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Howard Florey Institute, University of Melbourne, Victoria 3010, Australia
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Abstract |
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5 s) in blood pressure after bolus doses of methoxamine or vehicle in conscious, chronically instrumented rats during infusions of ANP (50 pmol kg–1 min–1). Compared with uninephrectomised control rats (n= 10), rats with 1K-1C had cardiac hypertrophy (55% increase in left ventricle:body weight (LV:BW) ratio; P < 0.05) and blunted vagal baroreflex gain (–0.93 ± 0.18 versus–0.50 ± 0.13 beats min–1 mmHg–1; P < 0.05). ANP did not augment baroreflex function in 1K-1C. Compared with their sedentary controls (n= 7), exercise-trained rats with cardiac hypertrophy (20% increase LV:BW ratio; P < 0.05) also had blunted ramp baroreflex bradycardia (–1.28 ± 0.23 versus–0.57 ± 0.09 beats min–1 mmHg–1; P < 0.05). In contrast, ANP more than doubled baroreflex bradycardia in exercise-trained rats (P < 0.05). The aetiology of cardiac hypertrophy therefore influenced whether ANP retained its vagal baroreflex enhancing properties.
(Received 2 March 2004;
accepted after revision 27 April 2004; first published online 6 May 2004)
Corresponding author R. L. Woods: Howard Florey Institute, University of Melbourne, Victoria 3010, Australia. Email: r.woods{at}hfi.unimelb.edu.au
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Introduction |
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8% increase in LV:BW ratio) (Thomas et al. 1998). In these rats with modest hypertrophy but no hypertension, the cardiac reflex actions of ANP were absent. The ability of ANP to enhance cardiac vagal reflex function in SHRs was therefore linked not to the blood pressure per se, but to the extent of cardiac hypertrophy. It remained to be established whether (i) the link between ANP and hypertension-induced cardiac hypertrophy is exclusively dependent on inherited features of the SHR, and (ii) the link reflects a conserved feature of cardiac hypertrophy regardless of its aetiology (e.g. physiological versus pathological). The major aim of the present study was to determine whether ANP enhances cardiac vagal baroreflexes in two models of non-genetic cardiac hypertrophy: renovascular hypertension (1K-1C) and chronic, voluntary exercise training.
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Methods |
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1K-1C surgery
Surgery was performed as previously described (Woods & Johnston, 1982). Rats at 6 weeks of age (n= 20, 183 ± 9 g) were anaesthetized with methohexitone sodium (Eli Lilly, West Ryde, Australia; 40 mg kg–1), atropine sulphate (Astra, West Ryde, Australia; 0.5 mg kg–1) and sodium pentobarbitone (Nembutal, Boehringer Ingelheim, Artarmon, Australia; 30 mg kg–1) injected intraperitoneally. Through a flank incision (retroperitoneal approach) one kidney was removed (n= 20). In 10 rats (1K-1C), a silver clip (i.d., 0.20–0.25 mm) was placed around the contralateral renal artery. In the other 10 rats (uninephrectomised controls), the contralateral renal artery was exposed but not clipped. Buprenorphin (Temgesic; 0.1 mg kg–1, I.M., Rickitt and Colman Pharmaceuticals) was given postoperatively for pain relief. Further surgery was performed to insert femoral catheters (see below) after 4–6 weeks. Of the 10 1K-1C rats, only six remained in the study; one rat did not become hypertensive (mean arterial pressure (MAP) of less than 130 mmHg), one died of malignant hypertension, and femoral catheters failed in two further 1K-1C rats.
Chronic exercise-training
One group of rats (n= 13; initial body weights, 136 ± 5 g) had access to a free-spinning, exercise wheel in their home cages for 10–12 weeks. Age-matched controls (n= 7; body weight, 138 ± 6 g) were housed individually in normal cages for the same 10–12-week period. Body weight was recorded at the end of each week, and distance ran was recorded daily. After the 10–12 weeks, all rats underwent femoral catheterization.
