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Biomedical subjects

H F Clemo

Publications and source records attributed to H F Clemo.

14 recordsLinked to original sources
PubMed1996

Efficacy of ibutilide for termination of atrial fibrillation and flutter.

The clinical utility of ibutilide fumarate (Corvert) for the acute conversion of atrial tachyarrhythmias to normal sinus rhythm has been demonstrated in several randomized, placebo-controlled clinical trials. The efficacy of intravenous ibutilide for rapid conversion of atrial flutter is in the range of 50-70%, whereas its efficacy for conversion of atrial fibrillation is 30-50%. Approximately 80% of atrial tachyarrhythmias that terminate do so within 30 minutes from the initiation of the intravenous infusion. Ibutilide is more effective than either intravenous procainamide or intravenous sotalol for conversion of atrial fibrillation and atrial flutter to sinus rhythm. Age, presence of structural heart disease, gender and concomitant medication do not appear to influence the efficacy of ibutilide; however, shorter duration of atrial fibrillation is a strong predictor of successful termination. Plasma concentration of ibutilide and QTc interval prolongation are not directly correlated with the success rate for conversion of atrial tachyarrhythmias. Ibutilide's greater efficacy compared with other antiarrhythmic drugs may be related to its ability to cause greater prolongation of atrial monophasic action potential duration relative to atrial cycle length. Termination of atrial flutter with ibutilide was preceded by increased atrial cycle length variability. Ibutilide rapidly and effectively converts atrial fibrillation and atrial flutter to sinus rhythm when administered as a 1-mg total dose followed by a second 1-mg dose. It should be used in conjunction with continuous electrocardiographic monitoring for at least 4 hours after the termination of the infusion, or until the QTc interval returns to baseline. Hypokalemia and hypomagnesemia should be corrected before the start of the infusion. An external cardiac defibrillator, intravenous magnesium, and an external transcutaneous cardiac pacemaker should be readily available for immediate use in the event that palymorphic ventricular tachyarrhythmias occur. Ibutilide is a new intravenous agent that safely and rapidly converts atrial fibrillation and atrial flutter to sinus rhythm.

Anti-Arrhythmia Agents↗
PubMed1996

Atrial natriuretic peptide and cardiac electrophysiology: autonomic and direct effects.

Atrial natriuretic peptide (ANP) has varied effects on cardiac electrophysiologic parameters including heart rate, intraatrial conduction time, and refractory period. ANP's vagoexcitatory and sympathoinhibitory actions as well as its direct actions on cardiac ion currents may be responsible for some of these effects. This review discusses the role of ANP in cardiac electrophysiology, its interactions with the autonomic nervous system and baroreceptor reflex, and its effects on cardiac ion currents.

Animals↗
PubMed1995

Stretch-activated channel blockers modulate cell volume in cardiac ventricular myocytes.

Stretch-activated channels (SAC) are postulated to regulate cell volume. While this hypothesis is appealing, direct evidence is lacking. Using digital video microscopy, we found that pharmacological blockade of SACs alters the cell volume of isolated rabbit ventricular myocytes during hypoosmotic stress. Under control conditions, relative cell volume increased from 1.0 to 1.311 +/- 0.019 after 10 min in 195 mosmol/l solution. The cation SAC blocker gadolinium (Gd3+; 10 microM) reduced the amount of swelling in hypoosmotic solution by 24% and induced a regulatory volume decrease otherwise not observed. In contrast, the anion SAC blocker 9-anthracene carboxylic acid (9-AC; 1 mM) increased swelling by 44% under the same conditions. Based on the direction of SAC currents, Gd3+ and 9-AC are expected to have opposite effects on cell volume. Furthermore, Gd3+ and 9-AC changed cell volume by only approximately 2% in isosmotic solutions when SACs are expected to be closed. This supports the idea that Gd3+ and 9-AC affect stretch-activated transport processes. In contrast, omitting bath Ca2+ did not alter cell volume under iso- or hypoosmotic conditions suggesting stretch-activated Ca2+ influx is not important in setting cell volume. Not all channels can affect cell volume. Opening ATP-sensitive K+ channels with aprikalim (100 microM) or blocking them with glibenclamide (1 microM) did not alter cell volume under isosmotic or hypoosmotic conditions. These data support the idea that SACs are involved in cardiac cell volume regulation.

Animals↗
PubMed1995

cGMP and atrial natriuretic factor regulate cell volume of rabbit atrial myocytes.

