Biomedical subjects

T Yang

Publications and source records attributed to T Yang.

At least 253 records · Page 14Linked to original sources

PubMed1993

Liquid chromatographic analysis of amino acids: using dimethylamino-azobenzenesulfonyl chloride and Hypersil ODS column to analyze the composition of apo B peptides.

A reliable high-performance liquid chromatography (HPLC) method is described for the separation of dimethylamino-azobenzenesulfonyl-amino acid (DABS-AA). The separation is accomplished by reversed-phase chromatography on a Hypersil ODS column (4.6 x 150 mm) with a Hewlett-Packard liquid chromatography system. In addition to the developed sample and solvent preparation procedure, this precolumn modification method using dimethylaminoazobenzene sulfonyl chloride (DABS-CL) for amino acid analysis is proved reliable and sensitive. Five apolipoprotein B-100 tryptic peptides, two of them containing cysteine, were demonstrated as examples for the general application of this method in amino acid analysis. It is a useful method for analysis of cysteine- and cystine-containing peptide and, furthermore, for determination of sulfhydryl and disulfide linkages of proteins.

Amino Acid Sequence↗

PubMed1993

Expression of endothelin-3 mRNA along rat nephron segments using polymerase chain reaction.

Endothelin (ET) is now known to be a family of three distinct peptides. Although many reports have studied the renal action of ET-1, comparatively little is known concerning ET-3. We previously reported that ET-1 mRNA is expressed in glomerulus (Glm) and inner medullary collecting duct (IMCD). In this study, microlocalization of mRNA coding ET-3 was carried out in the rat kidney using a reverse transcription and polymerase chain reaction (RT-PCR) assay of individual microdissected renal tubule segments along the nephron, Glm, vasa recta bundle, and arcuate arteries. Large signals for ET-3 PCR product were detected in proximal convoluted and straight tubules, cortical collecting duct, and outer medullary collecting duct. Glm, IMCD, and vasa recta bundle also expressed relatively large amounts of ET-3 mRNA. Small signals were found in medullary thick ascending limb, inner medullary thin limb, and arcuate artery. We detected ET-3 protein in tubule suspensions from cortex, outer medulla, and inner medulla of rat kidney. Furthermore, incubation with TGF-beta did not change ET-3 PCR signal, whereas ET-1 PCR signal was increased significantly by exposure to TGF-beta in Glm and IMCD. Thus, ET-3 and ET-1 are distributed differently along the nephron and are regulated in different manners. This suggests that ET-3 and ET-1 may affect kidney functions in different ways.

Animals↗

PubMed1993

Assessment of beat-by-beat control of heart rate by the autonomic nervous system: molecular biology technique are necessary, but not sufficient.

Vagus nerve activity can change heart rate substantially within one cardiac cycle, and the chronotropic effects decay almost completely within one cardiac cycle after cessation of vagal activity. The ability of the vagus nerves to regulate heart rate beat by beat can be explained in large part by the speed at which the neural signal is transduced to a cardiac response and by the rapidity of the processes that restore the basal heart rate when vagal activity ceases. Currently, the question of whether the cardiac cells can transduce the sympathetic neural signals rapidly enough to implement beatwise regulation is controversial. Emphasis on the speed of the processes that initiate the responses may, however, be misplaced. Instead, the processes that terminate the responses to autonomic neural activity (especially those processes that remove the released neurotransmitters) are probably the main determinants of the ability of the vagal and sympathetic systems to affect beatwise control. The norepinephrine (NE) released from the sympathetic nerve endings is removed from the cardiac tissues much more slowly than is the acetylcholine that is released from the vagal terminals. As a consequence of the potential deleterious effects associated with the slow removal of NE, the cardiac neural control system has evolved such that the sympathetic nerves ordinarily release NE at a slow rate. Hence, changes in sympathetic neural activity can alter cardiac behavior only slightly from beat to beat. Hence, beatwise control of cardiac function would be negligible, regardless of how swiftly the sympathetic nerve impulse is transduced to a change in cardiac performance.

Acetylcholine↗

PubMed1993

Effect of hyperosmolality on production and mRNA expression of ET-1 in inner medullary collecting duct.