Femoral catheterization
Rats were anaesthetized with methohexitone, atropine sulphate and sodium pentobarbitone as above. The femoral vessels were cleared distal to the profunda femoris, taking care not to damage the nerve. After tying the femoral vein distally, a polyethylene triple lumen catheter (o.d., 1.5 mm; i.d., 0.5 mm; Critchley Electrical Products, Auburn, NSW, Australia), which was filled with 0.9% saline, was inserted and tied securely into the femoral vein. This catheter enabled independent administration of vasoactive drugs, ANP or vehicle without the need to flush the catheter, thereby reducing volume load. The femoral artery was ligated distal to the insertion site and a Teflon-tipped single-lumen polyethylene catheter for measurement of arterial pressure (o.d., 0.45 mm; i.d., 0.3 mm; Small Parts, Miami, FL, USA) was inserted, threaded towards the abdominal aorta, and secured into the artery distal to the profunda femoris branch. Both cannulae were looped in the leg, passed superficially under the skin and exteriorized at the back of the neck. Tips of the catheters were occluded with pins. All lines were filled with heparinized saline (100 U in 0.9% saline). Neosporin antibiotic ointment (Glaxo Wellcome Ltd, Boronia, Australia) was applied to all incision wounds. Buprenorphine was administered postoperatively for pain relief. In a small number of rats (< 10%), femoral catheterization caused limb ischaemia and these animals were killed immediately by barbituate overdose and their data was not included. For all rats included in the present study, femoral catheterization did not cause obvious claudication of the limb, as assessed by a warm foot, normal retraction to foot pinch, and lack of signs of ischaemia such as limping or dragging of the limb.
Baroreflex tests
At least two days were allowed for postoperative recovery from cannulation before the first experiment. At the start of each experiment, the arterial catheter was connected to a transducer (Cobe transducer; Lakewood, CO, USA) and heart rate (HR) was measured using a tachograph (Baker Institute, Melbourne, Australia), triggered from the phasic blood pressure signal. Arterial blood pressure and HR were simultaneously recorded at a sampling rate of 200 Hz, using the AcqKnowledge data acquisition system (Biopac Systems, Goleta, CA, USA) connected to a Pentium computer. Venous catheters were filled with the appropriate drug solutions and the rat then left for at least 30 min to obtain a stable blood pressure and HR. Baroreflexes were measured using ‘ramp’ and ‘steady-state’ baroreflex methods (Woods et al. 1994; Thomas et al. 1997, 1998, 2002; Thomas & Woods, 2003), with or without ANP infusion (50 pmol kg–1 min–1). The ramp and steady-state reflexes were measured on separate days. The order of baroreflex tests and ANP or vehicle infusions was randomized between animals. For technical reasons, not all rats had both sets of reflex measurements completed (i.e. 2 days); however only data for each reflex test with matching saline vehicle and ANP infusion experiments have been included.
Ramp baroreflex, with a high proportion of non-arterial (cardiac) high pressure receptor input
This technique (Faris et al. 1980; Thomas et al. 2002) involved a rapid bolus injection of methoxamine (50–100 µg kg–1) to elicit a quick rise in arterial pressure (usually > 20 mmHg s–1) and rapid fall in HR. When arterial pressure had peaked, sodium nitroprusside (50 µg kg–1) was administered to cause blood pressure to return quickly to normal. A recovery period of 5–15 min was then allowed before any repeat test. At least six ramp tests were performed on each animal, equal numbers with and without ANP. For each ramp test, beat-by-beat HR was plotted against the corresponding beat-by-beat MAP (Woods et al. 1994; Thomas et al. 1997, 1998, 2002; Thomas & Woods, 2003). Blood pressure versus HR data were then plotted for all beats between 5 and 45 mmHg above resting blood pressure levels. The slope of each regression line equals the gain of that ramp test. Exceptions to the 45 mmHg maximum were the 1K-1C hypertensive rats, in which the methoxamine-induced rises in blood pressure were smaller than in other groups. For these, the values were taken between 5 and 35 mmHg above baseline. Resting MAP and HR were measured on each day prior to ramp testing.
Steady-state baroreflex, reflecting predominantly arterial baroreceptor activation
As described previously (Korner et al. 1972; Faris et al. 1980; Thomas et al. 2002), HR responses to changes in blood pressure were determined by slowly administered i.v. doses (over 10–15 s) of a pressor agent (methoxamine, 1–100 µg kg–1) alternated with a depressor agent (nitroprusside, 1–50 µg kg–1). The HR response was measured when the change in blood pressure reached steady-state 15–20 s after injection. The steady-state changes in MAP and HR were fitted to a sigmoid logistic equation: HR = P1 + P2/[1 + eP3(MAP–P4).], where P1 is the lower HR plateau, P2 is the HR range, P3 is a curvature coefficient and P4 is the MAP at the mid-point of the HR range (or BP50). The normalized (or range-dependent) gain =–P2 x P3/4.56. Usually 12 points were used to construct the steady-state curve, and changes in MAP were in the order of ± 50–60 mmHg.
