Search PubMed⌕ Search

Biomedical subjects

J N Weiss

Publications and source records attributed to J N Weiss.

At least 73 records · Page 4Linked to original sources
PubMed1996

Anomalous regulation of the Drosophila Na(+)-Ca2+ exchanger by Ca2+.

The Na(+)-Ca2+ exchanger from Drosophila was expressed in Xenopus and characterized electrophysiologically using the giant excised patch technique. This protein, termed Calx, shares 49% amino acid identity to the canine cardiac Na(+)-Ca2+ exchanger, NCX1. Calx exhibits properties similar to previously characterized Na(+)-Ca2+ exchangers including intracellular Na+ affinities, current-voltage relationships, and sensitivity to the peptide inhibitor, XIP. However, the Drosophila Na(+)-Ca2+ exchanger shows a completely opposite response to cytoplasmic Ca2+. Previously cloned Na(+)-Ca2+ exchangers (NCX1 and NCX2) are stimulated by cytoplasmic Ca2+ in the micromolar range (0.1-10 microM). This stimulation of exchange current is mediated by occupancy of a regulatory Ca2+ binding site separate from the Ca2+ transport site. In contrast, Calx is inhibited by cytoplasmic Ca2+ over this same concentration range. The inhibition of exchange current is evident for both forward and reverse modes of transport. The characteristics of the inhibition are consistent with the binding of Ca2+ at a regulatory site distinct from the transport site. These data provide a rational basis for subsequent structure-function studies targeting the intracellular Ca2+ regulatory mechanism.

Animals↗
PubMed1996

Effects of TNF-alpha on [Ca2+]i and contractility in isolated adult rabbit ventricular myocytes.

The mechanism of the acute negative inotropic effect of tumor necrosis factor-alpha (TNF-alpha) was studied in enzymatically isolated adult rabbit ventricular myocytes. In cells loaded with fura 2 acetoxymethyl ester (AM) and paced intermittently at 0.2 Hz, TNF-alpha at doses < or = 10,000 U/ml caused a significant reduction in active cell shortening at 20 min, without reducing the amplitude of the accompanying intracellular Ca2+ concentration ([Ca2+]i) transient. Similar results were obtained in cells loaded with indo 1-AM and paced continuously at 0.2 Hz during exposure to TNF-alpha (10,000 U/ml). The effect of TNF-alpha on cell shortening could be prevented by the nitric oxide (NO) synthase blocker NG-nitro-L-arginine methyl ester (L-NAME) but not its inactive enantiomer NG-nitro-D-arginine methyl ester (D-NAME). The NO scavenger hemoglobin also attenuated the effects of TNF-alpha. TNF-alpha also caused a significant increase in diastolic cell length without any change in diastolic [Ca2+]i. The effect on cell length was prevented by L-NAME but not D-NAME. In cells loaded with the pH indicator seminaphthorhodafluor-AM, TNF-alpha did not alter pH sufficiently to account for the negative inotropic effect. These data suggest that high doses of TNF-alpha can acutely induce NO synthesis in isolated myocytes and reduce contractility by decreasing myofilament [Ca2+]i responsiveness. The mechanism of this altered myofilament [Ca2+]i response is unknown but does not appear to be pH mediated.

Animals↗
PubMed1996

Dynamics of muscle sympathetic nerve activity in advanced heart failure patients.

Muscle sympathetic nerve activity (MSNA) is increased in patients with heart failure compared with healthy subjects. We applied spectral and correlation techniques to determine if qualitative as well as quantitative differences in MSNA differentiate heart failure patients from healthy subjects. We recorded MSNA, heart rate, and respiration in 11 heart failure patients and 10 healthy humans. Our results are as follows. 1) Statistically significant low-frequency modulation of MSNA at 0.029 +/- 0.002 Hz (mean +/- SE; range 0.026-0.038 Hz) was found in 10 of 11 heart failure patients but in only 2 of 10 healthy controls (differences between groups, P < 0.01; chi 2 test). 2) Heart rate and respiration also demonstrated significant low-frequency modulation in a similar range. 3) Spectral and correlation techniques revealed that low-frequency modulation of MSNA was highly correlated with low-frequency modulation of respiration in heart failure patients, but not in healthy subjects. In contrast, low-frequency modulation of MSNA did not correlate well with low-frequency modulation of heart rate. In summary, low-frequency modulation of respiration is coupled to low-frequency modulation of MSNA in heart failure patients, but not in normal subjects. We speculate that this low-frequency modulation of respiration may represent subclinical Cheyne-Stokes breathing, which has marked qualitative effects on MSNA in patients with heart failure.

