Impact of cardiac hypertrophy on arterial and ... - Wiley Online Library

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Exp Physiol 93.9 pp 1058–1064

Experimental Physiology – Research Paper

Impact of cardiac hypertrophy on arterial and cardiopulmonary baroreflex control of renal sympathetic nerve activity in anaesthetized rats Evelyn T. Flanagan1 , Maria M. Buckley1 , Claire M. Aherne1 , Fredolin Lainis1 , Munavvar Sattar2 and Edward J. Johns1 1 2

Department of Physiology, University College Cork, Cork, Republic of Ireland School of Pharmacy, Universiti Sains Malaysia, Penang, Malaysia

This study aimed to quantify the effect of cardiac hypertrophy induced with isoprenaline and caffeine on reflex regulation of renal sympathetic nerve activity by the arterial and cardiopulmonary baroreceptors. Male Wistar rats, untreated or given water containing caffeine and subcutaneous (s.c.) isoprenaline every 72 h for 2 weeks or thyroxine s.c. for 7 days, were anaesthetized and prepared for measurement of renal sympathetic nerve activity or cardiac indices. Both isoprenaline–caffeine and thyroxine treatment blunted weight gain but increased heart weight and heart weight to body weight ratio by 40 and 14% (both P < 0.01), respectively. In the isoprenaline–caffeine group, the maximal rate of change of left ventricular pressure and the contractility index were higher by 17 and 14% (both P < 0.01), respectively, compared with untreated rats. In the isoprenaline–caffeine-treated rats, baroreflex gain curve sensitivity was depressed by approximately 30% (P < 0/05), while the mid-point blood pressure was lower, by 15% (P < 0/05), and the range of the curve was 60% (P < 0.05) greater than in the untreated rats. An acute intravenous infusion of a saline load decreased renal sympathetic nerve activity by 42% (P < 0.05) in the untreated rats but had no effect in the isoprenaline–caffeine- or the thyroxinetreated groups. The isoprenaline–caffeine treatment induced cardiac hypertrophy with raised cardiac performance and an associated depression in the reflex regulation of renal sympathetic nerve activity by both high- and low-pressure baroreceptors. The thyroxine-induced cardiac hypertrophy also blunted the low-pressure baroreceptor-mediated renal sympatho-inhibition. These findings demonstrate that in cardiac hypertrophy without impaired cardiac function, there is a blunted baroreceptor control of renal sympathetic outflow. (Received 10 May 2008; accepted after revision 15 May 2008; first published online 16 May 2008) Corresponding author E. J. Johns: Department of Physiology, Aras Windle, University College Cork, Western Road, Cork, Republic of Ireland. Email: [email protected]

Cardiac hypertrophy involves a process of remodelling of ventricular muscle, which at a certain stage may result in a deterioration in cardiac performance and progression into heart failure (Kannel, 2000). One of the consequences of a depressed cardiac output is a reflex activation of the sympathetic nervous system (Zucker et al. 2004), which exacerbates the load on the heart. What has not been investigated in depth is whether in the initial stages of hypertrophy there might already be a derangement in the reflex regulation of the sympathetic nervous system. There is a body of evidence which has demonstrated that cardiac hypertrophy and damage can be induced DOI: 10.1113/expphysiol.2008.043216

experimentally following the chronic administration of isoprenaline alone (Teerlink et al. 1994; Leenen et al. 2001; Kitagawa et al. 2004) or in combination with caffeine (Heap et al. 1996). Activation of β-adrenoceptors initiates a protein kinase signalling cascade (Zou et al. 2001) and also involves the mitogen activated protein (MAP) kinase and Wnt signalling pathways (Akazawa & Komuro, 2003). The subsequent cellular response has been found to cause an upregulation and activation of the microphthalmia transcription factor (Tshori et al. 2006), the local generation of ventricular angiotensin II (Nagano et al. 1992), an increase in circulating angiotensin II (Leenen C 2008 The Authors. Journal compilation C 2008 The Physiological Society


