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Cardiovascular Research 1999 44(2):390-397; doi:10.1016/S0008-6363(99)00229-1
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Copyright © 1999, European Society of Cardiology

Stimulation of L-type Ca2+ current in human atrial myocytes by insulin

Sebastian Maiera,*, Friedbert Aulbacha, Andreas Simmb, Volkmar Langec, Heiner Langenfelda, Holger Behrea, Ulrich Kerstinga, Ulrich Waltera and Michael Kirsteina

aMedizinische Universitätsklinik Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany
bPhysiologische Chemie II, Theodor-Boveri-Institut für Biowissenschaften, Würzburg, Germany
cKlinik und Poliklinik für Herz- und Thoraxchirurgie der Universität Würzburg, Josef-Schneider-Strasse 6, 97080 Würzburg, Germany

* Corresponding author. Tel.: +49-931-201-2775; fax: +49-931-201-2775 s.maier{at}medizin.uni-wuerzburg.de

Received 20 October 1998; accepted 2 July 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: The L-type calcium current (ICa,L) in isolated human atrial myocytes was investigated as a possible target of insulin in the regulation of cardiac function. Methods: Atrial myocytes were obtained from patients undergoing cardiac surgery. Using the whole-cell configuration of the patch-clamp technique, we investigated the stimulation of ICa,L by insulin in single human atrial myocytes. Results: We found a dose-dependent stimulation of ICa,L by insulin at concentrations of 100 nM, 1 µM and 10 µM. Maximum stimulation of ICa,L over basal ICa,L was 140±12% (n=11) at 10 µM insulin. The maximum conductance of ICa,L was increased by 10 µM insulin from 4.0±0.3 nS to 8.3±1.0 nS (n=6). The stimulation of ICa,L by insulin was dose-dependent and reversible. Isoproterenol (10 nM) that stimulates ICa,L by 271±48% (n=10) over basal ICa,L acted faster than insulin. The half-maximum stimulation of ICa,L by isoproterenol and insulin (10 µM) was reached after 31±2 s and 52±5 s, respectively. The insulin effect shown was totally reversed by acetylcholine (3 µM) which is known to inhibit adenylyl cyclase activity/cAMP-production via Gi-proteins. Also, the selective insulin receptor tyrosine kinase inhibitor (hydroxy-2-naphthanelyl-methyl)phosphonic acid completely inhibited the insulin induced effect. Conclusion: Our data show that insulin stimulates the L-type calcium current in isolated human atrial myocytes in a dose-dependent and reversible manner which appears to involve the insulin receptor tyrosine kinase. Insulin regulation of ICa,L in human atrial myocytes may be an interesting system for the analysis of the metabolic syndrome in man.

KEYWORDS Acetylcholine; Ca-channel; Diabetes, G-proteins, Hormones


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Alterations in the availability of insulin or in the functions of its signalling pathways may be involved in a number of physiological and pathological processes in the heart including insulin resistance associated with aging [1], obesity [2], non-insulin-dependent diabetes mellitus [3], essential hypertension [3,4], and cardiac hypertrophy [5] as well as the cardiomyopathy observed in patients with diabetes mellitus [6,7]. In mammalian heart and in isolated cardiac muscle preparations, insulin exerts positive inotropic effects [8–12]. These cardiac effects include increases in maximum force generation, left ventricular dP/dtmax, cardiac output and faster relaxation times. Positive inotropic effects of insulin are independent of the myocardial glycolytic rate and substrate metabolism [8–10,13] and independent of adrenergic mechanisms [8].

Insulin alters cation fluxes in the myocardium, particularly that of Ca2+, and thereby changes mechanical force development in the heart [14]. We recently described that insulin stimulates the L-type calcium current in isolated rat cardiomyocytes using the whole cell patch clamp technique [15]. This increase of ICa,L was dose-dependent and reversible. Furthermore, additional data suggested that cAMP and the cAMP-dependent protein kinase (PKA) are involved in the stimulation of ICa,L by insulin in rat cardiomyocytes. In this study we used isolated atrial myocytes from patients who had cardiac surgery to study a possible insulin induced stimulation of ICa,L in human. Despite the limitations of this study due to small tissue specimens and due to the heterogeneity of patients, diseases, and pretreatment, the data obtained demonstrate that insulin stimulates the L-type calcium current in human cardiomyocytes.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Cell isolation
Single human cardiac myocytes were prepared according to the modified protocol of Bustamante et al. [16] obtained from patients (Table 1) undergoing cardiac surgery for bypass grafting. Small tissue specimens from the right atrium were used. Only rod-shaped and striated cells as signs for viability were used for measurements [16]. We observed also spontaneous contractions of these cells which was also induced by touching with the patch pipette. The investigation conforms with the principles outlined in the Declaration of Helsinki.


