Propafenone and lidocaine have a rate dependent negative dromotropic effect on intraventricular conduction. We investigated the use dependent actions of propafenone and lidocaine on intraventricular conduction in isolated guinea pig hearts perfused by the method of Langendorff. Of primary interest was how the number of stimuli of the conditioning train (S1) might influence the ventricular effective refractory period (VERP) when refractoriness is assessed at a high pacing rate. Propafenone (0.3 microM) and lidocaine (50 microM) caused a comparable prolongation of the intraventricular conduction time during sinus rhythm. During ventricular pacing in the presence of propafenone an abrupt decrease of the pacing cycle length (220 to 120 ms) resulted in an initial peak of rate dependent prolongation of the QRS interval that subsequently decreased to a stable steady-state level. Lidocaine also induced a rate dependent increase of the intraventricular conduction time up to a steady-state level. The time constant, characterizing the changes of the intraventricular conduction time after shortening the ventricular pacing cycle length from 220 to 120 ms was significantly (P < 0.01) longer in the presence of propafenone (tau = 31 +/- 4 beats; mean +/- SEM; n = 11) than for lidocaine (tau = 3 +/- 1; n = 10). Both drugs caused the greatest increase of the VERP when the number of conditioning stimuli (S1, interstimulus interval = 120 ms) was in the range of their respective time constant. However, when the number of conditioning stimuli was further increased, VERP progressively diminished. These effects may be explained by a shortening of the action potential during high rates that results in a decreased binding of propafenone to Na+ channels and by the direct shortening of repolarization period by lidocaine (Class IB drug).

Action Potentials↗

PubMed1997

Effects of calcium and deoxycholic acid on human colonic cell proliferation in vitro.

A high-fat and low-fiber diet is regarded as a major risk factor for colon cancer by increasing luminal contents of secondary bile acids. Calcium, on the other hand, has been implicated as a possible preventive agent in colon tumor development. In in vitro studies with human colonic epithelium, incubation with the secondary bile acid deoxycholic acid (DCA) induced hyperproliferation of colonic crypt cells which is regarded as a sign of preneoplastic transformation. In the present study the effects of calcium chloride (CaCl2) on DCA-induced hyperproliferation were tested at different stages of DCA-induced cell injury. Colonic biopsies from 36 patients (no tumors, polyps or IBD) were incubated with CaCl2 (1 and 10 mM) and 5 microM DCA which was added to the incubation medium either together with (experiment A), after (experiment B), or before CaCl2 (experiment C). Coincubation of the biopsies with DCA and 10 mM CaCl2 at the same time (experiment A) resulted in a significant reduction of whole crypt labeling index by 12% (p < 0.05), whereas in the other incubation experiments no significant growth-inhibitory effects could be demonstrated for CaCl2. These findings may best be explained by the formation of calcium-bound bile acid salts which lost most of their toxicity for the colonic cells.

Adult↗

PubMed1996

Effects of verapamil and diltiazem on the ventricular rate during simulated atrial flutter in isolated guinea pig hearts.

To compare the direct effects of verapamil and diltiazem on the ventricular rate during atrial flutter, we developed an atrial flutter model in guinea pig isolated hearts. Atrial flutter was simulated by rapid atrial pacing (cycle length = 50 ms). At this atrial pacing cycle length, the shape of the frequency of distribution of the ventricular cycle lengths was comparable to that during spontaneous atrial flutter. Verapamil (0.01, 0.03 microM) and diltiazem (0.03, 0.09 microM) caused a comparable prolongation of the atrioventricular conduction time and atrioventricular refractoriness. Also, the anterograde Wenckebach cycle length was increased to a comparable degree by both substances. The mean ventricular cycle length during atrial flutter was comparable prolonged by both substances. The prolongation of the maximal ventricular cycle length was significantly more pronounced in the presence of verapamil. The time dependence of drug-induced alterations in atrioventricular conduction time during abrupt changes of heart rate is significantly more pronounced in the presence of verapamil compared to diltiazem. In conclusion, the more pronounced effect of verapamil on the maximal ventricular cycle length compared to the action of diltiazem may be explained by the slow binding kinetic of this drug to the Ca2+ channel resulting in a longlasting blockade of the Ca2+ channel.

Animals↗

PubMed1996

Quantification of rate-dependent effects of verapamil, diltiazem, and digoxin on atrioventricular conduction.