Adolescent↗
PubMed1995

Regulation of the cardiac Na(+)-Ca2+ exchanger by Ca2+. Mutational analysis of the Ca(2+)-binding domain.

The sarcolemmal Na(+)-Ca2+ exchanger is regulated by intracellular Ca2+ at a high affinity Ca2+ binding site separate from the Ca2+ transport site. Previous data have suggested that the Ca2+ regulatory site is located on the large intracellular loop of the Na(+)-Ca2+ exchange protein, and we have identified a high-affinity 45Ca2+ binding domain on this loop (Levitsky, D. O., D. A. Nicoll, and K. D. Philipson. 1994. Journal of Biological Chemistry. 269:22847-22852). We now use electrophysiological and mutational analyses to further define the Ca2+ regulatory site. Wild-type and mutant exchangers were expressed in Xenopus oocytes, and the exchange current was measured using the inside-out giant membrane patch technique. Ca2+ regulation was measured as the stimulation of reverse Na(+)-Ca2+ exchange (intracellular Na+ exchanging for extracellular Ca2+) by intracellular Ca2+. Single-site mutations within two acidic clusters of the Ca2+ binding domain lowered the apparent Ca2+ affinity at the regulatory site from 0.4 to 1.1-1.8 microM. Mutations had parallel effects on the affinity of the exchanger loop for 45Ca2+ binding (Levitsky et al., 1994) and for functional Ca2+ regulation. We conclude that we have identified the functionally important Ca2+ binding domain. All mutant exchangers with decreased apparent affinities at the regulatory Ca2+ binding site also have a complex pattern of altered kinetic properties. The outward current of the wild-type Na(+)-Ca2+ exchanger declines with a half time (th) of 10.8 +/- 3.2 s upon Ca2+ removal, whereas the exchange currents of several mutants decline with th values of 0.7-4.3 s. Likewise, Ca2+ regulation mutants respond more rapidly to Ca2+ application. Study of Ca2+ regulation has previously been possible only with the exchanger operating in the reverse mode as the regulatory Ca2+ and the transported Ca2+ are then on opposite sides of the membrane. The use of exchange mutants with low affinity for Ca2+ at regulatory sites also allows demonstration of secondary Ca2+ regulation with the exchanger in the forward or Ca2+ efflux mode. In addition, we find that the affinity of wild-type and mutant Na(+)-Ca2+ exchangers for intracellular Na+ decreases at low regulatory Ca2+. This suggests that Ca2+ regulation modifies transport properties and does not only control the fraction of exchangers in an active state.

Amino Acid Sequence↗
PubMed1995

The effects of phenylephrine 2.5% versus phenylephrine 10% on pupillary dilation in patients with diabetes.

PURPOSE: A prospective, double-blind study was conducted to compare the clinical efficacy of a combination of 1% tropicamide and 2.5% phenylephrine and a combination of 1% tropicamide and 10% phenylephrine for pupillary dilation in patients with diabetes. METHODS: Either 2.5% phenylephrine in one eye and 10% phenylephrine in the other eye, 2.5% phenylephrine in both eyes, or 10% phenylephrine in both eyes was administered to 127 consecutive patients with diabetes. All patients received 1% tropicamide in both eyes. RESULTS: There was no statistically significant difference in the amount of pupillary dilation between the three groups. CONCLUSION: As 2.5% phenylephrine may produce a lower incidence of side effects than the 10% concentration, we advise the use of the lower concentration, particularly among patients with diabetes, who already exhibit a higher prevalence of vascular disease and autonomic dysfunction.

