Effects of diabetes and hypertension on myocardial Na⁺-Ca²⁺ exchange

Abstract

Abnormalities in cardiac function have been extensively documented in experimental and clinical diabetes. These aberrations are well known to be exaggerated when hypertension and diabetes co-exist. The objective of the present study was to examine whether alterations in the activity of the myocardial Na+-Ca2+ exchanger (NCX) can account for the deleterious effects of diabetes and (or) hypertension on the heart. To this aim, the following experimental groups were studied: (i) control; (ii) diabetic; (iii) hypertensive; and (iv) hypertensive-diabetic. Wistar rats served as the control group (C) while Wistar rats injected with streptozotocin (STZ, 55 mg/kg) served as the diabetic (D) group. Spontaneously hypertensive (SH) rats were used as the hypertensive group (H) while SH rats injected with STZ served as the hypertensive-diabetic (HD) group. Sarcolemma was isolated from the ventricles of the C, D, H, and HD groups and NCX activity was examined using rapid quenching techniques to study initial rates over a [Ca2+]o range of 10-160 microM. The Vmax of NCX was lower in the D group when compared with the C group (D, 2.96 +/- 0.26 vs. C, 4.0 +/- 0.46 nmol x mgprot(-1) x s(-1), P < 0.05), however combined diabetes and hypertension (HD) did not affect the Vmax of NCX activity (HD, 3.84 +/- 0.88 vs. H, 3.59 +/- 0.24 nmol x mgprot(-1) x s(-1), P > 0.05). However, analysis of the Km values for Ca2+ indicated that both the D and HD groups exhibited a significantly lower Km when compared with their respective control groups (D, 42 +/- 4 vs. C, 56 +/- 4 microM, P < 0.05; HD, 33 +/- 7 vs. H, 51 +/- 8 microM, P < 0.05). Immunoblotting using polyclonal antibodies (against canine cardiac NCX) exhibited the typical banding of 160, 120, and 70 kDa. The 120 kDa band is believed to represent the native exchanger with its post-translational modifications. Examination of the blots revealed a lower intensity of the 120 kDa band in the D group when compared with the C group, however, no significant difference in the HD group was observed. We speculate that the lower Vmax in the D group may be due to a reduced concentration of exchanger protein in the membrane. The absence of this defect in the HD group may be a result of compensatory mechanisms to the overall hemodynamic overload, however, this remains to be determined. The increased affinity for Ca2+ in both the D and HD groups (determined by the lower Km values) is an interesting finding and may be due to changes in sarcolemmal lipid bilayer composition secondary to diabetes-induced hyperlipidemia.

Calsequestrin expression and calcium binding is increased in streptozotocin-induced diabetic rat skeletal muscle though not in cardiac muscle

“…Thus, besides abnormal Ca 2+ -exchange mechanisms [13,15], altered Ca 2+ pumping into the SR lumen [14] and modified Ca 2+ release from the junctional SR [16] previously described in diabetic heart, Ca 2+ sequestration and thus the signal transduction process underlying excitation-contraction coupling and relaxation appear to be affected in diabetic skeletal muscle fibres. Possibly, the observed increase in the high-capacity Ca 2+ -binding elements CSQ and CLPs represents a compensatory mechanism of diabetic skeletal muscle.…”

“…Fibre type shifting due to chronic electrostimulation also results in changes in the abundance and isoform expression pattern of Ca 2+ -binding proteins [10]. In analogy, since diabetic skeletal and heart muscle fibres both exhibit abnormal Ca 2+ homeostasis and contractile weakness [11,12], and because various Ca 2+ -handling proteins such as the Na + /Ca 2+ -exchanger, the ryanodine receptor Ca 2+ -release channel and the SR Ca 2+ -ATPase were previously shown to be affected during the disease process in heart [13,14,15,16,17], it was of interest to study the fate of this terminal cisternae protein in an established animal model of diabetes, the streptozotocin-(STZ-) treated rat (for review see [18]). …”

“…This study shows for the first time that the relative density of a crucial sub-set of Ca 2+ -binding proteins is altered in STZ-induced diabetic skeletal muscle fibres and thereby supports the pathophysiological concept of abnormal Ca 2+ homeostasis in diabetes. Besides the previously established abnormal Ca 2+ cycling in diabetic heart [13,14,15,16,17], Ca 2+ sequestration and thus the signal transduction process underlying excitation-contraction coupling and relaxation appears to be altered in diabetic skeletal muscle fibres.…”

In vivo treatment with stobadine prevents lipid peroxidation, protein glycation and calcium overload but does not ameliorate Ca2+-ATPase activity in heart and liver of streptozotocin-diabetic rats: comparison with vitamin E

“…The increased intracellular concentration of calcium may be explained by the osmotic activity of high glucose (cell shrinkage), demonstrated to activate G protein(s), most likely through a stretch receptor, which in turn stimulates calcium channels inhibitable by verapamil, nifedipine and amlodipine, thus permitting a calcium influx into cardiac myocytes [9]. The increased cardiac affinity for calcium in diabetic rats was also reported to be due to changes in sarcolemmal lipid bilayer composition secondary to diabetes-induced hyperlipidaemia [35]. Diabetes-induced hyperlipidemia and the alterations in membrane phospholipids and fatty acids have been shown to depress membrane-bound enzyme activities, which influence intracellular calcium metabolism resulting in cardiac dysfunction [34].…”

Na+/Ca2+ EXCHANGER INHIBITOR AMELIORATES IMPAIRED ENDOTHELIUM‐DEPENDENT Na+ RELAXATION INDUCED BY HIGH GLUCOSE IN RAT AORTA

“…9 Accumulating evidence indicates that abnormal Na + /Ca 2+ exchanger activation contributes to both diabetic micro-and macroangiopathy. [9][10][11][12] KB-R7943, a Na + /Ca 2+ exchanger inhibitor, is widely used in the treatment of cardiovascular diseases. [13][14][15] KB-R7943 has been proved to be effective in treating saltdependent hypertension 13 and protecting against myocardial ischaemia/reperfusion injury by preventing cardiomyocyte Ca 2+ overload.…”