Left ventricular hypertrophy decreases slowly but not rapidly activating delayed rectifier potassium currents of epicardial and endocardial myocytes in rabbits.

BACKGROUND: Delayed rectifier K(+) currents are critical to action potential (AP) repolarization. The present study examines the effects of left ventricular hypertrophy (LVH) on delayed rectifier K(+) currents and their contribution to AP repolarization in both epicardial (Epi) and endocardial (Endo) myocytes. METHODS AND RESULTS: VH was induced in rabbits by a 1-kidney removal, 1-kidney vascular clamping method. Slowly (I(Ks)) and rapidly (I(Kr)) activating delayed rectifier K(+) currents were recorded by the whole-cell patch-clamp technique, and APs were recorded by the microelectrode technique. In normal rabbit left ventricular myocytes, I(Ks) densities were larger in Epi than in Endo (1.1+/-0.1 versus 0.43+/-0.07 pA/pF), whereas I(Kr) density was similar between Epi and Endo (0.31+/-0.05 versus 0.36+/-0.07 pA/pF) at 20 mV. LVH reduced I(Ks) density to a similar extent (approximately 40%) in both Epi and Endo but had no significant effect on I(Kr) in either Epi or Endo. Consequently, I(Kr) was expected to contribute more to AP repolarization in LVH than in control. This was confirmed by specific I(Kr) block with dofetilide, which prolonged AP significantly more in LVH than in control (31+/-3% versus 18+/-2% in Epi; 53+/-6% versus 32+/-4% in Endo at 2 Hz). In contrast, L-768,673 (a specific I(Ks) blocker) prolonged AP less in LVH than in control. The very small I(Ks) density in Endo with LVH is consistent with the greater incidence of early afterdepolarizations induced in this region by dofetilide. CONCLUSIONS: LVH induces a decrease in I(Ks) density and increases the propensity to develop early afterdepolarizations, especially in Endo.

Management and prevention of atrial fibrillation after cardiovascular surgery.

Atrial arrhythmias occur frequently after cardiac surgery. This article discusses the incidence of postoperative atrial arrhythmia as well as its prognosis, potential mechanisms of pathogenesis, and management. Prophylactic therapy for postoperative atrial arrhythmia is recommended because of the frequency of occurrence and the ease with which therapies can often be implemented. Treatments with pharmacologic and nonpharmacologic modalities are described. Management strategies for atrial arrhythmias that occur postoperatively, including pharmacologic and nonpharmacologic measures as well as anticoagulation recommendations, are discussed.

Pharmacologic and pharmacokinetic profile of class III antiarrhythmic drugs.

Cardiac arrhythmias frequently respond only to drugs that have as their predominant electrophysiologic effect the prolongation of repolarization and refractoriness. According to the Singh-Vaughan Williams classification, these drugs are known as class III agents. In the last few years, interest has increased in the development of class III antiarrhythmic drugs as alternatives to sodium channel blocking agents, which mainly affect cardiac conduction. Much of this interest results from a perceived danger of using drugs with sodium channel blocking properties, particularly in patients with ischemic heart disease, based on the results of the Cardiac Arrhythmia Suppression Trial (CAST) and several other trials. This article is a review of the pharmacology, including the pharmacokinetics and pharmacodynamics, of the most commonly used and investigated class III antiarrhythmic drugs. As will be seen from the discussion, each of these drugs has novel pharmacology that makes it applicable in specific clinical situations. Their putative effects on various arrhythmogenic mechanisms and their efficacy in treating specific target arrhythmias will be addressed.

Atrial fibrillation trials: will they teach us what we need to know?

Atrial fibrillation (AF) has captured the imagination of clinical investigators who have initiated trials to examine several aspects of this multifaceted arrhythmia. We will review the protocol designs of ongoing trials that are examining the relative value of rhythm versus rate control, new methods for pharmacologic restoration and maintenance of sinus rhythm (including prophylaxis after cardiac surgery), and nonpharmacologic interventions such as pacing and atrial defibrillation. We antic ipate that the results of these studies will have a major impact on the care of patients with AF in the new millennium.

Intravenous antiarrhythmic therapy in the acute control of in-hospital destabilizing ventricular tachycardia and fibrillation.

Ventricular tachycardia, which causes hemodynamic instability, and ventricular fibrillation do not occur frequently in any hospital. However, they usually occur in patients who have severe underlying cardiovascular disease such as myocardial ischemia/infarction or congestive heart failure, and they are associated with high mortality. Most of those deaths are due to an intractable arrhythmia, not suppressible with even the most potent antiarrhythmic drugs. Fortunately, during the last few years, our ability to suppress highly lethal ventricular arrhythmia has been enhanced by the approval of intravenous amiodarone. When used in appropriate patient populations, intravenous amiodarone has been successful in suppressing the most malignant arrhythmia, thus permitting aggressive and successful treatment of severe underlying cardiac conditions. This article reviews data on the use of parenteral antiarrhythmic drugs for the control of ventricular arrhythmia in patients in hospital, and will attempt to provide some guidance as to how these antiarrhythmic drugs may be used in specific patient populations to maximize their efficacy and safety. We will also make recommendations on the sequence of therapy for specific arrhythmias to optimize the chances of patient survival.

Analysis of glucagon-receptor interactions on isolated canine hepatocytes. Formation of reversibly and irreversibly cell-associated hormone.

