Cardioactive Drugs Research Articles

Three dimensional closed loop control of the human circulation

In the control of the circulation it is suggested there is merit in describing states which are the object of each therapy. Considering the determinants of venous return rather than those of cardiac output, we suggest that the mean systemic filling pressure is a parsimonious description of the volume state. A method is described of deriving a mean systemic filling pressure analogue based on stopping the flow in a notional regional systemic circulation. The mean systemic filling pressure (PM) forms a quantitative link between volume therapy and circulatory dynamics. The systemic vascular resistance is a conventional measure of the state of arteriolar resistance. We suggest that the ratio (PM - PRA)/PM (where PRA is the right atrial pressure) is a global measure of the effect of cardioactive drugs. Studies are reported in which the mean blood pressure, right atrial pressure and cardiac output are simultaneously controlled within desired tolerances using state based control.

Atrial Antitachycardia Pacing in Patients with Supraventricular Tachycardia: Clinical Experience with the Intertach Pacemaker

During a 3-year period, 22 patients with recurrent supraventricular tachycardia have been treated with antitachycardia pacemakers (Intermedics Intertach, 262-12, n = 17, and Intertach II, 262-16, n = 5). Eighty-two percent were female, the mean age was 44 +/- 14 years; 86% had atrioventricular node reentrant tachycardia. Symptoms had occurred over 11.8 +/- 7.1 years, with 3.6 hospital admissions per patient, despite 4.7 +/- 2.1 antiarrhythmic drugs. Following pacemaker implantation, during a follow-up of 14.8 +/- 11.5 months, only two patients have been readmitted to a hospital because of supraventricular tachycardia (mean 0.1 per patient). One patient is taking an antiarrhythmic agent, and four are taking beta adrenergic blocking agents. Thus, 23% are taking cardioactive drugs (it was anticipated that two patients would continue on drugs after pacemaker implantation). There have been no serious complications. Atrial antitachycardia is thus an effective therapy in carefully selected patients with recurrent supraventricular tachycardia, reducing hospital admissions for supraventricular tachycardia and reducing the need for antiarrhythmic drugs.

Long‐term follow‐up in isolated ventricular septal defect considered too small to warrant operation

An isolated ventricular septal defect (VSD) was diagnosed in 70 patients (39 men and 31 women, mean age 29 years, range 10-64 years). Surgery was judged unnecessary. The follow-up period was at least 10 years, or until death or 31 December 1988, comprising a mean duration of 21 (range 6-29) years. The mortality was 11/69 (one lost to follow-up), and was not significantly higher than in a matched 'normal' group. Six deaths were cardiac, four of which could probably be related to the VSD. The follow-up study revealed that: (1) 14 (22%) subjects had major, VSD-related complications, and cardiac surgery was indicated in eight patients; (2) six (10%) had minor complications. By the end of 1988, 24% of subjects had significant dyspnoea, 22% had chest pain and 19% used cardioactive drugs. Only 33% were receiving regular cardiac control in a hospital. Thus unoperated adults with a small VSD should be monitored closely, since this condition is far from benign.

Myocardial Protection: What the Anesthesiologist Does

The role of the anesthesiologist in myocardial protection is to optimize myocardial oxygen balance during the perioperative period. Nonpharmacological steps that can be taken to achieve this revolve around maintaining a satisfactory hemoglobin concentration and oxyhemoglobin saturation through maximizing ventilation. In addition, alkalosis and hypothermia should be prevented since they cause a left shift of the oxyhemoglobin dissociation curve, thus interfering with tissue oxygen delivery. Hypocarbia increases coronary vascular resistance. Blood volume must be adequate with an optimal hemoglobin concentration. Pharmacological measures should also be used, and it is important to continue through the perioperative period any previously administered cardioactive drugs. Furthermore, in the prebypass period, tachycardia may not be controlled by anesthetics; unless the tachycardia is paroxysmal, beta blockers are the drugs of choice. Depending on the cause, diastolic hypotension also needs to be treated either with volume, vasoconstrictors, or inotropes. Likewise, major hypertension can produce increased demand and, again depending on the cause, either anesthetics, vasodilators, beta blockers, or calcium blockers may be useful. Finally, myocardial ischemia without obvious cause probably should be treated with nitroglycerin or calcium blockers. During surgery, the effect of the anesthetic drugs on myocardial oxygen balance is important.