Atrial natriuretic factor (ANF) reduces the volume of atrial myocytes by inhibiting Na+/K+/2Cl- cotransport. We determined the role of cGMP and cAMP in ANF-induced shrinkage by using digital video microscopy to measure cell volume; volumes are reported relative to control. ANF (1 mumol/L) reversibly reduced atrial cell volume from 1.0 to 0.915 +/- 0.005 (mean +/- SEM). This effect was mimicked by 10 mumol/L 8-bromo-cGMP (8-Br-cGMP), which decreased myocyte volume to 0.894 +/- 0.007 with an ED50 of 0.99 +/- 0.05 mumol/L. In contrast, 100 mumol/L 8-bromo-cAMP (8-Br-cAMP) did not affect volume, and activating the cAMP pathway with 100 mumol/L 8-Br-cAMP did not alter the volume decrease caused by 8-Br-cGMP or ANF. Inhibition of Na+/K+/2Cl- cotransport with bumetanide (1 mumol/L) also reduced cell volume and prevented further shrinkage on subsequent exposure to 8-Br-cGMP. Similarly, 8-Br-cGMP (10 mumol/L) prevented further shrinkage by ANF. Block of Na(+)-H+ exchange, a participant in volume regulation in other cells, did not alter the response to 8-Br-cGMP. More evidence implicating cGMP was obtained by altering its metabolism. LY83583 (10 mumol/L), a guanylate cyclase inhibitor, blocked ANF-induced cell shrinkage. Zaprinast (100 mumol/L), a cGMP-specific phosphodiesterase inhibitor, markedly potentiated the effect of a threshold concentration of ANF (0.01 mumol/L). The actions of ANF, LY83583, and zaprinast on cGMP levels were verified by radioimmunoassay. These data strongly support the idea that the cGMP cascade is the intracellular signaling pathway responsible for ANF-induced atrial cell shrinkage.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Safety of pacemaker implantation in patients with transvenous (nonthoracotomy) implantable cardioverter defibrillators.

While several reports have documented the safety of implantation of transvenous pacemakers in patients with epicardial patch-based implantable cardioverter defibrillators (ICDs), the implantation of transvenous pacemakers in patients with transvenous (nonthoracotomy) ICDs has not been well-described. We present three patients with transvenous ICDs who subsequently underwent implantation of transvenous pacemakers without complication. Technical considerations and a testing, protocol for detection of pacemaker-ICD interactions are discussed.

Aged↗
PubMed1992

Modulation of rabbit ventricular cell volume and Na+/K+/2Cl- cotransport by cGMP and atrial natriuretic factor.

Previously we showed that atrial natriuretic factor (ANF) decreases cardiac cell volume by inhibiting ion uptake by Na+/K+/2Cl- cotransport. Digital video microscopy was used to study the role of guanosine 3',5'-monophosphate (cGMP) in this process in rabbit ventricular myocytes. Each cell served as its own control, and relative cell volumes (volume(test)/volume(control)) were determined. Exposure to 10 microM 8-bromo-cGMP (8-Br-cGMP) reversibly decreased cell volume to 0.892 +/- 0.007; the ED50 was 0.77 +/- 0.33 microM. Activating guanylate cyclase with 100 microM sodium nitroprusside also decreased cell volume to 0.889 +/- 0.009. In contrast, 8-bromo-adenosine 3',5'-monophosphate (8-Br-AMP; 0.01-100 microM) neither altered cell volume directly nor modified the response to 8-Br-cGMP. The idea that cGMP decreases cell volume by inhibiting Na+/K+/2Cl- cotransport was tested by blocking the cotransporter with 10 microM bumetanide (BUM) and removing the transported ions. After BUM treatment, 10 microM 8-Br-cGMP failed to decrease cell volume. Replacement of Na+ with N-methyl-D-glucamine or Cl- with methanesulfonate also prevented 8-Br-cGMP from shrinking cells. The data suggest that 8-Br-cGMP, like ANF, decreases ventricular cell volume by inhibiting Na+/K+/2Cl-cotransport. Evidence that ANF modulates cell volume via cGMP was also obtained. Pretreatment with 10 microM 8-Br-cGMP prevented the effect of 1 microM ANF on cell volume, and ANF suppressed 8-Br-cGMP-induced cell shrinkage. Inhibiting guanylate cyclase with the quinolinedione LY83583 (10 microM) diminished ANF-induced cell shrinkage, and inhibiting cGMP-specific phosphodiesterase with M&B22948 (Zaprinast; 100 microM) amplified the volume decrease caused by a low dose of ANF (0.01 microM) approximately fivefold. In contrast, neither 100 microM 8-Br-cAMP nor 50 microM forskolin affected the response to ANF. The effects of ANF, LY83583, and M&B29948 on cGMP levels in isolated ventricular myocytes were confirmed by 125I-cGMP radioimmunoassay. These data argue that ANF shrinks cardiac cells by increasing intracellular cGMP, thereby inhibiting Na+/K+/2Cl- cotransport. Basal cGMP levels also appear to modulate cell volume.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1991

Prevention of myocardial intracellular edema induced by St. Thomas' Hospital cardioplegic solution.