Baroreflexes in cardiac hypertrophy

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et al. 2001) and an activation of the ventricular Na+ –H+ exchanger (Ennis et al. 2003), all of which may contribute to ventricular myocyte hypertrophy. By contrast, relatively little is known of how the isoprenaline–caffeine-mediated structural changes may impact on cardiac function and whether this may cause potential derangements in basal and reflex regulation of the sympathetic nervous system. Indeed, it is this latter regulatory system with its impact on the neural control of the kidney together with the subsequent aldosterone secretion which becomes key in initiating the fluid retention associated with cardiac failure. There are both chemo- and mechanoreceptors embedded in the walls of the atria and ventricles of the heart, which sense the volume contained within the chambers (Hainsworth, 1991). The sensory information that arises from the cardiopulmonary area passes via the vagus nerve to centres in the medulla and brainstem which determine parasympathetic and sympathetic outflow (Coote, 2007). The possibility arises that, as cardiac hypertrophy occurs, the ability of these receptors to respond to differing levels of fluid contained within the circulatory system may be impaired. Furthermore, the sensitivity of the arterial baroreceptors and their ability to regulate renal sympathetic outflow may also be deranged. Indeed, there has been a report (Gava et al. 2004) that in mice treated chronically with isoprenaline, the sensitivity of the high-pressure baroreceptor control of heart rate was depressed. The question remains of whether other aspects of autonomic control might be defective following isoprenaline-induced cardiac hypertrophy. It was hypothesized that cardiac hypertrophy caused by isoprenaline treatment would impair the reflex regulation of renal sympathetic nerve activity following reflex activation of the arterial and cardiopulmonary baroreceptors. This was investigated by undertaking an evaluation of the baroreflex gain regulation of renal sympathetic nerve activity and the ability of an acute saline volume expansion to cause a reflex renal sympathoinhibition. In order to clarify the possible confounding issue of a drug-induced impact on the reflex regulation of renal sympathetic nerve activity, cardiac hypertrophy was also induced using chronic thyroxine administration.

water containing caffeine, at 62 mg ml−1 , and were injected with isoprenaline (5 mg kg−1 , S.C.) every 72 h for 2 weeks (Heap et al. 1996); or were given S.C. injections of thyroxine, at 1 mg kg−1 (Hu et al. 2003), each day for 7 days.

Methods

Rats were anaesthetized as above with femoral artery and vein cannulated for blood pressure monitoring and saline infusion. A Millar catheter with a high-fidelity pressure sensor designed for the rat (Model SPR-320, size 2F, Millar Instruments Inc., Houston TX, USA) was inserted into the right carotid artery and passed into the left ventricle. Insertion of a catheter of this size into the left ventricle has been shown previously (Wang et al. 2005) to have minimal impact on basal cardiac function. The animals were allowed to stabilize for 1.5– 2.0 h before measurements were taken. Baseline recordings

Male Wistar rats, weighing 220–260 g, were either bred inhouse or purchased from commercial suppliers (Harlan, Bicester, UK) and maintained under a 12 h–12 h light– dark regime at 20 ± 3◦ C and 35% humidity. All procedures were performed in accordance with European Community Directive 86/609/EC and with the approval of the local Animal Experimentation Ethical Committee at University College Cork. Groups of rats were maintained on a normal diet and tap water; or received a normal diet but drinking C 2008 The Authors. Journal compilation C 2008 The Physiological Society

