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(Hypertension. 1995;26:1100-1104.)
© 1995 American Heart Association, Inc.

Articles

Autonomic Dysfunction in Short-term Experimental Diabetes

C.Y. Maeda; T.G. Fernandes; H.B. Timm; M.C. Irigoyen

From the Laboratory of Cardiovascular Physiology, Department of Physiology, Biosciences Institute, University of Rio Grande do Sul, Brazil, and from PBIC Conselho Nacional de Desenvolvimento Científico e Tecnológico (C.Y.M., H.B.T.).

Correspondence to Maria Cláudia Irigoyen, MD, PhD, Department of Physiology, Biosciences Institute, University of Rio Grande do Sul, Brazil, Rua Sarmento Leite 500, Porto Alegre, Rio Grande do Sul 90050-170, Brazil.

	Abstract

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Abstract Previous data showed that diabetes induced by streptozotocin for 5 days causes changes in arterial pressure control and baroreflex regulation of heart rate in male Wistar rats. The impairment of baroreflex may be related to autonomic neuropathy as described by several investigators. The aim of this study was to identify autonomic changes in short-term experimental diabetes in rats (induced for 5 days with streptozotocin 65 mg IP). Intra-arterial blood pressure signals were obtained from 6 control group and 7 diabetic group rats and processed in a data acquisition system (CODAS, 1 kHz). Both vagal and sympathetic function were assessed through intravenous injections of methylatropine and propranolol. Streptozotocin induced hyperglycemia (18.9±1.8 versus 5.8±0.2 mmol/L) and reductions in mean arterial pressure (102±2 versus 117±3 mm Hg) and resting heart rate (298±14 versus 332±2 beats per minute). Sodium and potassium levels were not different between groups. The intrinsic heart rate was reduced in the diabetic group (302±10 versus 398±6 beats per minute). This group also exhibited depressed vagal and sympathetic tone (50% and 22%, respectively), reduction of vagal effect (42%), and no change in sympathetic effect. In conclusion, early autonomic dysfunction in short-term streptozotocin-induced diabetes seems to be related to changes in arterial pressure and baroreflex control.

Key Words: streptozocin • diabetes mellitus, experimental • baroreflex • heart rate • sympathetic nervous system

	Introduction

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Although diabetic neuropathy can affect both the somatic and autonomic nervous systems, autonomic neuropathy is a serious complication of diabetes associated with a high mortality rate.¹ The increased mortality rate may be related to the cardiovascular system and the loss of the autonomic reflex control leading to orthostatic hypotension, painless myocardial infarction, and sudden death.^{2 3} Indeed, diabetic individuals with normal cardiovascular reflexes have a lower incidence of mortality than diabetic individuals with abnormal autonomic reflex function.¹ Several investigators have studied the arterial baroreceptor reflex and its influence on parasympathetic and sympathetic control of the cardiovascular function. They evaluated baroreflex control of HR in diabetic patients⁴ and in different biological models of experimental diabetes.^{5 6} The results indicated that controversy existed concerning the influence of the following factors on cardiovascular parameters: short- and long-term diabetes and the animal species and experimental model of diabetes used.

The purpose of the present investigation was to analyze some mechanisms of baroreflex control of HR in rats with short-term (5-day) streptozotocin-induced diabetes.

