Heart rate variability is commonly interpreted as a measure of vagal tone. Changes in heart rate variability and more specifically respiratory sinus arrhythmia (RSA) are however also commonly observed when breathing is altered without changes in heart. This study examined how decreasing vagal tone through a low level (6%MVC) handgrip (HG) contraction and changing breathing frequency, alone or in combination, affected heart rate variability and respiratory sinus arrhythmia. ECG and respiratory recordings were obtained in 16 university students. Results show that decreasing breathing rate did not affect mean heart rate but resulted in a significant increase (p < 0.05) from baseline values in RSA amplitude (%) (SP: 0.11+/-0.07; SP-4: 0.14+/-0.07). On the other hand, under spontaneous breathing conditions sustained handgrip contraction resulted in a small yet significant increase in mean heart rate (SP: 62+/-6 bpm; SP-4: 69+/-11 bpm; p < 0.05) but was not associated with significant changes in RSA amplitude. The slope of the relationship between RSA amplitude and respiratory cycle duration was taken to reflect the vagal responsiveness to respiratory stimulation. A slight downward parallel shift from baseline was observed under sustained HG but significant differences in slope or y-intercept were not observed. These results suggest that indices of heart rate variability and respiratory sinus arrhythmia may be more appropriate indices of cardiac vagal efferent activity modulations by respiration than tonic activity.

A variety of drugs prolong cardiac repolarization (manifested as QT prolongation on ECG), although the major example are the so-called class III antiarrhythmics. However, antiarrhythmic drugs which prolong cardiac repolarization are not harmless, as they may also be proarrhythmic, inducing a potentially fatal arrhythmia known as torsade de pointes (TdP). Recently, it has become apparent that a wide variety of non-antiarrhythmic agents may also, as an entirely undesired side-effect, provoke TdP. TdP is also characteristic of the congenital long QT syndrome, one form of which is caused by mutations in the HERG gene which encodes the major repolarizing potassium channel, IKr. Furthermore, HERG appears to be the main molecular target for drugs which cause QT prolongation. This thesis investigates the cellular mechanism for QT prolongation, proarrhythmia and sudden death associated with several commonly prescribed non-antiarrhythmic drugs. Specifically, we studied the effects of an antimalarial agent, halofantrine, and five psychoactive agents, thioridazine, chlorpromazine, clozapine, amitriptyline and mianserin on the HERG channel. A better understanding of the way these drugs interact with HERG could facilitate the development of safer drugs. We used the whole-cell voltage clamp technique to study currents produced by stable transfection of HERG into Chinese hamster ovary cells (CHO-K1). Our HERG-transfected cells possessed a potassium channel with biophysical properties similar to HERG-transfected cells previously reported (e.g. Xenopus oocytes, human embryonic kidney cells 293) and also to human IKr. HERG currents were potently inhibited by E-4031, a defining pharmacological signature of IKr. Therefore, these cells provide an appropriate model for the study of this important current in isolation. Halofantrine is a widely used antimalarial agent which has been associated with QT prolongation, TdP and sudden death. Halofantrine blocked HERG tail currents potently with an IC50 of 196.9 nM. Channel inhibition was time-, voltage- and use-dependent. Halofantrine did not alter channel activation or deactivation kinetics but inactivation was accelerated and there was a 20 mV hyperpolarizing shift in the mid-activation potential of steady state inactivation. Block increased with increasing depolarizing pulse duration and was enhanced by pulses that render channels inactivated. This is the first report of HERG channel blockade by halofantrine and is the likely cellular mechanism for its proarrhythmic potential. Our data indicate preferential binding of halofantrine to the open and inactivated channel states. Cardiovascular mortality in psychiatric patients is high. Reports of sudden unexplained death in those taking antipsychotic drugs have raised concerns that part of this excess may be due to drug-induced arrhythmias. We found that thioridazine and chlorpromazine blocked HERG channels (IC50 1.07 ????M and 1.47????M respectively) at clinically relevant concentrations and this is likely the cellular mechanism for their ability to prolong QT interval and induce TdP. To date, HERG block by chlorpromazine has not been reported and the state dependence of channel blockade by these phenothiazines has not been studied. Our results indicate that both drugs preferentially bind to closed HERG channels on the basis that block was not time-, voltage- or use-dependent, did not alter channel activation or deactivation kinetics and was unaffected by the depolarizing pulse duration. Clozapine is the prototype of the newer atypical antipsychotic drugs and is more efficacious and better tolerated than the traditional agents. Serious cardiotoxicity have occurred in clozapine-treated patients including sudden death. We found that clozapine produced a tonic block on HERG channels indicating preferential binding to the closed channel state. The IC50 for block was 2.62 ????M. This is close to the therapeutic concentration of the drug (0.6 to 2 ????M) and concentrations above 10 ????M have been reported during overdoses. Although there have been no specific reports of QT prolongation or TdP in clozapine-treated patients, our data raises the possibility of proarrhythmia as another potential explanation for sudden death during clozapine treatment. Amitriptyline, a commonly prescribed tricyclic antidepressant, can induce a variety of cardiac rhythm disturbances. Most reports have attributed these effects to its Na+ channel blocking ability. We found that amitriptyline blocked HERG channels with an IC50 of 10 ????M. Such high concentrations can be achieved during overdoses. Thus HERG channel blockade likely underlies amitriptyline????s QT-prolonging effect. Channel inhibition by amitriptyline exhibited positive voltage- and use-dependence and increased progressively with further prolongation of depolarization during an envelope of tails protocol, indicating preferential binding to an activated (open/inactivated) state of the channel. In contrast to the tricyclics, the tetracyclic antidepressant, mianserin, is much safer and only very rarely associated with cardiac complications. HERG channel blockade by mianserin was the least potent among the 5 psychoactive drugs we studied, with an IC50 of 14.78 ????M, which is 30- to 40-fold higher than therapeutic plasma concentrations of the drug. This probably, in part, accounts for the lack of reports of QT prolongation or TdP with mianserin. Mianserin displayed preferential affinity for an activated state of HERG channels on the basis of voltage-dependent block, a hyperpolarizing shift in the voltage of half-maximal activation and an increase in block at low external potassium concentration. Our results show that HERG block is a common feature of many non-cardiac drugs and that this underlies their potential for QT prolongation and TdP. Although the proarrhythmic risk varies according to potency of HERG block (e.g. mianserin is a weak blocker and does not induce TdP), other factors such as drug metabolism, protein binding and myocardial concentrations are also important since the risk of proarrhythmia during clinical use differ significantly even among the more potent HERG blockers. The preferential binding of these drugs to different channel states together with their diverse chemical structures suggest the presence of multiple distinct binding sites for drugs on HERG channels. There is increasing awareness that many non-antiarrhythmic drugs can prolong the QT interval and provoke TdP. Cardiac safety is now a major issue in new drug development. Our model of HERG K+ channels stably expressed in a mammalian cell line (CHO-K1) provides a useful tool for screening, at the preclinical stage, the proarrhythmic potential of novel drugs intended for human use.