Interaction between methylxanthine and cardioactive drugs

Interaction between methylxanthine and cardioactive drugs

The Isolated Mouse Atria as a New Model for Testing Cardioactive Drugs with Special Reference to Doxorubicin (Adriamycin®)

Spontaneously beating isolated atria from mice were used as a new in vitro model to characterize the mechanism of the cardiotoxic action of the anthracycline cytostatic doxorubicin (Adriamycin). After stabilization at 28 degrees the atria showed a contractile rate and--force of 284 +/- 31 (S.D.) beats/min. and 49 +/- 6.5 mg. Doxorubicin (Dox) (10(-6)-10(-5) M) had a positive chronotropic action per se and decreased the pD2 for the chronotropic action of isoprenaline in a dose-dependent way. However only the effect of the higher concentration proved statistically significant, a concentration which also caused a marked decrease (63%) of the Emax. Pretreatment with Dox 15 mg/kg intraperitoneally 72 hr previously did not influence the pD2 but caused a significant increase in the Emax of the isoprenaline concentration response curve. The results indicate that Dox in vitro interferes with the beta-adrenoceptor function of isolated mouse atria in an unspecific way and that the subacute cardiotoxicity of Dox in mice is probably not due to interference with the beta-adrenoceptor system. Further it is concluded that isolated atria from mice may be a useful model for testing cardioactive drugs.

A single dose of cilazapril improves diastolic function in hypertensive patients

We studied the effect of a single dose of cilazapril, 5.0 mg orally, on systolic and diastolic cardiac function in eight hypertensive patients using a double-blind crossover placebo-controlled design. All patients had concentric left ventricular hypertrophy (measured by echocardiography), unimpaired systolic function (measured by radionuclide ventriculography), and long-standing hypertension treated by a combination of betablockers and diuretics. Radionuclide scintigraphy was performed with cilazapril and placebo, given one week apart. A two-week washout period of all cardioactive drugs preceded the study. Within three hours after oral administration of cilazapril, the time to peak filling rate of the left ventricle, expressed as a percentage of diastole, was reduced from 44.5 ±13.2 percent to 31.2 ±7.2 percent (p <0.05). Systolic blood pressure was also significantly reduced by cilazapril. Heart rate was slightly reduced. Left ventricular ejection fraction, peak filling rate, and the absolute time to peak filling rate were not significantly altered. Cilazapril improves a sensitive index of diastolic cardiac function in hypertensive patients.

A single dose of cilazapril improves diastolic function in hypertensive patients

We studied the effect of a single dose of cilazapril, 5.0 mg orally, on systolic and diastolic cardiac function in eight hypertensive patients using a double-blind crossover placebo-controlled design. All patients had concentric left ventricular hypertrophy (measured by echocardiography), unimpaired systolic function (measured by radionuclide ventriculography), and long-standing hypertension treated by a combination of beta-blockers and diuretics. Radionuclide scintigraphy was performed with cilazapril and placebo, given one week apart. A two-week washout period of all cardioactive drugs preceded the study. Within three hours after oral administration of cilazapril, the time to peak filling rate of the left ventricle, expressed as a percentage of diastole, was reduced from 44.5 +/- 13.2 percent to 31.2 +/- 7.2 percent (p less than 0.05). Systolic blood pressure was also significantly reduced by cilazapril. Heart rate was slightly reduced. Left ventricular ejection fraction, peak filling rate, and the absolute time to peak filling rate were not significantly altered. Cilazapril improves a sensitive index of diastolic cardiac function in hypertensive patients.

