, frequency was lower in NaCH3SO4 and the slope of the dose-response curve decreased. Intracellular recordings from sinus node cells showed that alinidine decreased the slope of the slow diastolic depolarisation and increased action potential duration, without altering the overshoot, the maximum diastolic potential, or the "take-off" potential. A possible explanation for these results is that alinidine restricts current through anion-selective channels. If so, the high potency of alinidine suggests that anionic current normally carries a substantial fraction of the current causing slow diastolic depolarisation.

Topics: Animals; Atrial Function; Atropine; Cardiovascular Agents; Clonidine; Dose-Response Relationship, Drug; Electrolytes; Female; Heart Atria; Heart Rate; Hydrogen-Ion Concentration; In Vitro Techniques; Isoproterenol; Male; Membrane Potentials; Myocardial Contraction; Rabbits; Sinoatrial Node

Radioactively labelled alinidine was administered intravenously (10 mg) and orally (40 mg) to 5 healthy volunteers and beagle dogs (3 animals for each administration route: 0.1 mg/kg body weight i.v. and 1 mg/kg body weight p.o.). Alinidine was totally absorbed in both species. Regardless of the route of administration man excreted the drug via the kidneys within 12 hours, almost entirely in the unchanged form. The blood plasma curves in man followed a multiexponential decline (t 1/2 alpha : 35 sec, t 1/2 beta : 44 min, t 1/2 gamma : 210 min). The maximum plasma levels of the drug were recorded in man, 45 min after oral administration. However, the rather slow decline of plasma radioactivity observed in dogs, corresponded well with the delayed urinary excretion of alinidine (50% of the administered dose) in this species. Dogs metabolized the drug extensively; seven different metabolites including the parent compound were isolated from canine urine. considerable interindividual differneces were found concerning the quantitive but not the qualitative metabolic pattern of alinidine in dogs. Structural analysis by mass spectrometry revealed oxidation, hydroxylation, and cleavage products of alinidine, altered in its imidazolin and/or allylic moiety. In both species no traces of clonidine were found, which was a predicted metabolite formed by the removal of the allylic sidechain of alinidine.

Topics: Administration, Oral; Animals; Autoradiography; Biotransformation; Carbon Radioisotopes; Cardiovascular Agents; Chemical Phenomena; Chemistry; Chromatography, Thin Layer; Clonidine; Dogs; Female; Humans; Injections, Intravenous; Kinetics; Male; Mass Spectrometry

Changes in the exercise ECG caused by five different drugs are presented. Analysis of these changes indicate that these are related to the hemodynamic effects of the drugs, rather than to reduction of myocardial ischemia. Calcium antagonists (Verapamil) as well as drugs which reduce heart rate (Alinidine, Propranolol) do not change the relation between ST depression and heart rate in a given patient. Drugs which lower ventricular volume (Molsidomine, Nitroglycerine) reduce the amount of ST depression at the same heart rate during exercise.

Topics: Cardiovascular Agents; Clonidine; Double-Blind Method; Electrocardiography; Exercise Test; Heart Rate; Hemodynamics; Humans; Propranolol; Vasodilator Agents; Verapamil

The pharmacokinetics of alinidine was investigated in two groups of volunteers: Group I (N=5) received on two occasions single doses of 14C-labelled drug given orally (40 mg) or intravenously (10 mg); Group II (N=6) received single oral doses 10, 30, or 90 mg dissolved in 20 ml water. The samples from Group I were analysed by two different and independent methods (RIA and counting total radioactivity). The results obtained by the two methods were identical, since the compound was not metabolized. The plasma concentrations and renal excretion data obtained from both groups were individually fitted to an open three compartment model. Independent of the route of administration and of the doses given, similar pharmacokinetic parameters were calculated for each group and each trial. The half lives of the distribution and elimination phases were t1/2 alpha: 36-41s, t1/2 beta: 9.9-11.1 min and t 1/2 gamma: 2.7-3.8h. There was a linear relationship between the dose administered and the resulting areas under the plasma concentration curves (AUC). Following a lag period (tau =0.19-0.22h), the peak plasma concentration was reached 0.6-1.2h after oral administration. Oral alinidine was 100% bioavailable.

Topics: Administration, Oral; Adult; Cardiovascular Agents; Clonidine; Humans; Kinetics; Male; Models, Biological; Radioimmunoassay

Topics: Cardiovascular Agents; Clonidine; Humans

The effects of alinidine (0.2-6.0 mg . kg-1), an N-allyl derivative of clonidine, were investigated on systemic and regional haemodynamics, in particular myocardial perfusion and performance in the domestic pig, during or in the absence of atrial pacing. The drug had a pronounced bradycardic action and also caused dose-dependent reductions in the maximum rate of rise in left ventricular pressure (max LVdP/dt) cardiac output (CO), arterial blood pressure and in the mean velocity of systolic wall thickening (VSWT) in the absence of atrial pacing. Since the duration of systole was prolonged by alinidine, the total wall thickening during systole (SWT) remained unchanged until the highest dose was given. When the heart rate was kept constant by atrial pacing, there were no changes in the maxLVdP/dt, CO or VSWT with with lower doses (less than 0.4 mg . kg-1) of alinidine. With higher doses, however, there was a significant reduction in these variables, demonstrating a clear negative inotropic action of the drug. The decrease in CO was entirely at the expense of its nutrient fraction (NCO), since systemic arteriovenous anastomotic flow remained unchanged. However, the reduction in NCO did not hamper tissue oxygenation either because of autoregulation within blood vessels (cerebral and renal), or because the tissues were able to extract more O2 from the blood. Similarly, despite the reduction of myocardial perfusion, no imbalance in the myocardial oxygen supply-demand relationship was noticed due to a simultaneous reduction of the myocardial work in both unpaced and paced hearts. Moreover, the changes in the intramyocardial blood flow were quite uniform. It is concluded that alinidine has a negative chronotropic and, in higher doses, a negative inotropic action. The cardiovascular profile of the drug suggests that it could be useful in patients with ischaemic heart disease.

Topics: Animals; Blood Pressure; Cardiac Output; Cardiovascular Agents; Cerebrovascular Circulation; Clonidine; Coronary Circulation; Electrocardiography; Heart; Heart Rate; Hemodynamics; Kidney; Myocardial Contraction; Oxygen Consumption; Pacemaker, Artificial; Perfusion; Stroke Volume; Swine; Vascular Resistance