During cardiac surgery, the heart is infused with cold crystalloid cardioplegic solutions such as St. Thomas' Hospital (StT) solution, which contains high concentrations of K+ and Mg2+. The high K+ and Mg2+ block impulse conduction and inhibit Ca2+ influx, thereby arresting the heart and reducing cardiac oxygen consumption. Nevertheless, myocardial edema and post-operative abnormalities have been noted after cardioplegia and attributed to ischemia and reflow or to hypothermia. We found, however, that cold StT (9 degrees C) was hypotonic and induced cell swelling in the absence of ischemic injury. Cell swelling in cold StT was not due to hypothermia alone, but rather was caused by KCl influx and was prevented by partially replacing Cl- with an impermeant anion. After exposure to cold StT, cells transiently shrank to less than control volume on rewarming in physiological saline (Tyrode's solution, 37 degrees C). The transient shrinkage was blocked by ouabain suggesting that Na+ loading of depolarized hypothermic cells and Na(+)-K+ pump activation on rewarming were responsible. Hypothermic ventricular cells seem to follow Donnan equilibrium, and the product of [K+] x [Cl-] in cardioplegic solutions affects cell volume in the absence of ischemic injury.

Animals↗
PubMed1991

Atrial natriuretic factor decreases cell volume of rabbit atrial and ventricular myocytes.

The effect of atrial natriuretic factor (ANF) on cell volume was studied using video microscopy of rabbit atrial and ventricular myocytes. Each cell served as its own control, and relative cell volumes were determined. ANF (1 microM) significantly decreased relative cell volume to 0.929 +/- 0.006 (n = 7) in atrial and 0.930 +/- 0.013 (n = 5) in ventricular myocytes (normalized to volume without ANF). Reduction of volume was detectable at greater than or equal to 0.01 microM ANF, and the ED50 was 0.072 +/- 0.007 microM (n = 15). The effect of ANF also was examined under hypotonic (0.55T, 168 mosmol/l) and hypertonic (1.82T, 560 mosmol/l) conditions; osmolarity was adjusted using mannitol with NaCl fixed at 65 mM. In 0.55T, 1 microM ANF decreased cell volume to 0.941 +/- 0.014 (n = 5) in atrial and 0.942 +/- 0.017 (n = 7) in ventricular cells (normalized to 0.55T without ANF). In contrast, 1 microM ANF had no effect on atrial (n = 13) or ventricular (n = 11) cell volume in 1.82T. The hypothesis that ANF decreases cell volume by inhibiting Na(+)-K(+)-2Cl- cotransport was tested by blocking the cotransporter with bumetanide (10 microM). After inhibition of Na(+)-K(+)-2Cl- cotransport, 1 microM ANF failed to reduce cell volume in either atrial (n = 6) or ventricular myocytes (n = 6). Block of ANF-induced cell shrinkage by bumetanide was not due to changes in cell volume, since similar results were obtained using atrial (n = 7) and ventricular (n = 7) cells swollen in hypotonic (0.80T, 244 mosmol/l) solution. Replacement of Na+ with N-methyl-D-glucamine or Cl- with methanesulfonate abolished the ability of both ANF and bumetanide to decrease volume of atrial and ventricular cells in 1T and 0.8T solution. These data suggest that ANF can decrease the volume of atrial and ventricular cells under isotonic and hypotonic conditions by a mechanism that may involve Na(+)-K(+)-2Cl- cotransport. An ANF-induced decrease in cell volume may act as negative feedback and inhibit the stretch-induced release of ANF from atrial and ventricular cells. Furthermore, it may contribute to cell volume maintenance in myocytes in the setting of congestive heart failure or myocardial hypoxia when ANF release is elevated.

Animals↗
PubMed1987

A microcomputer system for on-line study of atrioventricular node accommodation.