Thesis (M. D.)--University of New South Wales, 2002. / Also available online.

Thesis (M.S.)--University of Wisconsin--Madison, 1981. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 24-27).

No description available.

The antiarrhythmic actions of prostaglandins were first investigated using arrhythmias associated with cardiac ischemia in the dog and the rat. These studies were followed by investigations of the possible mechanisms of action, using rat heart tissue in intact, isolated, and cell culture preparations. Preliminary experiments in the dog revealed that prostaglandins E₂ and F₁α markedly reduced the number of premature ventricular contractions occurring within the first 25 minutes following coronary artery ligation. Prostaglandin E₂ or F₁α did not markedly alter the cardiovascular response to occlusion, making it unlikely that modulation of autonomic reflexes is a central factor in their antiarrhythmic action. Coronary ligation in the rat was used to compare the antiarrhythmic effectiveness of prostaglandins, lidocaine, and quinidine. Prostaglandins E₂, F₂β and quinidine were found to be the most effective against arrhythmias occurring within the first 25 minutes following occlusion, reducing the number of PVCs by 40 to 50 per cent. The number of flutter episodes and the number of animals dying from arrhythmias was also markedly decreased by prostaglandins E₂ and F₂β and by quinidine. Prostaglandins F₁α and A₂, and lidocaine had lesser effects. Prostaglandins had only minor effects on blood pressure or heart rate, which were not related to their antiarrhythmic activity. No significant differences were found in the infarct size with prostaglandin treatment. The effects of prostaglandins E₂, A₂ and F₂β, quinidine, and lidocaine were tested in in situ rat heart on electrically-induced flutter threshold and maximum following frequency. Flutter threshold was not changed by any of the prostaglandins tested, although lidocaine increased and quinidine decreased it. Prostaglandins caused a dose-dependent change in maximum following frequency which was usually less than 10 per cent of control. Lidocaine produced a marked increase and quinidine a marked decrease in maximum following frequency. The slight depressive action of prostaglandins does not correlate with their antidysrhythmic actions. Prostaglandins of the E, A, and F series were found to have only minimal effects on rate and force in isolated rat hearts. However, both PGE₂ and PGF₂β, delayed the loss of contractile force with time at 10⁻⁷ M. All prostaglandins tested markedly increased coronary flow rate at 10⁻⁵ M. The effects on the beating behavior of cultured rat heart cells of fourteen prostaglandins of the A, B, D., E, and F series were investigated in cultured rat heart cells. With the exception of PGF₂α, which produced a chronotropic response, prostaglandins had limited direct action in cultured rat heart cells. The effects of ouabain, calcium, potassium, dinitrophenol, and Cyanea toxin, together with prostaglandins, lidocaine, and quinidine on cultured rat heart cells were also investigated. Ouabain and calcium increased rate and fibrillatory movements, while potassium and dinitrophenol slowed rate and decreased rhythmic beating. Cyanea toxin produced a characteristic series of arrhythmogenic changes which were also used to test for antiarrhythmic activity in cultured heart cells. Lidocaine and quinidine were effective only against cellular arrhythmias caused by high calcium concentration, and prostaglandins were effective only against dinitrophenol-induced arrhythmias, indicating that there is no over-all "protective" effect of prostaglandins in cell culture. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Unknown

Thesis (Ph. D.)--University of Wisconsin, 1950. / Typescript (carbon copy). eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 39-41).

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published_or_final_version / Electrical and Electronic Engineering / Doctoral / Doctor of Philosophy

No description available.