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Biomedical subjects

G R Li

Publications and source records attributed to G R Li.

At least 37 records · Page 2Linked to original sources
PubMed1998

Transmural heterogeneity of action potentials and Ito1 in myocytes isolated from the human right ventricle.

Limited information is available about transmural heterogeneity in cardiac electrophysiology in man. The present study was designed to evaluate heterogeneity of cardiac action potential (AP), transient outward K+ current (Ito1) and inwardly rectifying K+ current (IK1) in human right ventricle. AP and membrane currents were recorded using whole cell current- and voltage-clamp techniques in myocytes isolated from subepicardial, midmyocardial, and subendocardial layers of the right ventricle of explanted failing human hearts. AP morphology differed among the regional cell types. AP duration (APD) at 0.5-2 Hz was longer in midmyocardial cells (M cells) than in subepicardial and subendocardial cells. At room temperature, observed Ito1, on step to +60 mV, was significantly greater in subepicardial (6.9 +/- 0.8 pA/pF) and M cells (6.0 +/- 1.1 pA/pF) than in subendocardial cells (2.2 +/- 0.7 pA/pF, P < 0.01). Slower recovery of Ito1 was observed in subendocardial cells. The half-inactivation voltage of Ito1 was more negative in subendocardial cells than in M and subepicardial cells. At 36 degrees C, the density of Ito1 increased, the time-dependent inactivation and reactivation accelerated, and the frequency-dependent reduction attenuated in all regional cell types. No significant difference was observed in IK1 density among the regional cell types. The results indicate that M cells in humans, as in canines, show the greatest APD and that a gradient of Ito1 density is present in the transmural ventricular wall. Therefore, the human right ventricle shows significant transmural heterogeneity in AP morphology and Ito1 properties.

Action Potentials↗
PubMed1997

Structure-function relationships in interphotoreceptor retinoid-binding protein (IRBP).

PURPOSE: Interphotoreceptor retinoid binding protein (IRBP) binds hydrophobic ligands in the retina. The polypeptide consists of 1230 amino acids in four 300 amino acid long repeats. We asked whether each of the four repeats can bind one retinoid or fatty acid analog. Our rationale was to make protein variants from the human cDNA bearing one or more of the repeats and examine binding capacities and dissociation constants. METHODS: Proteins were characterized by SDS-PAGE, western blotting, N-terminal sequencing, and CD spectroscopy. Binding properties with all-trans-retinol and 16-anthryloxy-palmitic acid (16-AP) were characterized by ligand fluorescence enhancement and curve fitting. RESULTS: Binding capacities varied according to the length of each protein. Each repeat possesses the capability of binding retinol and 16-AP. CONCLUSIONS: The data contrast with the idea that two or more repeats are needed to bind one molecule of ligand. Each repeat binds a retinoid and fatty acid analog, suggesting that each has multiple ligand binding sites or one binding site with affinity for different ligands. Last, these data fit well with the current model of multiple binding sites in IRBP derived from quadruplication of an ancestral monomeric binding protein.

Animals↗
PubMed1997

Properties of human atrial ICa at physiological temperatures and relevance to action potential.

There are no published characterizations of Ca2+ current (ICa) at physiological temperatures in human atrium. Depolarization of human atrial myocytes at 36 degrees C elicited ICa that peaked at +10 mV, with a mean maximum current density of 10.8 +/- 1.1 pA/pF and no evidence for T-type current. Overlap between activation and inactivation curves and incomplete inactivation during pulses comparable to normal action potential duration (APD) were compatible with the observed role of ICa in maintaining the plateau. ICa was frequency dependent between 0.1 and 2 Hz and ICa blockade with 0.2 mM Cd2+ reduced rate-dependent changes in APD: under control, APD at 90% repolarization was 230 +/- 15 ms at 0.1 Hz and 178 +/- 14 ms at 2 Hz (decrease of 52 +/- 5 ms); with Cd2+, values were 121 +/- 7 ms at 0.1 H2 and 115 +/- 6 ms at 2 Hz (decrease of 6 +/- 3 ms, P < 0.01) Isoproterenol (1 microM) increased ICa and prolonged APD from 138 +/- 13 to 199 +/- 15 ms (P < 0.01). These results indicate that, in human atrial cells at 36 degrees C, the properties of L-type ICa contribute importantly to the rate-dependent and autonomic control of APD.

