Abstract
Isolated diastolic dysfunction is found in almost half of asymptomatic
patients with well-controlled diabetes and may precede diastolic
heart failure. However, mechanisms that underlie diastolic dysfunction
during diabetes are not well understood. We tested the hypothesis
that isolated diastolic dysfunction is associated with impaired myocardial
Ca(2+) handling during type 1 diabetes. Streptozotocin-induced diabetic
rats were compared with age-matched placebo-treated rats. Global
left ventricular myocardial performance and systolic function were
preserved in diabetic animals. Diabetes-induced diastolic dysfunction
was evident on Doppler flow imaging, based on the altered patterns
of mitral inflow and pulmonary venous flows. In isolated ventricular
myocytes, diabetes resulted in significant prolongation of action
potential duration compared with controls, with afterdepolarizations
occurring in diabetic myocytes (P < 0.05). Sustained outward K(+)
current and peak outward component of the inward rectifier were reduced
in diabetic myocytes, while transient outward current was increased.
There was no significant change in L-type Ca(2+) current; however,
Ca(2+) transient amplitude was reduced and transient decay was prolonged
by 38\% in diabetic compared with control myocytes (P < 0.05). Sarcoplasmic
reticulum Ca(2+) load (estimated by measuring the integral of caffeine-evoked
Na(+)-Ca(2+) exchanger current and Ca(2+) transient amplitudes) was
reduced by approximately 50\% in diabetic myocytes (P < 0.05). In
permeabilized myocytes, Ca(2+) spark amplitude and frequency were
reduced by 34 and 20\%, respectively, in diabetic compared with control
myocytes (P < 0.05). Sarco(endo)plasmic reticulum Ca(2+)-ATPase-2a
protein levels were decreased during diabetes. These data suggest
that in vitro impairment of Ca(2+) reuptake during myocyte relaxation
contributes to in vivo diastolic dysfunction, with preserved global
systolic function, during diabetes.
- action
- angiopathies,
- animals;
- atpases,
- blotting,
- calcium
- calcium,
- calcium-transporting
- cells,
- channels,
- cytology/metabolism;
- diabetes
- diabetic
- diastole,
- drug
- effects/metabolism;
- effects;
- electrocardiography;
- experimental,
- heart
- l-type,
- male;
- mellitus,
- metabolism
- metabolism/physiology;
- metabolism/physiopathology;
- metabolism;
- muscle
- physiology;
- potassium
- potentials,
- rats,
- rats;
- reticulum
- reticulum,
- sarcoplasmic
- signaling,
- ventricles,
- western;
- wistar;
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