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  		Table 1 Characteristics of patients: in all patients, oral medication was terminated at least 12 h prior to surgery; all patients received the same anesthesia: barbiturate, benzodiazepine, antibiotic, morphine and neuroleptic

 
2.2 Chemicals
Collagenase, protease, insulin (from bovine pancreas), (–)-isoproterenol and acetylcholine were purchased from Sigma (Deisenhofen, Germany). (Hydroxy-2-naphthanelyl-methyl)phosphonic acid was purchased by Biomol (Hamburg, Germany). All other chemicals were analytical grade and obtained from Merck (Darmstadt, Germany).

2.3 Electrophysiological recordings
Membrane currents were measured at room temperature (19–23°C) using the whole-cell configuration of the patch-clamp technique [17]. The control superfusion solution (external) and the pipette filling solution (internal) were designed to block K+ currents. External solution contained (in mmol/l) NaCl 107.1, CsCl 30, MgCl2 1.8, CaCl2 1.8, NaHCO3 4, glucose 5, sodium pyruvate 5, HEPES 10, and NaH2PO4·2H2O 0.8, adjusted to pH 7.4 with NaOH. The internal solution contained in (mmol/l) CsCl 119.8, MgCl2 4, creatine phosphate disodium salt 5, Na2ATP 3.1, NaGTP 0.42, EGTA 5, CaCl2 0.062 (pCa 8.5), and HEPES 10, adjusted to pH 7.2 with CsOH.

An aliquot of the myocyte suspension was transferred to a plastic Petri dish where the myocytes were allowed to settle for 5 min before being superfused continuously by gravity with external solution at a rate of about 1 ml/min. The Petri dish was placed on the stage of an inverted microscope (IMT-2, Olympus, Hamburg, Germany).

Patch pipettes were fabricated from borosilicate glass capillaries (Kimax-51, Witz-Scientific, Holland, OH, USA) and filled with internal solution. Liquid junction potentials between the internal and external solutions were compensated for in each experiment. After successfully obtaining a gigaseal, a suction pulse combined with an electrical pulse (500 mV, 1 ms) was applied to establish the whole-cell mode. Sealed atrial myocytes were brought in front of the opening of a microcapillary with a tip diameter of 750 µm. The distance between the cell and the opening of the capillary was about 375 µm. Microcapillaries were perfused by external solution by gravity at a rate of about 10 µl/min. In control experiments with calcium in the bath solution and a calcium free solution flowing out of the microcapillary, ICa,L disappeared completely and instantaneously when the cell was brought to the laminar flow out of the capillary. Five additional microcapillaries mounted in a row allowed superfusion solutions to be changed within 2 s by moving the capillaries. Drugs were added to the external solution and electrophysiological measurements were performed under basal conditions and in the presence of drugs. ‘Basal’ conditions refer to the absence of either insulin, isoproterenol or acetylcholine.

Command pulses and data acquisition were performed with an EPC-9 patch-clamp amplifier controlled by the PULSE software (HEKA, Lambrecht, Germany) on a Macintosh computer. High-resolution currents were low-pass filtered at 2.9 kHz, acquired at a sampling rate of 10 kHz and stored on a hard disk for off-line analysis.

In order to examine the L-type Ca2+ current (ICa,L), cells were voltage-clamped at a holding potential of –50 mV to inactivate the Na+ current, and 200 ms depolarizing pulses to +10 mV were applied at 0.1 Hz (see inset in Fig. 1). For the determination of current—voltage relationships of ICa,L (Fig. 2A) and of ICa,L inactivation curves (Fig. 2B), a double-pulse voltage-clamp protocol was used [18]. Briefly, every 2 s, the membrane potential of the cell, which was maintained at its holding value of –50 mV, experienced the following sequence of events: conditioning pulses ranging from –60 to +60 mV for 200 ms, –50 mV for 3 ms, and a test-pulse to +10 mV for 200 ms (see inset in Fig. 2B).


