Biomedical subjects

M Aomine

Publications and source records attributed to M Aomine.

At least 19 recordsLinked to original sources

PubMed2004

Diabetes mellitus decreases hippocampal release of neurotransmitters: an in vivo microdialysis study of awake, freely moving rats.

Possible diabetes mellitus-induced changes in hippocampal monoaminergic activities were studied to understand the relationships between neurotransmitter levels and various abnormalities in freely moving diabetic rats. We used both experimentally (STZ rats) and spontaneously diabetic rats (WBN/Kob rats) as the diabetic animal model, and compared the findings with those obtained from non-diabetic rats (C rats). Measurement of neurotransmitters (serotonin and dopamine) was carried out using an in vivo microdialysis method. We found that: 1) the basal level of serotonin in the hippocampus was lowest in WBN rats, followed by STZ rats, then by C rats. The level of serotonin in WBN rats was about a half of that in C rats; 2) the basal level of dopamine was also significantly lower in the diabetic WBN and STZ rats than in C rats. The data show that diabetes mellitus decreases in the monoamine release from the hippocampus in both experimentally and spontaneously diabetic rats.

Animals↗

PubMed2001

Postrest contraction in the ventricular papillary muscle of spontaneously diabetic WBN/Kob rat.

In the present study, we investigated the characteristics of the postrest contraction (PRC) in chronic diabetic ventricular muscle. We used WBN/Kob rats of 7-8 weeks as the spontaneously diabetic animal and Wistar rats of 7-8 weeks as the control. We found: (1) No significant differences were seen in the amplitude, the contracting speed, and the relaxing speed of electrically stimulated twitch tension between control and WBN/Kob rats. In addition, the relationship between amplitude of twitch tension and stimulus cycle lengths (0.2-5 sec) was very similar in both animals. (2) The ratios of the first twitch tension (T1) of PRC with various rest intervals (5-600 sec) to the steady-state tension (Tss) were significantly smaller in the diabetic rats than in the controls. (3) When the preparation was stimulated at shorter cycle lengths, the recovery process of PRC was separated into at least two components (fast and slow components). In the diabetic rats, the time constant (tau) of both components was significantly longer than in controls. (4) After caffeine (10(-3) M) treatment, tau of the fast component in the control rats became longer, whereas it remained unchanged in diabetic rats. These findings suggest a dysfunction of the intracellular calcium handling system in spontaneously diabetic heart that is likely to include impaired calcium sequestration and/or extrusion.

Animals↗

PubMed2000

Potassium chloride depolarization enhances MPP+-induced hydroxyl radical generation in the rat striatum.

We determined that extracellular potassium ion concentration, [K+]o-induced depolarization, enhances 1-methyl-4-phenylpyridinium ion (MPP+)-induced hydroxyl radical (*OH) generation in the rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of *OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Induction of high concentration KCl (70 mM) drastically increased formation of *OH trapped as DHBA by the action of MPP+. When dopamine (DA) was administered to the high KCl-treated animals, a marked elevation of DHBA was observed, compared with MPP+-only-treated animals, that showed a positive linear correlation between DA and *OH formation trapped as DHBA (R2 = 0.979) in the dialysate. When corresponding experiments were performed with iron (II), the same results were obtained: a positive linear correlation between the release of iron (II) and DHBA (R2 = 0.988) in the dialysate. These results suggest that [K+]o-induced depolarization enhances the formation of *OH products of efflux/oxidation due to MPP+.

1-Methyl-4-phenylpyridinium↗

PubMed2000

Electrophysiological properties of ventricular muscle obtained from spontaneously diabetic mice.

The electrophysiological properties of cardiac muscle in KK/Ta mouse (hereafter referred to as KK mouse), an animal model of human non-insulin-dependent diabetes mellitus, were investigated, and the findings compared with those obtained from a non-diabetic control mouse (C57BL/6J mouse; referred to as B6 mouse). The ages of the B6 mice were 23.9 +/- 5.4 weeks (n = 24) and those of the KK mice used were 25.7 +/- 10.8 weeks (n = 34). The KK mice had mild obesity, hyperglycemia and hyperinsulinemia. Ventricular muscles from both mice were examined by light microscopy. Partial myocardial fibrosis and filament disorder in the ventricular muscles were found only in the KK mice. The resting membrane potential of the ventricular muscle was less negative in the KK mice than in the control mice. The maximum rate of rise in the upstroke of the action potential was significantly decreased in the KK mice compared with that of the control mice. These suggest a decrease in a time-independent K+ current (IK1) in the KK mice. The duration of the action potential (APD) at all levels of repolarization was significantly longer in the KK mice than in the B6 mice. A blocker of transient outward current (I(to)), 4-aminopyridine, significantly prolonged the APD of the B6 mice, but failed to prolong it in the KK mice, suggesting that Ito in the diabetic mice is very small. A Ca2+ channel blocker, CoCl2, dramatically lengthened all levels of APD in both groups, suggesting that there is no difference between B6 mice and KK mice in L-type Ca2+ current via Ca2+ channels. These suggest the malfunction or deficiency of ionic channels which carry, at least Ito and IK1 in diabetic mice.