Cardiac hypertrophy measurements
At the end of all experiments, rats were killed by barbiturate overdose (Euthatal, pentobarbitone sodium 350 mg ml–1, i.v., Rhone Merieus) and the heart was excised via a midline incision and placed in 0.9% saline. Hearts were trimmed of extraneous tissue and squeezed to remove any blood before being rolled dry and weighed. The left ventricle plus septum were dissected and weighed for measurement of left ventricular (LV) weight and the data were expressed as a ratio to body weight (BW).
Statistical analysis
The primary hypothesis tested in all experiments was that ANP enhanced baroreflex activity. This was done by within-animal comparison. For statistical analyses on repeated ramp tests, made during both ANP and vehicle (saline) infusions in each animal, two-way analysis of variance with repeated measures was used. Effects of ANP on resting values prior to ramp tests, and on all parameters in the steady-state baroreflex measurements, were determined by paired t test. Between-group comparisons (i.e. uninephrectomised control versus 1K-1C or sedentary versus exercise-trained) were made with unpaired t tests, using a Bonferroni adjustment for multiple comparisons where a data set was used more than once. All data are represented as mean ±S.E.M. P < 0.05 was considered significant.
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Results |
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MAP was elevated in the 1K-1C hypertensive rats by 50–70 mmHg (n= 6, P < 0.05; Table 1) compared with uninephrectomised controls (n= 10), whereas HR (Table 1) and body weight (303 ± 8 g versus 310 ± 5 g, respectively) were not. The LV weights (1.07 ± 0.05 g) of 1K-1C rats were 50% higher than in the uninephrectomised control rats (0.71 ± 0.02 g) and the values of LV:BW ratio were 55% higher in the 1K-1C rats (3.55 ± 0.17 versus 2.28 ± 0.06 mg g–1, P < 0.05 for all comparisons; Fig. 1).
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The exercise-trained rats (n= 7) ran an average distance of 9.0 ± 0.6 km per day over 10–12 weeks and their body weights (306 ± 7 g) were lower than the sedentary controls (n= 7; 346 ± 12 g, P < 0.05). The mean LV:BW ratio of the exercise-trained group (2.77 ± 0.07 mg g–1) was 22% higher than that of the sedentary controls (2.27 ± 0.04 mg g–1, P < 0.05; Fig. 1). The absolute LV weights of exercise-trained rats (0.85 ± 0.02 g) were not significantly greater than those of sedentary controls (0.78 ± 0.03 g). However, the sedentary controls included one exceptionally large rat with a proportionately large LV, but with an LV:BW ratio within the normal range. Without this rat, absolute LV weights in the exercise-trained rats were 11% greater than those of sedentary rats (P < 0.05). Resting HR was lower in the exercise-trained rats (P < 0.05; Table 1).
Ramp vagal baroreflex gain and effects of ANP
The gain of the ramp vagal baroreflex in 1K-1C rats was approximately half that of uninephrectomised controls (P < 0.05; Fig. 2). A component of this difference could have been due to the methoxamine-induced maximum rise and rate of rise in arterial pressure being less in the 1K-1C rats (Table 1), a limitation due to their resting hypertension. However to test the effect of ANP, comparisons were made between matched ramp increases in blood pressure in the same animal. ANP increased ramp reflex gain in uninephrectomised control rats by 27 ± 5% (P < 0.05, n= 7; Fig. 2). By contrast, ANP did not alter ramp reflex gain in 1K-1C rats (n= 6; Fig. 2).
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Chronic exercise training itself reduced ramp baroreflex gain, compared to this reflex in sedentary controls (Fig. 3B and D). ANP increased the ramp reflex gain in exercise-trained rats by 123 ± 30% (P < 0.05, n= 7; Fig. 3C and D), and in sedentary rats by 34 ± 10% (P < 0.05, n= 7; Fig. 3A and B).
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The normalized gain of the steady-state arterial baroreflex in 1K-1C hypertensive rats was 50% lower than in uninephrectomised controls (P < 0.05; Table 2 and Fig. 5A and B). This was due to an attenuated HR range (P < 0.05; Table 2 and Fig. 5A and B). The arterial baroreflex curve in 1K-1C was also shifted upwards on the arterial pressure axis, reflecting the elevated resting MAP (Table 2 and Fig. 5A and B). ANP did not affect any parameter of the steady-state curves of 1K-1C or uninephrectomised rats, except the peptide lowered resting MAP in the 1K-1C group (P < 0.05; Table 2 and Fig. 5A and B).