Figure 1
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  		Fig. 1 Stimulation of ICa,L by insulin. ICa,L was activated in human atrial myocytes by test pulses to +10 mV from a holding potential of –50 mV every 10 s (filled circles). External solution was switched to an insulin containing solution (A) 1 µM and (B) 10 µM, indicated by horizontal bars. Current traces before (a) and after addition of insulin (b) are shown in the insets. Cell capacitance was 119 pF and RS was 1.9 M{Omega} (A) and 56 pF and 4.3 M{Omega} (B) in the experiments shown.

 

Figure 2
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  		Fig. 2 Effects of insulin on the voltage-dependent characteristics of ICa,L. The protocol used in human atrial myocytes to construct current—voltage relations (A), activation curves (d{infty}) and availability curves (f{infty}) (B) is shown in the inset of (A). Conditioning-pulse (CP) potentials were separated from the test pulse (TP) by a 3 ms return to –50 mV. Pulse pairs were applied every 2 s. The results from one single cell are shown in (A) and (B). (A) For construction of the current—voltage relation ICa,L during CP it was plotted against CP potentials. (B) To construct the availability curves ICa,L during TP it was normalized to the current obtained at TP after the holding potential (–50 mV) and plotted against CP. Cell capacitance was 136 pF and RS was 5.2 M{Omega}.

 
For characterization of the activation (current—voltage relation) the method described by Isenberg and Klöckner [19] was used. Briefly summarized, the apparent reversal potential ECa and the maximum conductance were estimated by extrapolation from the steep linear ascending part of the I–V relation to the zero-current axis and its slope. The peak conductance (gCa,L) for each membrane potential (V) was then calculated with the following equation: gCa,L=ICa,L/(V–ECa). The peak conductances were normalized to the maximum conductance and the resulting curve was fitted by a Boltzmann distribution, d{infty}=1/{1+exp[(V1/2–V)/{alpha}]}, where d{infty} is the normalized conductance, V1/2 is the membrane potential at which the conductance is activated at its half-maximum value, and {alpha} is the slope factor. The potential of the half-maximum available ICa,L was determined by linear interpolation of the availability curve.

2.4 Data analysis and statistics
ICa,L was measured on-line as the difference between the peak inward current and the average current during the last 10 ms of the 200-ms pulse. Cell membrane capacitance and series resistance (RS) were measured but not compensated for by exponential analysis of current responses to 5-mV pulses at regular intervals. The estimated voltage clamp error in our setup was about 1 mV. Only measurements with RS≤10 M{Omega} were analyzed. For off-line data analysis the IGOR software from WaveMetrics (Lake Oswego, Oregon, USA) was used.

Results are presented as mean±SEM. Differences between means were tested for statistical significance by Student's t-test for paired or unpaired samples, as necessary. Differences were considered significant at the level of P<0.01 or less, as indicated.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
ICa,L was recorded in human atrial myocytes using the whole-cell configuration of the patch-clamp technique. Basal ICa,L activated by a voltage step from –50 mV to +10 mV was 120±14 pA (n=28). The ICa,L density, which represents the ratio of ICa,L amplitude to the membrane capacitance, was 1.2±0.1 pA/pF (n=28). Pipette resistance (Rp) was 1.3±0.1 M{Omega} (n=28), series resistance (RS) was 4.3±0.4 M{Omega} (n=28), and cell capacity (C) was 100±7 pF (n=28).