Action Potentials↗
PubMed1997

Antisense oligodeoxynucleotides directed against Kv1.5 mRNA specifically inhibit ultrarapid delayed rectifier K+ current in cultured adult human atrial myocytes.

Several cloned K+ channel subunits are candidates to underlie macroscopic currents in the human heart, but direct evidence bearing on their role is lacking. The Kv1.5 K+ channel subunit has been suggested to play a potential role in human cardiac ultrarapid delayed rectifier (IKur) and transient outward (Ito) currents. To evaluate the role of proteins encoded by the Kv1.5 gene, we incubated cultured human atrial myocytes for 48 hours in medium containing antisense phosphorothioate oligodeoxynucleotides directed against octodecameric segments of the Kv1.5 mRNA coding sequence, the same concentration of homologous oligodeoxynucleotides with four mismatch mutations, or vehicle (control group). Cells exposed to antisense showed a highly significant (approximately 50%) reduction in IKur whether measured by step current at the end of a 400-millisecond depolarizing pulse, tail current at -20 mV, or current sensitive to a concentration of 4-aminopyridine (50 mumol/L) that is highly selective for IKur compared with control cells or cells exposed to mismatch oligodeoxynucleotides. In contrast, Ito was not different among the three experimental groups. When cultured human ventricular myocytes were exposed to Kv1.5 antisense oligodeoxynucleotides with the same controls, no changes occurred in either Ito or the sustained current at the end of a depolarizing pulse. We conclude that Kv1.5 channel subunits are essential to the expression of IKur and do not play a role in Ito in cultured human atrial myocytes. These studies provide the first direct evidence with an antisense approach for the equivalence between a macroscopic cardiac K+ current and a cloned K+ channel subunit and offer insights into the molecular electrophysiology of the human heart.

Adult↗
PubMed1997

Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation.

Rapid electrical activation, as occurs during atrial fibrillation (AF), is known to cause reductions in atrial refractoriness and in adaptation to heart rate of the atrial refractory period, which promote the maintenance of AF, but the underlying ionic mechanisms are unknown. In order to determine the cellular and ionic changes caused by chronic atrial tachycardia, we studied right atrial myocytes from dogs subjected to 1, 7, or 42 days of atrial pacing at 400/min and compared them with myocytes from sham-operated dogs (pacemaker inserted but not activated). Rapid pacing led to progressive increases in the duration of AF induced by bursts of 10-Hz stimuli (from 3 +/- 2 seconds in sham-operated dogs to 3060 +/- 707 seconds in dogs after 42 days of pacing, P < .001) and reduced atrial refractoriness and adaptation to rate of the atrial refractory period. Voltage-clamp studies showed that chronic rapid pacing did not alter inward rectifier K+ current, rapid or slow components of the delayed rectifier current, the ultrarapid delayed rectifier current, T-type Ca2+ current, or Ca(2+)-dependent Cl- current. In contrast, the densities of transient outward current (Ito) and L-type Ca2+ current (ICa) were progressively reduced as the duration of rapid pacing increased, without concomitant changes in kinetics or voltage dependence. In keeping with in vivo changes in refractoriness, action potential duration (APD) and APD adaptation to rate were decreased by rapid pacing. The response of the action potential and ionic currents flowing during the action potential (as exposed by action-potential voltage clamp) to nifedipine in normal canine cells and in cells from rapidly paced dogs suggested that the APD changes in paced dogs were largely due to reductions in ICa. We conclude that sustained atrial tachycardia reduces Ito and ICa, that the reduced ICa decreases APD and APD adaptation to rate, and that these cellular changes likely account for the alterations in atrial refractoriness associated with enhanced ability to maintain AF in the model.

Action Potentials↗
PubMed1997

Effects of class III antiarrhythmic drugs on transient outward and ultra-rapid delayed rectifier currents in human atrial myocytes.