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Discussion |
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This study addressed two independent, though related, questions. In the first, we asked whether the sensitizing action of ANP on cardiac reflexes, which was absent in SHRs with cardiac hypertrophy (Thomas et al. 1997, 1998), was also absent in a second model of pathological cardiac hypertrophy. The data from renovascular hypertensive (1K-1C) rats showed clearly that this was the case. In combination with previous findings (Thomas et al. 1998), the data suggest a common mechanism linked to pathological cardiac hypertrophy, independent of the aetiology of hypertension.
In the second question, we asked whether the ability of ANP to sensitize non-arterial baroreflex bradycardia was preserved in physiological cardiac hypertrophy. We found that it was preserved, even enhanced, in chronically exercise-trained rats with raised LV:BW ratios. These results further extend previous findings and point to a differential effect of ANP on reflex bradycardia, depending upon whether heart size was increased pathologically or physiologically (see Fig. 4).
Was the hypertrophic stimulus from exercise training sufficient?
The exercise-trained rats in the present study increased their LV:BW ratio by 22% and LV weights by 9%. This exercise-induced cardiac hypertrophy was comparable to that which we previously showed to be sufficient to prevent the sensitizing actions of ANP on baroreflex bradycardia in ACE-inhibitor treated SHRs (Thomas et al. 1998). In that earlier study, the sensitization of cardiac vagal reflexes by ANP was absent in SHRs that were allowed to develop only modest cardiac hypertrophy (increase in LV:BW ratio of 8%), subsequent to postweaning treatment with an ACE inhibitor (Thomas et al. 1998). However if the hypertrophy was completely prevented, ANP was effective at enhancing cardiac vagal reflex function (Thomas et al. 1998). We conclude that the physiological hypertrophy produced by exercise training was enough to test the principle that the lack of action of ANP was not a generic feature of enlarged hearts. Only pathological cardiac hypertrophy appears to block the sensitizing action of ANP on cardiac reflexes. This lack of effect is evidently associated with the hypertrophy rather than the hypertension, because in our previous study, simply maintaining the blood pressure at normal levels did not restore the sensitivity to ANP but preventing the hypertrophy did (Thomas et al. 1998).
Free-wheel exercise training model
In the present study, spontaneous, daily wheel running was a model of chronic exercise training with inherent advantages (Collins & DiCarlo, 1997). In this unstressful protocol, rats ran during their normally active period at night. In keeping with the effects of chronic exercise training, these rats had a modest bradycardia at rest (10%). The disadvantage of this model is that it relies on each animal maintaining an interest in running. Whereas all rats ran for the first few weeks, only about half of the initial large group sustained the exercise at a rate sufficient to produce significant cardiac hypertrophy. Although not reported here, ‘lazy’ rats that did not run enough to develop cardiac hypertrophy were intermediate in all aspects (including the effects of ANP) between the sedentary and the exercise-trained rats. We therefore believe that this selection of animals did not distort the nature of our conclusions.
1K-1C renovascular hypertension model
In agreement with previous work, we found that 1K-1C hypertensive rats displayed a markedly attenuated arterial (steady-state) baroreflex with reductions in both sympathetic and parasympathetic ends of the reflex relation (Farah et al. 2001) and a marked reduction in ramp reflex gain, as in SHRs (Thomas et al. 1997, 1998). The 1K-1C renovascular model of hypertension has some features in common with, but others that are different from, the SHR. Chronic 1K-1C hypertension has its primary aetiology in the kidney, is volume-dependent and has less elevation of sympathetic and plasma renin activity (e.g. Oparil, 1986; Pamnani et al. 2000) than other hypertensive models such as the SHR. Despite the distinctly different causes and characteristics of hypertension in SHRs and 1K-1C rats, ANP was similarly ineffective in both.
Ventricular hypertrophy – baseline effects on vagal baroreflexes
As previously reported by others (e.g. Seals & Chase, 1989; Collins & DiCarlo, 1997; Liu et al. 2002), we found no deficit in the vagal HR response to arterial (steady-state) baroreceptor stimulation in chronically exercise-trained animals. However, we did find a marked reduction in gain of the bradycardic response to activation of non-arterial (presumed ventricular) high pressure receptors, as reflected in the 50% reduction in ramp reflex gain. This was true of both physiological and pathophysiological hypertrophy models studied here and of the SHR model studied previously (Thomas et al. 1997, 1998). The reasons for this are unclear.
One factor to consider is a possible change in the efficacy of vagal efferent neurotransmission. While this does not appear to apply in SHRs (Head, 1994), it has been reported to occur in 1K-1C hypertensive rats (Farah et al. 2001) and with chronic exercise training (Negrao et al. 1992). In a more severe model of exercise training than that of the present study, Negrao and coworkers found a reduction in the bradycardic response to electrical stimulation of the efferent vagus (Negrao et al. 1992). However in the present experiments, the lower plateau (parasympathetic end) of the steady-state baroreflex relation was unchanged by exercise training. It therefore seems unlikely that efferent vagal neurotransmission was greatly changed in our model.
