Diminishment of Contractions Associated with Depolarization-Evoked Activation of Ca²⁺ Channels in Diabetic Rat Aorta

Abstract

Alterations in contractile responses of aortic rings mediated by activation of Ca²⁺ channels were investigated in rats with streptozotocin-induced diabetes. Eight to 12 weeks of diabetes resulted in a marked decrease in the contractile response of aortic rings to high K⁺. In contrast, diabetic aortas exhibited significantly greater contractions in response to noradrenaline compared to age-matched controls. In the presence of 15 ml K⁺, the Ca²⁺ channel agonist Bay K 8644 consistently produced concentration-dependent contractions in control aortas. On the other hand, the half of diabetic aortas did not respond to Bay K 8644. As a result, the contractile response to Bay K 8644 was significantly less in diabetic aortas compared to controls. There was no significant difference in basal ⁴⁵Ca²⁺ uptake between control and diabetic aortas. However, the uptake of ⁴⁵Ca²⁺ induced by high K⁺ was significantly less in diabetic aortas than in controls, and pretreatment with the Ca²⁺ channel antagonist nifedipine abolished both responses. The resting membrane potentials were not significantly different between control and diabetic aortas. Furthermore, no difference was found in the magnitude of depolarization evoked by increasing K⁺ concentrations between the two groups of tissues. There were no significant differences in the density and the dissociation constant for [³H]-(+)-PN200-110, a radiolabeled Ca²⁺ channel antagonist, between aortic membranes from control and diabetic rats. These data indicate that the contractile responses to high K⁺ and Bay K 8644 are specifically diminished in diabetic aortas. These diminished responses are not due to a difference in the number of Ca²⁺ channels, but may be related to an alteration in activation of the channels by membrane depolarization.

Altered L-type Ca2+ channel currents in vascular smooth muscle cells from experimental diabetic rats

“…The contractile response evoked by K ϩ depolarization has been found to be diminished (4,8), increased (26), or not influenced (1,14) in diabetic blood vessels, depending on the experimental models, vascular tissue types, and the duration of diabetes. For instance, the contraction and 45 Ca uptake of aortic tissues induced by high K ϩ were both suppressed in STZ-induced 2-to 3-mo diabetic rats (7). These results suggested the abnormalities of VDCC in diabetic vascular SMCs.…”

Diabetes is associated with impairment of uterine contractility and high Caesarean section rate

“…In other smooth muscles mainly studied in diabetic animals, both increased and decreased agonist responses are reported (e.g. [34–36]) and no consistent mechanism has been identified.Our data with high K + stimulation showed a significant decrease in amplitude of force and Ca rise in diabetic samples. There is no consistency in the reported effects of high K+ on other smooth muscle preparations from diabetic tissues, with similar findings to ours reported by some [36–38], but no change or increase by others [20, 39].…”

“…[34–36]) and no consistent mechanism has been identified.Our data with high K + stimulation showed a significant decrease in amplitude of force and Ca rise in diabetic samples. There is no consistency in the reported effects of high K+ on other smooth muscle preparations from diabetic tissues, with similar findings to ours reported by some [36–38], but no change or increase by others [20, 39]. Our data are consistent with those of Wang et al [40], who also found decreased L-type Ca 2+ current density discussed below, but our data could also be due to decreased channel expression and altered channel kinetics.…”

“…Therefore, a defect in channel activation, function or expression may occur as a consequence of the diabetic environment. Despite the large number of studies from diabetic animals reporting impaired contractility, few studies have investigated the underlying mechanisms or measured intracellular Ca 2+ .Studies of resting membrane potential show no significant changes with diabetes [36, 44, 45], suggesting that K + channel activity is unaltered. Reduction in release of Ca 2+ from the sarcoplasmic reticulum, Ca 2+ sparks, and activators of Ca-activated K channel (BK) channels was reported in coronary micro-vessels with diabetes in pigs [46].…”

Diabetes-induced activation of protein kinase C inhibits store-operated Ca 2+ uptake in rat retinal microvascular smooth muscle

“…Several studies have found that KCl depolarisation-induced changes in [Ca 2+ ] i and contractions are diminished in both macrovascular and microvascular smooth muscle cells from diabetic rats [27,28,29,30,31] and this is thought to occur through a reduction in the density of voltage-dependent L-type Ca 2+ channels [32] (VDCC). In our study, the action of high K + was maintained in the retinal MVSM cells from diabetic rats suggesting that neither the VDCCs themselves nor their activation require- PKC activation (PMA).…”