4-Aminopyridine↗

PubMed1999

Antiarrhythmic effects of magnesium on rat papillary muscle and guinea pig ventricular myocytes.

1. Despite widespread use of magnesium ion (Mg2+) for antiarrhythmic purposes, little direct information is available regarding its antiarrhythmic mechanisms. To elucidate the possible cellular mechanism, the effects of Mg2+ on early afterdepolarization (EAD), delayed afterdepolarization (DAD), triggered activity (TA), transient inward current (TI) and aftercontraction (AC) were examined in various cardiac preparations. The effects of Mg2+ on myoplasmic Ca2+ concentration were also studied. 2. The effects of Mg2+ on AC, induced by overdrive stimulation, were studied in isolated rat ventricular papillary muscle superfused with low K+ solution. In enzymatically isolated guinea pig myocytes, EAD, DAD and/or TA were induced after overdrive stimulation under conditions of superfusion with low K+ solution, using the whole-cell current-clamp method, and TI was also induced by the whole-cell voltage-clamp method. 3. Immediately after changing the solutions, containing varying concentrations of Mg2+, the effects of Mg2+ were examined. In addition, effects of Mg2+ on Ca transient were studied, using fura-2. 4. We found that: (1) in the rat papillary muscle, 10 mM Mg2+ effectively inhibited AC, which was produced after stimulation at both 3.3 Hz and 5 Hz, although 5 mM Mg2+ was without effect in the case of AC induced after 5-Hz stimulation; (2) in the myocytes, 5 mM Mg2+ did not inhibit DADs, EADs and TA, but 10 mM Mg2+ inhibited them completely; (3) the amplitude and frequency of TI decreased significantly in the presence of 10 mM Mg2+; and finally (4) 10 mM Mg2+ inhibited the Ca transient underlying DAD and/or TA. 5. The findings suggest, but do not prove unequivocally, that Mg's actions are probably due to a combination of a shift of the threshold of various ion channels to less negative potentials, a decrease in Ca2+ influx via Ca channels, a block of several K channels, and/or a block of Na-Ca exchanger. In conclusion, the present study indicates that extracellular Mg2+, via whatever mechanism, exerts antiarrhythmic activities.

Animals↗

PubMed1999

Protective effect of histidine on hydroxyl radical generation induced by potassium-depolarization in rat myocardium.

We investigated the efficacy of histidine on potassium-depolarization induced hydroxyl radical (*OH) generation in the extracellular fluid of rat myocardium by a flexibly mounted microdialysis technique (O system). After the rat was anesthetized, a microdialysis probe was implanted in the left ventricular myocardium, and then sodium salicylate in Ringer's solution (0.5 nmol/microl per minute) was infused to detect the generation of *OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (DHBA). Infusion of KCl (70 mM) clearly produced an increase in *OH formation. However, when KCl in the presence of a high concentration of histidine (25 mM) was infused through the microdialysis probe, KCl failed to increase the 2,3-DHBA formation. To examine the effect of histidine on ischemia-reperfusion of the myocardium, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery (LAD). When the heart was reperfused, a marked elevation of the levels of 2,3-DHBA was observed in the heart dialysate. However, when corresponding experiments were performed with histidine (25 mM)-pretreated animals, histidine prevented the ischemia-reperfusion induced *OH formation trapped as 2,3-DHBA. These results indicate that histidine may protect against K+-depolarization-evoked *OH generation in rat myocardium.

Animals↗

PubMed1996

Inhibition of contractile tension by capsaicin in isolated rat papillary muscle.