The effects of hyperosmolality on the production and mRNA expression of endothelin-1 (ET-1) in inner medullary collecting duct (IMCD) were examined in the present study. Osmolality in incubation media was changed from 290 to 490 or 690 mosmol/kgH2O by adding NaCl, urea, mannitol, or raffinose. A preliminary experiment was carried out using tubule suspension from the inner medulla. Hyperosmolality by NaCl stimulated ET-1 accumulation in rats (from 323.5 +/- 76.3 to 478.0 +/- 108.4 and 573.7 +/- 47.8 pg.mg protein-1 x 24 h-1 in 290, 490, and 690 mosmol/kgH2O, respectively) and rabbits. In contrast, hyperosmolality by urea markedly decreased ET-1 accumulation and hyperosmolality by mannitol showed no effect on it. We next examined whether hyperosmolality changes ET-1 mRNA. After incubation in isotonic or hypertonic solution for 6 h, ET-1 mRNA was determined using reverse transcription and polymerase chain reaction (PCR) in microdissected IMCD and glomerulus. Hyperosmolality by NaCl and raffinose significantly increased the PCR products of ET-1 mRNA in IMCD, whereas mannitol did not. The stimulatory effect of hyperosmolality by NaCl on ET-1 mRNA expression was not observed in glomerulus. Our data suggested a stimulatory effect of hyperosmolality on production and mRNA expression of ET-1 in IMCD but not in glomerulus.

Animals↗

PubMed1993

Effects of intense antecedent sympathetic stimulation on sympathetic neurotransmission in the heart.

We studied the effects of intense sympathetic stimulation on the chronotropic responses of the heart to subsequent test stimulations of the cardiac autonomic nerves in dogs anesthetized with alpha-chloralose. Such intense sympathetic stimulations (which we refer to as "release stimulations") are known to release neuropeptide Y as well as norepinephrine. The changes in cardiac cycle length evoked by vagal and sympathetic test stimulations were progressively more attenuated as we increased the frequency and duration of the antecedent sympathetic release stimulations. We found that 2.5 minutes after a maximal release stimulation (30 Hz for 5 minutes), the mean +/- SEM chronotropic responses to the vagal and sympathetic test stimulations were diminished to 36.5 +/- 1.6% and 54.7 +/- 1.3% respectively, of the prestimulation responses. The mean times for the chronotropic responses to the vagal and sympathetic test stimulations to recover to their control values were 52.0 +/- 1.3 and 63.2 +/- 2.9 minutes, respectively. This enduring effect suggests the action of a neuropeptide, such as neuropeptide Y. Phentolamine potentiated the inhibitory effects of the sympathetic release stimulations. The chronotropic responses to isoproterenol infusions were not affected appreciably by antecedent sympathetic release stimulation. We conclude, therefore, that the inhibitory effects of antecedent sympathetic release stimulation on cardiac sympathetic neurotransmission are mediated prejunctionally, probably via an inhibition of the neuronal release of norepinephrine by neuropeptide Y.

Acetylcholine↗

PubMed1993

Intense sympathetic stimulation releases neuropeptide Y but fails to evoke sustained coronary vasoconstriction in dogs.

We determined whether a 3-minute period of intense cardiac sympathetic stimulation, which is known to release neuropeptide Y (NPY), elicits a sustained poststimulatory coronary vasoconstriction in anesthetized dogs that had received propranolol. We also periodically measured the cardiac chronotropic responses to test vagal stimulations; these responses served as an index of the neuronal release of NPY. In a group of 11 animals, the coronary vascular resistance increased by 14 +/- 4% during the sympathetic stimulation. After cessation of stimulation, however, coronary vascular resistance returned rapidly to its control value. The cardiac responses to the test vagal stimuli were attenuated by approximately 40% after cessation of sympathetic stimulation, and this inhibitory effect persisted for approximately 60 minutes. In a second group of eight dogs, we determined whether the intense sympathetic stimulation potentiates the coronary vascular responses to exogenous norepinephrine (NE). Before sympathetic stimulation, standard intracoronary infusions of NE increased coronary vascular resistance by 14 +/- 2%. Intense antecedent sympathetic stimulation did not alter the coronary vascular responses to subsequent NE infusions. However, the chronotropic responses to test vagal stimuli were initially attenuated by approximately 30%, and this inhibitory effect persisted for approximately 1 hour. In a third group of four dogs, we found that exogenous NPY significantly potentiated the coronary vasoconstriction evoked by NE infusions. The coronary vascular responses to combined infusions of NE and NPY were consistently greater (by approximately 13%) than the sum of the responses to these substances when they were infused separately. We conclude that, even though sufficient NPY appears to be released from the sympathetic nerve endings to inhibit vagal neurotransmission, the quantity of NPY released into the coronary blood vessels under the conditions of our experiments appears to be insufficient either to elicit a sustained coronary vasoconstriction or to potentiate the vasoconstrictor effects of intracoronary NE infusions.

