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Symposium Report |
1 Department of Physiology, University of Greifswald, Karlsburg, Germany
Abstract
Renal mechanisms and the sympathetic nervous system contribute to the development of arterial hypertension. Renal transplantation experiments in spontaneously hypertensive rats (SHRs) were performed to investigate how the sympathetic nervous system and the kidneys interact during the development and maintenance of hypertension. Our findings indicate that the rise in arterial pressure that occurs after transplantation of a kidney from a SHR into normotensive recipients is not mediated by elevations in sympathetic activity. However, chronic reductions in sympathetic tone reduce the rise in arterial pressure which can be induced by SHR renal grafts in normotensive recipients. Untreated SHRs transplanted with a kidney from sympathectomized donors have lower arterial pressure and reduced sodium sensitivity of arterial pressure compared to SHRs transplanted with a kidney from hydralazine-treated donors. It is concluded that chronic non-adapting changes in sympathetic activity modulate the degree to which renal mechanisms can cause hypertension in SHRs. Severe reduction in sympathetic tone during early ontogeny causes long-term changes in renal function that mitigate hypertension development in SHRs even when the extrarenal neuro-hormonal environment is restored.
(Received 21 October 2004;
accepted after revision 23 November 2004; first published online 16 December 2004)
Corresponding author O. Grisk: Department of Physiology, University of Greifswald, Greifswalder Strasse 11c, D17495 Karlsburg, Germany. Email: grisko{at}uni-greifswald.de
Arterial hypertension is a major cause of morbidity and mortality from coronary heart disease, renal failure and stroke. The aetiology of approximately 90% of all cases of human arterial hypertension is not precisely known and therefore referred to as primary or essential hypertension. The development of primary hypertension involves both environmental and heritable factors. Experimental animals with inherited forms of hypertension such as spontaneously hypertensive rats (SHRs) from the Okamoto-Aoki strain have been extensively investigated for basic understanding of the genetics and the pathophysiology of primary hypertension as well as for the development of antihypertensive drugs. In the past, a multitude of comparative studies at all levels of integration have been performed in SHRs and normotensive inbred rats to identify functional abnormalities which could help to explain why SHRs develop hypertension.
The sympathetic nervous system can alter arterial pressure via its powerful effects on cardiac output, peripheral vascular resistance and renal function. In addition, sympathetic innervation influences DNA synthesis, gene expression and morphology of its target organs. The following findings support the view that the sympathetic nervous system contributes to the development of hypertension in SHRs. (1) The sympathetic innervation density and catecholamine content of several organs including the kidneys is higher in SHRs than in normotensive rats (Head, 1989). (2) Peripheral sympathetic nerve activity including renal sympathetic nerve activity and its reactivity to environmental stressors is increased in SHRs (DiBona & Kopp, 1997). (3) Renal denervation delays the development of hypertension in SHRs (DiBona & Kopp, 1997). (4) Neonatal sympathectomy chronically lowers arterial pressure in SHRs (Folkow et al. 1972).
Data from animal experiments and mathematical models lead to the concept that the ability of the kidneys to match water and electrolyte excretion with intake is of paramount importance for the determination of long-term arterial pressure (Guyton & Coleman, 1969). Hypertension was proposed to be a consequence of altered body fluid volume and electrolyte regulation with the critical impairment localized in the kidneys. The following findings support the view that alterations in renal function are involved in the development of hypertension in SHRs. (1) The pressure–natriuresis relationship is shifted to elevated renal perfusion pressure (Roman, 1987). (2) Renal afferent vascular resistance is increased (Norrelund et al. 1994). (3) Proximal tubular sodium reabsorption is elevated (Aldred et al. 2000). (4) The sensitivity of the tubulo-glomerular feedback mechanism is increased (Dilley & Ahrendshorst, 1984). (5) The activity of a (chemically unidentified) hormonal arterial pressure-lowering factor released from the kidneys is reduced (Karlström et al. 1991). (6) Renal grafts from SHRs induce arterial hypertension in histocompatible recipients (Kawabe et al. 1979).
The latter finding fits the concept that the kidneys play a key role in the pathogenesis of (primary) arterial hypertension. Similar findings have been obtained in renal transplantation studies with other genetically hypertensive rat strains. The experimental approach of renal cross-transplantation between genetically hypertensive and non-hypertensive animals allows the investigation of mechanisms by which kidneys from genetically hypertensive animals cause arterial pressure to rise. Kidney-specific gene transfer can be performed if recombinant inbred rat strains or congenic rats are available. Further, the contribution of the kidney to the effects of experimental interventions on long-term arterial pressure can be studied. A prerequisite is histocompatibility between donor and recipient rats. This article summarizes recent findings on the involvement of the sympathetic nervous system in the development of hypertension in recipients of a SHR kidney (renal post-transplantation hypertension). In addition, the role of sympathetic innervation of the kidneys during early ontogeny for hypertension in SHRs is discussed.