Adolescent↗
PubMed1994

Surface charge and properties of cardiac ATP-sensitive K+ channels.

ATP-sensitive K+ (KATP) channels are present in a wide variety of tissues. The sensitivity of these channels to closure by cytosolic ATP (ATPi) varies significantly among different tissues and even within the same tissue. The purpose of this study was to test the hypothesis that negative surface charges modulate the sensitivity of the KATP channels to ATPi by influencing surface potential in the vicinity of the ATP-binding site(s) of the channel. Unitary currents through KATP channels were measured in inside-out membrane patches excised from rabbit ventricular myocytes using the patch-clamp technique. Agents known to be effective at screening negative surface charges were applied to the cytosolic surface of the patches, and their effects on ATP sensitivity were examined. These agents included Mg2+ (2-15 mM), Ba2+ (2-10 mM), and the polycations protamine (0.01-10 microM), poly-L-lysine (500 microM), and poly-L-arginine (0.5 microM). The divalent cations and the various polycations all dramatically reduced the concentration of ATPi required to half-maximally suppress current through KATP channels (Kd), from approximately 100 microM in the absence of these agents to 1.6-8 microM in their presence. The effects were dose dependent. Protamine also reduced the sensitivity of KATP channels to block by cytosolic ADP. The sensitivity of KATP channels to block by ATP was independent of membrane potential, suggesting that the ATP-binding site is not located within the transmembrane voltage field. The effects of the polycation poly-L-lysine on ATP sensitivity were also independent of membrane potential or the direction (inward or outward) of current through KATP channels. In addition to increasing ATP sensitivity, Mg2+, Ba2+, and the polycations all caused dose-dependent block of inward and outward currents through KATP channels over similar concentration ranges as their effects on ATP sensitivity. The block of inward current by polycations was not associated with reduction of single-channel conductance or evidence of fast open channel block. However, the polycations did cause a modest reduction in single-channel conductance of outward current. These results are consistent with the presence of negative surface charges that reduce the local ATP concentration at the ATP-binding site(s) on the channel, relative to the bulk cytosolic ATP concentration. Screening these negative surface charges with divalent cations or polycations decreases the local ATP gradient, resulting in a decrease in the apparent Kd for ATP.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Diphosphate↗
PubMed1994

Potassium loss during myocardial ischaemia and hypoxia: does lactate efflux play a role?

In heart, the available evidence suggests that transmembrane lactate flux is mediated predominantly by an H(+)-lactate transporter with properties similar, but not identical, to the H(+)-monocarboxylate transporter present in many other tissues. Passive (electro-)diffusion of HL and L- comprise only minor components of total transmembrane lactate flux over the range of lactate concentrations relevant to normal physiological and pathophysiological states. The cardiac H(+)-lactate transporter is non-electrogenic, and transport is partially inhibited by potassium, possibly by competition for the H+ binding site on the carrier. However, K+ is cotransported with lactate very inefficiently, if at all, compared to H+. From these observations, a direct mechanism coupling potassium efflux to lactate efflux, by either an electrogenic or a non-electrogenic mechanism, is unlikely to account for the majority of net potassium loss during myocardial ischaemia or hypoxia, unless the properties of transmembrane lactate flux are markedly altered by the ischaemic and hypoxic environment. Nevertheless, it is intriguing that alterations in pHi, pHo, and transmembrane pH gradients in ischaemic cardiac muscle and fatigued skeletal muscle have effects on net potassium loss that qualitatively parallel the predicted effects on L- efflux. In view of the lack of evidence for a direct link between potassium and lactate efflux in the heart, it is likely that this apparent relationship is either coincidental or indirect, mediated through a series of intermediate transport processes. The nature of these interactions remain to be defined. Further studies are still needed to solve the puzzle of what causes net cellular potassium loss during myocardial ischaemia and hypoxia.

Biological Transport↗
PubMed1994

Effects of trypsin on cardiac ATP-sensitive K+ channels.

