Evaluation of baroreflex function in young spontaneously hypertensive rats

Abstracts

FUNDAMENTO: A literatura tem descrito dados contraditórios em relação ao início da diminuição da função barorreflexa em ratos espontaneamente hipertensos. OBJETIVO:Este estudo foi realizado para avaliar a função barorreflexa em ratos jovens de 13 semanas espontaneamente hipertensos. MÉTODOS:Foram estudados ratos machos Wistar Kyoto (WKY) (n=15) e ratos espontaneamente hipertensos (REH) de 13 semanas (n=15). Cânulas foram inseridas na artéria aorta abdominal através da artéria femoral direita para medir a pressão arterial média (PAM) e a freqüência cardíaca (FC). A função barorreflexa foi calculada como a derivada da variação da FC em função da variação da PAM (ΔFC/ΔPAM), quando submetida a teste com uma dose depressora de nitroprussiato de sódio (50µg/kg) e com uma dose pressora de fenilefrina (8µg/kg) através de cânula inserida na veia femoral direita em ratos espontaneamente hipertensos e WKY. Diferenças com um valor de p < 0.05 foram consideradas estatisticamente significantes. RESULTADOS:Ratos espontaneamente hipertensos: ΔPAM=43,5 mmHg±5,2, ΔFC=-59,7 ppm±17,9 e ΔFC/ΔPAM=1,3 ppm/mmHg±0,1 testados com fenilefrina; Wistar Kyoto: ΔPAM=&56mmHg±3, ΔFC=*-114,9ppm±11,3 e ΔFC /ΔPAM =#1,9ppm/mmHg±0,3 testados com fenilefrina; ratos espontaneamente hipertensos: ΔPAM=-45,6mmHg±8,1, ΔFC=40,1ppm±11,6 e ΔFC/ΔPAM=0,9ppm/mmHg±0,5 testados com nitroprussiato de sódio; Wistar Kyoto: ΔPAM=-39,8mmHg±6,2, ΔFC=51,9ppm±21,8 e ΔFC/ΔPAM=1,4ppm/mmHg±0,7 testados com nitroprussiato de sódio (*p<0,05; #p<0,01; &p<0,001). CONCLUSÃO: Nossos resultados mostram que ratos espontaneamente hipertensos de 13 semanas apresentaram redução da função barorreflexa quando testados com fenilefrina.

Hipertensão; baroreflexo; sistema nervoso central; idade de início

FUNDAMENTO: La literatura ha descrito datos contradictorios con relación al inicio de la disminución de la función barorrefleja en ratas espontáneamente hipertensas. OBJETIVO: Se realizó este estudio con el objetivo de evaluar la función barorrefleja en ratas jóvenes de 13 semanas, espontáneamente hipertensas. MÉTODOS: Se estudiaron ratas machos Wistar Kyoto (WKY) (n=15) y ratas espontáneamente hipertensas (REH) de 13 semanas de edad (n=15). Se insertaron cánulas en la arteria aorta abdominal -a través de la arteria femoral derecha- para medir la presión arterial media (PAM) y la frecuencia cardiaca (FC). Se calculó la función barorrefleja como la derivada de la variación de la FC en función de la variación de la PAM (ΔFC/ΔPAM). Dicho cálculo se efectuó tras prueba con una dosificación depresora de nitroprusiato de sodio (50µg/kg) y también con una dosificación para presión arterial de fenilefrina (8µg/kg) a través de una cánula insertada en la vena femoral derecha tanto de ratas espontáneamente hipertensas como de WKY. Se consideraron estadísticamente significantes diferencias con un valor de p < 0.05. RESULTADOS: Ratas espontáneamente hipertensas sometidas a prueba con fenilefrina: ΔPAM=43,5 mmHg±5,2, ΔFC=-59,7 ppm±17,9 y ΔFC/ΔPAM=1,3 ppm/mmHg±0,1; Wistar Kyoto probadas con fenilefrina: ΔPAM=&56mmHg±3, ΔFC=*-114,9ppm±11,3 y ΔFC /ΔPAM =#1,9ppm/mmHg±0,3. Ratas espontáneamente hipertensas probadas con nitroprusiato de sodio: ΔPAM=-45,6mmHg±8,1, ΔFC=40,1ppm±11,6 y ΔFC/ΔPAM=0,9ppm/mmHg±0,5; Wistar Kyoto sometidas a prueba con nitroprusiato de sodio: ΔPAM =-39,8mmHg±6,2, ΔFC=51,9ppm±21,8 y ΔFC /ΔPAM =1,4ppm/mmHg±0,7 (*p<0,05; #p<0,01; &p<0,001). CONCLUSIÓN: Nuestros resultados muestran que ratas espontáneamente hipertensas de 13 semanas de edad presentaron reducción de la función barorrefleja cuando probadas con fenilefrina.