3.1 Insulin stimulation of ICa,L
Fig. 1 shows a representative example of the stimulatory effect of 1 µM (Fig. 1A) and 10 µM (Fig. 1B) insulin on ICa,L. Washout of insulin reduced ICa,L to its basal amplitude, demonstrating that the effect was fully reversible. Averaging the results of 11 experiments 10 µM insulin increased ICa,L by 140±12% over basal (P<0.001, n=11). The maximum insulin effect was obtained after 132±10 s and the half-maximum effect was reached after 52±5 s (n=8). The time to peak was shortened from 7.1±0.4 ms (basal) to 5.4±0.4 ms by 10 µM insulin (n=8, P<0.001). The current—voltage relation, activation and inactivation voltage-dependencies of ICa.L are shown in Fig. 2. The current—voltage relation was shifted to more negative potentials by 10 µM insulin (V1/2=8.2±1.3 mV (basal) vs. 4.8±1.5 mV (insulin), n=6, P<0.005) whereas the slope factor ({alpha}) of the activation curve was not affected (7.3±0.3 mV/e-fold (basal), 7.7±0.2 mV/e-fold (insulin), n.s.). The apparent reversal potential of ICa,L was not altered by 10 µM insulin (62.1±1.5 mV (basal) vs. 60.2±0.7 mV (insulin). The maximum conductance gmax was increased from 4.0.±0.3 nS (basal) to 8.3±1.0 nS by 10 µM insulin (n=6, P<0.01). The availability curve was shifted to more hyperpolarized potentials (half-maximum at –13.0±1.3 mV (basal) vs. –17.2±1.2 mV (insulin), n=6, P<0.005). In some experiments we observed a small current at the end of the test pulse under control conditions which was slightly increased after application of insulin and isoproterenol. Analysis of the amplitude of the end-pulse current (4±7 pA for control and –13±10 pA after 10 µM of insulin) showed no significant differences.

3.2 Dose-dependency of insulin-induced increase of ICa,L
The insulin-induced increase of ICa,L was dose-dependent (Fig. 3). The threshold of the insulin-induced increase of ICa,L was 100 nM, and the maximum increase of ICa,L was obtained with 10 µM. Insulin increases ICa,L in a dose-dependent manner. 100 nM insulin increased ICa,L by 12±3% (P<0.01, n=8) over basal and 1 µM by 60±16% (P<0.01, n=8). Maximum stimulation of ICa,L over basal ICa,L was 140±12% (P<0.001, n=11) at 10 µM insulin.


Figure 3
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  		Fig. 3 Dose-dependent insulin-induced increase of ICa,L in human atrial myocytes. Increase of ICa,L over basal current is shown in percent±SEM for different insulin concentrations (100 nM, 1 µM and 10 µM) and for 10 nM isoproterenol.

 
3.3 Effect of the selective insulin receptor tyrosine kinase inhibitor (hydroxy-2-naphthanelylmethyl)phosphonic acid (=HNMPA-(AM)3) on insulin-induced increase of ICa,L
Cells with insulin (10 µM)-stimulated ICa,L were exposed to 1 mM of the selective insulin receptor tyrosine kinase inhibitor HNMPA-(AM)3 in the external solution. The increase of ICa,L by insulin alone was totally reversed to basal values when cells were pre-treated with HNMPA-(AM)3 for 15 min and insulin was then washed-in in addition to HNMPA-(AM)3. The stimulation of ICa,L caused by isoproterenol and the basal ICa,L were not affected by HNMPA-(AM)3 (n=3).The treatment of HNMPA-(AM)3 alone was without effect on ICa,L.

3.3.1 Comparison of insulin- and isoproterenol-induced increases of ICa,L
In a concentration of 10 nM, isoproterenol increased ICa,L by 271±48% (n=10, P<0.001) over basal values. Half of the maximum effect was reached after 31±2 s (n=8) with isoproterenol (10 nM) as compared to 52±5 s (n=8) with 10 µM insulin (P<0.005).

3.3.2 Effect of acetylcholine on insulin-stimulated ICa,L
A significant but small effect of acetylcholine (3 µM) on the basal L-type calcium current in human atrial myocytes was detected (depression by 7.5±1.5%, n=4). Then, the effect of 3 µM acetylcholine on insulin (10 µM) stimulated ICa,L was measured. Acetylcholine completely reversed the stimulatory effect of insulin (10 µM) to basal values (n=4, Fig. 4). After removal of acetylcholine and insulin, a rebound stimulation of ICa,L was observed perhaps due to a slower wash-out of the insulin effect compared to that of acetylcholine. As expected, isoproterenol (10 nM) pre-stimulated ICa,L was inhibited when acetylcholine was added.