	Methods

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Experiments were performed on male Wistar rats (Animal Quarter House of the Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil) weighing between 220 and 280 g and housed in individual cages with free access to tap water and standard rat food. Animals were made diabetic by a single injection of streptozotocin (65 mg/kg IP, Sigma Chemical Co). Streptozotocin was dissolved in citrate buffer (pH 4.5) and injected within 5 minutes. Controls were injected with citrate buffer. The rats fasted overnight before streptozotocin injection. Four days after the injection of streptozotocin, two catheters filled with 0.06 mL saline were implanted under ether anesthesia into the femoral artery (PE-10) and vein (PE-50) for direct measurement of AP and for drug administration, respectively. Rats fed and watered ad libitum were studied 1 day after catheter placement; the rats were conscious and allowed to move freely during the experiments. The arterial cannula was connected to a strain-gauge transducer (Narco Bio-Systems Miniature Pressure Transducer RP 1500), and blood pressure signals were recorded during a 1-hour period by a microcomputer equipped with an analog-to-digital converter board (CODAS, 1-kHz sampling frequency, Dataq Instruments, Inc). The recorded data were analyzed on a beat-to-beat basis to quantify changes in mean AP and HR. Increasing doses of phenylephrine (0.25 to 8 ug/mL) and sodium nitroprusside (2.5 to 80 µg/mL) were given as sequential bolus injections (0.1 mL) to produce at least four pressure responses ranging from 5 to 40 mm Hg, as described in detail elsewhere.⁷ A time interval between doses was necessary for the blood pressure to return to baseline. Peak increases or decreases in mean AP after phenylephrine or sodium nitroprusside injections and the corresponding peak reflex changes in HR were recorded for each dose of the drug. Baroreflex sensitivity was expressed by values derived by fitting a regression line through points relating all changes in HR related to the induced changes in mean AP. The pressure responsiveness to intravenous phenylephrine and sodium nitroprusside was also evaluated by a dose-effect relation. Before recording AP pulses, blood samples (0.5 mL) were collected through the arterial catheter to measure basal glucose using the colorimetric enzymatic test (Enz color, Bio Diagnostica). Plasma sodium and potassium levels were determined with a flame photometer. The blood collections to biochemical measurements were performed in the morning with rats in the fasted state.

Both vagal and sympathetic tone were studied^{8 9 10} by injections of methylatropine (3 mg/kg IV, Sigma) and propranolol (4 mg/kg IV, Sigma) at a maximal volume per injection of 0.2 mL.^{9 10} On the first day of study the resting HR was recorded in the quiet, unrestrained rat kept in its own cage. Immediately after the resting HR was recorded methylatropine was injected. Because the HR response to methylatropine reaches its peak in 10 to 15 minutes,¹⁰ this time interval was standardized before the HR measurement. Propranolol was injected 15 minutes after methylatropine injection, and again the response was measured after 10 to 15 minutes The IHR was evaluated after simultaneous blockade by propranolol and methylatropine. On the second day of study propranolol was administered first to obtain the inverse sequence of blockade. The vagal effect was evaluated as the difference between the maximum HR after the methylatropine injection and the control HR. The sympathetic effect was evaluated as the difference between the control HR and minimum HR after propranolol injection. The vagal tone was calculated as the difference between the IHR and the HR after propranolol injection. The sympathetic tone was determined as the difference between the HR after methylatropine injection and the IHR.

The sensitivity of the muscarinic receptors on the heart was tested by intravenous injections of methacholine in increasing doses (1.2, 2.4, and 4.8 µg per rat) with intervals of 5 minutes between doses in another set of normal and streptozotocin-treated rats (n=4 each). The experiments were performed in accordance with the "Position of the American Heart Association on Research Animal Use."

Data Analysis
Data are reported as mean±SEM, and Student's unpaired t test was used to compare values obtained between groups. Baroreflex sensitivity was evaluated by regression line analysis of different groups, and the slope was tested by t test for nonpaired data. Differences with methacholine injections were compared by ANOVA for repeated measures, and the post hoc test used was the Newman-Keuls test. Changes were considered significant at a value of P<.05 for all tests.

	Results

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As can be seen in the Table, streptozotocin-induced diabetes induced changes in glycemia (18.9±1.8 versus 5.8±0.2 mmol/L in the control group, P.05) and in body weight (247±8 versus 272±7 g in the control group, P.05). The 5-day streptozotocin-induced diabetes group had significantly reduced systolic AP (119±2 versus 137±3 mm Hg in the control group, P.05), diastolic AP (84±2 versus 99±2 mm Hg, P.05), and mean AP (102±2 versus 117±3 mm Hg in the control group, P.05). Resting HR decreased significantly in the diabetic rats compared with control rats (290±13 versus 332±2 bpm, P.05).

View this table: [in this window] [in a new window]   Table 1. Characterization of Nondiabetic and Diabetic Groups

Baroreflex sensitivity expressed by the slope of regression line relating changes between HR and mean AP shows that reflex tachycardia elicited by sodium nitroprusside was significantly reduced after diabetes (-2.06±0.4 versus -4.00±0.5 in the control rats, P<.013). Reflex bradycardia elicited by phenylephrine was similar in streptozotocin-treated and control rats (-0.91±0.3 versus -1.83±0.4 in the control group, P=.098). (Fig 1A). The vasodepressor responses to sodium nitroprusside are shown in Fig 1B. For the dose range used in these experiments we showed that there were no differences between the diabetic and the control rats. On the other hand, progressive doses of phenylephrine caused a significant increase in AP in control and diabetic rats. However, the vasopressor response to phenylephrine was significantly decreased in diabetic rats compared with control rats (Fig 1C), as indicated by the slope of the regression line relating phenylephrine doses to changes in mean AP (5.22 versus 8.83 mm Hg/µg·mL^-1 in control rats).