A variety of class III antiarrhythmic agents have been shown to block the delayed rectifier current, but their effects on other K+ currents, particularly in human tissues, are less clear. We studied the concentration-dependent actions of the class III compounds d-sotalol, E-4031 and ambasilide on the transient outward current (I(to)) and the ultra-rapid delayed rectifier current (I(Kur)) in human atrial myocytes. d-Sotalol and E-4031 failed to alter I(to) or I(Kur) at concentrations up to 500 and 50 microM, respectively. In contrast, ambasilide produced a concentration-dependent inhibition of I(to) and I(Kur), with statistically significant effects at 10 microM and maximum effects at 100 microM. The 50% inhibitory concentration of ambasilide averaged 23 +/- 2 microM and 34 +/- 3 microM for I(to) and I(Kur) respectively. Ambasilide did not alter the voltage-dependence of activation or inactivation of I(to), or the voltage-dependence of I(Kur), and it did not affect I(to) recovery from inactivation. On the other hand, ambasilide accelerated I(to) inactivation, by introducing a more rapid component that accelerated with increasing drug concentration. Furthermore, block of both I(to) and I(Kur) developed over time after the onset of depolarization, with time constants of 5.8 +/- 0.8 msec and 2.5 +/- 0.4 msec at concentrations of 10 and 50 microM for I(to) and 6.1 +/- 0.8 msec and 2.1 +/- 0.3 msec at 10 and 50 microM for I(Kur). We conclude that neither d-sotalol nor E-4031 affects I(to) or I(Kur), whereas ambasilide produces efficacious open-channel block of both currents, in human atrial myocytes.

Aminobenzoates↗
PubMed1997

[Is surgery useful in kidney cancer with lymph node invasion?].

SUMMARY: lymph node involvement in renal cell carcinoma is factor of very poor prognosis. In a series of 55 node-positive patients, 33 (60%) had simultaneous renal vein or vena cava invasion and 32 (58.2%) had metastases. Gross lymph node involvement was found in 39 patients (70.9%). Patients without venous invasion or metastasis may have a prolonged survival. In this group, those with microscopic nodal involvement can be cured, as the 10 and 15-year the actuarial survival rate is 54.5% Formal lymphadenectomy might have played a role in these results. Surgery can be performed when vein invasion is present without metastasis, but the prognosis is generally poor. Survival does not seem to be influenced by surgery when metastasis is present, regardless of the vein status.

Actuarial Analysis↗
PubMed1997

[Treatment of erectile disorders with androgens: When? How?].

Erectile dysfunction associated to low circulating androgens is characterized by a low testosterone due to hypogonadism of hypothalamic-pituitary or testicular origin. Long term androgen administration is unacceptable unless biology has demonstrated hypogonadism with a low testosterone level not related to hyperpolactinemia. Intramuscular testosterone or transdermal dihydrotestosterone can be used with a similar clinical effect but a different biological impact regarding aromatase activity. Whatever may be the type of androgen supplementation, one should use low dosage with frequent administration in order to obtain stable and physiologic plasmatic values. On account of androgen impact on prostate and cardiovascular system, careful pretreatment screening should eliminate an occult prostate cancer and a vascular thrombosis risk in a complaining and informed patient. Clinical and biological parameters should be periodically followed throughout androgen therapy.

Algorithms↗
PubMed1997

[Renal oncocytoma. Report of 13 cases].

We report 13 cases of renal oncocytoma. Urinary symptoms occurred in only 3 cases. The patient's age ranged from 41 to 74 years with an average of 62.3 years. The mean tumor diameter was 5.6 cm (range: 1.5-14). Diagnostic features of ultrasonography, CT scan and, in some instances, angiography were suggestive of renal oncocytoma in 2 patients, but never affirmative, 4 patients were treated by partial nephrectomy. No local or metastatic recurrence was observed with a mean follow-up of 30.8 months, ranging from 6 to 96 months. We assume that the term renal oncocytoma should be restricted to tumors exclusively composed of regular oncocytic cells with an eosinophilic granular mitochondria-rich cytoplasm and an absence of malignant potential. Diagnostic imaging characteristics may sometimes suggest the diagnosis of renal oncocytoma, but cannot eliminate the main differential diagnosis, i.e. granular renal cell adenocarcinoma. When the tumor is small and unifocal, nephron sparing surgery may be considered. Whether or not the diagnosis has been confirmed by fine needle aspiration, conservative surgery must be controlled by intraoperative frozen sections of the tumor and surgical margins.

Adenoma, Oxyphilic↗
PubMed1996

Characterization of an ultrarapid delayed rectifier potassium channel involved in canine atrial repolarization.

