Aminoguanidine prevents the impairment of cardiac pumping mechanics in rats with streptozotocin and nicotinamide-induced type 2 diabetes

Abstract

Background and purpose: Aminoguanidine (AG), an inhibitor of advanced glycation endproducts, has been shown to prevent arterial stiffening and cardiac hypertrophy in streptozotocin (STZ) and nicotinamide (NA)-induced type 2 diabetes in rats. Our aims were to examine whether AG produced benefits on cardiac pumping mechanics in the STZ and NA-treated animals in terms of maximal systolic elastance (E(max)) and theoretical maximum flow (Q(max)).

Experimental approach: After induction of type 2 diabetes, rats received daily injections of AG (50 mg kg(-1), i.p.) for 8 weeks and were compared with age-matched, untreated, diabetic controls. Left ventricular (LV) pressure and ascending aortic flow signals were recorded to calculate E(max) and Q(max), using the elastance-resistance model. Physically, E(max) reflects the contractility of the myocardium as an intact heart, whereas Q(max) has an inverse relationship with the LV internal resistance.

Key results: Both type 2 diabetes and AG affected E(max) and Q(max), and there was an interaction between diabetes and AG for these two variables. The E(max) and Q(max) were reduced in rats with type 2 diabetes, but showed a significant rise after administration of AG to these diabetic rats. Moreover, the increase in Q(max) corresponded to a decrease in total peripheral resistance of the systemic circulation when the STZ and NA-induced diabetic rats were treated with AG.

Conclusions and implications: AG therapy prevented not only the contractile dysfunction of the heart, but also the augmentation in LV internal resistance in rats with STZ and NA-induced type 2 diabetes.

Figure 1

The solid curves show the measured ascending aortic flow signal (a) and left ventricular pressure waveform (b) in one control rat. (b) The dashed line represents the isovolumic pressure curve at an end-diastolic volume, which is estimated by fitting a sinusoidal function to the isovolumic portions of the measured left ventricular pressure. (c) Shows the measured data (solid line) and model-generated data (dashed line) when the elastance-resistance model is fitted over t_ej<t<t_pisomax, where t_ej is the onset of ventricular ejection and t_pisomax is the time of peak isovolumic pressure. P(t), the measured left ventricular pressure; P_iso(t), the estimated isovolumic pressure.

Figure 2

Effects of type 2 diabetes and AG on (a) estimated peak isovolumic pressure P_isomax, (b) effective LV end-diastolic volume V_eed and (c) maximal systolic elastance E_max (n=15 per group). E_max can be determined by the ratio of P_isomax to V_eed and (d) E_maxn is the value of E_max normalized for LV weight. AG, aminoguanidine; LV, left ventricular; NC, normal controls; STZ-NA, diabetic rats at 8 weeks after being administered streptozotocin and nicotinamide. ^*Significant difference (P<0.05) from the control group (NC). ^†Significant difference (P<0.05) from the STZ-NA group.

Figure 3

(a) The effects of type 2 diabetes and AG on theoretical maximum flow Q_max (n=15 per group). Q_max was also plotted against total peripheral resistance of the systemic circulation R_p (b). An inverse relationship between Q_max and R_p is evident after pooling the data from all groups. The solid line is obtained when a linear regression of Q_max on R_p is performed on data from all the rats studied, having the linear equation Q_max=46.3601–0.2320 × R_p with r=0.5098; P<0.0001. AG, aminoguanidine; NC, normal controls; STZ-NA, diabetic rats at 8 weeks after being administered streptozotocin and nicotinamide. ^*Significant difference (P<0.05) from the control group (NC). ^†Significant difference (P<0.05) from the STZ-NA group.