Animals↗

PubMed1993

Different localization and regulation of two types of vasopressin receptor messenger RNA in microdissected rat nephron segments using reverse transcription polymerase chain reaction.

Recent studies have revealed that arginine vasopressin (AVP) has at least two types of receptors in the kidney: V1a receptor and V2 receptor. In this study, microlocalization of mRNA coding for V1a and V2 receptors was carried out in the rat kidney using a reverse transcription and polymerase chain reaction. Large signals for V1a receptor PCR product were detected in the glomerulus, initial cortical collecting duct, cortical collecting duct, outer medullary collecting duct, inner medullary collecting duct, and arcuate artery. Small but detectable signals were found in proximal convoluted and straight tubules, inner medullary thin limbs, and medullary thick ascending limbs. Large signals for V2 receptor mRNA were detected in the cortical collecting duct, outer medullary collecting duct, and inner medullary collecting duct. Small signals for V2 receptor were found in the inner medullary thick limbs, medullary thick ascending limbs, and initial cortical collecting duct. Next, we investigated V1a and V2 receptor mRNA regulation in the dehydrated state. During a 72-h water restriction state, the plasma AVP level increased and V2 receptor mRNA decreased in collecting ducts. In contrast, V1a receptor mRNA did not change significantly. Thus, the two AVP receptor subtypes are distributed differently along the nephron, and these mRNAs are regulated differently in the dehydrated state.

Animals↗

PubMed1993

[Helicobacter pylori associated gastritis: a primary study of ammonia and urea in gastric juice and mucus in gastric mucosa].

The mucosa of 46 patients with histological chronic gastritis were cultured for helicobacter pylori (HP) and the ammonia and urea in their gastric juice were also determined. The results showed the average ammonia concentration (1.22 +/- 0.23 mmol/L) in HP positive patients was higher than that of HP negative patients (0.72 +/- 0.25 mmol/L), (P < 0.05). But the average urea concentration (0.45 +/- 0.29 mmol/L) in HP positive patients was lower than that of HP negative patients (2.71 +/- 1.20 mmol/L), (P < 0.05). The higher the level of ammonia stands, the more severe the gastritis is. (rs = 0.556). On the other hand, the quantity of mucus was elevated in 18 patients among 28 patients with HP eradicated by drug treatment, which was significantly different from the patients with HP not eradicated. It is suggested that the epithelium of gastric mucosa and the mucus are the chief components of the gastric mucosa barrier; the presence of HP increases ammonia, and thus damages the gastric epithelium and reduces the quantity of mucus. Consequently, the protective gastric mucosa barrier is damaged, and then comes the liability to HP-associated gastritis.

Ammonia↗

PubMed1992

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.

Arrhythmias, Cardiac↗

PubMed1992

Effects of altered extracellular potassium and pacing cycle length on the class III antiarrhythmic actions of dofetilide (UK-68,798) in guinea-pig papillary muscle.