Treatment with trypsin of the cytoplasmic surface of excised inside-out membrane patches from guinea pig ventricular myocytes altered multiple regulatory properties of ATP-sensitive K+ (KATP) channels including their sensitivity to intracellular ATP (ATPi), intracellular ADP (ADPi), glibenclamide, and cromakalim. The single-channel conductance, reversal potential, and inward rectification (in the presence of intracellular Mg2+) were unaltered after trypsin treatment. KATP channels also remained sensitive to intracellular Ca(2+)-induced rundown after trypsin treatment (n = 6). The effects of trypsin were not prevented by including either 15 mM ATPi (n = 7), 1 mM ADPi (n = 4), or 10 microM glibenclamide (n = 4) during exposure to trypsin, suggesting that occupancy of these binding sites did not prevent access of trypsin to the proteolytic sites responsible for its effects. Treatment of excised membrane patches with 1 mM phenylglyoxal (n = 4) or 5 mM glyoxal (n = 4), which cleave polypeptides at arginine residues, did not increase the dissociation constant for suppression of KATP channels by ATPi. Because trypsin cleaves peptides at both arginine and lysine residues, these results suggest that modification of the regulatory properties of KATP channels by trypsin may result from proteolytic digestion of lysine residues located in cytosolic regions of the channel protein.

Adenosine Diphosphate↗
PubMed1994

Lactate transport in mammalian ventricle. General properties and relation to K+ fluxes.

Net cellular L-lactate efflux associated with accelerated anaerobic glycolysis has been implicated as a potential cause of the marked cellular K+ loss contributing to lethal cardiac arrhythmias in ischemic heart and to impaired function of fatigued skeletal muscle. To examine the mechanisms of transsarcolemmal L-lactate movement in the heart, isolated guinea pig ventricular myocytes were loaded with the fluorescent H+ or K+ indicators, carboxy SNARF-1 or PBFI, respectively, under whole-cell patch-clamp conditions. With H+ as the only permeable monovalent cation, a rapid increase in extracellular L-lactate concentration ([L-]o) from 0 to 30 mmol/L at constant pHo (7.35) caused an intracellular acidification averaging 0.18 +/- 0.02 pH units in 60 seconds (n = 7), reflecting L-lactate influx in association with H+ influx (or OH- efflux). Under voltage-clamp conditions, no significant electrogenic current was associated with H(+)-coupled L-lactate influx, and membrane potential (-75 to +75 mV) had no effect on the degree of acidification produced by 30 mmol/L [L-]o, indicating that L-lactate influx was predominantly nonelectrogenic. Acidification in response to increased [L-]o was saturable (Km, approximately 5 mmol/L), partially stereospecific for L-lactate over D-lactate, and inhibited by 55 +/- 7% and 82 +/- 7% by the monocarboxylate carrier inhibitors alpha-cyano-4-hydroxycinnamate and mersalyl acid, respectively, consistent with a carrier-mediated transport mechanism. Extracellular K+ inhibited H(+)-coupled L-lactate influx by 36 +/- 2%, suggesting that K+ either inhibited or substituted for H+ in cotransport with L-lactate. However, in myocytes loaded with PBFI, no significant increase in [K+]i was detected during exposure to 30 mmol/L [L-]o, suggesting that only a minor component, if any, of L-lactate influx was cotransported or codiffused with K+.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1994

Reasons for high drop-out rate with self-injection therapy for impotence.

One hundred and eighty patients, average age of 58 years (range 24-75) were evaluated for impotence and were advised to undergo pharmacologic self-injection therapy with either papaverine/Regitine (90%) or prostaglandin E1 (10%). Follow-up was available from 2 months to 3 years (average 11 months). The cause of impotence was determined by hormonal testing, Rigiscan and psychological testing. The etiology of impotence was organic (70%), psychogenic (20%), and mixed (10%). After the initial test injection 22% of patients did not enroll in the self-injection program or were lost to follow-up. The group with psychogenic impotence had the highest satisfaction/usage rate at 42%. Overall only 20% of patients were satisfied long-term and were actively using self-injection therapy. Of the 140 patients available for follow-up, 112 patients (80%) discontinued self-injection therapy. The reasons for discontinued usage were alternate treatment (prosthesis or vacuum device) 15%, return or improvement of erections 8%, partner dissatisfaction or loss of partner 10%, or complications of injection therapy 10%. Cost was not a factor for discontinued use. Loss of interest caused 57% of patients to stop using self-injection therapy. Although pharmacologic self-injection therapy is initially promising there is a high drop-out rate at long-term follow-up.