1. Depolarizing pulses positive to 0 mV elicit a transient outward current (Ito) and a sustained 'pedestal' current in canine atrial myocytes. The pedestal current was highly sensitive to 4-aminopyridine (4-AP) and TEA, with 50% inhibitory concentrations (EC50) of 5.3 +/- 0.7 and 307 +/- 25 microM, respectively. When the pedestal current was separated from Ito with prepulses or by studying current sensitive to 10 mM TEA, it showed very rapid activation and deactivation. We therefore designated the current IKur,d, for 'ultrarapid delayed rectifier, dog'. IKur,d inactivation was bi-exponential, with mean time constants of 609 +/- 91 and 5563 +/- 676 ms during a 20 s pulse to +40 mV. 2. The reversal potential of IKur,d tail currents are dependent on extracellular potassium concentration ([K+]o; slope, 54.7 mV decade-1). The envelope of tails test was satisfied and the current inwardly rectified at > or = +40 mV. The current was insensitive to E-4031, dendrotoxin and chloride substitution, but was inhibited by barium, with an EC50 of 1.65 mM. Lanthanum ions caused a positive shift in voltage dependence without producing direct inhibition. 3. Single-channel activity was observed in cell-attached, inside-out and outside-out patches. Upon depolarization from -50 to +30 mV, single channels had similar time constants and [K+]o dependence to whole-cell current. Channel open probability (Po) increased with depolarization in a saturable fashion and the Po-voltage relation had a half-activation voltage and slope factor similar to whole-cell IKur,d. 4. Unitary channel current was linearly related to depolarization potential to +40 mV; at more positive potentials, inward rectification occurred. The unitary conductance was 20.3 and 35.5 pS for an [K+]o of 5.4 and 130 mM, respectively. Single-channel activity was strongly inhibited by 50 microM 4-AP or 10 mM TEA. Both 4-AP and TEA decreased open time, suggesting open-channel block. 5. Selective inhibition of IKur,d with 50 microM 4-AP or 0.3-5 mM TEA prolonged canine atrial action potentials, indicating that IKur,d contributes to canine atrial repolarization. The single-channel and macroscopic properties of IKur,d have many similarities to those of currents carried by Kv3.1 cloned channels and our findings thus suggest a possible role for Kv3.1 channels in cardiac repolarization.

4-Aminopyridine↗
PubMed1996

Micrometastatic adrenal invasion by renal carcinoma in patients undergoing nephrectomy.

OBJECTIVE: To examine adrenal invasion by renal cell carcinoma (RCC), particularly by adrenal micrometastasis, to determine whether adrenalectomy should be performed during radical nephrectomy. PATIENTS AND METHODS: From 1987 to 1994, 129 patients with RCC (90 men and 39 women, mean age 61.4 years, range 22-81) underwent radical nephrectomy with associated adrenalectomy because they had risk factors for adrenal invasion (tumour size > 5 cm. or tumour of the superior pole). Pathological examinations were carried out systematically and records of these examinations reviewed. The tumour size was recorded and the frequency of invasion calculated. RESULTS: There were 10 cases where the gland was invaded: one was a synchronous contralateral metastasis and nine (7%) were ipsilateral invasions of which two were tumours in the superior pole that invaded the gland by direct extension and the other seven invaded the gland by distant metastasis, six being micrometastatic (4.7%). A single micrometastasis was found in two cases (1.5%). There was no adrenal invasion by tumours of < 5 cm in diameter from the superior pole. When only tumours > 5 cm in diameter were considered, the ipsilateral invasion rate was 11% (9/80) and the micrometastatic rate was 7.5% (6/80). CONCLUSION: Adrenalectomy need not be performed routinely in small tumours which are detected early, but the possibility of adrenal micrometastasis from larger tumours (> 5 cm) should be considered.

Adrenal Gland Neoplasms↗
PubMed1996

Transmembrane chloride currents in human atrial myocytes.

The present study was designed to evaluate the presence of basal, swelling-induced, and cAMP-dependent Cl- currents in human atrial myocytes studied with the whole cell patch-clamp technique. Under basal conditions, a small outwardly rectifying background conductance was noted that reversed close to 0 mV and was not altered by Cl- replacement. Isoproterenol (1 microM), forskolin (3 microM), and 8-bromoadenosine 3',5'-cyclic monophosphate (50 microM) did not increase membrane conductance, even when responsiveness to isoproterenol was confirmed by an increase in Ca2+ current and when perforated-patch techniques (nystatin) were used. Exposure to hyposmotic solutions increased cell volume and induced a whole cell conductance that showed outward rectification, was inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (100 microM), and responded to changes in Cl- gradient in a fashion consistent with a Cl(-)-selective conductance, with estimated relative permeabilities of 1, 0.25, and 0.07 for Cl-, methanesulfonate, and aspartate, respectively. The results suggest that human atrial cells lack basal and adenosine 3',5'-cyclic monophosphate-dependent Cl- current but manifest a substantial Cl- conductance in the presence of cell swelling.