The effects of altered extracellular K+ concentrations ([K+]o) and pacing cycle lengths (CLs) on the electrophysiological actions of dofetilide (UK-68,798), a potent class III antiarrhythmic agent, were examined in isolated guinea-pig ventricular papillary muscle. At a normal [K+]o (4 mM) and at CL between 300 and 5000 msec, dofetilide (10 nM) significantly increased the action-potential duration (APD) and the effective refractory period (ERP), whereas other action-potential parameters were unaffected. Elevation of [K+]o to 10 mM reduced membrane diastolic potential (MDP), action-potential amplitude (APA), and the maximum rising velocity of the action-potential upstroke (Vmax). These changes were accompanied by a small shortening of APD90, but with an increase in ERP; i.e., the ERP/APD90 ratio was increased. Dofetilide also significantly lengthened APD90 at 10 mM [K+]o and at each CL. Even at the short cycle lengths (300 and 500 msec), dofetilide-induced increases in APD90 were not attenuated whether [K+]o was at 4 or 10 mM. These results indicate that at various pacing CLs, 10 nM dofetilide increases myocardial APD and ERP to a similar extent without significant reverse use-dependence when the cell membrane is normally polarized or partially depolarized by elevated [K+]o. Dofetilide may, therefore, be expected to be beneficial in the treatment of cardiac tachyarrhythmias related or unrelated to regional myocardial hyperkalemia during myocardial ischemia.

Action Potentials↗

PubMed1992

Class III antiarrhythmic action by potassium channel blockade: dofetilide attenuates hypoxia induced electromechanical changes.

OBJECTIVE: The aim was to examine the electromechanical effects of dofetilide, a new class III antiarrhythmic agent, in isolated guinea pig ventricular muscle during hypoxia. METHODS: Hypoxia was induced by superfusing guinea pig right ventricular papillary, muscles with Tyrode's solution gassed with 95% N2 + 5% CO2 [PO2 = 5.3(SEM 1.3) kPa]. Prior to hypoxia, the preparations were either pretreated for 30 min with 0.1 microM dofetilide (n = 6) or with 100 microM glibenclamide (a blocker of ATP sensitive K+ channels, n = 6), or not pretreated (n = 6). Sixteen additional preparations were exposed to 1 mM nicorandil (an activator of ATP sensitive K+ channels) in the absence (n = 6) and presence of dofetilide (n = 6) or glibenclamide (n = 4). Transmembrane action potentials and developed force were recorded using conventional microelectrode techniques and a force transducer. RESULTS: During normoxia, dofetilide markedly increased APD90 from 236(SEM 6) ms to 298(7) ms (p < 0.05) and the effective refractory period (ERP) from 248(5) ms to 315(6) ms (p < 0.05). In the drug free group, 60 min hypoxia decreased APD90 by 47(5)% (p < 0.05), ERP by 48(4)% (p < 0.05) and developed force by 71(6)% (p < 0.05) of baseline, respectively. These hypoxia induced effects were significantly attenuated after pretreatment with dofetilide or glibenclamide. Nicorandil decreased APD90 by 45(5)% (p < 0.05), ERP by 44(6)% (p < 0.05), and developed force by 69(10)% (p < 0.05) of baseline, respectively. Pretreatment with dofetilide or glibenclamide also significantly attenuated the nicorandil induced decreases in APD90, ERP, and developed force. CONCLUSIONS: Dofetilide, like glibenclamide, effectively attenuates hypoxia and nicorandil induced action potential shortening and the associated reduction in contractile force. Thus dofetidile would be expected to retain its antiarrhythmic efficacy during myocardial hypoxia or ischaemia.

Action Potentials↗

PubMed1992

Class III antiarrhythmic action and inotropy: effects of dofetilide in acute ischemic heart failure in dogs.

We studied the hemodynamic and metabolic effects of the novel class III antiarrhythmic agent dofetilide (UK-68,798) in acute ischemic heart failure. In pentobarbital-anesthetized dogs, heart failure was induced by microembolization of the area supplied by the main left coronary artery until a stable left ventricular (LV) end-diastolic pressure of 27 +/- 2 mm Hg was achieved. Embolization depressed LV systolic pressure, LV dP/dtmax, LV dP/dtmin, and cardiac output. None of these parameters were changed following i.v. infusion of dofetilide 5, 10, or 25 micrograms/kg, during spontaneous and paced cycle length of 300 ms (n = 9). Heart rate decreased by 12 +/- 8, 19 +/- 7, and 21 +/- 7 beats/min (p less than 0.05), while QT time increased by 23 +/- 7, 33 +/- 9, and 40 +/- 10 ms (p less than 0.05) after 5, 10, and 25 micrograms/kg, respectively. Ventricular effective refractory period increased from 128 +/- 10 to 153 +/- 11 ms after 25 micrograms/kg (n = 4). Arterial concentration and net myocardial uptake of glucose, lactate, and free fatty acids were not significantly influenced by dofetilide. In conclusion, dofetilide, at doses that prolonged repolarization, was devoid of cardiodepressive effects in acute ischemic heart failure.