Adult↗
PubMed1993

Biosynthesis and initial processing of the cardiac sarcolemmal Na(+)-Ca2+ exchanger.

Based on the deduced amino-acid sequence of the cardiac Na(+)-Ca2+ exchanger, there are six potential N-linked glycosylation sites and a potential cleaved signal sequence. To study the post-translational modifications of the exchanger, in vitro translation was examined in the presence and absence of canine pancreatic microsomes. Glycosylation, detected as endoglycosidase H induced shifts in molecular size, was examined for proteins having different numbers of potential N-linked glycosylation sites by using full and partial length RNA transcripts. In the presence of microsomes, the molecular mass of the full-length clone increased from 110 to 113 kDa. Endoglycosidase H treatment led to a reduction to 108 kDa, indicating that glycosylation increases the molecular mass by approx. 5 kDa and a signal sequence of approx. 2 kDa is cleaved during processing. Analysis of molecular-mass shifts obtained with partial transcripts suggested that glycosylation occurs at position N-9. This was confirmed by site-directed mutagenesis studies. A molecular mass of approx. 120 kDa was measured for Western blots of cardiac sarcolemmal membrane or oocytes expressing the wild-type exchanger. The molecular mass was reduced by approx. 10 kDa for the N9Y mutant or from exchanger obtained from a baculovirus-infected insect cell line where glycosylation does not occur. The giant excised patch technique was used to determine the functional consequences of glycosylation. Na(+)-Ca2+ exchange current was examined in patches from oocytes expressing either the wild-type or N9Y mutant. The non-glycosylated mutant exhibited the same properties as the native exchanger with respect to voltage, sodium dependence, and the effects of chymotrypsin. The results indicate that glycosylation does not affect exchanger function in Xenopus oocytes and help to define exchanger topology.

Amino Acid Sequence↗
PubMed1993

Metabolic regulation of cardiac ATP-sensitive K+ channels.

Activation of ATP-sensitive K+ (KATP) channels has been implicated as a cause of increased cellular K+ efflux and action potential duration (APD) shortening during myocardial ischemia, hypoxia, and selective glycolytic inhibition, since selective KATP channel antagonists partially or completely block increased cellular K+ efflux and APD shortening under these conditions. During substrate-free hypoxia or myocardial ischemia in intact rabbit ventricle, unidirectional K+ efflux rate during systole approximately doubled and APD decreased by approximately 40% after 10 minutes. In patch-clamped guinea pig ventricular myocytes, similar changes could be produced by activation of < 0.5% of the maximal KATP channel conductance. Furthermore, from studying the desensitizing effects of ADPi on the ATP sensitivity of KATP channels in excised inside-out patches, it was estimated that the rapid changes in the cytosolic ATP/ADP ratio during ischemia and hypoxia were of sufficient magnitude to activate KATP channels to this degree. During selective glycolytic inhibition, however, the global cytosolic ATP/ADP ratio in intact heart remained normal despite an increase in cellular K+ efflux comparable to ischemia and hypoxia. In patch-clamped saponin-permeabilized ventricular myocytes, KATP channels were preferentially suppressed by glycolytic ATP production compared to ATP generated by mitochondria or by the creatinine kinase reaction, and functional glycolytic enzymes were found to be associated with KATP channels in excised membrane patches. We hypothesize that sarcolemma-associated glycolytic enzymes may be important in maintaining a high local cytosolic ATP/ADP ratio in the vicinity of KATP channels, where sarcolemmal ATPases are tending to depress the local ATP/ADP ratio.

Action Potentials↗
PubMed1993

Modulation of voltage-dependent sodium and potassium currents by charged amphiphiles in cardiac ventricular myocytes. Effects via modification of surface potential.