Figure 4
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  		Fig. 4 Time course of insulin and isoproterenol stimulation of ICa,L and inhibition by acetylcholine with subsequent rebound. ICa,L was activated in human atrial myocytes by test pulses to +10 mV from a holding potential of –50 mV every 10 s (filled circles). External solution was first switched to an insulin (10 µM) or insulin (10 µM) and acetylcholine (3 µM) containing solution and second to an isoproterenol (10 nM) or isoproterenol (10 nM) and acetylcholine (3 µM) containing solution, indicated by horizontal bars. Note that the rebound current after insulin removal is lower than after isoproterenol removal. Cell capacitance was 88 pF and RS value was 4.2 M{Omega}.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
We describe for the first time that insulin stimulates ICa,L in human atrial cardiomyocytes. For the demonstration of selective ICa,L activation conditions were used in which sodium channels are inactivated. Potassium channels were blocked by cesium. The increase of ICa,L by insulin was dose-dependent, reversible and primarily due to an increase of the maximum conductance. A slight slowing of the current inactivation was also observed.

Different Ca2+ channels are activated or inhibited by insulin in frog atrial cells, but these channels have not been characterized as L-type Ca2+ channels [20]. In single ventricular myocytes from embryonic chick hearts and in human atrial myocytes, insulin had apparently no effect on ICa,L but increased the resting steady-state calcium influx through R-type calcium channels via PTX- and CTX sensitive G-proteins [21]. Our laboratory recently reported that insulin increases ICa,L in rat ventricular myocytes [15]. A decrease of ICa,L by insulin was seen in vascular smooth muscle cells and contributes to insulin-induced vasodilation [22].

In our present study with human atrial myocytes, insulin concentrations are in the same range as used in the majority of previously published in vitro and in vivo studies reporting effects on cardiac contractility or intracellular calcium [8,13,23]. These doses effective in vitro are higher than the insulin concentrations normally found in blood which are reported to be between 0.3 and 3 nM [24]. We cannot explain this difference in insulin doses effective in vivo vs. in vitro investigations. One possible explanation could be that the local insulin concentrations in heart are much higher than in blood as has been reported [24]. Also, other unknown factors may increase the insulin sensitivity in vivo.

The positive inotropic action of catecholamines is caused — at least in part — by an increased Ca2+ influx through L-type Ca2+ channels [25–28]. We hypothesize that the known positive inotropic potency of insulin [8–13] is also mediated by the observed increase of ICa,L induced by insulin. An increase of ICa,L induces an augmented calcium dependent calcium release from the sarcoplasmic reticulum and thus providing the calcium required for contraction [29,30]. Catecholamine-stimulation of ICa,L in heart is primarily mediated by cAMP and cAMP-dependent protein kinase [31–34].

Presently, we have only limited information on the signalling pathway of ICa,L stimulation by insulin in cardiac myocytes. The fact that the effect of insulin on ICa,L is detectable within 1 min suggests a receptor-mediated process which does not involve a myriad of signalling steps. Also, the insulin effect on ICa,L was abolished by 1 mM (hydroxy-2-naphthanelyl-methyl)phosphonic acid, a selective insulin receptor tyrosine kinase inhibitor [35] in our study, indicating that the insulin receptor tyrosine kinase is involved in the mechanism of insulin action. Additionally, isoproterenol and insulin stimulated ICa,L is inhibited by acetylcholine. Pertussis toxin sensitive G proteins (Gi) couple muscarinic M2 receptors to adenylyl cyclase and mediate the inhibitory effects of acetylcholine on ICa,L [36,37]. By this mechanism, acetylcholine antagonizes the β-adrenergic receptor mediated stimulation of cAMP and ICa,L [38], as also confirmed in our present study. Interestingly, insulin increased cAMP and cGMP content in human vascular smooth muscle cells, [39] and insulin activates the adenylyl cyclase system in a bivalve mollusc [40]. Recently, we reported that insulin increases cAMP and ICa,L, the latter effect in a Rp-cAMPS-sensitive manner in rat cardiomyocytes [15]. These data implicate the cAMP/PKA system as mediator of the insulin effects on ICa,L. For human atrial myocytes, however, further experiments are necessary to reveal the involvement of cAMP/PKA in insulin induced stimulation of ICa,L.

Similar to other studies [41] we found a clear stimulation of ICa,L by 10 nM isoproterenol. Stimulation of ICa,L by isoproterenol in our study was faster and more sensitive in comparison to insulin. Other features of ICa,L in our study, such as the insulin-induced increase in maximum conductance and the small shift of potential-dependent parameters were similar to the effects of isoproterenol reported by other workers [32].