View larger version (17K): [in this window] [in a new window]   Figure 1. Line graphs showing (A) effects of streptozotocin-induced diabetes on the bradycardic and tachycardic responses to pressor changes induced by increasing doses of phenylephrine and sodium nitroprusside, respectively; (B) mean AP response to sodium nitroprusside in diabetic and control rats; and (C) mean AP response to phenylephrine in diabetic and control rats as expressed by the slope of regression line: 5.22 and 8.83 mm Hg/(µg·mL-1), respectively (P.05). For B, the slopes of the lines obtained by linear regression analysis were -3.75 and -4.37 mm Hg/(µg·mL-1), respectively. Diabetic indicates rats with diabetes induced for 5 days by treatment with streptozotocin; Nondiabetic, nondiabetic control rats.

Fig 2 shows the control HR and IHR and the HR responses to drug blockades. The basal HR before drug blockades was lower in streptozotocin-treated rats (291±4 versus 324±10 bpm in control rats, P<.05). The IHR obtained after methylatropine and propranolol blockade was significantly lower in streptozotocin-treated rats (302±10 versus 398±6 bpm in control rats, P<.05). Methylatropine injection produced an HR increase significantly higher in the control group than in the streptozotocin-treated group (79±17 versus 138±12 bpm). Propranolol injection caused a small decrease in HR in both groups (22±8 versus 6±6 bpm in control rats, P=.123). The vagal tone (Fig 2) was significantly reduced in the streptozotocin-treated group compared with the control rat group (39±7 versus 78±8 bpm in control rats, P<.05) whereas the sympathetic tone was not significantly different (55±12 versus 71±8 bpm in control rats, P=.286).

View larger version (12K): [in this window] [in a new window]   Figure 2. Graphs showing sympathetic (S) and vagal (V) tonus in nondiabetic control rats and rats with streptozotocin-induced diabetes (see "Methods" for calculation). Arrows indicate control HRs. *Significant difference between nondiabetic control rats and diabetic rats (P.05).

Although the control HR was lower in rats with streptozotocin-induced-diabetes than in control rats (290±13 versus 332±2 bpm, P<.05), the HR decreases in response to three doses of methacholine were not different in both groups. The bradycardic responses induced by progressive doses of methacholine were -70±15 versus -58±17 bpm, -120±18 versus -118±20 bpm, and -180±25 versus -170±20 bpm in the normal rats versus the streptozotocin-treated rats.

	Discussion

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The present investigation confirms our preliminary findings that streptozotocin injection (5 days) decreases AP when evaluated in the same rat⁶ or in different rat groups. Moreover, the present results indicate that short-term streptozotocin-induced-diabetes produces the following in conscious rats: (1) impairment of baroreflex-mediated tachycardia at a time when reflex-mediated bradycardia is preserved, (2) impairment of vagal function evaluated by vagal tonus and effect, and (3) reduction of IHR.

Several studies in diabetic patients have demonstrated an impairment of baroreflex-mediated bradycardia in response to an increase in AP.^{4 11} On the other hand, reflex tachycardia in response to a decrease in AP has been reported to be normal⁴ or impaired.¹²