Modulation of voltage-dependent sodium and potassium currents by charged amphiphiles was investigated in cardiac ventricular myocytes using the patch-clamp technique. Negatively charged sodium dodecylsulfate (SDS) increased amplitude of INa, whereas positively charged dodecyltrimethylammonium (DDTMA) decreased INa. Furthermore, SDS shifted the steady-state activation and inactivation of INa in the negative direction, whereas DDTMA shifted the curves in the opposite direction. These shifts provided an explanation for the changes in current amplitude. Activation and inactivation kinetics of INa were accelerated by SDS but slowed by DDTMA. These changes in both steady-state gating and kinetics of INa are consistent with a decrease of the intramembrane field by SDS and an increase of the field by DDTMA due to an alteration of surface potential after their insertion into the outer monolayer of the sarcolemma. The effect of SDS on the steady-state inactivation of INa was concentration dependent and partially reversed by screening surface charges with increased extracellular [Ca2+]. These amphiphiles also altered the activation of the delayed rectifier K+ current (IK,del), producing a shift in the negative direction by SDS but in the positive direction by DDTMA. These results suggest that the insertion of charged amphiphiles into the cell membrane alters the behavior of voltage-dependent INa and IK,del by changing the surface charge density, and consequently the surface potential and implies, although indirectly, that the lipid surface charges are important to the voltage-dependent gating of these channels.

Animals↗
PubMed1993

ATP-sensitive K+ channel modification by metabolic inhibition in isolated guinea-pig ventricular myocytes.

1. ATP-sensitive K+ (K+ATP) channels are believed to make an important contribution to the increased cellular K+ efflux and shortening of the action potential duration (APD) during metabolic inhibition, hypoxia, and ischaemia in the heart. The mechanisms by which the activity of the K+ATP channel is regulated during conditions of metabolic impairment are not completely clear. Extrinsic factors such as increased [ADP]i, acidosis, and stimulation of adenosine receptors appear to decrease the K+ATP channel's sensitivity to closure by [ATP]i. The purpose of this study was to determine whether the K+ATP channel itself is intrinsically altered by the processes associated with metabolic impairment. 2. Isolated guinea-pig ventricular myocytes were metabolically inhibited in glucose-free 1.8 mM Ca2+ Tyrode solution containing 9 microM rotenone and 0.9 microM carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) while recording unitary currents through K+ATP channels in cell-attached patches. When K+ATP channel activity became maximal, the patch was excised (inside-out) into 150 mM K+ bath solution containing different ATP concentrations. The Kd for suppression by [ATP]i ([ATP]i causing half-maximal suppression of current through K+ATP channels) was markedly increased to 305 microM (n = 9) compared to patches excised from control myocytes not exposed to metabolic inhibitors (Kd = 46 microM, n = 28). 3. A [Ca2+]i-dependent process was involved in K+ATP channel modification during metabolic inhibition. Removal of extracellular Ca2+ during metabolic inhibition led to an intermediate decrease in the ATP sensitivity of the K+ATP channels (Kd = 120 microM, n = 6). In myocytes that were pretreated with 10 microM ryanodine in addition to removing extracellular Ca2+, the reduction in ATP sensitivity was completely prevented (Kd = 23 microM, n = 6). 4. In inside-out membrane patches excised from control non-metabolically inhibited myocytes, elevated free [Ca2+]i (2 microM) did not alter the sensitivity of the K+ATP channel to closure by [ATP]i, suggesting that in metabolically inhibited myocytes elevated [Ca2+]i acted indirectly. K+ATP channel run-down was found to increase the sensitivity of K+ATP channels to closure to [ATP]i (Kd = 16 microM, n = 13). 5. Inside-out membrane patches excised from control non-metabolically inhibited myocytes were also exposed to various proteases, phospholipases and other reagents that may be activated during metabolic inhibition. Trypsin and chymotrypsin treatment increased the Kd from 39 to 213 microM (n = 8) and 110 microM (n = 5), respectively. Calpain I had no apparent effect on the Kd.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1993

Amiodarone and post-MI patients.