An improved method to correct the QT interval of the electrocardiogram for changes in heart rate

The adequacy of the Bazett formula to correct for heart rate-induced changes in the QT interval of the electrocardiogram has been frequently questioned. In the present study, a simple linear equation was derived, which in anesthetized dogs corrects more adequately for changes in heart rate than the Bazett formula. Regression analysis of experimental data yielded the following equation: QT c = QT − 0.087 (RR − 1000) = QT − 87 ( 60 HR − 1) The reliability of this equation was investigated in experiments on anesthetized dogs with different cardioactive drugs with a known mechanism of action.

Differential effects of amiodarone and propranolol on lipid dynamics and enzymatic activities in cardiac sarcolemmal membranes

The amphiphilic cationic cardioactive drugs (pindolol, propranolol and amiodarone) were tested for their effects on lipid dynamics (measured by fluorescence depolarization) and on enzymatic activities up to 1 mM in purified cardiac sarcolemmal vesicles from adult rat. The vesicles were enriched 12- to 37-fold (with respect to tissue homogenate) in Na +/K + ATPase, K +-stimulated p-nitrophenylphosphatase, 5'nucleotidase and adenylate cyclase, all of which are believed to be components of sarcolemma. Phospholipids and cholesterol content were enriched 5- and 13-fold respectively. There was very little contamination of the sarcolemmal vesicles by sarcoplasmic reticulum (as judged by Ca 2+ ATPase and glucose-6-phosphatase activities) or mitochondria (as judged by cytochrome- c-oxidase activity). Pindolol had no effect on lipid dynamics and enzyme activities except for the isoproterenol-stimulated adenylate cyclase. The latter was also totally inhibited at 1 μM by propranolol which inhibited Mg 2+ ATPase and increased fluidity above 20 μM. Amiodarone affected all the enzyme activities (except Na +/K + ATPase): isoproterenol-stimulated adenylate ( IC 50 = 30 μ M) , Mg 2+ ATPase ( ic 50 = 20 μ M) and K +-stimulated- p-nitrophenylphosphatase were inhibited; 5'nucleotidase was activated above 2 μM. By contrast with propranolol, amiodarone decreased lipid mobility. The effect was linear with the concentration of the drug above 1 μM.

Effect of calcium entry and β blockade during infrarenal aortic clamping

Clamping and declamping during aortic surgery produce a hemodynamically significant myocardial stress. The cardiovascular (CV) response to this stress may be adversely altered by calcium antagonists and β-adreno-receptor blockade employed to control symptomatic coronary artery disease. This study evaluated the effect of verapamil (V), propranolol (P), and their combination (P + V) on the CV response to infrarenal abdominal aortic cross-clamping and declamping in anesthetized dogs. Six dogs received P as a bolus of 0.5 mg/kg 20 min before clamping. Six additional dogs received V as a 300 μg/kg bolus followed by a V infusion of 6 μg/kg/min for 20 min before clamping. A third group of six dogs received the P bolus followed 20 min later by the V regimen (P + V). In both the V and P + V groups, 6 μg/kg/min V was infused throughout the clamping and declamping sequence. A fourth group of six control dogs received no cardioactive drugs during the experiment. Heart rate, mean aortic blood pressure, left ventricular end-diastolic pressures, peak rate of rise of left ventricular pressure, cardiac output, and systemic vascular resistance were measured in all animals before aortic cross-clamping, at 5 and 40 min after clamping, and 5 min after declamping. The results demonstrated additive negative chronotropic and inotropic properties of P + V therapy with a more significantly adverse effect than that of either drug alone. The implications of this study warrant added caution when patients treated with these drugs undergo abdominal aortic surgery.

The effect of drugs and lead maturation on atrial electrograms during sinus rhythm and atrial fibrillation