Another potential mechanism for the reduced ramp reflex gain after exercise training could be altered sensitivity to rapid stretch of ventricular vagal afferents. There has been no study specifically measuring activity of these afferents with exercise training although it has been reported that responses to low pressure (presumed atrial) receptors are unchanged (Scislo et al. 1993). It is plausible that mechanical factors associated with a thicker-walled LV would have reduced the stretch stimulus seen by ventricular mechanoreceptors during the rapid pressure rise of the ramp test. This would be expected to apply to physiological and pathological hypertrophy models. Finally, unidentified central reflex mechanisms might conceivably have changed the gain, specifically of cardiac baroreflexes in exercised animals and of both cardiac and arterial baroreflexes in hypertensive rats. While it remains possible that a similar explanation underlies the reduced ramp reflex gain in all rats with cardiac hypertrophy, the ability of ANP to enhance that reflex gain was clearly different, depending on the aetiology of the hypertrophy.
Possible mechanism(s) for hypertensive hypertrophy preventing the action of ANP
The target for ANP is likely to be on, or closely associated with, cardiac vagal afferents (Thomas et al. 1998, 2002). It seems plausible that features in the ventricular afferent receptor membrane, its mechanosensory coupling or the local milieu are disturbed by pathological cardiac hypertrophy. These changes could then be responsible for wiping out the actions of ANP. ANP acts through one of the natriuretic peptide guanylyl cyclase receptors (Thomas & Woods, 2003) and it is possible that these receptors and/or their downstream consequences are down-regulated in hypertensive hypertrophy. Indeed, there are modestly elevated circulating and cardiac tissue levels of ANP in hypertension (e.g. review by de Bold et al. 2001) which are associated with a down-regulation of natriuretic peptide receptors in most organs (e.g. review by Anand-Srivastava, 1997). However, it has not been reported whether this also applies to particulate guanylyl cyclase natriuretic peptide receptors in the heart. By contrast, chronic exercise training is generally not associated with elevated plasma ANP levels (Miller et al. 1990; Rogers et al. 1991; Azizi et al. 1995) and the activity of natriuretic peptide receptors are unchanged in adrenal, kidney and lung (Suda et al. 2000). Again, no information is available on natriuretic peptide receptors in exercise-trained hearts.
The mechanisms for the loss of sensitivity to ANP in pathological cardiac hypertrophy are not yet clear. If the defect is not in the natriuretic peptide receptors, it could be due to any of a number of structural, biochemical or hormonal changes associated with pathological cardiac hypertrophy. Circulating angiotensin levels are unlikely to be a factor as circulating angiotensin levels do not remain chronically elevated in either 1K-1C rats (Woods & Johnston, 1982) or SHRs (Watanabe et al. 1983). However, a role for local tissue angiotensin cannot be excluded. It is not known whether other humoral factors involved in hypertensive cardiac hypertrophy (e.g. Dorn & Brown, 1999), such as prostanoids (e.g. Hintze, 1987) and nitric oxide (e.g. Araujo et al. 1995), have any influence on cardiac sensory afferent activity.
Selectivity of ANP for non-arterial baroreceptor reflexes
ANP did not improve arterial baroreflex gain or heart rate range (steady-state experiments) in any of the four groups of rats in the present study. These results support previous findings in normal and hypertensive rats (e.g. Ebert & Cowley, 1988; Woods et al. 1994; Thomas et al. 1997, 1998). This lack of effect on arterial baroreflexes supports the proposal that ANP does not act primarily on autonomic effectors, or on arterial baroreceptors themselves. Rather, these and previous observations (Woods et al. 1994; Thomas et al. 1997, 1998) support a selective action of ANP on reflexes from non-arterial (cardiac) afferents (Thomas et al. 2002).
Summary and perspective
We have found that the aetiology of cardiac hypertrophy appears to determine whether or not ANP enhances non-arterial baroreflex bradycardia. Reflex bradycardic action of ANP may be considered as a cardiac compensatory mechanism for the ventricle exposed to rapid changes in afterload. The absence of this protective action may contribute to the pathology of the hypertension. The natriuretic peptide system could be one of the few endogenous systems able to counteract the other harmful neurohumoral players in the progression from hypertensive cardiac hypertrophy to heart failure.
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P < 0.05, 1K-1C versus UNINEPH.