1. We examined effects of capsaicin (10(-9) - 10(-5) M), a pungent agent extracted from red pepper, on the contractile tension of rat ventricular papillary muscles stimulated at various cycle lengths (0.2, 0.5, 1, 2 and 5 sec). 2. Capsaicin produced a marked concentration-dependent decrease in the amplitude, the rate of rise (dp/dt) and the rate of relaxation (dr/dt) of the tension. 3. However, the half relaxation time and the time to peak tension of the tension were slightly affected by the agent. 4. The negative inotropic effect of capsaicin was stimulus cycle length (CL) dependent. In particular, IC50 (50% inhibitive concentration) of the agent in the amplitude of the tension was stimulus CL dependent. That is, the values of IC50 were around 10(-7) M at longer CLs (1, 2 and 5 sec), and the value of IC50 at CL 0.2 sec was 4 x 10(-6) M. 5. These capsaicin-induced negative inotropic effects were reversible. Other studies from our laboratory show that the negative inotropic effects may be largely due to a decrease in Ca2+ current.

Animals↗

PubMed1996

Capsaicin does not inhibit the intracellular calcium handling process in rat ventricular papillary muscle.

1. We studied the effects of capsaicin, a pungent agent extracted from red pepper, on rested-state contraction (RSC) of isolated rat ventricular papillary muscles. 2. The RSC was induced by stimulation, after a rest interval of 5 sec to 10 min, after the twitch tension of the muscle preparation stimulated at the regular stimulus frequency of cycle lengths of 5, 1 or 0.2 sec attained the steady state. 3. Drug effects were evaluated on the RSC in the presence of capsaicin 10(-5) M, caffeine 10(-2) M or ryanodine 10(-7) M, respectively. 4. All drugs inhibited the RSC but to different degrees. Ryanodine was the most effective in inhibiting RSC, followed by caffeine and capsaicin, in that order. However, the inhibitory mode varied, depending on the drugs. 5. These findings suggest that capsaicin may not inhibit the function of intracellular Ca2+ store in rat cardiac muscle.

Alkaloids↗

PubMed1993

The negative inotropic effects of amiodarone on isolated guinea pig heart: a possible role of Na(+)-Ca2+ exchange.

1. The negative inotropic effects of amiodarone (AM) were studied in isolated, isometrically contracting ventricular papillary muscles from guinea pigs. 2. AM, 4.4 x 10(-5) M, significantly decreased ouabain (10(-6) M)-induced increase in the developed tension. 3. Manganese (10(-2) M), a partial blocker of Na(+)-Ca2+ exchange, attenuated the AM's negative inotropy. 4. Theophylline (1.5 x 10(-2) M), an inhibitor of phosphodiesterase, produced a marked increase in the tension (about twice compared to the ouabain effect). 5. However, the magnitude of decrease by AM in the tension in the presence of theophylline was similar to that in the case of ouabain. 6. Tetrodotoxin (TTX) decreased the contraction by about a half, and then subsequent addition of AM in the presence of TTX led to a further decrease in the tension. 7. Eventually co-existence of TTX and AM led to a decrease in tension of same degree, compared to the decrease in tension by AM alone. 8. The results suggest that a large portion of negative inotropic action of AM may, at least, reflect interference with the Na(+)-Ca2+ exchange mechanism. 9. This interference with the Na(+)-Ca2+ exchange mechanism may exert a strong negative inotropic effect of the drug, in combination with a decrease in Ca2+ influx via Ca2+ channels and/or an impairment of Ca(2+)-sequestration.

Amiodarone↗

PubMed1993

Bepridil prolongs the action potential duration of guinea pig ventricular muscle only at rapid rates of stimulation.

1. We examined the electromechanical effects of the calcium antagonist, bepridil (1-20 microM), on isolated guinea pig ventricular muscles, driven at various stimulus frequencies (0.1, 0.5, 1, 2 and 5 Hz) in Tyrode's solution containing various K+ concentrations (1.4-43.2 mM). 2. Conventional microelectrode and tension-recording techniques were used. 3. We found that bepridil decreased the maximum upstroke velocity (Vmax) of the action potential with no change in the resting membrane potential (RMP). 4. The former effect depended on both stimulus frequency and the drug concentration used. 5. Bepridil lengthened the duration of the action potential at the level of 25% repolarization (APD25) at the highest frequency (5 Hz), but shortened it at lower frequencies (< or = 2 Hz). 6. The drug also lengthened the APD90 at the highest frequency (5 Hz) but without significant effect at lower frequencies (< or = 2 Hz). 7. Bepridil depolarized the RMP at relatively low extracellular K+ concentrations (< or = 2.7 mM), accompanied by a prolongation of APD90. 8. There were no such effects at much higher K+ concentrations (> or = 5.4 mM), and the drug markedly depressed the Vmax and the action potential amplitude. 9. The drug eliminated the positive staircase phenomenon of twitch contraction, in a concentration-dependent manner. 10. All these findings taken together suggest that bepridil prolongs the action potential duration by inhibiting outward potassium currents (IK and IK1), at rapid rates of stimulation (approximately 300/min), which is comparable to the physiological heart rate of a guinea pig. 11. The prolongation of APD seemed to be secondary to the bepridil-induced reduction of intracellular Ca2+ concentration, [Ca2+]i.