We have investigated the interactions of ligand with the canine hepatic glucagon receptor. Whereas time courses for radiolabeled glucagon binding to receptor and dissociation from receptor revealed fast and slow components at both 30 and 4 degrees C, time courses of ligand dissociation revealed a third component of irreversibly cell-associated (nondissociable) ligand only at the higher temperature. Related experiments identified that (a) the initial rate of formation of nondissociable ligand was slower than that of dissociably bound hormone; (b) the fraction of ligand bound to nondissociable sites achieved a plateau during extended incubations, whereas that bound to dissociable sites was seen to rise and then slowly to fall; (c) the kinetics of formation of a nondissociable ligand was consistent with linked, sequential reactions; (d) dissociable ligand-receptor complexes formed at 4 degrees C were converted to nondissociable complexes during subsequent incubation at 30 degrees C, and (e) nondissociable sites were filled by prior incubation of cells with unlabeled ligand. Analysis of receptor-bound hormone resulting from the incubation of cells with 125I-labeled glucagon and selected concentrations of either glucagon or [[127I]iodo-Tyr10]glucagon at steady state revealed in each case four components of receptor-bound ligand: those corresponding to high and low affinity components of dissociably bound ligand and to high and low affinity components of nondissociably bound ligand. Implications of these findings are considered in terms of mechanisms for the formation of irreversibly bound hormone and for the distribution of hormone among the various components of hepatic glucagon-binding sites.

Classification and pharmacology of antiarrhythmic drugs.

Despite the emergence of several forms of nonpharmacologic therapy for cardiac arrhythmias, antiarrhythmic drugs continue to play an important role in the management of patients with this common clinical problem. The key to the proper use of antiarrhythmic drugs is a thorough knowledge of their mode of action and pharmacology. The pharmacology of antiarrhythmic drugs is particularly important because patients with cardiac arrhythmias frequently have multiorgan disease, which may influence the metabolism and elimination of antiarrhythmic drugs. The accumulation of toxic amounts of these agents can lead to dire effects including, but not limited to, ventricular proarrhythmia and malignant bradycardia. The goals of pharmacologic therapy of cardiac arrhythmia are to provide the maximum benefit in terms of arrhythmia suppression while maintaining patient safety. To accomplish these goals, a knowledge of the pharmacology of several antiarrhythmic drugs is mandatory.

Comparison of the primary structures of clathrin light chains from bovine brain and adrenal gland by peptide mapping.

The structures of the polymorphic forms of clathrin light chains were analyzed by two peptide mapping procedures. Comparison of the products of partial digestion by V8 protease showed no common peptides between LCA and LCB from bovine brain. No similarities between clathrin light chains and tropomyosin chains from bovine brain and skeletal muscle were detected with this technique. The peptides produced by complete tryptic digestion of LCA and LCB from bovine brain and bovine adrenal gland were analyzed by reverse phase h.p.l.c. For both LCA and LCB the polypeptides from different tissues showed considerable homology. LCA from brain and adrenal gland shared 10 out of a total of 15 peptides. LCB from brain and adrenal gland shared 10 out of 14 peptides. In contrast, when LCA was compared with the LCB chain from the same tissue very few peptides were shared; 4/23 for brain and 3/21 for adrenal gland. These results strongly indicate that, within a tissue, LCB is not related to LCA by post-translational processing and that each chain is encoded by a separate gene. The data also demonstrate the close homology of the different forms of LCA and LCB expressed in different tissues within the same organism. Thus the polymorphic differences of clathrin light chains within a tissue are greater than those between tissues.

Atrial Fibrillation.

Atrial fibrillation will present the most significant arrhythmia management challenge for clinicians in the new millennium, particularly as the percentage of elderly patients and longevity increase worldwide. The clinical manifestations of the arrhythmia are wide ranging: paroxysmal to permanent modes of occurrence and asymptomatic to severely symptomatic presentations. Perhaps most important, the major risks of atrial fibrillation are stroke and death. Current therapies remain heavily focused on pharmacologic efforts to reduce the severity of primary symptoms and to prevent stroke and other thromboembolic complications by means of anticoagulation. It has not yet been proven that prevention of atrial fibrillation will prolong survival, however. Nonpharmacologic therapies remain under intense basic and clinical investigation as promising means to improve outcome further for patients suffering from atrial fibrillation.

TFIIH inhibits CDK9 phosphorylation during human immunodeficiency virus type 1 transcription.

Tat stimulates human immunodeficiency virus, type 1 (HIV-1), transcription elongation by recruitment of the human transcription elongation factor P-TEFb, consisting of CDK9 and cyclin T1, to the TAR RNA structure. It has been demonstrated further that CDK9 phosphorylation is required for high affinity binding of Tat/P-TEFb to the TAR RNA structure and that the state of P-TEFb phosphorylation may regulate Tat transactivation. We now demonstrate that CDK9 phosphorylation is uniquely regulated in the HIV-1 preinitiation and elongation complexes. The presence of TFIIH in the HIV-1 preinitiation complex inhibits CDK9 phosphorylation. As TFIIH is released from the elongation complex between +14 and +36, CDK9 phosphorylation is observed. In contrast to the activity in the "soluble" complex, phosphorylation of CDK9 is increased by the presence of Tat in the transcription complexes. Consistent with these observations, we have demonstrated that purified TFIIH directly inhibits CDK9 autophosphorylation. By using recombinant TFIIH subcomplexes, our results suggest that the XPB subunit of TFIIH is responsible for this inhibition of CDK9 phosphorylation. Interestingly, our results further suggest that the phosphorylated form of CDK9 is the active kinase for RNA polymerase II carboxyl-terminal domain phosphorylation.