Hipertensión; barorreflejo; sistema nervioso central; edad de inicio

ORIGINAL ARTICLE

^IUniversidade Federal de São Paulo (UNIFESP), São Paulo, SP - Brazil

^IIFaculdade de Medicina do ABC, Santo André, SP - Brazil

Mailing address

SUMMARY

BACKGROUND: The literature describes contradictory data regarding the onset of the baroreflex reduction in spontaneously hypertensive rats.

OBJECTIVE:This investigation was undertaken to evaluate the baroreflex function in 13-week-old spontaneously hypertensive rats.

METHODS:Male Wistar Kyoto (n=15) and spontaneously hypertensive rats (n=15) aged 13 weeks were studied. Cannulas were inserted in the abdominal aortic artery through the right femoral artery to measure mean arterial pressure and heart rate. Baroreflex function was calculated as the derivative of the variation of HR in function of the MAP variation (Δheart rate/Δmean arterial pressure) tested with a depressor dose of sodium nitroprusside (50µg/kg) and with a pressor dose of phenylephrine (8µg/kg) in the right femoral venous approach through an inserted cannula in awake spontaneously hypertensive rats and Wistar-Kyoto. Differences with p values < 0.05 were considered statistically significant.

RESULTS:Spontaneously hypertensive rats: Δmean arterial pressure=43.5mmHg±5.2, Δheart rate=-59.7ppm±17.9 and Δheart rate/Δmean arterial pressure=1.3ppm/mmHg±0.1 tested with phenylephrine; Wistar Kyoto: Δmean arterial pressure=&56mmHg±3, Δheart rate=*-114.9ppm±11.3 and Δheart rate/Δmean arterial pressure=#1.9ppm/mmHg±0.3 tested with phenylephrine; spontaneously hypertensive rats: Δmean arterial pressure=-45.6mmHg±8.1, Δheart rate=40.1ppm±11.6 and Δheart rate/Δmean arterial pressure=0.9ppm/mmHg±0.5 tested with sodium nitroprusside; Wistar Kyoto: Δmean arterial pressure=-39.8mmHg±6.2, Δheart rate=51.9ppm±21.8 and Δheart rate/Δmean arterial pressure=1.4ppm/mmHg±0.7 tested with sodium nitroprusside (*p<0.05; #p<0.01; &p<0.001).

CONCLUSION: Our results showed that 13-week-old spontaneously hypertensive rats presented reduced baroreflex function when tested with phenylephrine.

Key words:Hypertension; baroreflex/control; central nervous system; age of onset.

Introduction

Several factors (neural, humoral, myogenic) are involved in the onset of hypertension and different animal models have been used to study this pathology, such as the renal hypertension model, the DOCA-salt hypertension model, the neurogenic hypertension model and the genetic model of hypertension in spontaneously hypertensive rats (SHR). SHR is a suitable model to study hypertension development as it is similar to humans with essential hypertension. These similarities include a genetic predisposition to high blood pressure with no specific etiology, increased total peripheral resistance without volume expansion and similar responses to drug treatment¹.