Action Potentials↗

PubMed1992

[Antiarrhythmic effects of magnesium on single ventricular myocytes].

Despite magnesium ions (Mg)'s widespread use for antiarrhythmic purposes, little is known concerning its antiarrhythmic mechanisms. We, therefore, examined Mg effects on delayed afterdepolarization (DAD), early afterdepolarization (EAD), triggered activity (TA) and aftercontraction (AC), using isolated ventricular cells and/or ventricular papillary muscle. In the experiments using the multicellular preparation, ACs were measured, with the use of a strain gauge. ACs were induced in isolated rat papillary muscle superfused with low K+ (0.5 mM) medium, after a train stimulation (2-5 Hz, 10-30 beats). In the experiments concerning cardiac myocytes, the effects of Mg on transient inward current (TI), which is responsible for DAD, were studied using a whole-cell voltage-clamp method applied on isolated guinea pig ventricular cells. And action potentials were also induced by current clamp (10 ms) and the effects of Mg on DAD, EAD and TA were examined. TI, DAD, EAD and TA were induced by use of pipette solution with high Ca2+ (0.7 mM) and low EGTA (0.1 mM).(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1992

Effects of amiodarone on triggered activity induced by overdrive stimulation in Ca2+ overloaded ventricular muscle from guinea pig.

1. The acute effects of amiodarone, a powerful antiarrhythmic drug, on transient depolarizations (TDs) and/or triggered activity (TA) induced by an overdrive stimulation in the condition of low potassium (2.7 mM) and high calcium (5.4 mM) solution were evaluated on isolated ventricular papillary muscles from guinea pig, by means of conventional microelectrode techniques. 2. The amplitude of the induced TDs was enhanced by increase in stimulus number and frequency during overdrive stimulation, and the coupling interval of TDs was shortened. 3. Amiodarone (4.4 x 10(-5) M) significantly decreased the amplitude of TDs, and prolonged the coupling interval. 4. On the other hand, superfusion with a higher concentration (4.4 x 10(-4) M) of amiodarone tended to induce automatic activity. 5. Possible implications with respect to the antiarrhythmic activity of amiodarone are discussed.

Amiodarone↗

PubMed1991

Acetylcholine reverses isoproterenol-induced depression of Vmax in residual Na channel-dependent action potentials of guinea-pig cardiac muscles.

We examined effects of acetylcholine (ACh) on isoproterenol (ISP)-induced changes of the upstroke velocity of the action potential (Vmax) in isolated 13.5 mM K(+)-depolarized atrial muscles from guinea-pigs, using conventional glass microelectrode techniques. In some experiments, ventricular muscles were also used, for purposes of comparison. ISP (0.1 microM) decreased the fast component of Vmax (Vmax,fast) and increased the slow component of Vmax (Vmax, slow) of the atrial muscle, as has been noted in ventricular muscle. ACh (0.1 microM) reversed or antagonized these effects of ISP. However, in the presence of atropine (0.1 microM), the antagonism disappeared. In the presence of the Ca2+ channel blocker, D600 (1 microM), the depressant effect of ISP on the Vmax,fast was augmented while ACh exerted a much less restorative effect on the ISP-induced, depressed Vmax,fast. Similar findings were obtained in low (0.36 and 0.072 mM) Ca2+ media. To investigate the possible involvement of GTP-binding protein (Gi) on these ACh effects, we performed similar experiments using atrial muscles obtained from guinea pigs pre-treated with pertussis toxin (150 micrograms/kg) for 48 h. In these preparations, the depressant effect of ISP on the Vmax,fast remained unaffected, while the reversing effect of ACh on the ISP-induced depression of Vmax,fast either specifically diminished or disappeared. These results show that ACh antagonizes the ISP-induced Vmax changes via stimulation of muscarinic ACh receptors and that this effect is presumably mediated by Gi and modified by intracellular Ca2+. Clinical implications are discussed.