The calcium channel blocking agents, verapamil and diltiazem, and the digitalis compound, digoxin, caused drug specific rate-dependent changes of the atrioventricular conduction time (AVCT). The purpose of this study was to investigate this rate adaptation of the AVCT in isolated guinea pig hearts perfused by the method of Langendorff to get an insight in drug-specific binding kinetic to the respective channel. In the presence of 10 nM verapamil, 30 nM diltiazem, or 0.6 nM digoxin, the atrioventricular conduction time was prolonged to a comparable degree during sinus rhythm. The drug-specific time constant, characterizing the rate-dependent adaptation of the AVCT, in the presence of a substance was comparable if evaluated after abruptly changing the heart rate from the pacing cycle length of 240 ms to 180 ms (tau-on) or from 180 to 240 ms (tau-off). The adaptation of the AVCT in the presence of verapamil (tau-on = 178 +/- 45 beats, tau-off = 125 +/- 33 beats, mean +/- SEM) was more pronounced than in the presence of digoxin (tau-on = 144 +/- 24 beats, tau-off = 98 +/- 15 beats) or diltiazem (tau-on = 70 +/- 11 beats, tau-off = 98 +/- 15 beats). In conclusion, the differences in the rate adaptation of the AVCT may be explained by the drug-specific association and dissociation kinetic to the calcium channel, slow in the case of verapamil, and fast in the case of dilitiazem, whereas this phenomenon in the presence of digoxin may be explained by its direct effects on passive membrane properties.

Adaptation, Physiological↗

PubMed1996

How to measure AV nodal refractoriness in the presence of verapamil, amiodarone, digoxin, and diltiazem.

On the AV node the negative dromotropic action of verapamil, amiodarone, digoxin, and diltiazem is known to be rate dependent. The effective refractory period of the AV node (AV-ERP) at a short cycle length is related to the AV conduction at that cycle length. We investigated how the number of stimuli during the conditioning train (S1) (during measurement of refractoriness at a high pacing rate [cycle length = 180 ms]) might influence the AV-ERP in isolated guinea pig hearts in a Langendorff preparation. Verapamil (10 nM), amiodarone (10 microM), digoxin (0.6 nM), and diltiazem (30 nM) caused a comparable prolongation of the AV conduction time (AVCT). All four drugs caused a significant prolongation of the AV-ERP when evaluated by a standard stimulation protocol with a conditioning train of 10 stimuli (10 S1) at a pacing cycle length of 180 ms followed by the test stimulus (S2). When the number of stimuli during the conditioning train (S1) was increased (> 10), until the prolongation of AVCT reached steady state, the AV-ERP in the presence of verapamil (132 +/- 4 vs 141 +/- 3 ms; P < 0.05, mean +/- S.E.M.) and diltiazem (143 +/- 3 vs 151 +/- 3 ms; P < 0.05) was prolonged significantly further. These results indicate that the effect of drugs on AV-ERP should be measured with a modified stimulation protocol, whereby the number of conditioning stimuli is comparable to the time constant characterizing the prolongation of AVCT at fast pacing rates.

Amiodarone↗

PubMed1995

Effects of semotiadil, a novel Ca2+ channel antagonist, on the electrical activity of Langendorff-perfused guinea pig hearts in comparison with diltiazem, amlodipine and nifedipine.

Semotiadil, a new Ca2+ antagonist with a high vasoselectivity, in high concentrations depresses AV nodal conduction in a frequency-dependent manner. The aim of the present study was to investigate the effects of semotiadil on intact cardiac conduction and the pacemaker system in comparison with diltiazem, amlodipine and nifedipine. The effects were studied in isolated guinea pig hearts perfused by the method of Langendorff. Both semotiadil and diltiazem decreased markedly the sinus rate in a concentration-dependent manner whereas this was not the case in the presence of amlodipine and nifedipine. Semotiadil (10 microM) markedly prolonged sinus node recovery time and in the presence of diltiazem (10 microM) in 5 out of 7 experiments an intermittent sinus node arrest occurred. Atrioventricular conduction and the effective refractory period of the AV node were most affected by diltiazem and semotiadil. The Ca2+ channel blocking compound semotiadil showed the most pronounced rate-dependent effects on the AV node. In the presence of diltiazem the QT interval became even shorter than in untreated hearts. In contrast, semotiadil did not act on the QT interval. In conclusion, as semotiadil exerts a clear rate-dependent effect on AV nodal conduction with a long time constant, it mimics the electrophysiological behavior of a substance of the verapamil type.