In cardiovascular physiology, the baroreflex or baroreceptor reflex is one of the body's homeostatic mechanisms to maintain blood pressure. It provides a negative feedback loop in which the elevated blood pressure reflexively causes blood pressure to decrease; similarly, the decreased blood pressure depresses the baroreflex, causing blood pressure to rise. The system relies on specialized neurons (baroreceptors) in the aortic arch, carotid sinuses and elsewhere to monitor changes in blood pressure and relay them to the brainstem. Subsequent changes in blood pressure are mediated by the autonomic nervous system². Previous studies on the development of young SHR baroreflex function have yielded conflicting results, when compared to normotensive rats (Wistar-Kyoto - WKY)³. Morrinson et al⁴ indicated that the baroreceptor function is approximately the same between SHR and WKY aged 15 weeks. However, studies of Lundin et al⁵ showed that SHR of the same age presented reduced baroreflex function. A precise knowledge of early development damage to the baroreflex function is essential to understand hypertension as a disease process^6,7. In view of these contradicting data, we aimed at evaluating baroreflex function in 13-week-old SHR tested with sodium nitroprusside and phenylephrine and verify whether there was a reduction in the baroreflex in SHR at this age.

Methods

Animals

The animals were cared for in compliance with the ''Principles of Laboratory Animal Care'' formulated by the National Institutes of Health (publication no. 96-23, revised, 1996) and were approved by the Animal Ethics Committee of our University (number 1071/06). Experiments were performed on male spontaneously hypertensive rats (SHR) (13 weeks old, 260-300 grams, n=15) and Wistar Kyoto (WKY) rats (13 weeks old, 260-300 grams, n=15) obtained from the Centro de Desenvolvimento de Modelos Experimentais para a Medicina e Biologia (CEDEME). The temperature was maintained at 22ºC, air humidity at nearly 60% and the light-dark cycle was controlled and established as twelve hours each. Animals had free access to food and water.

Arterial pressure recording in awake rats

Under anesthesia with halothane, a polyethylene cannula (PE 10 connected to a PE 50) was inserted into the abdominal aorta through the right femoral artery for the measurement of the mean arterial pressure (MAP) and heart rate (HR). A second cannula was inserted into the femoral vein for drug administration. Both cannulas were tunneled subcutaneously and exposed on the back of the rat to allow access when the animal was conscious. The MAP was measured with a strain gauge transducer (Statham P23Db) connected to a low-level direct-current preamplifier coupled to a polygraph (Beckman model R-611). HR was derived from arterial pressure waves with a cardiotachometer (coupler type 9875B). Studies were performed in conscious rats 24 hours after the surgical procedures, to allow animals to recover from the anesthetic effects. The experiments were initiated approximately 30 minutes after the period of their adaptation to laboratory song and light conditions⁸.

Baroreflex test

The baroreflex was tested with a pressor dose of phenylephrine (PE-bolus-8 µg/kg IV; Sigma Chemical) and depressor doses of sodium nitroprusside (NPNa-bolus-50 µg/kg IV; RBI)⁹. The baroreflex was calculated as the derivation of HR in function of the MAP variation (ΔHR/ΔMAP)¹⁰. There was an interval of at least 15 minutes between the infusions to allow the recovery of basal values.

Statistical analysis

Values are reported as the means ± standard deviation of means. HR, MAP, ΔHR, ΔMAP and ΔHR/ΔMAP were compared between SHR and WKY. After the distributions were evaluated through the Kolmogorov normality test, the Student's T test was used to verify differences between normal distributions and the Mann-Whitney test was used to assess differences between non-parametric distributions. The significance level was set at p<0.05 for all statistical tests.

Results

Body weight was not significantly different between spontaneously hypertensive rats (SHR) (270g±8) and Wistar-Kyoto (WKY) (298g±5) (p>0.05). SHR presented a higher heart rate (HR) (p<0.05) and higher mean arterial pressure (MAP) (p<0.05) (Table 1). According to the literature, the higher MAP and HR in SHR aged 13 weeks were to be expected.