Animals↗
PubMed1996

Properties of sodium and potassium currents of cultured adult human atrial myocytes.

Cultured cell systems are valuable for the study of regulation of phenotypic expression, but little is known about the electrophysiological properties of human cardiac tissues in culture. The present studies were designed to determine the feasibility of maintaining human atrial myocytes in primary culture and to assess changes in Na+ (INa) and K+ (Ito, transient outward, and Ikur, ultra-rapid delayed rectifier) currents. Within 24 h of culture, cells assumed an avoid shape, which they maintained for up to 7 days. The voltage dependence, kinetics, and density of INa were unchanged in culture. The activation properties of Ito (kinetics and voltage dependence) were not altered, but Ito density (current normalized to cell capacitance) was reduced and inactivation properties were altered (negative shift in voltage dependence and slowed kinetics) in cultured compared with fresh cells. The absolute current amplitude, kinetics, voltage dependence, and 4-aminopyridine sensitivity of IKur were unchanged, but current density was increased. All changes in ionic currents occurred within 24 h of culture and remained stable for the next 4 days. We conclude that human atrial myocytes can be maintained in primary culture, that the qualitative properties of INa, Ito, and IKur remain constant but that some quantitative changes occur, and that cultured human atrial myocytes may be valuable for studies of the molecular mechanisms and regulation of cardiac channel function in humans.

4-Aminopyridine↗
PubMed1996

Transient outward and delayed rectifier currents in canine atrium: properties and role of isolation methods.

Although the dog is the principal species used for in vivo studies of atrial arrhythmias, little is known about currents governing canine atrial repolarization. Cells were isolated from dog atria by exposure to collagenase of tissue in vitro ("chunk cells") and by arterial perfusion ("perfusion cells"). Whole cell voltage clamp revealed transient outward K+ current (Ito1), Ca(2+)-dependent Cl- current (Ito2), and delayed rectifier K+ current (IK). Ito1 recovered rapidly and showed little frequency dependence. Two components of IK were present as follows: a rapidly activating E-4031-sensitive current with marked inward recitification and a slower-activating E-4031-insensitive component. Ito1 and IK resembled corresponding currents previously described in human atrium. Transient outward currents were similar in chunk and perfusion cells, but IK was seen in 4% of chunk cells vs. 99% of perfusion cells (P < 0.001). Suppression of each identified current retarded canine action potential repolarization. We conclude that Ito1, Ito2, and both components of IK are present in dog atrium, IK is much more sensitive to the isolation method than Ito1 or Ito2, and the properties of two important repolarizing currents (Ito1 and IK) previously described in human atrium are similar to those in dog atrium.

Action Potentials↗
PubMed1996

Protein kinase C activates ATP-sensitive K+ current in human and rabbit ventricular myocytes.

Mediators involved in ischemia preconditioning such as adenosine and norepinephrine, can activate protein kinase C (PKC), and a variety of observations suggest that both PKC and ATP-sensitive K+ current (I (KATP) play essential roles in ischemic preconditioning. PKC is therefore a candidate to link receptor binding to I(KATP) activation, but it has not been shown whether and how PKC can activate I(KATP) in the heart. The present study was designed to determine whether PKC can activate I(KATP) in rabbit and human ventricular myocytes. Under conditions designed to minimize Na+ and Ca2+ currents, dialysis of rabbit ventricular myocytes with pipette solutions containing reduced [ATP] elicited I(KATP)++, with a 50% effective concentration (EC50)of 260 micromol/L. In cells that failed to show I (KATP) under control conditions, superfusion with 1 micromol/L phorbol 12,13-didecanoate (PDD) elicited I(KATP) in a fashion that depended on pipette [ATP], with an [ATP] EC 50 of 601 micromol/L. PDD-induced I(KATP) activation was concentration dependent, with an EC 50 of 7.1 nmol/L. The highly selective PKC inhibitor bisindolylmaleimide totally prevented I(KATP) activation by PDD, and in blinded experiments, 1 micromol/L PDD elicited I(KATP) in eight of nine cells, whereas its non-PKC-stimulating analogue 4 alpha-PDD failed to elicit I(KATP) in any of the five cells tested (P = .003). Similar experiments were conducted in human ventricular myocytes and showed that 0.1 micromol/L PDD elicited I( KATP) at pipette [ATP] of 100 and 400 micromol/L (five of five cells at each concentration) but not at 1 mmol/L [ATP] (none of five cells). We conclude that PKC activates I(KATP) in rabbit and human ventricular myocytes by reducing channel sensitivity to intracellular ATP. This finding has potentially important implications for understanding the mechanisms of ischemic preconditioning.