Acetylcholine↗

PubMed1990

The inhibitory actions of amiodarone on rested-state contraction in isolated guinea-pig ventricular muscle.

1. To assess the mechanism(s) of the negative inotropic effects of amiodarone (AM), an effective anti-arrhythmic agent, the effects of AM on rested-state contraction (RSC) were studied in isolated ventricular papillary muscle from control (untreated) and AM-pretreated guinea-pigs. 2. The RSC was induced by stimulation, following a 30 sec- or 10 min-rest period. 3. The drug's effects were evaluated on an initial response (Ti) and steady-state response (Tss) of the RSC at the end of 1 min-stimulus train at 3.3 Hz. 4. In normal physiological solution, the magnitude of Ti was 2.1 times that of Tss in papillary muscles from untreated animals, but, 1.3 times, in AM-pretreated ones. 5. The effects of superfused AM (4.4 x 10(-5)M) were also evaluated in both muscle types. 6. The drug markedly decreased Ti and Tss in both control and AM-pretreated specimens. 7. However, the depression by superfused AM of RSC in control specimens was more likely to be marked than in AM-pretreated ones. 8. Further, verapamil and caffeine, which affect SR function, also depressed the RSC. 9. These results suggest that the negative inotropic actions of AM, at least in part, reflect a decrease in Ca2+ via Ca2+ channels and an impairment of Ca2(+)-sequestrating system.

Amiodarone↗

PubMed1990

Negative inotropic effects of amiodarone on isolated guinea pig papillary muscle.

STUDY OBJECTIVE: The aim of the study was to investigate the inotropic effects on isolated papillary muscle of acute and chronic exposure to amiodarone. DESIGN: Papillary muscles were obtained from untreated and amiodarone pretreated guinea pigs, and tension recording and conventional glass microelectrode techniques were used to assess the effects of amiodarone. SUBJECTS: Guinea pigs of either sex weighing 300-500 g were used: 65 untreated and 18 amiodarone pretreated (20 mg.kg-1.d-1 for 3 1/2 weeks). MEASUREMENTS AND RESULTS: Acute amiodarone exposure (4.4 X 10(-6)-1.1 X 10(-3) mol.litre-1) caused a concentration dependent negative inotropic effect, which was also frequency dependent (0.1-5 Hz), with greater effect at higher stimulation frequencies. Time to peak tension and resting tension increased, while rate of development and relaxation of twitch contraction were slower. Amiodarone caused a dose dependent depression or abolition of slow response action potentials and of contraction in both untreated and amiodarone pretreated specimens. In amiodarone pretreated muscle, contractile forces did not differ significantly from control preparations. Chronic exposure to amiodarone attenuated the negative inotropic effects of acute amiodarone superfusion. CONCLUSIONS: The negative inotropic action of amiodarone may reflect a decrease in Na+ influx via Na+ channels and/or Ca2+ influx via Ca2+ channels, and/or an impairment of Ca2+ sequestration, alone or in combination. The differences in contractile response in relation to acute and chronic amiodarone exposure may be relevant to clinical actions of amiodarone.

Action Potentials↗

PubMed1990

Chronic diabetes mellitus prolongs action potential duration of rat ventricular muscles: circumstantial evidence for impaired Ca2+ channel.

STUDY OBJECTIVE: The aim of the study was to investigate the effects of chronic diabetes mellitus on electromechanical properties of ventricular papillary muscles. DESIGN: Conventional glass microelectrodes and tension recording techniques were used in isolated hearts of rats made diabetic for 30-40 weeks by single intravenous injections of streptozotocin. SUBJECTS: Experimental animals were male Wistar rats of 200-250 g. Diabetic rats (n = 14) were given streptozotocin 65 mg.kg-1; controls (n = 15) were given vehicle only. MEASUREMENTS AND MAIN RESULTS: (1) The maximum upstroke velocity of the action potential duration of diabetic muscles was decreased compared to control, with no difference in the resting potential. (2) At all stimulation frequencies (0.2, 1 and 5 Hz), and particularly the lower ones, the action potential duration of diabetic muscles was longer than control. (3) In diabetic muscles, frequency dependent shortening of the late phase of action potential duration (APD75, APD90) was more pronounced, and frequency dependent lengthening of the early phase (APD25, APD50) was less pronounced. (4) A blocker of transient outward current, 4-aminopyridine, lengthened the early phase of action potential durations by the same amount in diabetic and control muscles. (5) A Ca2+ channel blocker, CoCl2, dramatically shortened all levels of action potential duration, with much greater effect on diabetic muscles. (6) Ryanodine lengthened the early phase of action potential duration and shortened the late phase in both diabetic and control muscles. It enhanced the difference between the groups in the early phase. (7) Developed tension in the presence of ryanodine (ryanodine resistant tension component) was greater in diabetic muscles than in control. CONCLUSIONS: The findings suggest that altered Ca2+ current, but not altered Na(+)-Ca2+ exchange current or altered transient outward current, significantly prolongs action potential duration in diabetic rat ventricular muscles.