ΔHR (Figure 1A) and ΔMAP (Figure 1B) were significantly different between the groups when baroreflex sensitivity was tested with PE. The variation in cardiovascular parameters were reduced in SHR (ΔHR: p<0.05; ΔMAP: p<0.001). Figure 2A and Figure 2B showed no significant differences between SHR and WKY regarding ΔHR (p>0.05) and ΔMAP (p>0.05) when tested with NPNa. WKY showed higher variations in MAP, while SHR presented higher variations in HR.

Baroreflex function (ΔHR/ΔMAP) was tested with PE and NPNa. A significant difference was observed between the groups, with WKY presenting higher values (p<0.01) (Figure 3A). Moreover, mean values of ΔHR/ΔMAP, when tested with NPNa, were also higher in WKY (p>0.05) (Figure 3B).

Discussion

Our investigation was undertaken to evaluate baroreflex function in 13-week-old spontaneously hypertensive rats (SHR) tested with sodium nitroprusside (NPNa) and phenylephrine (PE) and verify whether there was any difference between this study model and Wistar-Kyoto (WKY) rats of the same age. Our data showed that baroreflex sensitivity, when tested with PE, was decreased in SHR aged 13 weeks. Mean arterial pressure variation (ΔMAP), heart rate variation (ΔHR) and ΔHR/ΔMAP, when tested with PE, were significantly higher in WKY. However, ΔHR and ΔHR/ΔMAP, when tested with NPNa, were not significantly higher in WKY, while SHR showed higher ΔMAP.

The mechanisms that cause the reduction in the baroreflex function in SHR are not completely understood¹¹. Some studies demonstrated that the carotid body in the adult SHR is significantly larger than in normotensive rats^12-14, whereas other studies indicated that the decreased baroreflex function in SHR is due to impaired levels of norephinephrine, epinephrine and dopamine in the carotid body^14-16 and medulla oblongata areas that regulate the cardiovascular system^4,8. Furthermore, there have been reports that AT1 (angiotensin) receptor densities are increased in SHR, compared to the levels found in normotensive control rats^17,18. Rossi et al¹⁹ indicated that endogenous endothelin receptor mechanisms are involved in the hypertensive state observed in SHR. Moreover, recent investigations described the importance of oxidative stress²⁰, nitric oxide²¹ and the small GTPase rho-quinase²² during baroreflex function development in SHR. Bertagnoli et al²⁰ suggested that exercise training reduces oxidative stress, which is associated to an improvement in baroreflex sensitivity in SHR. Waki et al²¹ have shown that endogenous nitric oxide synthase activity in the medulla oblongata of SHR is increased when compared to WKY; it plays a major role in the preservation of the hypertension and decreases the cardiac baroreceptor reflex gain, which are features of this animal model. According to Ito et al²², although the inhibition of endogenous rho-kinase in the medulla oblongata augments the baroreflex control of heart rate in WKY and SHR, it improves the impaired baroreflex function in SHR. Earlier studies that described a significant difference in blood pressure between WKY and SHR at 3/ weeks of age²³ or at birth²⁴ were based on the assessment of a few animals. However, the age at which the baroreflex function starts to decrease in SHR has yet to be demonstrated.

In our findings, SHR presented lower depressor responses with PE, but higher depressor responses with NPNa, when compared to WKY. These contradictory data were unexpected. Gonzalez et al²³ electrically stimulated the aortic nerves of 15-week-old SHR using a wide range of stimulus frequencies. The depressor responses produced by these stimulations were significantly smaller in SHR than those in WKY. It was also reported in the same study that inhibition of the greater splanchnic nerve activity due to aortic nerve stimulation was found to be significantly smaller in SHR than in WKY and control of the sympathetic nerve activity was higher in SHR than in WKY. Judy et al^24,25 assessed the baroreceptor function through the spontaneous variation in MAP and sympathetic nerve activity in SHR and WKY between 5 and 40 weeks of age and verified that young SHR (5 weeks old) presented reduced baroreflex sensitivity. However, HR variation was not evaluated as in the present study.

