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Background: Experimental models are essential for clarifying the pathogenesis of diabetes mellitus (DM).

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Background: The complex interactions that exist between the pacemaker current, If, and the parasympathetic nervous system could significantly influence the course of patients undergoing chronic therapy with the If blocker ivabradine. We thus aimed to assess the effects of chronic ivabradine therapy on autonomic modulation and on the cardiovascular response to in situ and in vitro parasympathetic stimulation. The right atrial expression of HCN genes, encoding proteins for If, was also evaluated.Methods: Sympathetic and parasympathetic heart rate variability parameters and right atrial HCN(1-4) RNA levels were analyzed in 6 Control and 10 ivabradine-treated male Wistar rats (IVA; 3 weeks, 10 mg/kg/day). The heart rate (HR) and systolic blood pressure (SBP) responses to in situ electrical stimulation of the vagus nerve (2–20 Hz) were assessed in 6 additional Control and 10 IVA rats. The spontaneous sinus node discharge rate (SNDR) response to in vitro cholinergic receptors stimulation using carbamylcholine (10−9–10−6 mol/L) was also assessed in these later rats.Results: Ivabradine significantly increased vagal modulation and shifted the sympatho-vagal balance toward vagal dominance. In Control, in situ vagus nerve stimulation induced progressive decrease in both the SBP (p = 0.0001) and the HR (p< 0.0001). Meanwhile, in IVA, vagal stimulation had no effect on the HR (p = 0.16) and induced a significantly lower drop in SBP (p< 0.05). IVA also displayed a significantly lower SNDR drop in response to carbamylcholine (p< 0.01) and significantly higher right atrial HCN4 expression (p = 0.02).Conclusion: Chronic ivabradine administration enhanced vagal modulation in healthy rats. In addition, ivabradine reduced the HR response to direct muscarinic receptors stimulation, canceled the cardioinhibitory response and blunted the hemodynamic response to in situ vagal stimulation. These data bring new insights into the mechanisms of ivabradine-related atrial proarrhythmia and suggest that long-term If blockade may protect against excessive bradycardia induced by acute vagal activation.

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The results show a significantly more intense DE-induced anticoagulation in diabetic rats that does not seem to be solely related to altered kidney function, and demonstrate that plasma cholesterol can significantly affect DE anticoagulation in this setting.

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Context. Studies of platelet function in diabetics are inconsistent, some studies reporting higher platelet reactivity, while others showed no change.Objective. We aimed to evaluate platelet indices and in vitro platelet aggregation in rats with long-lasting (28 weeks) diabetes mellitus.Design. Twelve controls and 14 diabetic rats were investigated. Diabetes was induced in 11-week-old rats using streptozotocin (60 mg/kg,i.p.). Platelet indices and in vitro adenosine diphosphate (ADP)-, protease-activated receptor 4 (PAR4) agonist-, and arachidonic acid (AA)-induced platelet aggregation were assessed at the age of 38 weeks.Results. Compared to controls, diabetic rats presented lower platelet count and plateletcrit (both p≤0.001), and higher mean platelet volume (p<0.01). ADP-(p=0.04) and AA-induced (p<0.01) platelet aggregation were lower in diabetic compared with control rats, whereas PAR4 agonistinduced platelet aggregation was similar between the two groups (p=1.00).Conclusions. This study demonstrates a paradox of high intrinsic platelet reactivity and low in vitro ADP-and AA-induced platelet aggregation in diabetic rats compared with non-diabetic controls. The relevance of in vitro platelet aggregation to the contribution of platelets to in vivo thromboembolic events in diabetic rats remains questionable.