Although insulin is capable of exerting positive inotropic effects independent of catecholamines, insulin may act in concert with catecholamines on the cellular level.

In this study only data of non-diabetic patients are presented. A diabetic cardiomyopathy has been shown in patients with normal coronary arteries and without atherosclerosis or hypertension [42–46]. There is convincing evidence from studies at the cellular level that in diabetes an abnormal intracellular handling of Ca2+ contributes to diabetic cardiomyopathy [14,42,43,45–48]. Isolated myocytes from diabetic rats show contractile dysfunction that depend on changes of Ca2+ regulation [49]. Altered cardiac Ca2+ metabolism may therefore play a role in metabolic disorders associated with hyperinsulinemia, insulin resistance, and hypertension [46,50,51]. Future investigations will hopefully unravel the mechanism of L-type calcium channel stimulation by insulin and its role in cardiac physiology and pathophysiology.

Time for primary review 27 days.


   Acknowledgements
 
We thank A. Katzer for her excellent technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (Ki 606/1-1).


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

  1. DeFronzo R.A. Glucose intolerance and aging. Diabetes Care (1981) 4:493–501.[Abstract]
  2. Sims E.A.H., Danforth E. Jr., Horton E.S., et al. Endocrine and metabolic effects of experimental obesity in man. Recent. Prog. Horm. Res. (1973) 29:457–496.[Medline]
  3. DeFronzo R.A., Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care (1991) 14:173–194.[Abstract]
  4. Ferrannini E., Buzzigoli G., Bonadonna R., et al. Insulin resistance in essential hypertension. New Engl. J. Med. (1987) 317:350–357.[Abstract]
  5. Paternostro G., Clarke K., Heath J., Seymour A.-M.L., Radda G.K. Decreased GLUT-4 mRNA content and insulin-sensitive deoxyglucose uptake show insulin resistance in the hypertensive rat heart. Cardiovasc. Res. (1995) 30:205–211.[Abstract/Free Full Text]
  6. Regan T.J., Lyons M.M., Ahmed S.S. Evidence for cardiomyopathy in familial diabetes mellitus. J. Clin. Invest. (1977) 60:884–899.[Medline]
  7. Hamby R.I., Zoneraich S., Sherman L. Diabetic cardiomyopathy. J Am Med Assoc (1974) 229:1749–1754.[Abstract/Free Full Text]
  8. Lucchesi B.R., Medina M., Kniffen F.J. The positive inotropic action of insulin in the canine heart. Eur. J. Pharmacol. (1972) 18:107–115.[CrossRef][Web of Science][Medline]
  9. Lee J.C., Downing S.E. Effects of insulin on cardiac muscle contraction and responsiveness to norepinephrine. Am. J. Physiol. (1976) 230:1360–1365.[Abstract/Free Full Text]
  10. Rieker R.P., Lee J.C., Downing S.E. Positive inotropic action of insulin on piglet heart. Yale J. Biol. Med. (1975) 48:353–359.[Web of Science][Medline]
  11. Jacobsen F., Christensen N.J. Stimulation of heart rate by insulin: Uninfluenced by β-adrenergic receptor blockade in rabbits. Scand. J. Clin. Lab. Invest. (1979) 39:253–256.[CrossRef][Web of Science][Medline]
  12. Bhagat B., Burke W.J., Dhalla N.S. Insulin-induced enhancement of uptake of noradrenaline in atrial stripes. Br. J. Pharmacol. (1981) 74:325–332.[Web of Science][Medline]
  13. Reikeras O., Gunnes P., Sorlie D., et al. Haemodynamic effects of low and high doses of insulin during β-receptor blockade in dogs. Clin. Physiol. (1985) 5:455–467.[Web of Science][Medline]
  14. Pierce G.N., Kutryk M.J., Dhalla N.S. Alterations in Ca2+ binding by and composition of the cardiac sarcolemmal membrane in chronic diabetes. Proc. Natl. Acad. Sci. USA (1983) 80:5412–5416.[Abstract/Free Full Text]
  15. Aulbach F., Simm A., Maier S., et al. Insulin stimulates the L-type Ca2+ current in rat cardiac myocytes. Cardiovasc. Res. (1999) 42:113–120.[Abstract/Free Full Text]