General preparations

All rats had their food restricted overnight prior to the study but had access to water. The animals were prepared for measurement of renal sympathetic nerve activity, as described previously (Zhang et al. 1997; Huang & Johns, 2001), and cardiac indices (Wang et al. 2005). Briefly, the rats were anaesthetized by the administration of 1 ml (I.P.) of a chloralose–urethrane mixture (16.5 and 250 mg ml−1 , respectively) and maintained with supplemental doses of 0.05 ml every 30 min. Cannulae (Portex polypropylene, outer diameter, 0.96 mm) were inserted into the right femoral artery, to monitor blood pressure and heart rate, and into the right femoral vein for the infusion of sustaining saline (3 ml h−1 of NaCl, 9 g l−1 ). A catheter was inserted into the bladder (Portex polypropylene, outer diameter, 1.57 mm) to allow urine to drain. The left kidney was exposed via a flank incision, the renal sympathetic nerves were isolated, cleared of connective tissue, placed on bipolar stainless-steel recording electrodes and sealed into place with dental glue (Zhang et al. 1997). The animals were allowed 2 h to stabilize from the surgical preparation. Blood pressure was monitored using a pressure transducer (Spectromed, Oxnard, CA, USA) and an amplifier (Grayden Electronics, Birmingham, UK). Renal sympathetic nerve activity was amplified with a gain of 100 000 and high- and low-pass filters set at 2 and 0.2 kHz, respectively. The blood pressure and renal sympathetic nerve signals were distributed into an audio amplifier and onto the monitor screen of the computer (Zhang et al. 1997). The signals were digitized to enable generation of a mean blood pressure and integrated renal sympathetic nerve activity, which were stored onto the hard disc every 1 s and used in later off-line analysis using LabVIEW software (National Instruments, Austin, TX, USA). Cardiac function

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Table 1. Comparison of basal characteristics of control rats with those treated with isoprenaline and caffeine for 2 weeks or thyroxine for 1 week Control (n = 7) Body weight before treatment (g) Body weight following treatment (g) Weight gained (g) Heart weight (mg) Heart weight/body weight ratio (× 10−3 ) ∗P

Caffeine and isoprenaline treatment (n = 8)

208 ± 3 233 ± 6 25 ± 4 674 ± 20 2.87 ± 0.05

218 ± 2 224 ± 5 5 ± 2∗∗ 958 ± 50∗∗ 4.01 ± 0.13∗∗

Thyroxine treatment (n = 7) 257 ± 10 270 ± 8 13 ± 2.3∗ 880 ± 62∗ 3.26 ± 0.17∗∗

< 0.05 and ∗∗ P < 0.001, isoprenaline/caffeine or thyroxine treated versus normal.

of blood pressure, heart rate, maximal rate of change in left ventricular pressure (dP/dt max ) and contractility index were taken over 10 min. The dP/dt max is a measure of the initial velocity of ventricular contraction, while contractility index represents the change in left ventricular pressure as a function of time and is taken as the slope of the waveform over the whole of systole. Signals from the blood pressure transducer and Millar catheter were amplified using a Powerlab (ADInstruments, Chalgrove, UK) and recorded on a computer for later off-line analysis. Baroreflex gain curves

Baroreflex control of sympathetic nerve activity was assessed as previously described (Huang et al. 2006) by administration of I.V. doses of phenylephrine and nitroprusside (10 μg in a volume of 0.2 ml for each) which was then flushed in with a saline infusion at 18 ml h−1 over 40 s and resulted in a 50–60 mmHg increase or decrease in blood pressure, respectively. It was then possible to generate a dynamic baroreflex gain curve by plotting the change in blood pressure against that for renal sympathetic nerve activity. The baseline value of renal sympathetic nerve activity was that measured over the 5 min prior to the first injection of phenylephrine or nitroprusside, and was taken as 100%, and all other readings were expressed as a percentage of these values. A four-parameter logistic equation (Kent et al. 1972) was used to generate sigmoidal baroreflex gain curves in which the average values for renal sympathetic nerve activity were calculated for each 5 mmHg change in blood pressure using the 1 s data stored on the hard drive (Huang et al. 2006). Calculations were then performed to determine the range (A1) over which baroreceptor control operated, the maximal slope or sensitivity of the relationship (A2), the mid-range mean blood pressure of the curve (A3) and the lowest point to which renal sympathetic nerve activity could be suppressed (A4). Volume expansion

