Cardiac dysfunction in the Goto-Kakizaki rat

Abstract.

Experimental study of cardiac function in the diabetic heart has focussed mostly on models of Type I diabetes. We studied cardiac function in the Goto-Kakizaki (GK) rat, an inbred model of spontaneous non-obese, Type II diabetes.

Methods:

Both isolated perfused hearts and isolated ventricular myocytes from GK and matched control Wistar rat hearts were studied. Percent myocyte twitch shortening (%TS) and corresponding intracellular calcium transients (indo-1 fluorescence ratio, R) were measured over a range of stimulation frequencies (0.5–2.5 Hz; 32 °C, n = 16–24 cells). In isolated Langendorff-perfused hearts, we measured systolic LV pressure (LVP_max), left ventricular end diastolic pressure (LVEDP), maximal rate of LV pressure rise (LV dP/dt_max) and fall (LV dP/dt_min) and isovolumic LV relaxation (exponential time constant, T) both at baseline and during brief (10 minutes) hypoxia.

Results:

The %TS and corresponding indo-1 R were similar between GK and control myocytes at all stimulation frequencies (e.g. at 2.5 Hz: % TS = 8.6 ± 0.77 and 8.2 ± 0.19; R = 0.19 ± 0.009 and 0.18 ± 0.018, GK and control respectively, P = NS). Similarly, there were no significant differences in baseline LVP_max (129 ± 6.2 and 135 ± 9.6 mmHg; GK and control respectively, P = NS), LV dP/dt_max (3169.5 ± 165.80 and 3390.6 ± 232.60 mmHg/s; GK and control respectively, P = NS), LV dP/dt_min or T (24 ± 0.7 and 25 ± 0.6 ms, GK and control respectively, P = NS). During 10 min hypoxia, LV dP/dt_max decreased significantly more, and LVEDP and T increased signifi- cantly more, in GK compared to control hearts (LV dP/dt_max: 668.90 ± 32.8 versus 1027.10 ± 84.0 mmHg/s; LVEDP: 21.4 ± 4.3 versus 11.6 ± 0.6 mmHg; T: 102 ± 13.8 versus 56 ± 3.0 ms; GK versus control respectively; all P < 0.05). These abnormalities in GK hearts were reversed with acute addition of insulin (0.01 i. u./ml) to the perfusion buffer.

Conclusion:

The GK model of Type II diabetes displays a mild cardiomyopathy evident as exaggerated diastolic dysfunction during hypoxia. The mechanism is likely to involve substrate deficiency.