  16. Bustamante J.O., Watanabe T., Murphy D.A., McDonald T.F. Isolation of single atrial and ventricular cells from the human heart. Can. Med. Assoc. J. (1982) 126:791–793.[Abstract]
  17. Hamill O.P., Marty A., Neher E., Sakmann B., Sigworth F.J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. (1981) 391:85–100.[CrossRef][Web of Science][Medline]
  18. Fischmeister R., Hartzell H.C. Mechanism of activation of acetylcholine on calcium current in single cells from frog ventricle. J. Physiol. (Lond.) (1986) 376:183–202.[Abstract/Free Full Text]
  19. Isenberg G., Klöckner U. Calcium currents of isolated bovine ventricular myocytes are fast and of large amplitude. Pflugers Arch. (1982) 395:30–41.[CrossRef][Web of Science][Medline]
  20. Nakipova O.V., Lazarev A.V., Kshutashvili T.S., Krupenin V.A., Freidin A.A. Insulin regulation of 2 kinetically different types of calcium current. Fiziol. Zh. SSSR (1989) 75:804–812.[Medline]
  21. Bkaily G., Economos D., Potvin L., et al. Blockade of insulin sensitive steady-state R-type Ca2+ channel by PN 200–110 in heart and vascular smooth muscle. Mol. Cell. Biochem. (1992) 117:93–106.[Web of Science][Medline]
  22. Standley P.R., Zhang F., Ram J.L., Zemel M.B., Sowers J.R. Insulin attenuates vasopressin-induced calcium transients and a voltage-dependent calcium response in rat vascular smooth muscle cells. J. Clin. Invest. (1991) 88:1230–1236.[Web of Science][Medline]
  23. Pierce G.N., Ganguly P.K., Dzurba A., Dhalla N.S. Modification of the function of cardiac subcellular organelles by insulin. Adv. Myocardiol. (1985) 6:113–125.[Medline]
  24. Rosenzweig J.L., Havrankova J., Lesniak M.A., Brownstein M., Roth J. Insulin is ubiquitous in extrapancreatic tissues of rats and humans. Proc. Natl. Acad. Sci. USA (1980) 77:572–576.[Abstract/Free Full Text]
  25. Hartzell H.C., Méry P.-F., Fischmeister R., Szabo G. Sympathetic regulation of cardiac calcium current is due exclusively to cAMP-dependent phosphorylation. Nature (1991) 351:573–576.[CrossRef][Medline]
  26. Bouron A., Potreau D., Raymond G. The L-type calcium current in single hypertrophied cardiomyocytes isolated from the right ventricle of ferret heart. Cardiovasc. Res. (1992) 26:662–670.[Abstract/Free Full Text]
  27. Aggarwal R., Boyden P.A. Altered pharmacologic responsiveness of reduced L-type calcium currents in myocytes surviving in the infarcted heart. J. Cardiovasc. Electrophysiol. (1996) 7:20–35.[Web of Science][Medline]
  28. Frace A.M., Méry P.-F., Fischmeister R., Hartzell H.C. Rate-limiting steps in the β-adrenergic stimulation of cardiac calcium current. J. Gen. Physiol. (1993) 101:337–353.[Abstract/Free Full Text]
  29. Niggli E., Lipp P. Subcellular features of calcium signalling in heart muscle: What do we learn? Cardiovasc. Res. (1995) 29:441–448.[Free Full Text]
  30. Isenberg G., Etter E.F., Wendt-Gallitelli M.-F., et al. Intrasarcomere [Ca2+] gradients in ventricular myocytes revealed by high speed digital imaging microscopy. Proc. Natl. Acad. Sci. USA (1996) 93:5413–5418.[Abstract/Free Full Text]
  31. Osterrieder W., Brum G., Hescheler J., et al. Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current. Nature (1982) 298:576–578.[CrossRef][Medline]
  32. Josephson I.R., Sperelakis N. Phosphorylation shifts the time-dependence of cardiac Ca++ channel gating currents. Biophys. J. (1991) 60:491–497.[Web of Science][Medline]
  33. Zong X., Schreieck J., Mehrke G., et al. On the regulation of the expressed L-type calcium channel by cAMP-dependent phosphorylation. Pflugers Arch. (1995) 430:340–347.[CrossRef][Web of Science][Medline]