Animals↗

PubMed1992

Electromechanical action of dofetilide and D-sotalol during simulated metabolic acidosis in isolated guinea pig ventricular muscle.

We examined the electromechanical effects of two class III antiarrhythmic agents, dofetilide (UK-68,798) and D-sotalol, in acidic myocardium. Right ventricular papillary muscle preparations isolated from guinea pigs were divided into three groups (n = 6 per group): (a) drug-free, (b) dofetilide (10 nM), and (c) D-sotalol (30 microM). At normal extracellular pH (pH = 7.32 +/- 0.01), dofetilide and D-sotalol lengthened action potential duration (APD) to a similar extent, i.e., by 18-20%. Effective refractory period (ERP) increased in parallel, whereas membrane diastolic potential (MDP), action potential amplitude (APA), maximum velocity of depolarization (Vmax), and developed force (DF) were not significantly affected. Metabolic acidosis (pH = 6.78 +/- 0.01) was simulated by reducing the bicarbonate concentration of the Tyrode's solution from 20 to 6 mM. Superfusion with acidic solution alone for 30 min markedly decreased Vmax and DF, whereas APD and ERP were lengthened slightly. The acidosis-induced decreases in Vmax and DF were not affected by pretreatment with dofetilide or D-sotalol. In acidic superfusate, both agents still significantly increased APD and ERP to the same extent that they did at normal pH. The results indicate that metabolic acidosis, a major component of myocardial ischemia, does not attenuate the class III antiarrhythmic action of dofetilide and D-sotalol.

Acidosis↗

PubMed1992

Class III antiarrhythmic action and inotropy: effects of almokalant in acute ischaemic heart failure in dogs.

We studied the haemodynamic and metabolic effects of the novel class III antiarrhythmic agent almokalant (H 234/09) in acute ischaemic heart failure at a dose prolonging ventricular repolarization. In pentobarbital anaesthetized dogs, heart failure was induced by microembolization of the area supplied by the main left coronary artery until a stable left ventricular end-diastolic pressure (LVEDP) of 32 +/- 2 mmHg was achieved. Embolization depressed LV dP/dt(max), LV dP/dt(min), left ventricular systolic pressure (LVSP) and cardiac output. After intravenous infusion of almokalant (0.35 micrograms/kg) LV dP/dt(max) and LV dP/dt(min) were not significantly changed at paced cycle length of 300 msec., whereas LVSP and aortic pressure decreased both at spontaneous and paced cycle length of 300 msec. LVEDP remained unchanged. Heart rate decreased from 185 +/- 7 to 167 +/- 5 beats/min., and corrected QT-time (QTc) increased from 9.5 +/- 0.3 to 10.4 +/- 0.5 msec. Arterial concentration and net myocardial uptake of glucose, lactate and free fatty acids were not significantly influenced by almokalant. In conclusion, almokalant at a dose prolonging ventricular repolarization had no negative inotropic effect in acute ischaemic heart failure.

Acute Disease↗

PubMed1992

Sequence of excitation as a factor in sympathetic-parasympathetic interactions in the heart.

We determined the influence of differences in the time of initiation of sympathetic and vagal stimulation (both at 10 Hz) on the cardiac autonomic interactions in 16 open-chest anesthetized dogs. We always ended the concurrent sympathetic and vagal stimulations simultaneously. Sympathetic stimulation alone for 1 minute increased heart rate by 90 +/- 7 (mean +/- SEM) beats per minute, and vagal stimulation alone for 1 minute decreased heart rate by 67 +/- 5 beats per minute; i.e., the algebraic sum of these responses was an increase of 23 beats per minute. However, combined sympathetic and vagal stimulation for 1 minute actually decreased heart rate by 35 beats per minute; i.e., the vagal effects predominated. When vagal stimulation was initiated first, the chronotropic responses to combined stimulation were not significantly affected by the duration of antecedent vagal stimulation. However, when sympathetic stimulation was initiated first, the vagal predominance (disparity between the summated individual responses and the combined response) progressively diminished as we increased the duration of antecedent sympathetic stimulation. The vagal predominance diminished from a value of 67 +/- 21 beats per minute when the stimulations were initiated simultaneously to a value of 37 +/- 21 beats per minute when the duration of antecedent sympathetic stimulation was 10 minutes. Sympathetic stimulation releases not only norepinephrine but also neuropeptide Y, and this neuropeptide inhibits vagal neurotransmission. Our data suggest, therefore, that the longer the antecedent sympathetic stimulation, the greater the inhibition of vagal neurotransmission (presumably by the neuropeptide Y) and, therefore, the less pronounced the vagal predominance.