Following the period of stabilization, a 5 min control value of blood pressure and integrated renal sympathetic

nerve activity was recorded. This basal value of renal sympathetic nerve activity was taken as 100% and at each time point the percentage reduction from the basal value was calculated. A volume expansion challenge was then performed whereby saline was infused via the femoral vein at a rate of 0.25% body weight per minute for 30 min, during which data were collected continuously. In the later off-line analysis, the mean value over each 5 min block of time was determined. A recovery period of 30 min was allowed in order for variables to return to baseline levels. At the end of the experiment, the animals were heparinized (200 units per rat) and killed with an overdose of anaesthetic given I.V. Twenty minutes later, a background level of renal sympathetic nerve activity was measured and the hearts removed, drained of blood, dried and weighed. The background level of renal sympathetic nerve activity was removed from all readings taken in the acute experiments for the generation of the baroreflex gain curves and the volume expansion studies. Statistics

A comparison of means between groups was performed using one-way ANOVA and paired and unpaired Student’s t test when appropriate. The profile of the responses during volume expansion was compared using two-way repeated measures ANOVA (Sigma Stat, San Jose, CA, USA). Significance was taken when P < 0.05. Results General

The effect of the isoprenaline and caffeine treatment on body weight gain, heart weight and heart weight to body weight ratio is shown in Table 1. It can be seen that although there were slight differences in the starting weights of the two groups of rats, the gain in weight over the 2 week period was significantly (P < 0.05) less in the group treated with isoprenaline and caffeine than the group maintained on a regular diet. Table 1 also shows that both heart weights and heart weight to body weight ratios were significantly (P < 0.01 to 0.001) higher in the treated compared with the control rats. The C 2008 The Authors. Journal compilation C 2008 The Physiological Society



Table 2. Comparison of cardiac characteristics of control rats with those treated with isoprenaline and caffeine for 2 weeks

Blood pressure (mmHg) Heart rate (beats min−1 ) dP/dt max (mmHg s−1 × 10−3 ) Contractility index (1/s) ∗P

Control (n = 9)

Heart hypertrophy (n = 7)

102 ± 7 460 ± 22 10.59 ± 0.78 156 ± 7

104 ± 8 453 ± 16 12.43 ± 0.56∗ 178 ± 9∗

< 0.01 compared with control group.

thyroxine administration (Table 1) resulted in a significant (P < 0.05) reduction in weight gain over the 1 week treatment period, at which time both heart weight and heart weight to body weight ratios were significantly (P < 0.01 and P < 0.05, respectively) higher compared with the untreated group of rats. Cardiac function

A second group of control and isoprenaline–caffeinetreated rats was used to evaluate cardiac function, and the data are presented in Table 2. It can be seen that blood pressures and heart rates were not different in the control and isoprenaline–caffeine groups. In terms of cardiac function, dP/dt max and contractility index were both significantly (P < 0.01) elevated, by 17 and 14% respectively, following the 2 weeks of treatment with isoprenaline and caffeine. Baroreflex studies

A further group of control rats was used in this study and had basal blood pressures and heart rates of 103 ± 2 mmHg 430 ± 33 beats min−1 , while in the isoprenaline–caffeine-treated group these values were 94 ± 4 mmHg and 388 ± 15 beats min−1 , respectively, and not significantly different from each other. Basal integrated renal sympathetic nerve activity, at 6.75 ± 0.80 μV s−1 in control rats and 7.66 ± 0.96 μV s−1 in the isoprenaline– caffeine-treated group, were not different in the two groups. Figure 1 shows the overall baroreflex gain curves for renal sympathetic nerve activity for the control and isoprenaline–caffeine groups of rats, and it can be seen that in the treated rats the curve was shifted upwards and to the left with a lower slope. This was reflected in the algorithm parameters, in that the range of the baroreflex curve (A1) for renal sympathetic nerve activity was similar in both treated and control groups of rats, at 93 ± 1 versus 96 ± 1 μV s−1 , but that the sensitivity of the relationship (A2) was lower in the treated than the control rats, at 0.14 ± 0.02 versus 0.20 ± 0.03 μV s−1 mmHg−1 (P < 0.05), as was the mid-point blood pressure (A3), 96 ± 5 versus 113 ± 2 mmHg (P < 0.05). Conversely, the minimal value of the curve (A4) was higher in the C 2008 The Authors. Journal compilation C 2008 The Physiological Society