4-Aminopyridine↗

PubMed1990

The making of diabetic guinea pigs by streptozotocin and high incidence of triggered activity in the ventricular muscle.

Myoplasmic Ca2+ metabolism is reported to be impaired in diabetic rat heart. We studied the possibility that the ventricular muscles of diabetic guinea pig are prone to develop delayed afterdepolarizations (DADs) and triggered activity (TA), because DADs and TA are believed to be a possible index of increased level of intracellular Ca2+ concentration. To establish an experimental diabetic model from the guinea pig, male animals were divided into four groups: 1) control group: intracardiac injection of citrate buffer; 2) IP group: intraperitoneal injection of streptozotocin (STZ, 200 mg/kg); 3) IC group: intracardiac injection of STZ; and 4) Ins-IC group: intracardiac injection of STZ after pretreatment with insulin (20 IU/kg). We found that: 1) only in the Ins-IC group was the fasting plasma glucose concentration (determined 40 days after STZ injection) significantly higher than in the control group; 2) oral glucose tolerance test performed 40 days after treatment also showed glucose intolerance in the Ins-IC group. These findings evinced the successful making of diabetic guinea pigs by an intracardiac one-shot injection of STZ during development of insulin-induced hypoglycemia. In vitro electrophysiological experiments were performed on ventricular papillary muscle from diabetic animals (Ins-IC group) by conventional glass microelectrode techniques. Transmembrane action potentials were elicited by pulse trains with various rates (2-5 Hz) and durations (10-30 stimuli) in the presence of ouabain (1 microM) and various Ca2+ concentrations (1.8-7.2 mM). The incidence of TA in the muscles from diabetic animals was significantly higher (chi 2-test, p less than 0.05) than that from controls. The findings gave evidence that Ca2+ homeostasis in the myocardium of diabetic guinea pigs is impaired, and this may be a cause of arrhythmia.

Action Potentials↗

PubMed1990

Increased susceptibility to hypoxia of prolonged action potential duration in ventricular papillary muscles from diabetic rats.

The action potential duration (APD) of ventricular muscles obtained from diabetic animals is reported to be prolonged. We studied the effect of varied periods of diabetes on APD prolongation using isolated ventricular papillary muscles from streptozocin-injected rats. We found that a diabetic period greater than 30 wk was necessary for the evolution of significant prolongation of APD. We then studied the effect of repeated hypoxia (PO2 40 mmHg) and normoxia (PO2 300 mmHg) on prolonged APD of diabetic muscles and compared the findings with those from control rats. Transmembrane potentials were recorded with conventional glass microelectrodes. Under normoxic conditions, the APDs of diabetic muscles were significantly prolonged, the maximum upstroke velocity of action potentials tended to be decreased, and the resting membrane potential was not changed significantly compared with controls. The first hypoxia (20 min) shortened the APD in both diabetic and control rats but more so in diabetic rats, thereby making the APD of diabetic rats virtually identical to the control rat APD during the hypoxia. On subsequent reoxygenation (30 min), these hypoxia-induced changes were almost recovered. The second hypoxia (20 min) produced more severe shortening of the APD in both muscle types, and the effect was again far greater in diabetic rats than controls, ending with a reversed sequence of APDs and the APD of diabetic muscles much shorter than the controls. Excessive shortening of APD in diabetic muscles during hypoxic conditions was speculated to be due to greater increases in the outward K+ current through ATP-regulated K+ channels that may be secondary to the more severe reduction of intracellular ATP concentrations in diabetic versus control hearts.

Action Potentials↗