No abstract

Experiments were designed to characterize endothelium-dependent relaxation in thoracic aortic rings obtained from streptozotocin-induced diabetic rats. When the degree of the peak relaxation was compared, the endothelium-dependent relaxant responses to acetylcholine, histamine, or ADP in precontracted aortic rings showed that there was no significant difference between diabetic and control vessels. However, the time courses appeared quite different. The endothelium-dependent relaxant responses in diabetic vessels were more transient than those in control vessels. In addition, the rapid fade of the endothelium-dependent responses observed in diabetic vessels was significantly suppressed by pretreatment with superoxide dismutase. Pretreatment with catalase, deferoxamine, allopurinol, or indomethacin did not prevent the rapid fade of the endothelium-dependent relaxation. The endothelium-independent relaxation induced by nitric oxide also faded more quickly in diabetic vessels; this impairment was less pronounced in the presence of superoxide dismutase. These results suggest that the transient nature of the endothelium-dependent relaxation is more marked in diabetic rat aorta as a result of an enhanced accumulation of superoxide anion.

1 The aim of this study was to determine whether endothelium-dependent hyperpolarization and relaxation are altered during experimental diabetes mellitus. Membrane potentials were recorded in mesenteric arteries from rats with streptozotocin-induced diabetes and age-matched controls. The resting membrane potentials were not signi®cantly di erent between control and diabetic mesenteric arteries (755.3+0.5 vs 755.6+0.4 mV). However, endothelium-dependent hyperpolarization produced by acetylcholine (ACh; 10 78 ± 10 75 M) was signi®cantly diminished in amplitude in diabetic arteries compared with that in controls (maximum 710.4+1.1 vs 717.2+0.8 mV). Furthermore, the hyperpolarizing responses of diabetic arteries were more transient. 2 ACh-induced hyperpolarization observed in control and diabetic arteries remained unaltered even after treatment with 3610 74 M N G -nitro-L-arginine (L-NOARG), 10 75 M indomethacin or 60 u ml 71 superoxide dismutase. 3 Endothelium-dependent hyperpolarization with 10 76 M A23187, a calcium ionophore, was also decreased in diabetic arteries compared to controls (78.3+1.4 vs 718.0+1.9 mV). However, endothelium-independent hyperpolarizing responses to 10 76 M pinacidil, a potassium channel opener, were similar in control and diabetic arteries (720.0+1.4 vs 719.2+1.1 mV). 4 The altered endothelium-dependent hyperpolarizations in diabetic arteries were almost completely prevented by insulin therapy. Endothelium-dependent relaxations by ACh in the presence of 10 74 M L-NOARG and 10 75 M indomethacin in diabetic arteries were also reduced and more transient compared to controls. 5 These data indicate that endothelium-dependent hyperpolarization is reduced by diabetes, and this would, in part, account for the impaired endothelium-dependent relaxations in mesenteric arteries from diabetic rats.

1 Electrophysiological effects of MS-551, a new class III antiarrhythmic drug, were examined and compared with those of (+)-sotalol in rabbit ventricular cells. 2 In rabbit ventricular muscles stimulated at 1.0 Hz, MS-551 (0.1-10 LM) and (+)-sotalol (3-100I1M) prolonged action potential duration (APD) and effective refractory period without affecting the maximum upstroke velocity of phase 0 depolarization (V.,a). The class III effect of MS-551 was approximately 30 times more potent than that of (+)-sotalol. 3 Class III effects of MS-551 and (+)-sotalol showed reverse use-dependence, i.e., a greater prolongation of APD at a longer cycle length. 4 In rabbit isolated ventricular cells, 3 gM MS-551 and 100 JLM sotalol inhibited the delayed rectifier potassium current (IK) which was activated at more positive potentials than -50 mV and saturated around + 20 mV. 5 MS-551 at a higher concentration of 10 JAM decreased the transient outward current (Ito) and the inward rectifier potassium current (IKI) although 100 tLM sotalol failed to inhibit these currents.6 MS-551 is a non-specific class III drug which can inhibit three voltage-gated K+ channels in rabbit ventricular cells.

The present work was carried out in order to determine whether a decrease in cardiac Na+‐Ca2+ exchanger (NCX) activity observed in diabetes is caused by a reduction in NCX protein and mRNA levels and to elucidate the significance of this decrease in alterations in [Ca2+]i homeostasis in diabetic cardiomyocytes. The NCX current was significantly reduced in ventricular myocytes freshly isolated from streptozotocin‐induced diabetic rat hearts, and its current density was about 55 % of age‐matched controls. Diabetes resulted in a 30 % decrease in cardiac protein and mRNA levels of NCX1, a NCX isoform which is expressed at high levels in the heart. The reduced NCX current and the decreased protein and mRNA levels of NCX1 in diabetes were prevented by insulin therapy. Although both diastolic and peak systolic [Ca2+]i were not different between the two groups of myocytes, increasing external Ca2+ concentration to high levels greatly elevated diastolic [Ca2+]i in diabetic myocytes. Inhibition of NCX by reduction in extracellular Na+ by 50 % could produce a marked rise in diastolic [Ca2+]i in control myocytes in response to high Ca2+, as seen in diabetic myocytes. However, cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum Ca2+ pump ATPase, did not modify the high Ca2+‐induced changes in diastolic [Ca2+]i in either control or diabetic myocytes. Only in papillary muscles from diabetic rats did the addition of high Ca2+ cause a marked rise in resting tension signifying a partial contracture that was possibly due to an increase in diastolic [Ca2+]i. In conclusion, the diminished NCX function in diabetic myocytes shown in this study results in part from the decreased levels of cardiac NCX protein and mRNA. We suggest that this impaired NCX function may play an important role in alterations in Ca2+ handling when [Ca2+]i rises to pathological levels.