Amiodarone is a viable drug for preventing sudden cardiac death, particularly during the first year after MI. If larger trials confirm the aforementioned prospective trials of Ceremuzynski et al, Cairns et al, and the BASIS trial, the efficacy of amiodarone would outweigh the risk of its side effects during the first year after MI. Based on the long-term observation from the BASIS trial, the duration of amiodarone therapy need not be more than 1 year--which, as we have learned, is when these post-MI patients would benefit most from the drug. It is also likely that the effects of amiodarone would complement those of aspirin and angiotensin converting enzyme inhibitors. The SAVE, CONSENSUS II, and SOLVD trials demonstrated that captopril and enalapril did not reduce the mortality rate during the first year after MI, nor did they reduce the sudden cardiac death rate. Their beneficial effects became evident only during the second year and thereafter. Unlike other antiarrhythmic agents of various classes, amiodarone possesses antiarrhythmic properties but does not exert deleterious effects on ventricular function. More studies are needed to determine if the benefit of amiodarone could be enhanced by combination therapy (eg, angiotensin converting enzyme inhibitors, aspirin, or beta-blockers). Whether amiodarone will provide the same protection for patients who have poor left ventricular function or congestive heart failure is not known. The European and VA cooperative studies should help answer this question. If it turns out that amiodarone is beneficial, one must then determine whether higher doses of the drug will offer more protection, and, if so, if that greater protection would be offset by increased toxicity. How much amiodarone should be given to offer the most protection with the least risk? Another intriguing research question is this: If we treat patients with amiodarone for more than 1 year, would the drug continue to improve the mortality rate in subsequent years? Other studies are needed in patients at very high risk of sudden cardiac death (ie, those who have a low ejection fraction and high-density VPDs). A study comparing amiodarone and sotalol in high-risk patients for sudden cardiac death is also needed. These clinical studies should be carried out with basic science research investigating the actions of amiodarone at the molecular and cellular level in order to give us a better understanding of how the drug works.

Amiodarone↗
PubMed1992

Controlling cardiac chaos.

The extreme sensitivity to initial conditions that chaotic systems display makes them unstable and unpredictable. Yet that same sensitivity also makes them highly susceptible to control, provided that the developing chaos can be analyzed in real time and that analysis is then used to make small control interventions. This strategy has been used here to stabilize cardiac arrhythmias induced by the drug ouabain in rabbit ventricle. By administering electrical stimuli to the heart at irregular times determined by chaos theory, the arrhythmia was converted to periodic beating.

Action Potentials↗
PubMed1992

Fertility rates with delayed fibrin glue: vasovasostomy in rats.

OBJECTIVE: To determine if fibrin glued vasovasostomy had comparable fertility rates to sutured vasovasostomy. DESIGN: Twenty adult male Sprague-Dawley rats underwent bilateral vasectomy. Two weeks after vasectomy, 10 rats had a bilateral sutured vasal anastomosis consisting of four mucosal and four seromuscular sutures with 10-0 nylon. The second group of 10 rats underwent bilateral fibrin glue vasal anastomosis consisting of two transmural sutures with 10-0 nylon followed by application of fibrin glue. One month after vasectomy reversal, each male rat was mated with a female rat for a period of 2 weeks. SETTING: Animal laboratory. PATIENTS PARTICIPANTS: Twenty male Sprague-Dawley rats. INTERVENTIONS: Bilateral vasectomies in 20 male Sprague-Dawley rats. Two weeks after vasectomy, 10 rats had bilateral sutured vasal anastomosis, and 10 rats had bilateral glued vasal anastomosis. MAIN OUTCOME MEASURES: Pregnancy after vasectomy reversal. RESULTS: Ten of 10 rats in the sutured group produced offspring for a fertility rate of 100%. Eight of 10 rats in the fibrin glue group produced offspring for a fertility rate of 80%. There was no statistically significant difference in the pregnancy rates between the two groups at the 95% confidence interval. CONCLUSION: Fibrin glue-delayed vasectomy reversal produces comparable fertility rates compared with conventional sutured vasectomy reversal in the rat.

Adhesives↗