Antitachycardia devices need more accurate means to identify arrhythmias. Previous studies have found that sinus rhythm can be distinguished from a variety of tachyarrhythmias by algorithms that are based on time-domain and frequency-domain analysis of intracardiac electrograms. Amplitude distribution analysis (time-domain) and power density spectral analysis (frequency-domain) are two of the techniques that have seemed to hold promise. However, previous studies have not evaluated whether lead maturation or drugs such as lidocaine, propanolol, verapamil, or isoproterenol can interfere with the ability of these algorithms to distinguish among cardiac rhythms. In the present study, five dogs had permanent atrial pacing leads placed. On a series of days, recordings were made from the atrial leads during sinus rhythm and induced sustained atrial fibrillation, both before and after administration of cardioactive drugs. For up to 1 month after implantation, progressive lead maturation did not prevent differentiation of atrial fibrillation from sinus rhythm by either amplitude distribution analysis or power density spectral analysis. However, the difference between the power density spectra of sinus rhythm and atrial fibrillation became progressively less with time. Isoproterenol, lidocaine, verapamil, and propranolol had no consistent effects on amplitude distribution analysis of atrial electrograms during sinus rhythm or atrial fibrillation. However, there were marked effects of drugs on amplitude distribution characteristics in individual dogs. Propranolol and lidocaine produced consistent changes in power density spectra during sinus rhythm and atrial fibrillation, respectively; both drugs reduced the ability of power density spectral analysis to differentiate sinus rhythm from atrial fibrillation. These results indicate that the incorporation of algorithms based on waveform analysis into antitachycardia devices may be a more formidable challenge than previously recognized.

Treatment of ventricular arrhythmias

Within the past 20 years, our knowledge concerning the epidemiology, natural history, and treatment of VT has expanded greatly. A variety of effective pharmacologic, surgical and electrical therapies for VT are now available to the clinician. Patients who present with ventricular, tachyarrhythmias should undergo a comprehensive medical evaluation directed at identifying and treating such factors as ischemia, congestive heart failure, valvular heart disease, sensitivity to cardioactive drugs, and metabolic derangements. Many patients who present with asymptomatic ventricular arrhythmias do not require specific antiarrhythmic drug therapy. However, certain patients who have already suffered a life-threatening arrhythmia or who are at high risk for such arrhythmia should be vigorously treated with specific antiarrhythmic therapy guided for that individual patient. The efficacy of any antiarrhythmic treatment should be assessed by ECG monitoring, exercise testing, and/or electrophysiologic study. In the near future, potentially revolutionary new electrical therapies for ventricular tachyarrhythmias will be evaluated. It is to be hoped that these devices used in combination with pharmacologic and surgical therapies may dramatically reduce the incidence of sudden cardiac death in high-risk patients.

Studies on cardio-active crude drugs; I. Effect of coumarins on cultured myocardial cells.

Studies on cardio-active crude drugs; I. Effect of coumarins on cultured myocardial cells.

Measurement of Cardioactive Drugs in Biological Samples by HPLC

Abstract Unmodified silica columns used with non-aqueous, usually methanolic, eluents containing an ionic modifier provide simple, flexible systems for the HPLC analysis of a wide range of basic cardioactive drugs and some quaternary ammonium compounds. Retention and peak shape are influenced primarily by eluent pH and ionic strength although changes in eluent composition and in the stationary phase may also prove useful. Recently it has been found that chemically-bonded strong cation exchange materials provide enhanced retention for analytes which are poorly retained on silica alone. Solvent extracts and elution fractions from bonded-phase extraction tubes may be analysed directly and, in addition to low-wavelength UV and fluorescence, electrochemical oxidation detection may be used routinely for a wide range of analytes including secondary and tertiary aliphatic amines.

Factors contributing to left ventricular diastolic dysfunction in long-term type I diabetic subjects.

Although non-invasive studies in type I diabetic subjects indicate left ventricular (LV) diastolic dysfunction, the contribution of borderline or mild hypertension to such changes is obscure. Thus, digitized M-mode echocardiograms were obtained in 32 (18 men) young (less than 50 years) normotensive controls and 32 (21 men) long-term (greater than or equal to 12 years) type I diabetics with blood pressures ranging from normal to hypertensive. All diabetics were without clinical heart disease, none were previously treated for hypertension or using cardioactive drugs. Heart rate, systolic and diastolic blood pressures were higher in diabetic than control subjects. Their LV end-diastolic dimension was smaller, whereas wall thickness, LV mass index and fractional shortening were similar to controls. In diabetics, however, the normalized peak filling rate was decreased and the rapid filling period fraction of diastole increased. In multivariate analysis, diabetes and LV mass independently and inversely influenced the normalized peak filling rate, while fractional shortening did so positively. Furthermore, diabetes and systolic blood pressure independently influenced the rapid filling period fraction of diastole. This study is the first to demonstrate systolic blood pressure and LV mass as independent contributors to subclinical LV diastolic abnormalities in diabetics. These findings may therefore indicate the need to treat even mild hypertension in diabetics in an effort to delay the development of cardiopathy.