Adenosine Triphosphate↗
PubMed1996

Evidence for two components of delayed rectifier K+ current in human ventricular myocytes.

Previous voltage-clamp studies have suggested that the delayed rectifier current (IK) is small or absent in the human ventricle and, when present, consists only of the rapid component (IKr); however, molecular studies suggest the presence of functionally important IK in the human heart, specific IKr blockers are known to delay ventricular repolarization and cause the long QT syndrome in humans, and we have shown that the expression of IK is strongly influenced by cell isolation techniques. The present experiments were designed to assess the expression of IK in myocytes obtained by arterial perfusion of right ventricular tissue from explanted human hearts. Of 35 cells from three hearts, 33 (94%) showed time-dependent currents typical of IK. The envelope-of-tails test was not satisfied under control conditions but became satisfied in the presence of the benzenesulfonamide E-4031 (5 micromol/L). E-4031 suppressed a portion of IK in 32 of 33 cells, with properties of the drug-sensitive and -resistant components consistent with previous descriptions of IKr and the slow component (IKs), respectively. Action potential duration to 95% repolarization at 1 Hz was prolonged by E-4031 from 336+/-16 (mean +/- SEM) to 421 +/- 19ms (n = 5, P < .01), indicating a functional role for IK. Indapamide, a diuretic agent previously shown to inhibit IKs selectively, suppressed E-4031-resistant current. The presence of a third type of delayed rectifier, the ultrarapid delayed rectifier current (IKur), was evaluated with the use of depolarizing prepulses and low concentrations (50 micromol/L) of 4-aminopyridine. Although these techniques revealed clear IKur in five of five human atrial cells, no corresponding component was observed in any of five human ventricular myocytes. We conclude that a functionally significant IK, with components corresponding to IKr and IKs, is present in human ventricular cells, whereas IKur appears to be absent. These findings are important for understanding the molecular, physiological, and pharmacological determinants of human ventricular repolarization and arrhythmias.

4-Aminopyridine↗
PubMed1996

Adrenergic modulation of ultrarapid delayed rectifier K+ current in human atrial myocytes.

The ultrarapid delayed rectifier K+ current (IKur) in human atrial cells appears to correspond to Kv1.5 cloned channels and to play an important role in human atrial repolarization. Kv1.5 channels have consensus sites for phosphorylation by protein kinase A and C, suggesting possible modulation by adrenergic stimulation. The present study was designed to assess the adrenergic regulation of IKur in human atrial myocytes. Isoproterenol increased IKur in a concentration-dependent manner, with significant effects at concentrations as low as 10 nmol/L. The effects of isoproterenol were reversible by washout or by the addition of propranolol (1 mumol/L). Isoproterenol's effects were mimicked by the direct adenylate cyclase stimulator, forskolin, and by the membrane-permeable form of cAMP, 8-bromo cAMP. Isoproterenol had no effect on IKur when the protein kinase A inhibitor peptide, PKI(6-22)amide, was included in the pipette solution; in a separate set of experiments in which isoproterenol alone increased IKur by 45 +/- 9% relative to control, subsequent superfusion with isoproterenol in the presence of the protein kinase inhibitor H-7 failed to alter IKur. In contrast to isoproterenol, phenylephrine (in the presence of propranolol to block beta-adrenegic effects) induced a concentration-dependent inhibition of IKur, with significant effects observed at concentrations as low as 10 mumol/L. The inhibitory actions of phenylephrine were reversed by the addition of prazosin and prevented by coadministration with a highly selective inhibitor of protein kinase C, bisindolylmaleimide. These results indicate that beta-adrenergic stimulation enhances, whereas alpha-adrenergic stimulation inhibits, IKur and suggest that these actions are mediated by protein kinase A and protein kinase C, respectively. The modulation of IKur by adrenergic influences is a potentially novel control mechanism for human atrial repolarization and arrhythmias.

8-Bromo Cyclic Adenosine Monophosphate↗