Contribution of the sympathetic nervous system to the development of renal post-transplantation hypertension
There is evidence that surgically denervated rat kidneys become reinnervated by sympathetic nerves within 4–6 weeks and reinnervation of kidney grafts may occur both in humans and experimental animals. A positive correlation between arterial pressure and the degree of sympathetic reinnervation of the kidneys after renal denervation has been found in SHRs (Winternitz et al. 1980). We tested whether reinnervation of SHR kidney grafts contributes to the development of renal post-transplantation hypertension in recipients of a SHR kidney (Grisk et al. 1999). SHR kidneys were transplanted into histocompatible recipients. As recipients F1 hybrid (F1H) rats from crossing SHRs and Wistar Kyoto (WKY) rats were used. Three weeks after transplantation, renal grafts underwent either sham-denervation or denervation surgery. After a 6-week observation period, mean arterial pressure was 172 ± 4 mmHg in recipients that underwent sham-denervation and 170 ± 5 mmHg in animals following denervation surgery (n.s). Based on tissue noradrenaline (norepinephrine) contents we did not obtain evidence for sympathetic reinnervation during the observation period (Grisk et al. 1999). Tissue noradrenaline measurements and immunohistochemical observations in rats did not provide evidence for sympathetic reinnervation of kidney grafts for up to 9 months after renal transplantation (Grisk et al. 2001). Therefore we can exclude the possibility that sympathetic reinnervation of kidney grafts contributes to the development of renal post-transplantation hypertension in rats.
Signals arising from the SHR kidney may cause generalized activation of the sympathetic nervous system which could contribute to chronic elevation of arterial pressure in recipients of a SHR kidney graft. With adrenal tyrosine hydroxylase mRNA expression level used as a marker for chronic sympathetic activity we found no evidence for chronic elevation of sympathetic tone in recipients of a SHR kidney compared to syngeneically transplanted F1H 3 weeks after transplantation (Grisk et al. 2000). Mean arterial pressure was 30 mmHg higher in recipients of a SHR kidney compared to syngeneically transplanted F1H at that time after transplantation. Analysis of splanchnic sympathetic nerve activity in conscious freely moving animals did not reveal differences in amplitude and frequency of synchronized discharges between recipients of a SHR kidney graft and controls. Sympathetic nerve activity and arterial pressure did not respond differently to intracerebroventricular administration of the 
2-adrenoreceptor agonist guanabenz in the two groups (Fig. 1).
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F1H rats obtained from crossing SHRs and WKY rats have been used in most renal transplantation studies involving SHR kidneys because there is no histocompatible normotensive recipient strain. With the generation of a normotensive congenic rat strain (BB.1K) homozygous for a 2-cM segment of SHR chromosome 20 including the genes of the major histocompatibility complex we were able to perform true cross-transplantations between normotensive rats and SHRs (Grisk et al. 2002a). Arterial pressure was normalized in SHRs with a kidney graft from normotensive donors. Further, we found that chronic arterial pressure after transplantation of a SHR kidney depends on the genetic background of the recipient. This indicates that genetically determined extrarenal factors contribute to the level of renal post-transplantation hypertension (Fig. 2).
We tested the hypothesis that variation in chronic sympathetic activity could be such an extrarenal factor. As reliable comparative measurements of sympathetic activity are almost impossible to perform in freely moving rats over a time period of weeks, sympathetic activity was artificially reduced in one recipient group (F1H) by neonatal sympathectomy while the other recipient group was sham-treated. Arterial pressure recordings at 9–10 weeks of age revealed a 20-mmHg difference between both groups. Animals were transplanted with a SHR kidney and both native kidneys removed. Six weeks after renal transplantation, mean arterial pressure was elevated by 20 mmHg in sympathectomized animals while the rise was 35 mmHg in animals with the sympathetic nervous system intact. Thus, reduction in sympathetic activity did not just lead to a parallel downward shift of arterial pressure values prior to and after transplantation of a SHR kidney but reduced the arterial pressure rise after transplantation of a SHR kidney (Grisk et al. 2002b).
Effect of sympathetic renal innervation on hypertension development in SHRs
It is well established that neonatal sympathectomy chronically lowers arterial pressure in SHRs. Because of the important role of the kidney in determining chronic arterial pressure we tested whether the chronic arterial pressure-lowering effect of neonatal sympathectomy could be transferred with renal grafts from SHRs sympathectomized shortly after birth to untreated SHRs (Grisk et al. 2002b). In the control experiment we transplanted kidneys from hydralazine-treated SHRs into untreated SHRs. Arterial pressure did not differ between sympathectomized and hydralazine-treated donor animals. Seven weeks after renal transplantation and resection of both native kidneys, mean arterial pressure was 145 ± 5 mmHg in SHRs with a graft from sympathectomized donors versus 164 ± 6 mmHg in SHRs with a graft from hydralazine-treated donors (P < 0.05). Sodium sensitivity of arterial pressure was reduced in recipients of a kidney from sympathectomized donors (Fig. 3). Similar results have been obtained with chronic treatment of SHR kidney donors with angiotensin-converting enzyme (ACE) inhibitors (Smallegange et al. 2003).
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Conclusions
Elevated sympathetic activity is not a mediator of renal post-transplantation hypertension in recipients of a SHR kidney. However, long-term non-adapting changes in sympathetic activity modulate the extent to which a SHR kidney graft can cause arterial pressure to rise. On the other hand, gross reduction in sympathetic tone starting during early ontogeny causes alterations in SHR renal function that chronically lower arterial pressure after transplantation into previously untreated SHR recipients where the extrarenal neuro-hormonal systems are not greatly altered. These effects are not specific for neonatal sympathectomy. They can also be achieved by blockade of the renin–angiotensin system during early life. It remains to be clarified whether both types of interventions have similar chronic effects on kidney function in SHRs.
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Acknowledgements
The work of the author was supported by the Deutsche Forschungsgemeinschaft.
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significant difference versus control conditions. Reproduced with permission from the American Society of Physiology.
, n
= 10) and SHRs with a kidney graft from hydralazine-treated SHR donors (•, n
= 10). Reproduced with permission from the American Society of Physiology.