An automated on-line programmable stimulator and interval measurement system was developed to study atrioventricular node (AVN) accommodation. This dedicated microcomputer system measures and stores the stimulus-to-His bundle (S-H) interval from His bundle electrogram (HBE) recordings. Interval measurements for each beat are accurate to within 500 microsecond. This user-controlled system has been used to stimulate at any rate up to 6.5 Hz and to measure intervals up to 125 ms in isolated perfused guinea pig hearts. A built-in timer-reset mechanism prevents failure of the system in the absence of a His potential (i.e., 2:1 AV block). It may be modified for use in clinical studies or other experimental systems and has the ability to measure other physiological intervals. The system provides the precision in pacing and accuracy in the measurement of AVN conduction time that is necessary for meaningful analysis of AVN accommodation and has the simplicity of design and use that is not available in previously described systems. Furthermore, this computer system can be used not only in studies involving AV conduction, but also in any setting where programmed stimulation and interval measurement and recording need to be performed simultaneously.

Animals↗
PubMed1987

Antagonism of the effects of adenosine and hypoxia on atrioventricular conduction time by two novel alkylxanthines: correlation with binding to adenosine A1 receptors.

Adenosine has been shown to have a negative dromotropic effect and has been implicated in mediating atrioventricular conduction disturbances induced by hypoxia. This study was designed to determine the ability of various alkylxanthines including two novel derivatives, i.e., BW A533U and BW A1433U, to 1) attenuate adenosine- and hypoxia-induced atrial to His bundle (AH) interval prolongation, 2) compete for binding of 125I-aminobenzyladenosine to ventricular membranes and 3) inhibit myocardial phosphodiesterase. In normoxic isolated perfused hearts (n = 20) instrumented for measurement of atrioventricular conduction time and left ventricular pressure, BW A1433U (0.1 microM) or BW A533U (5 microM) attenuated AH interval prolongation induced by adenosine (5 microM) by 90%, but neither xanthine derivative attenuated the AH interval prolongation induced by acetylcholine (0.11 microM), digoxin (0.91 microM) or D600 (1.3 microM). In four additional hearts, BW A1433U at concentrations of up to 10 microM had no effect on left ventricular pressure or AH interval. BW A1433 or BW A533U (50 microM) inhibited myocardial cyclic AMP phosphodiesterase by only 11.5 +/- 1.6 and 26.6 +/- 2.6%, respectively. Schild analysis of adenosine concentration-response curves obtained in the absence and presence of BW A533U and BW A1433U (n = 14) yielded pA2 values of (mean +/- S.E.M.) 6.32 +/- 0.10 and 7.70 +/- 0.08, respectively. pKd values for BW A533U and BW A1433U binding to adenosine receptors on ventricular membranes were 6.36 and 6.94, respectively. In a separate series of 19 hearts, BW A533U and BW A1433U were shown to attenuate hypoxia-induced AH interval prolongation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1986

Effect of adenosine on atrioventricular conduction. I: Site and characterization of adenosine action in the guinea pig atrioventricular node.

Adenosine has a negative dromotropic effect and modulates hypoxia-induced atrioventricular (AV) conduction delay. To further characterize the negative dromotropic effect of adenosine in the guinea pig heart, we determined the site of adenosine-induced AV conduction block; the effect of uptake and deamination of adenosine on its concentration-negative dromotropic effect, and the adenosine receptor that mediates this action. In isolated AV node preparations (n = 16), adenosine in a dose-dependent manner decreased significantly the duration and amplitude of the action potential of atrionodal and nodal cells and, in addition, markedly depressed the maximum rate of rise of the action potential of nodal cells. At high concentrations (greater than 20 microM), adenosine rendered nodal cells inexcitable. In isolated perfused hearts (n = 7), adenosine (5.7 microM) prolonged total AV conduction time by 21 +/- 2 msec. Of this prolongation, 83% was due to an increase in the nodal-to-His-bundle interval and the remaining 17% to an increase in the atrionodal to nodal interval. Infusion of adenosine to cause a 50% increase (EC50) in atria-to-His bundle (AH) interval prolongation resulted in a perfusate (arterial) adenosine concentration of 5.0 +/- 0.6 microM and effluent (venous) adenosine concentrations of 2.8 +/- 0.4 microM, i.e., an arteriovenous difference of 44% (n = 4). When adenosine uptake and deamination were inhibited with dipyridamole (0.5 microM) plus erythro-9-(2-hydroxy-3-nonyl)adenine (5 microM), respectively, the EC50s were 0.28 +/- 0.02 (perfusate) and 0.32 +/- 0.03 microM (effluent). These data indicate that when nucleoside metabolism is inhibited, arterial and venous concentrations of adenosine reach equilibrium. In an additional 10 hearts, the following rank order of potency of adenosine agonists in causing AH interval prolongation was found: N6-cyclopentyladenosine greater than N6-(L-2-phenyl-isopropyl)adenosine greater than 5'-N-ethylcarboxyamidoadenosine greater than or equal to 2-chloroadenosine greater than adenosine, which is compatible with activation of an A1-type receptor. In summary: the site of adenosine-induced AV conduction block is the nodal zone of the AV node, when adenosine uptake and deamination are inhibited, adenosine in concentrations similar to that released by hypoxia causes significant AH interval prolongation, and the adenosine receptor mediating the negative dromotropic effect of adenosine is of the A1-type.