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treated compared with the control rats, 54 ± 7 versus 33 ± 2 μV s−1 (P < 0.05). Volume expansion study

Another three groups of rats were used for this study, and the blood pressures and heart rates following surgery and the recovery period in the control, isoprenaline–caffeine and thyroxine groups were not significantly different, at 86 ± 4, 97 ± 4 and 87 ± 4 mmHg and 407 ± 10, 389 ± 16 and 387 ± 23 beats min−1 , respectively. Infusion of the saline load had no effect on blood pressure but significantly depressed heart rate by some 7% in all groups (P < 0.05). It can be seen in Fig. 2 that at the end of the 30 min period of volume expansion, renal sympathetic nerve activity was depressed by 42% (P < 0.05) in the control group of rats. By contrast, in the isoprenaline- and caffeine-treated rats at the end of the 30 min period of volume expansion, renal sympathetic nerve activity showed a small, but not statistically significant, rise of some 15%, while in the thyroxine-treated rats it did not change. The magnitude of the reduction in renal sympathetic nerve activity in the control group of rats was statistically different (P < 0.05) from that of the isoprenaline–caffeine- and thyroxinetreated rats. Discussion

The primary objective of this study was to evaluate the change in responsiveness of renal sympathetic nerve activity to baroreceptor-mediated regulation when heart hypertrophy was induced by administration of isoprenaline and caffeine. Isoprenaline administration was

Figure 1. Baroreceptor gain curves are shown for a control group of rats (n = 10) and for a group of isoprenaline- and caffeine-treated rats with cardiac hypertrophy (n = 10) The curve is shifted to the left and upwards with a greater range in the isoprenaline–caffeine-treated rats. RSNA, renal sympathetic nerve activity.

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used because it has been shown in previous studies to cause hypertrophy and remodelling of ventricular myocytes, when given either alone or with caffeine (Teerlink et al. 1994; Heap et al. 1996; Leenen et al. 2001; Ennis et al. 2003). In the present study, this treatment was clearly effective in causing cardiac hypertrophy, since not only was heart weight greater in absolute terms in the isoprenaline- and caffeine-treated rats but it was also raised as reflected by the heart weight to body weight ratio. Total heart weight was measured in this instance with no distinction being made between ventricles and atria, although previous reports indicate that the increase in mass takes place primarily in the ventricles (Leenen et al. 2001). The findings of the present investigation are comparable to those reported in the mouse, in which cardiac hypertrophy was observed, and in the rat when the β 2 -adrenoceptor agonist clenbuterol was given (Burniston et al. 2002). It was evident that with the development of cardiac hypertrophy there was an elevation in both dP/dt max and contractility index compatible with enhanced performance, suggesting that the workload of the heart had been raised by this treatment. The underlying causes of the heart hypertrophy are unclear, but a number of conflicting factors will come into play as a consequence of chronic β-adrenoceptor

Figure 2. A comparison of the magnitudes of the renal sympatho-inhibition induced by an acute saline volume expansion in normal, isoprenaline/caffeine and thyroxine treated rats This graph demonstrates that there was a decrease in renal sympathetic nerve activity (RSNA) in control rats from the basal value taken as 100% (filled bars; n = 6) following 30 min of saline volume expansion (open bars; n = 6), whereas in the isoprenaline- and caffeine-treated (I/CHH) and thyroxine-treated rats (THH) renal sympathetic nerve activity did not change in response to the 30 min saline volume expansion.


