Tianen Yang

Alfuzosin Delays Cardiac Repolarization by a Novel Mechanism

The United States Food and Drug Administration (FDA) uses alfuzosin as an example of a drug having QT risk in humans that was not detected in nonclinical studies. FDA approval required a thorough clinical QT study (TCQS) that was weakly positive at high doses. The FDA has used the clinical/nonclinical discordance as a basis for mandatory TCQS, and this requirement has serious consequences for drug development. For this reason, we re-examined whether nonclinical signals of QT risk for alfuzosin were truly absent. Alfuzosin significantly prolonged action potential duration (APD)60 in rabbit Purkinje fibers (p < 0.05) and QT in isolated rabbit hearts (p < 0.05) at the clinically relevant concentration of 300 nM. In man, the QT interval corrected with Fridericias formula increased 7.7 ms, which exceeds the 5.0-ms threshold for a positive TCQS. Effects on hKv11.1, hKv4.3, and hKv7.1/hKCNE1 potassium currents and calcium current were not involved. At 300 nM, ∼30× Cmax, alfuzosin significantly increased whole-cell peak sodium (hNav1.5) current (p < 0.05), increased the probability of late hNav1.5 single-channel openings, and significantly shortened the slow time constant for recovery from inactivation. Alfuzosin also increased hNav1.5 burst duration and number of openings per burst between 2- and 3-fold. Alfuzosin is a rare example of a non-antiarrhythmic drug that delays cardiac repolarization not by blocking hKv11.1 potassium current, but by increasing sodium current. Nonclinical studies clearly show that alfuzosin increases plateau potential and prolongs APD and QT, consistent with QT prolongation in man. The results challenge the FDA grounds for the absolute primacy of TCQS based on the claim of a false-negative, nonclinical study on alfuzosin.

Modulation of Coronary Vascular Resistance in Female Rabbits by Estrogen and Progesterone

Objective: To study the roles of estradiol and various progestins on the regulation of coronary flow in female rabbits. Methods: Ovariectomized adult female rabbits were treated with estradiol, with progesterone (or one of the following synthetic progestins: megace, norethindrone, or medroxyprogesterone acetate), or with both an estradiol and a progestin. Hearts were isolated and perfused at constant pressure by a modified Langendorff technique. Changes in coronary flow were determined at baseline and in response to direct infusion into the coronary circulation of NG-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide (NO) synthase. Results: Coronary flow rates were 40-50% greater in hearts of animals treated with estradiol than in control hearts of animals not treated with the hormone. Treatment of the animals with progestin alone had little effect on coronary flow. However, when administered with estradiol, it abrogated the estradiol-related increase in coronary flow. The increments in coronary flow evoked by estradiol were virtually abolished by L-NNA, an inhibitor of NO synthase. In hearts of animals treated with estradiol plus progesterone, L-NNA had no additional inhibitory effect on coronary flow to that of progesterone. Conclusion: Estradiol decreases coronary vascular resistance (CVR) and hence increases coronary flow. Progestins attenuate this effect of estradiol.

Analysis of vagally induced sinus arrhythmias

Vagal stimulation at precise times in successive cardiac cycles can elicit sinus arrhythmias. Two mechanisms have been identified that can, but do not necessarily, cause these vagally induced sinus arrhythmias. First, changes in cycle length elicited by a given concentration of acetylcholine (ACh) depend on the phase of the pacemaker cell action potential when the ACh binds to muscarinic receptors. Second, acetylcholinesterase degrades ACh rapidly enough for the mean concentration of ACh per cardiac cycle to vary from cycle to cycle. We used a mathematical model of the underlying cellular physiology, to examine whether these mechanisms are responsible for arrhythmogenesis. Computer simulation showed that both mechanisms contribute to the vagally induced sinus arrhythmias.

Effects of ionic channel antagonists barium, cesium, and UL-FS-49 on vagal slowing of atrial rate in dogs

In response to a brief vagal stimulus, the atrial rate initially slows, then transiently accelerates, and slows a second time. We determined the effects of three antagonists to two ionic channels on this characteristic triphasic pacemaker response. Brief bursts of vagal stimulation were delivered to anesthetized dogs, and atrial cycle lengths were recorded. Either barium, cesium, or UL-FS-49 was administered. Barium, which primarily blocks the acetylcholine-sensitive potassium current (IK,ACh), attenuated the initial vagally induced bradycardia by > 50% without affecting the subsequent acceleration or the secondary slowing. Cesium and UL-FS-49 [both of which primarily block the pacemaker current (If)] did not affect the initial vagal slowing of atrial rate but abolished the acceleratory portion of the response. The secondary slowing was abolished by cesium but not by UL-FS-49. We conclude that the initial rapid atrial response to acetylcholine is mediated mainly by the IK,ACh, with little contribution from the If. The subsequent acceleration is mediated by activation of the If.In response to a brief vagal stimulus, the atrial rate initially slows, then transiently accelerates, and slows a second time. We determined the effects of three antagonists to two ionic channels on this characteristic triphasic pacemaker response. Brief bursts of vagal stimulation were delivered to anesthetized dogs, and atrial cycle lengths were recorded. Either barium, cesium, or UL-FS-49 was administered. Barium, which primarily blocks the acetylcholine-sensitive potassium current ( I K,ACh), attenuated the initial vagally induced bradycardia by >50% without affecting the subsequent acceleration or the secondary slowing. Cesium and UL-FS-49 [both of which primarily block the pacemaker current ( I f)] did not affect the initial vagal slowing of atrial rate but abolished the acceleratory portion of the response. The secondary slowing was abolished by cesium but not by UL-FS-49. We conclude that the initial rapid atrial response to acetylcholine is mediated mainly by the I K,ACh, with little contribution from the I f. The subsequent acceleration is mediated by activation of the I f.

Beneficial effects of estrogen on cardiac stunning in female rabbits.

Objective: To determine the effect of estrogen treatment on the contractile, relaxation, and chronotropic responses of hearts of female rabbits to cessation of perfusion. Methods: Adult female rabbits were treated either with estradiol or with the vehicle (control). The hearts were then isolated and perfused at constant pressure by the Langendorff technique. A saline-filled balloon connected to a pressure transducer was inserted in the left ventricle in order to assess the mechanical function of the isolated heart. Cardiac stunning was induced by halting the perfusion of the coronary vasculature for four successive periods of 1, 3, 5, and 5 minutes, followed by reperfusion between nonperfusion periods. Changes in cardiac function induced by the cessation of perfusion were assessed by monitoring the changes in heart rate and in left ventricular pressure ([dP/dt]max as an index of ventricular contractility and [dP/dt]min as an index of ventricular relaxation). Changes in coronary flow were determined at baseline and following reperfusion. Results: Halting coronary perfusion decreased (dP/dt)max and (dP/dt)min and slowed left ventricular contractions both in control and in estrogen-treated hearts. The depressant effects of flow cessation on left ventricular (dP/dt)max and (dP/dt)min were smaller in estrogen-treated hearts than in control hearts. Treatment with estrogen had no effect on the changes on the heart rate in responses to cessation of flow and to reperfusion. Treatment with estrogen increased coronary flow by 40%. Coronary reperfusion increased coronary flow transiently, but the effects did not differ signifiicantly between control and estrogen-treated hearts. Conclusion: Short-term treatment of adult female rabbits with doses of estrogen that are physiologic for the rabbit exerts a protective effect on cardiac contractility from repetitive periods without perfusion.