Action Potentials↗
PubMed1986

Effect of adenosine on atrioventricular conduction. II: Modulation of atrioventricular node transmission by adenosine in hypoxic isolated guinea pig hearts.

Adenosine as well as hypoxia and ischemia are known to cause atrioventricular conduction block. To test the hypothesis that adenosine is the primary mediator of hypoxia-induced atrioventricular conduction delay in isolated perfused guinea pig hearts, we characterized a) the time courses of hypoxia-induced adenosine release and delay in atrioventricular conduction, b) the relationships between oxygen tension, adenosine concentration in the effluent, and atria-to-His-bundle interval, and c) the adenosine receptor mediating the negative dromotropic effect of hypoxia. Oxygen tension and effluent adenosine levels were linearly related with a correlation coefficient (r) of -0.85 and a slope of -6.3 +/- 0.37 pmol/min/g/torr. Likewise, oxygen tension and atria-to-His-bundle interval prolongation were linearly related with r = -0.85 and a slope of -0.180 +/- 0.013 msec/torr. The EC50 of effluent adenosine in causing atria-to-His-bundle prolongation was 0.26 +/- 0.02 microM. Adenosine deaminase, an enzyme that deaminates adenosine to inosine and is limited to the extracellular space, significantly attenuated (61%) the atria-to-His-bundle interval prolongation caused by hypoxia. This prolongation was further reduced (81%) by a combination of adenosine deaminase and theophylline, an adenosine receptor blocker. Adenosine deaminase also reduced (by 95%) the atria-to-His-bundle interval prolongation in normoxic recipient hearts caused by the effluent of hypoxic donor hearts. Several adenosine antagonists, i.e., theophylline, 8-phenyltheophylline, and 8-(p-sulfophenyl)theophylline antagonized in a dose-dependent manner the negative dromotropic effect of exogenous adenosine and hypoxia. Schild analysis of the antagonism of hypoxia-induced atria-to-His-bundle interval prolongation by 8-(p-sulfophenyl)theophylline yielded the following pA2 values: 5.30 +/- 0.25 and 5.28 +/- 0.31 using oxygen tension and effluent adenosine vs. AH interval prolongation, respectively. 8-(p-Sulfophenyl)theophylline also antagonized to an equal extent atria-to-His-bundle interval prolongations of similar magnitude caused either by adenosine or hypoxia. We conclude that 1) adenosine is the primary mediator of hypoxia-induced atrioventricular conduction delay, and 2) the adenosine receptor that mediates the negative dromotropic effect of hypoxia is similar to that of exogenous adenosine.

Adenosine↗
PubMed1984

Effects of adenosine and adenine nucleotides on the atrioventricular node of isolated guinea pig hearts.

The primary goal of this study was to determine whether the slowing of atrioventricular (AV) conduction by ATP is caused by ATP per se or is mediated by adenosine formed from ATP degradation. We assessed the effects of ATP, beta, gamma-methylene ATP, ADP, AMP, and adenosine on AV conduction time in the isolated perfused guinea pig heart. The cardiac effluent was collected and analyzed for its content of adenine nucleotides and nucleosides. Perfused ATP was rapidly and almost completely broken down to AMP and adenosine; only 2.5 +/- 0.5% of the infused ATP was recoverable in the effluent. A significant correlation was found between the effluent concentration of adenosine and atria-to-His bundle (A-H) conduction time. Compounds that altered the effect of adenosine on A-H conduction likewise altered the effect of ATP: (1) aminophylline, a competitive antagonist of adenosine, antagonized the ATP-induced A-H prolongation; (2) adenosine deaminase, the enzyme responsible for the deamination of adenosine to inosine, reduced the effect of ATP by 82%; (3) the adenosine transport blockers NBMPR and dipyridamole markedly enhanced the effect of ATP; and (4) EHNA, an inhibitor of adenosine deaminase, potentiated the effect of ATP. Furthermore, the less hydrolyzable ATP analog, beta, gamma-methylene ATP, was less potent than ATP in causing A-H prolongation. We conclude that the adenosine-like action of ATP on the guinea pig AV node requires that ATP first be degraded to adenosine.

Adenine↗