  34. Ravens U., Wettwer E., Ohler A., Amos G.J., Mewes T. Electrophysiology of ion channels of the heart. Fundam. Clin. Pharmacol. (1996) 10:321–328.[Web of Science][Medline]
  35. Saperstein R., Vicario P.P., Strout H.V., et al. Design of a selective insulin receptor tyrosine kinase inhibitor and its effect on glucose uptake and metabolism in intact cells. Biochemistry (1989) 28:5694–5701.[CrossRef][Web of Science][Medline]
  36. Brown A.M. Vagal control of the heart: experimental basis and clinical implications. Levy M.N., Schwartz P.J., eds. (1994) Armonk, NY: Futura Publishing. 133–146.
  37. McDonald T.F., Pelzer S., Trautwein W., Pelzer D.J. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol. Rev. (1994) 74:365–505.[Free Full Text]
  38. Levy M.N., Pappano A.J. Vagal control of the heart: experimental basis and clinical implications. Levy M.N., Schwartz P.J., eds. (1994) Armonk, NY: Futura. 241–259.
  39. Trovati M., Massucco P., Mattiello L., et al. Insulin increases cyclic nucleotide content in human vascular smooth muscle cells: a mechanism potentially involved in insulin-induced modulation of vascular tone. Diabetologia (1995) 38:936–941.[Web of Science][Medline]
  40. Pertseva M.N., Plesneva S.A., Shpakov A.O., Rusakov Y., Kuznetsova L.A. Involvement of the adenylyl cyclase signaling system in the action of insulin and mollusc insulin-like peptide. Comp. Biochem. Physiol. B (1995) 112:689–695.[CrossRef][Medline]
  41. Andersen A.S., Kjeldsen T., Wiberg F.C., et al. Identification of determinants that confer ligand specificity on the insulin receptor. J. Biol. Chem. (1992) 267:13681–13686.[Abstract/Free Full Text]
  42. Gotzsche O. Myocardial cell dysfunction in diabetes mellitus. A review of clinical and experimental studies. Diabetes (1986) 35:1158–1162.[Abstract]
  43. Gotzsche L.B.H., Rosenqvist N., Gronbæk H., Flyvbjerg A., Gotzsche O. Increased number of myocardial voltage-gated Ca2+ channels and unchanged total β-receptor number in long-term streptozotocin-diabetic rats. Eur. J. Endocrinol. (1996) 134:107–113.[Abstract/Free Full Text]
  44. Tahiliani A.G., McNeill J.H. Diabetes-induced abnormalities in the myocardium. Life Sci. (1986) 38:959–974.[CrossRef][Web of Science][Medline]
  45. Heyliger C.E., Prakash A., McNeill J.H. Alterations in cardiac sarcolemmal Ca2+ pump activity during diabetes mellitus. Am. J. Physiol. Heart Circ. Physiol. (1987) 252:H540–H544.[Abstract/Free Full Text]
  46. Allo S.N., Lincoln T.M., Wilson G.L., et al. Non-insulin-dependent diabetes-induced defects in cardiac cellular calcium regulation. Am. J. Physiol. Cell Physiol. (1991) 260:C1165–C1171.[Abstract/Free Full Text]
  47. Resnick L.M. Cellular calcium and magnesium metabolism in the pathophysiology and treatment of hypertension and related metabolic disorders. Am. J. Med. (1992) 93:11S–20S.[CrossRef][Medline]
  48. Lagadic-Gossmann D., Buckler K.J., Le Prigent K., Feuvray D. Altered Ca2+ handling in ventricular myocytes isolated from diabetic rats. Am. J. Physiol. Heart Circ. Physiol. (1996) 270:H1529–H1537.[Abstract/Free Full Text]
  49. Ren J., Davidoff A.J. Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes. Am. J. Physiol. Heart Circ. Physiol. (1997) 272:H148–H158.[Abstract/Free Full Text]
  50. Lind L., Hvarfner H., Pollare T., Lithell H., Ljunghall S. Fasting insulin, calcium metabolism and the electrocardiogram in hypertensive subjects. J. Intern. Med. (1992) 232:335–339.[Web of Science][Medline]
  51. Reaven G.M., Lithell H., Landsberg L. Hypertension and associated metabolic abnormalities — the role of insulin resistance and the sympathoadrenal system. New Engl. J. Med. (1996) 334:374–381.[Free Full Text]

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