stimulation. There would be a decreased afterload owing to peripheral vasodilatation induced by stimulation of β 2 adrenoceptors. In contrast, it would have been expected that β 1 -adrenoceptor activation would have raised heart rate, but this was not the case in the chronic state and, indeed, heart rate tended to be lower in most groups, as had been reported previously in the rat (Heap et al. 1996) and in the mouse treated chronically with isoprenaline (Gava et al. 2004). It is also likely that the isoprenaline– caffeine treatment would have stimulated renin release, hence production of plasma angiotensin II, which would also have contributed to the cardiac hypertrophy (Leenen et al. 2001). Interestingly, although the starting weights of the control and isoprenaline–caffeine groups were the same, the weight gain over the 2 week period in the latter group was minimal. This was probably due either to an increased energy usage by the cardiac muscle or to the direct catabolic action of the catecholamine on skeletal muscle tissue (Burniston et al. 2002). The baroreflex gain curve for renal sympathetic nerve activity in the isoprenaline–caffeine-treated rats was distinctly different from the control rats, indicating that important changes had taken place. An essential feature was that the maximal slope or sensitivity (A2) of the curve was reduced in the cardiac hypertrophy group, which indicated that mechanisms had come into play to blunt the impact of sensory input from the carotid sinus/aortic arch baroreceptors in exerting a normal reflex regulation of sympathetic outflow to the kidney. It was further apparent from the baroreflex gain curves for renal sympathetic nerve activity that the baroreflex operated over a wider range of blood pressure and with a lower operating mid-point compared with the control rats. These particular changes, together with the decrease in maximal sensitivity of the curve, indicate that the baroreflex operates in a very different way under these conditions of cardiac hypertrophy. Interestingly, in the mice with isoprenaline–caffeine-induced cardiac hypertrophy, the heart rate baroreflex gain curves were depressed, although in this case the gain curve would also include a contribution from the parasympathetic nervous system. The underlying causes are unclear, but one possibility is a change in cardiac afferent input impinging on the high pressure baroreceptor control of sympathetic outflow. The acute saline volume expansion protocol was comparable to that reported previously by this group using anaesthetized rats and a similar rate of saline infusion (Wongmekiat & Johns, 2003) and caused a reflex renal sympatho-inhibition of similar magnitude (Wong & Johns, 1999). The underlying mechanism was most probably the raised volume in the low-pressure system stimulating stretch receptors in the cardiopulmonary area as shown by (Hainsworth, 1991) in the dog and (Lovick et al. 1993) in the rat, to initiate a reflex suppression C 2008 The Authors. Journal compilation C 2008 The Physiological Society



of sympathetic outflow to the kidney. However, in the heart hypertrophy groups the acute volume expansion failed to suppress renal sympathetic nerve activity, which remained at, or slightly above, the basal level. The reason for the blockade of this reflex is unclear, but there are reports (Kent et al. 1972; Veelken et al. 1996) that activation of 5-HT 3 receptors in the heart attenuates the normal volume expansion-mediated suppression of renal sympathetic nerve activity. This would indicate that inappropriate stimulation of the receptors in the heart or pulmonary region could modify the sensitivity of the cardiopulmonary receptors to respond to acute changes in volume within the circulatory system. It may well be that a similar situation pertains in the present study, in that in the heart hypertrophy group, an inappropriate basal sensory input prevents further response to the saline load. There have been reports in rat models of low-output cardiac failure, following coronary artery ligation (DiBona & Sawin, 1994; Patel, 2000) and, indeed, in man in the early stages of heart failure (Modesti et al. 2004) that there was an inability to suppress renal sympathetic outflow in response to a saline load. The observations of the present study would suggest that the failure of the cardiopulmonary reflex to respond to changes in volume occurs even before there is an overt deficit in cardiac performance. One concern of the present model was that isoprenaline or caffeine alone or in combination was the cause of the deranged baroreflex control rather than the cardiac hypertrophy itself. This was tested using an alternative approach, in which thyroxine was administered over a period of 1 week and its impact on the renal sympathoinhibition was examined in response to an acute saline volume expansion. It was evident that the thyroxine treatment depressed weight gain and increased heart weight and heart weight to body weight ratio, indicative of cardiac hypertrophy. These cardiac changes are most probably due to an action of thyroxine on cardiac remodelling and an increase in β-adrenoceptors in the heart (Hu et al. 2003). In these conditions, the acute saline volume expansion challenge failed to elicit a renal sympatho-inhibition, which was very comparable to that observed in the isoprenaline- and caffeine-induced cardiac hypertrophy model. These findings strongly support the contention that it is the hypertrophy rather than the drug treatment that is an important causal factor in determining the integrity of the reflex. The question arises as to the site of the deficits in the reflex regulation of renal sympathetic nerve activity as a consequence of the heart hypertrophy; whether it occurs along the efferent, central or efferent pathways or at all levels. A key nucleus within the brain involved in mediating the renal sympatho-inhibition to an acute volume load is the paraventricular nucleus (PVN; Coote, 2005). In coronary artery ligation models of cardiac C 2008 The Authors. Journal compilation C 2008 The Physiological Society

