Relationship between cardiovascular dysfunction and hyperglycemia in streptozotocin-induced diabetes in rats

Streptozotocin (STZ)-induced diabetes in rats is characterized by cardiovascular dysfunction beginning 5 days after STZ injection, which may reflect functional or structural autonomic nervous system damage. We investigated cardiovascular and autonomic function, in rats weighing 166 ± 4 g, 5-7, 14, 30, 45, and 90 days after STZ injection (N = 24, 33, 27, 14, and 13, respectively). Arterial pressure (AP), mean AP (MAP) variability (standard deviation of the mean of MAP, SDMMAP), heart rate (HR), HR variability (standard deviation of the normal pulse intervals, SDNN), and root mean square of successive difference of pulse intervals (RMSSD) were measured. STZ induced increased glycemia in diabetic rats vs control rats. Diabetes reduced resting HR from 363 ± 12 to 332 ± 5 bpm (P < 0.05) 5 to 7 days after STZ and reduced MAP from 121 ± 2 to 104 ± 5 mmHg (P = 0.007) 14 days after STZ. HR and MAP variability were lower in diabetic vs control rats 30-45 days after STZ injection (RMSSD decreased from 5.6 ± 0.9 to 3.4 ± 0.4 ms, P = 0.04 and SDMMAP from 6.6 ± 0.6 to 4.2 ± 0.6 mmHg, P = 0.005). Glycemia was negatively correlated with resting AP and HR (r = -0.41 and -0.40, P < 0.001) and with SDNN and SDMMAP indices (r = -0.34 and -0.49, P < 0.01). Even though STZ-diabetic rats presented bradycardia and hypotension early in the course of diabetes, their autonomic function was reduced only 30-45 days after STZ injection and these changes were negatively correlated with plasma glucose, suggesting a metabolic origin.

Cardiovascular control in experimental diabetes

Several studies have reported impairment in cardiovascular function and control in diabetes. The studies cited in this review were carried out from a few days up to 3 months after streptozotocin administration and were concerned with the control of the circulation. We observed that early changes (5 days) in blood pressure control by different peripheral receptors were maintained for several months. Moreover, the impairment of reflex responses observed after baroreceptor and chemoreceptor stimulation was probably related to changes in the efferent limb of the reflex arc (sympathetic and parasympathetic), but changes also in the central nervous system could not be excluded. Changes in renal sympathetic nerve activity during volume expansion were blunted in streptozotocin-treated rats, indicating an adaptive natriuretic and diuretic response in the diabetic state. The improvement of diabetic cardiovascular dysfunction induced by exercise training seems to be related to changes in the autonomic nervous system. Complementary studies about the complex interaction between circulation control systems are clearly needed to adequately address the management of pathophysiological changes associated with diabetes

Time course of changes in heart rate and blood pressure variability in streptozotocin-induced diabetic rats treated with insulin

Autonomic neuropathy is a frequent complication of diabetes associated with higher morbidity and mortality in symptomatic patients, possibly because it affects autonomic regulation of the sinus node, reducing heart rate (HR) variability which predisposes to fatal arrhythmias. We evaluated the time course of arterial pressure and HR and indirectly of autonomic function (by evaluation of mean arterial pressure (MAP) variability) in rats (164.5 + 1.7 g) 7, 14, 30 and 120 days after streptozotocin (STZ) injection, treated with insulin, using measurements of arterial pressure, HR and MAP variability. HR variability was evaluated by the standard deviation of RR intervals (SDNN) and root mean square of successive difference of RR intervals (RMSSD). MAP variability was evaluated by the standard deviation of the mean of MAP and by 4 indices (P1, P2, P3 and MN) derived from the three-dimensional return map constructed by plotting MAPn x [(MAPn+1) - (MAPn)] x density. The indices represent the maximum concentration of points (P1), the longitudinal axis (P2), and the transversal axis (P3) and MN represents P1 x P2 x P3 x 10(-3), STZ induced increased urinary glucose in diabetic (D) rats compared to controls (C). Seven days after STZ, diabetes reduced resting HR from 380.6 + 12.9 to 319,2 + 19.8 bpm, increased HR variability, as demonstrated by increased SDNN, from 11.77 + 1.67 to 19.87 + 2.60 ms, did not change MAP, and reduced P1 from 61.0 + 5.3 to 51.5 + 1.8 arbitrary units (AU), P2 from 41.3 + 0.3 to 29.0 + 1.8 AU, and MN from 171.1. + 30.2 to 77.2 + 9.6 AU of MAP. These indices, as well as HR and MAP, were similar for D and C animals 14, 30 and 120 days after STZ. Seven-day rats showed a negative correlation of urinary glucose with resting HR (r=-0.76, P=0.03) as well as with the MN index (r=-0.83, P=0.01). We conclude that rats with short-term diabetes mellitus induced by STZ presented modified autonomic control of HR and MAP which was reversible. The metabolic control may influence the results, suggesting that insulin treatment and a better metabolic control in this model may modify arterial pressure, HR and MAP variability.

Streptozotocin diabetes modifies arterial pressure and baroreflex sensitivity in rats

Although an increased prevalence of hypertension is associated with insulin-dependent diabetes, little is known about the effect of streptozotocin (STZ) diabetes on arterial pressure (AP) regulation in rats. Changes in AP induced by STZ, as well as associated factors in blood pressure regulation such as baroreflex sensitivity, plasma ren activity (PRA), plasma glucose and insulin levels and endothelium participation, were studied in male Wistar rats weighing 287 + or - 10 g. The same seven conscious rats were used for all measurements before and after STZ diabetes. AP pulses were stored on a videotape recorder and processed by a data acquisition system. Baroreflex sensitivity was evaluated by measuring heart rate (HR) changes induced by AP variations produced by phenylephrine and sodium nitroprusside injection. The effect of inhibition of nitric oxide synthesis with N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg iv bolus plus infusion at 20 mg kg-1h-1) on AP was evaluated in another set of rats (6 normal and 5 submitted to STZ treatment). STZ induced hyperglycemia (306 + or - 19 mg/dl), a reduction in mean arterial pressure (MAP, from 116 + or - 5 to 101 + or - 4 mmHg) and no changes in HR (320 + or - 10 vs 298 + or - 14 bpm). The tachycardic response to arterial pressure decreases was impaired (-2.29 + - 0.5 vs -4.5 + or - 0.7 bpm/mmHg, in control) while the bradycardic response to arterial pressure increases was unchanged. Pressure responsiveness to phenylephrine was impaired after STZ (3.78 + or - 0.4 vs 6.73 + or - 0.8 mmHg µU-1 ml-1, in control). Plasma insulin (6.7 + or - 0.6 vs 5.3 + - 1.2 µU/ml) and PRA (6.8 + or - 0.8 vs 7.9 + or - 1.6 ng ANGI ml-1h-1) were similar before and after STZ. L-NAME induced similar increases in normal (+44.67 + or - 0.41 mmHg) and STZ-diatetic rats (+46.50 + or - 15 mmHg). These data show that 5-day STZ diabetes decreases AP and induces impairment of baroreflex sensitivity. These changes do not seem to be related to plasma insulin levels, PRA or nitric oxid synthesis