Dietary Lipid Modulation of Myocardial (3-Adrenergic Mechanisms, Ca2+-Dependent Automaticity, and Arrhythmogenesis in the Marmoset

Dietary lipid supplements high in either saturated fatty acids derived from sheep perirenal fat or polyunsaturated fatty acids (65% linoleic acid) derived from sunflower seed oil were fed to marmoset monkeys (Callithrix jacchus) for 20 months. The effect of these long-term dietary lipid supplements on myocardial contractile function and their influence on responses to isoprenaline and external calcium concentration were examined using isolated papillary muscles and atria. Isoprenaline potency was increased by the sheep fat-supplemented diet, which induced significant three- to eightfold leftward parallel shifts of isoprenaline dose-response curves for papillary muscle and left atrial inotropy and right atrial chronotropy. The antagonist potency of propranolol was not influenced by diet. The incidence of isoprenaline-induced spontaneous tachyarrhythmias in electrically driven papillary muscles and left atria was reduced by the sunflower seed oil-supplemented diet and increased by the sheep fat diet, as were the spontaneous beat rate and calcium-dependent automaticity of right atria. These results show that dietary lipids can significantly modify stimulus-response coupling and alter the susceptibility to arrhythmogenesis in the heart of the nonhuman primate, and indicate that nutritional interventions may modify responses to cardioactive drugs as well as influence the development of cardiac disease.

Protective effect of different cardioactive drugs on the energy metabolism of the ischaemic myocardium

Protective effect of different cardioactive drugs on the energy metabolism of the ischaemic myocardium

Modulation of Output from an Isolated Gastropod Heart: Effects of Acetylcholine and FMRFamide

ABSTRACT In this study, two cardioactive drugs, acetylcholine (ACh) and the tetrapeptide FMRFamide, are perfused through the isolated systemic heart of the gastropod, Busycon canaliculatum. Their effect is examined in terms of the regulation of output, and is then related to the in vivo regulation of stroke volume. ACh decreases cardiac output by reducing both stroke volume and heart rate. End-diastolic volume and cardiac reserve increase with drug concentration. These effects are accompanied by a slowing in the rise time of the electromyogram prepotential and an increase in the duration of the plateau phase. Low concentrations of FMRFamide increase output by accelerating the heart rate. Stroke volume is only affected at higher concentrations (5× 10−7moll−1), and then negatively. End-diastolic volume is reduced. Between 10−9 and 10−8moll−1, FMRFamide increases the rise time of the prepotential and the amplitude of the plateau; the duration of the plateau is markedly shortened. At 5× 10−7mol l−1 and above, the plateau is extended and the cardiac reserve is reduced to zero. The two drugs have opposite effects on the characteristics of the aortic pressure pulse: ACh reduces the amplitude of the pulse, but increases its duration.

Isosorbide 5-mononitrate in the treatment of left ventricular failure following acute myocardial infarction.

Eleven patients with acute left ventricular failure following acute myocardial infarction (mean pulmonary capillary wedge pressure [PCW]>20 20 mmHg) were entered into an open, haemodynamic study of oral isosorbide-5-mononitrate (ISMN). Left ventricular failure was resistant to intravenous diuretic therapy. No patient received concurrent cardioactive drugs nor further diuretic therapy during the study period. Haemodynamic data were acquired via a flow-directed thermodilution catheter placed in the pulmonary artery. Baseline data were acquired prior to the intravenous administration of an ISMN challenge. Thereafter, oral ISMN (20 mg, 8 hourly) was administered over 48 h.