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failure, there is a raised sympathetic drive originating from raised activity within the parvocellular neurons of the PVN, which seems to result from an attenuation of the inhibitory action of endogenous GABA (Zhang et al. 2002). Moreover, it would seem that there are other neurotransmitters and neuromodulators, such as nitric oxide and angiotensin II, which act at the PVN and along the efferent pathways, whose function is deranged in cardiac failure (Zucker & Wang, 1991; Weiss et al. 2003) and contributes to the blunting of the renal sympathoinhibition during volume expansion. Whilst a major focus has been the deficits in baroreceptor reflex regulation of renal sympathetic nerve activity, it is also apparent that the ability of the somatosensory system to initiate a sympatho-excitation is also blunted in cardiac failure induced by cardiac pacing in dogs (O’Leary, 2006). There is also evidence that sensory information arising from the cardiac receptors themselves is defective in paced dogs with congestive heart failure (Greenberg et al. 1973; Zucker et al. 1977) and may occur before a decrease in cardiac function takes place. The present study was not designed to investigate the site or sites where deficits arose, but it is likely that there will be deficiencies along all parts of the reflex. This investigation set out to define the effect of a 2 week period of isoprenaline and caffeine treatment to induce a cardiac hypertrophy on the high- and lowpressure baroreflex regulation of renal sympathetic nerve activity. The hypertrophy was associated with enhanced indices of cardiac performance. However, the sensitivity of the baroreflex gain curve for renal sympathetic nerve was reduced, while the acute saline volume expansionmediated reflex renal sympatho-inhibition was absent in the isoprenaline- and caffeine-treated rats. Moreover, cardiac hypertrophy induced by chronic thyroxine admininstration also resulted in a blockade of the renal sympatho-inhibition in response to the acute saline volume expansion challenge. Together, these observations indicate that during the initial phase of cardiac hypertrophy, and before a decrease in cardiac function becomes apparent, there are marked deficiencies in the reflex regulation of sympathetic outflow to the kidney. References Akazawa H & Komuro I (2003). Roles of cardiac transcription factors in cardiac hypertrophy. Circ Res 92, 1079–1088. Burniston JG, Ng Y, Clark WA, Colyer J, Tan LB & Goldspink DF (2002). Myotoxic effects of clenbuterol in the rat heart and soleus muscle. J Appl Physiol 93, 1824–1832. Coote JH (2005). A role for the paraventricular nucleus of the hypothalamus in the autonomic control of heart and kidney. Exp Physiol 90, 169–173. Coote JH (2007). Landmarks in understanding the central nervous control of the cardiovascular system. Exp Physiol 92, 3–18.

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Acknowledgements F.L. was in receipt of a Health Research Board Summer Scholarship. C 2008 The Authors. Journal compilation C 2008 The Physiological Society