Ohta et al²⁶ reported alterations in the afferent components of chemoreflex and baroreflex in 15-week-old SHR by aortic depressor nerve stimulation (depressor stimulus) and by carotid sinus nerve stimulation (pressor stimulus). They observed higher depressor responses in WKY and higher pressor responses in SHR. Lee et al²⁷ estimated baroreceptor responses in 6-10 month-old SHR by electrically stimulating the glossopharyngeal nerve and higher depressor responses were observed in SHR; however, bradycardia was reduced in SHR. In this study, our hypothesis was that SHR would present lower depressor and pressor responses; this fact was not observed regarding HR responses to intravenous NPNa. Methodological aspects may explain the differences in results among the aforementioned studies, as they used different procedures to evaluate pressor and depressor responses; moreover, we have not found in the literature any study that evaluated the baroreflex function tested with PE and NPNa in SHR younger than 14 weeks. Perhaps, SHR did not increase their MAP variability, similarly to WKY with PE, due to the fact that they presented high blood pressure.

Our findings showed that male 13-week-old SHR presented decreased baroreflex function. Nevertheless, conflicting data were described in the literature, considering the decreased baroreflex function observed in young SHR when evaluated through sympathetic activity control. Different studies showed that baroreflex function in young SHR is approximately the same as^4,5 or lower than^25,26 the one observed in WKY. The study by Morrinson and Whitehorn⁴ demonstrated that the sympathetic hyper-reactivity in 15-week-old SHR did not correlate with the baroreceptor reflex, which was approximately similar to that of WKY, and they concluded that it could not confirm that the decreased baroreflex function in young SHR was due to their sympathetic hyperreactivity. Ricksten et al²⁸ recorded spontaneous variations in MAP, HR and rectified mean splanchnic nerve activity in conscious undisturbed 15 weeks old WKY and SHR. The variability in MAP was not significantly different, but HR variability tended to be lower in SHR. The variability in splanchnic nerve activity was not significantly different between SHR and WKY. Our data also showed lower HR variability in SHR, but the study by Rickstein et al²⁸ showed that the variability was not tested with drugs. Nagai et al²⁹ compared autonomic activity and baroreflex sensitivity in age-matched conscious groups of WKY and SHR aged 4-14 weeks. They verified that prazosin-sensitive and atropine-sensitive indices were associated with the elevation in blood pressure in both groups as well as that the pressor and depressor responses were not statistically different between SHR and WKY. It is possible that these results do not corroborate our data because different drugs were used.

Despite the fact that WKY presented higher cardiovascular parameter variability when ΔMAP was tested with NPNa, SHR showed higher values than WKY. We have not found any evidence in the literature demonstrating which drug provides more reliable information about the baroreflex function. We believe that PE is a more reliable drug to evaluate baroreflex when compared to NPNa, as the latter causes venodilation and it may influence cardiac input and impair ΔHR, ΔMAP and, consequently, ΔHR/ΔMAP³⁰.

In conclusion, we showed that 13-week-old SHR presented significantly reduced baroreflex when tested with PE.

Authors' contributions

All authors participated in the design of the study and the writing of the manuscript, as well as the approval of the final version of the manuscript.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of doctoral submitted by Vitor E. Valenti, from Universidade Federal de São Paulo - Escola Paulista de Medicina - UNIFESP/EPM.

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Evaluation of baroreflex function in young spontaneously hypertensive rats

Vitor E. Valenti^{I, II}; Celso Ferreira^{I, II}; Adriano Meneghini^II; Marcelo Ferreira^II; Neif Murad^II; Celso Ferreira Filho^{I, II}; João Antônio Correa^II; Luiz Carlos de Abreu^II; Eduardo Colombari^II

Publication Dates

• Publication in this collection
  17 Apr 2009
• Date of issue
  Mar 2009

History

• Received
  11 Jan 2008
• Accepted
  20 Feb 2008
• Reviewed
  08 Feb 2008