The relative contribution of parasympathetic and sympathetic activity to the impairment of baroreflex function has not been clearly understood. Different mechanisms may be acting in baroreflex control of HR in insulin-dependent or non–insulin-dependent diabetes mellitus.¹² Moreover, the different findings^{4 11 12} may be attributed to time-dependent changes in HR control. The present study performed in a streptozotocin-induced rat model of diabetes is an attempt to investigate mechanisms of baroreflex dysfunction in short-term diabetes. The normal bradycardic response and impaired tachycardiac response to AP changes that we found in the present experiments contrast with the enhanced and the reduced bradycardic responses to increases in AP observed respectively by Sasaki and Buñag¹³ and Chang and Lund.¹⁴ Time-dependent changes caused by metabolic disorders due to hyperglycemia or insulinopenia¹⁵ and decreases in cardiac adrenergic receptors¹⁶ may be possible explanations for the opposite findings. Indeed, an imbalance of adrenergic and cholinergic changes could result in either an increase or a decrease in baroreflex regulation of HR, since it was demonstrated that baroreflex sensitivity changes from hypersensitivity after 8 weeks¹³ to a later state of hyposensitivity after 48 weeks.¹⁴ The controversial data regarding changes in baroreflex sensitivity after diabetes may be attributed to differences in experimental and analytical approaches. The time after diabetes induction^{6 13 17} and the methodological analysis of baroreceptor sensitivity^{10 18} as well as the animal model used¹⁹ can change the interpretation of the data. It is well demonstrated, for example, that when one normalizes HR responses to the same changes in AP it is easier to compare groups⁷ with different levels of pressure responsiveness to vasoactive drugs. In the present experiments the reduction in responsiveness to phenylephrine after streptozotocin treatment as well as the impairment of the tachycardic response indicate that changes in vascular reactivity and baroreflex sensitivity may be related to the hypotension observed in diabetic subjects, as previously demonstrated.⁶ On the other hand, we found that the responsiveness of vascular smooth muscles to sodium nitroprusside was not different in control and diabetic rats, in contrast to the findings of others.^{17 18}

The vagal effect was markedly reduced in streptozotocin-treated rats. Similarly, the vagal tone was significantly decreased in the streptozotocin-treated group. Therefore, both the vagal effect and the vagal tone indicated a reduction of the vagal function in rats with streptozotocin-induced-diabetes. Other studies support a cardiac vagal neuropathy in experimental diabetes. These investigators found a decrease in acetylcholine concentration²⁰ and a functional defect in cardiac cholinergic nerves.²¹ We found a reduced vagal function and a normal bradycardic response to increases in AP. Moreover, the methacholine injection revealed similar reactivity in both control rats and those with streptozotocin-induced diabetes, suggesting that the reduced vagal tone was not due to defective muscarinic receptors. Although the resting bradycardia may be attributed to a change in sinoatrial node with a consequent reduced IHR, the normal bradycardic response in rats with streptozotocin-induced diabetes may occur by functional changes in cardiac cholinergic mechanisms. Indeed, it was demonstrated that coupling of cholinergic receptors to adenylate cyclase is altered in streptozotocin-treated rats, because the content of G_i proteins in the cardiac tissue was found to be increased after treatment with streptozotocin.²² Moreover, the interactions between sympathetic and parasympathetic systems are complex, suggesting a different vagal action at different levels of sympathetic function.²³ Besides functional changes in cholinergic or adrenergic mechanisms we cannot exclude morphological changes at this early stage of the diabetic state, since Monckton and Pehowich²⁴ reported degenerative changes in the autonomic nervous system of streptozotocin-treated rats. They found changes in axons from the sympathetic paravertebral chain within 24 hours after treatment with streptozotocin. Finally, the weight loss that we observed in streptozotocin-treated rats may be taken into account as changes in the autonomic function, since it was demonstrated that weight loss affects the autonomic function in humans.²⁵

The impaired baroreflex control of HR and changes in vagal or sympathetic function in rats with streptozotocin-induced diabetes are probably not correlated with the serum sodium and potassium levels that we found in this group.

In summary, our data suggest that resting bradycardia after streptozotocin treatment is likely to be due to an alteration of the pacemaker cell function that causes the depressed IHR, since the impairment of vagal function evaluated by pharmacological blockade did not change the bradycardic response to AP increases. Decreased baroreceptor sensitivity, impaired central mediation of the reflex, or even complex interactions of the sympathetic and parasympathetic branches to the heart may contribute to the impairment of the baroreflex function.

	Selected Abbreviations and Acronyms

 

AP = arterial pressure bpm = beats per minute HR = heart rate IHR = intrinsic heart rate

	Acknowledgments

 
This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Financiadora de Estudos e Projetos (FINEP), Fundação de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS), and Propesp-UFRGS. We thank Laboratório Marques Pereira for assistance with biochemical analysis.

Received June 19, 1995; first decision August 18, 1995; accepted September 21, 1995.

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