Amlodipine↗

PubMed1995

Comparison of the frequency-dependent effects on the atrioventricular node of verapamil, amiodarone, digoxin, and diltiazem in isolated guinea pig hearts.

To slow ventricular rate during supraventricular tachycardia, a drug must have a strong rate-dependent depressant effect on atrioventricular (AV) conduction. We investigated the frequency-dependent effects of verapamil, amiodarone, digoxin, and diltiazem on AV conduction time (AVCT) in isolated guinea pig heart perfused by Langendorff method. Verapamil (0.01 microM), amiodarone (10 microM), digoxin (0.6 nM), and diltiazem (0.03 microM) caused comparable prolongation of AVCT and also a comparable reduction in sinus rate. To evaluate the time dependence of drug-induced alterations in AVCT, we abruptly increased the atrial pacing rate and shortened the pacing cycle length (CL) from 240 to 180 ms. The resulting time constant was longest in the presence of verapamil (tau = 194 +/- 45 beats, mean +/- SEM) and the shortest during perfusion with diltiazem (tau = 89 +/- 9 beats). The magnitude of AVCT prolongation after abrupt increase in pacing rate was significantly greater for digoxin as compared with all other drugs tested. The calculated beat-to-beat increase in AVCT evaluated by dividing the magnitude of AVCT prolongation by the time constant tau was greatest with diltiazem, which may explain the high efficacy of diltiazem in controlling ventricular rate during atrial fibrillation.

Amiodarone↗

PubMed1993

A comparison of the effects of adenosine and verapamil on the conduction and pacemaker system of isolated guinea pig hearts.

Adenosine and verapamil are effective in the treatment of supraventricular arrhythmias. Also, both substances can provoke sinus node arrest or a third-degree atrioventricular (AV) block with a ventricular escape rhythm. The aim of this study was to compare the effects of adenosine and verapamil on sinus rate and on the rate of the ventricular escape rhythm while a third-degree AV block was induced by both drugs. Experiments were performed on isolated spontaneously beating guinea pig hearts perfused by the method of Langendorff. A third-degree AV block was induced by adenosine at a concentration of 30 microns and by verapamil at a concentration of 1 micron. Adenosine (30 microns) reduced sinus rate only moderately whereas it nearly halved the rate of the ventricular escape rhythm compared with that produced by cutting the AV node. In contrast, verapamil left the rate of the ventricular escape rhythm unchanged but nearly halved the spontaneous sinus rate compared with control conditions. In conclusion, adenosine and verapamil given at dosages with comparable effect on the AV node have markedly different effects on different pacemakers in the same heart. In the treatment of supraventricular arrhythmias, adenosine probably should be used with great caution since it can cause a very slow ventricular escape rhythm.

Adenosine↗

PubMed1992

Investigation of dialysis membranes with atomic force microscopy.

AFM was used to investigate dialysis membranes made of regenerated cellulose by the cuoxam process. The membranes were either Cuprophan or experimental samples, modified with different amounts of diethylaminoethylcellulose (DEAE). Atomic force microscopes with optical-lever detection systems were used to image the dry membranes in air as received from the manufacturer as well as wet membranes in a swollen state under water. Differences could be observed between modified and unmodified as well as between dry and wet membranes.

Cellulose↗

PubMed1990

Morphometry of the aging heart.

Myocardial structure was studied in seven geriatric patients (cases), aged 79 to 91, and ten younger adult patients (controls), aged 22 to 52. Myocardial sections of posterior left ventricle (PLV), anterior left ventricle (ALV), and ventricular septum (VS) were studied using computerized morphometry. Each section of heart (PLV, ALV, or VS region) was divided into three zones: subepicardial (epi), midmyocardial (myo), and subendocardial (endo). Interstitial collagen content and nuclear and cell diameters of myocytes were obtained. Large scars were excluded. Student's t-test was used to evaluate differences, which were considered significant at a level of P less than 0.001. No significant zonal or regional variation in collagen content was found in control hearts, where interstitial trichrome-positive tissue comprised 6.61% of the myocardium. By contrast, elderly hearts showed a distinct increase in interstitium in the PLV region (18.3%), as compared with ALV and VS, and as compared with control hearts (P less than 0.001). Relative myocyte hypertrophy with aging was most prominent in a zonal midmyocardial distribution (P less than 0.001). Myocyte nuclei showed shrinking with age in the subepicardial zone (P less than 0.001). These findings indicate there are specific age-related alterations in myocardium, which may relate to functional abnormalities seen in the elderly.

Adult↗