Studies on new phosphodiesterase inhibitors. I. Synthesis of 1-(2,3-epoxypropoxy)-2(4)-fluorobenzenes and 1-(2-hydroxy-3-morpholinopropoxy and piperazino)fluorobenzene derivatives.

A series of 1-(2,3-epoxypropoxy)-2(4)-fluorobenzenes and their corresponding 1-(2-hydroxy-3-morpholinopropoxy and piperazino)fluorobenzene derivatives (8a--f) were synthesised via a short synthetic route in good chemical yields and were evaluated for inotropic and chronotropic activity in isolated guinea-pig atria preparation. The compounds act as potential phosphodiesterase (PDE) inhibitors with desirable biological activity and have considerable promise in heart therapy.

Determination of myocardial depolarization and repolarization times using the unipolar ventricular evoked potential: contrasting effects of stimulus interval and isoprenaline in the isolated perfused rabbit heart.

The effects of changes in stimulus interval and the infusion of isoprenaline upon myocardial depolarization and repolarization times have been determined using the unipolar ventricular evoked potential. An isolated perfused rabbit heart was the experimental vehicle and the stimulus-to-R wave (St-R) and R wave-to-end (R-E) of complex time intervals were used as measures of depolarization and repolarization times, respectively. Variation in the stimulus interval was shown to have highly statistically significant effects upon both of the parameters of the unipolar paced evoked potential that were investigated. Myocardial repolarization time is increased at longer intervals, while activation time is reduced. Isoprenaline was found to reduce the duration of the R-E interval of the unipolar ventricular evoked potential when infused at a constant rate at a fixed stimulus interval. At the maximum concentration of the drug, when stimulus interval was just shorter than the intrinsic RR interval, it was estimated that one third of the total change in the R-E interval was due purely to the effects of decreased stimulus interval. It proved impossible to identify any effect of isoprenaline infusion upon the St-R interval. The absence of any effect of isoprenaline on the St-R interval of the evoked potential suggests that it may serve as a monitor of purely stimulus interval dependent variations of the signal.

An animal model for the chronic study of ventricular repolarisation and refractory period.

We have developed a simple model permitting stable, chronic measurements of ventricular repolarisation and refractory period to be made in conscious, unsedated, unrestrained animals. The model utilises the ventricular paced evoked response, recorded from permanent pacemaker electrodes implanted into the right ventricle of New Zealand White rabbits. After a "bedding in" period of 18-21 d, measured variables are stable for long periods; the stimulus to T wave interval of the evoked response remains stable up to at least 150 d after electrode insertion. The principal advantage of the model lies in the control of heart rate by pacing, eliminating the requirement for unreliable methods of correction of repolarisation data for sinus rate. Surgical techniques are straightforward. The model can also be used for studies involving recordings of the intrinsic (non-paced) intracardiac electrogram, as the quality of the signal obtained is consistently superior to standard methods of recording the electrocardiogram in animals. The stimulus-T interval of the paced evoked response has been found to correlate significantly (r = 0.96) with action potential duration measured by transmembrane microelectrode recordings in the isolated, arterially perfused interventricular septum.

In vitro estimation of the electrical performance of bipolar pacing electrode systems.

With the current interest in bipolar stimulation, there is a need for greater understanding of the electrical contributions of the two electrodes in this type of pacing. This has been investigated using a specially designed cell in which an electrode under test was immersed in a buffered saline solution (pH 7.42) at 37-38 degrees C. Four electrode types were studied: a single stimulating electrode (6 mm2 dish tip, Pt-black coated) and three indifferent electrodes. The indifferent electrodes were a 41 mm2 polished Pt ring, a Pt-black coated version of the same electrode, and a titanium pacemaker enclosure which was included to allow comparison with the unipolar situation. These electrodes were tested individually against a chlorided silver reference electrode of negligible (1-2 omega) impedance, the results being processed in such a way as to allow estimation of the properties of the stimulating electrode taken in combination with each of the indifferents. Constant current pulses (1-10 mA amplitude, 0.5 and 1.0 ms duration) were applied and measurements made from the resulting voltage waveforms. These were v1 and v2, the potential at the leading and trailing edge of the pulse, and v3, the post-pulse potential at 20 ms following the trailing edge. The potential v2--v1 is electrode dependent and allows the determination of the energy loss due to polarization to be calculated. Sinusoidal AC signals (0.1 Hz-10 kHz, 20 microA maximum amplitude) were also employed, allowing determination of sensing impedance. Under all conditions, the calculated performance of the stimulating electrode with the coated ring was nearly equivalent to that with the pacemaker enclosure.(ABSTRACT TRUNCATED AT 250 WORDS)

The ventricular intracardiac unipolar paced-evoked potential in an isolated animal heart.

The endocardial unipolar paced evoked response has excited a great deal of interest due to its possible use in the measurement of the metabolic state of the body and other pacer-related areas. Although rate-responsive pacing utilizing this signal has been clinically evaluated, little is known regarding the behavior of the components of this waveform under normal physiological conditions. We have developed an electronic circuit which allows the recording of the evoked response within a few milliseconds of a pacing stimulus of 5 V and 0.5 ms duration being applied using a single unipolar, smooth platinum electrode of 14 mm2 surface area. The paced evoked response was measured using a total of 20 isolated rabbit heart preparations. Five were run for 8 hours and the remaining fifteen were run for 5 hours. Our results indicate that the waveform components of the evoked response remain stable while the preparation is viable, but that two of the time-related measurements change with loss of viability. A significant lengthening of the stimulus-R interval was seen together with a dramatic shortening of the R-T period. The net result of these changes was an overall reduction of 17% in the complex duration. In addition, we found the R-T shortening to be a sensitive measure of myocardial integrity. We conclude that the combination of our interface charge elimination circuit and the isolated heart preparation has proved a useful system for the investigation of the paced evoked potential. Furthermore, the loss of myocardial viability has a complex action on this response.

Platinum pacemaker electrodes: origins and effects of the electrode-tissue interface impedance.

Investigation of the unipolar properties of the paced-evoked response requires special measures to eliminate the post-stimulus potential, and this in turn requires a knowledge of the properties of the electrode-tissue interface which is not supplied by any single source in the literature. We have therefore drawn together published information and some of our own experimental results. The behavior of a particular type of pacemaker electrode was investigated in vitro under a range of conditions. The application of DC potentials revealed an extremely nonlinear voltage-current characteristic with conduction thresholds at about +1 V and -1 V. Small signal AC response to applied voltages well within these values (20 mV pk-pk) was found to be linear when a nonpolarizable counterelectrode was used. Nonlinearities were introduced by the use of a stainless steel counterelectrode. The response of an in vitro model of a paced patient to voltage pulses (amplitude 5 V, duration 0.5 ms) was also investigated. We have made extensive use of previously published work to demonstrate the mechanisms underlying these results and also their relationship to each other. We have concluded with some theoretical comments upon the design requirements for a device to eliminate the post-stimulus afterpotential in order to detect the paced-evoked response.