Animals↗

PubMed1992

Stabilities and properties of multilinked hemoglobins.

Crosslinking of both human and dog hemoglobin has been done with a variety of reagents to produce singly, doubly and multiply crosslinked hemoglobins. Succinate and glutarate diaspirins did not crosslink deoxy human hemoglobin in good yield, in contrast to the fumarate analog (DBSF). Deoxy dog Hb did not react well with DBSF, but oxy dog Hb did react, giving crosslinked tetramers as well as dimers on SDS electrophoresis. Crosslinking with a short, rigid reagent (difluorodinitrobenzene) resulted in a similar product for both oxy and deoxy hemoglobin that had high stability and oxygen affinity. The trilinker, tris-chloroethylamine, produced a more stable product than the corresponding crosslinker, bis-chloroethylamine. Double crosslinking oxy Hb with DBSF and dimethylpimelimidate or with DBSF followed by deoxygenation and recrosslinking with DBSF gave products with higher denaturation temperatures. The diaspirin double crosslinked product had high oxygen affinity.

Animals↗

PubMed1991

Thermal stability of hemoglobin crosslinked in the T-state by bis(3,5-dibromosalicyl) fumarate.

Bis(3,5-dibromosalicyl) fumarate was used to crosslink oxyhemoglobin between Lys 82 beta 1 and Lys 82 beta 2 (Walder, J. A., et al. (1979) Biochemistry 18, 4265) and deoxyhemoglobin between Lys 99 alpha 1 and Lys 99 alpha 2 (Chatterjee R.Y., et al. (1986) J. Biol. Chem. 261, 9929). Thermal denaturations demonstrated that alpha crosslinked hemoglobin (alpha 99XLHb A) has the same stability as the beta crosslinked one (beta 82XLHb A). Both alpha and beta crosslinked methemoglobins have a denaturation temperature in 0.9 M guanidine of 57 degrees C compared to 41 degrees C of Hb A. The second product from the T-state crosslinking reaction was found to be crosslinked between the beta chains by chain separation and amino acid analysis. The possible positions for this crosslink are limited to the bisphosphoglycerate binding site in the three-dimensional structure. Its stability is comparable to that of the alpha 99XLHb A or beta 82XLHb A. These modified hemoglobins are potential blood substitutes.

Amino Acids↗

PubMed1991

Negative chronotropic effect of a novel class III antiarrhythmic drug, UK-68,798, devoid of beta-blocking action on isolated guinea-pig atria.

1. The chronotropic effects of a novel class III antiarrhythmic drug, UK-68,798, and the beta-adrenoceptor blocker, propranolol, for comparison, were studied on spontaneously beating right atria isolated from guinea-pigs in the absence and presence of increasing concentrations of isoprenaline (10(-10)-10(-4) M). 2. UK-68,798 (10(-9)-10(-5) M) decreased spontaneous atrial rate by 6-21%. Propranolol (10(-8) -10(-6) M) also had a negative but significantly smaller chronotropic effect. 3. UK-68,798 dose-dependently reduced the maximal positive chronotropic effect induced by isoprenaline, but without significantly shifting the concentration-response curve for isoprenaline in a parallel fashion. A pD'2 value of 5.88 was obtained. As expected, propranolol displayed a competitive inhibition with a pA2 value of 8.21. 4. The results demonstrate a negative chronotropic effect of UK-68,798, which is not associated with a beta-adrenoceptor blocking action. We suggest that the negative chronotropic effect is linked with potassium channel blockade and thereby the class III antiarrhythmic action of UK-68,798.

Adrenergic beta-Antagonists↗