Copyright © 2004, European Society of Cardiology
Renovascular effects of sympathetic cotransmitters ATP and NPY are age-dependent in spontaneoulsy hypertensive rats
Department of Internal Medicine I, Marienhospital Herne, Ruhr-University Bochum, Hölkeskampring 40, 44625 Herne, Germany
* Corresponding author. Medizinische Klinik I, Marienhospital Herne, Klinikum der Ruhr-Universität Bochum, Hölkeskampring 40 D-44625 Herne, Germany. Tel.: +49 2323 499 1671; fax: +49 2323 499 302. Email address: christian.rump{at}ruhr-uni-bochum.de
Received 29 June 2004; revised 8 December 2004; accepted 13 December 2004
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Objective: Hypertension is characterized by sympathetic overactivity. Neuropeptide Y (NPY) and ATP are cotransmitters of norepinephrine (NE) and regulate renovascular resistance. The present study analyzes sympathetic nonadrenergic neurotransmission in hypertensive (SH-SP) and normotensive (WKY) rats. In addition, adult and young hypertensive rats were compared to investigate the role of aging on sympathetic nonadrenergic cotransmission in hypertensive disease.
Methods: Pressor responses to renal nerve stimulations (RNS) and drugs were measured on isolated perfused kidneys of young (8–10 weeks) and adult (18–24 weeks) WKY, and SH-SP rats.
Results: RNS evoked contractions at 1 Hz were resistant to blockade by the 
-adrenoceptor antagonist phentolamine (1 µM) but abolished by the P2 receptor blocker suramin (100 µM). Compared to adult WKY, RNS-induced pressor responses were unchanged in adult SH-SP and young WKY, but significantly greater in young SH-SP rats. The NPY-Y1 receptor antagonist BIBP3226 (1 µM) reduced phentolamine-resistant pressor responses in adult and young WKY, young SH-SP, but not in adult SH-SP rats. In contrast to WKY and young SH-SP rats, exogenously perfused NPY (0.1 µM) was unable to potentiate RNS-induced, phentolamine-resistant pressor responses in adult SH-SP rats. NE and the stable ATP analogue ,β-mATP increased the perfusion pressor response more potently in adult SH-SP than in WKY rats.
Conclusions: Neuronally released NPY plays a major role in potentiating RNS-induced nonadrenergic pressor responses in kidneys of WKY and young SH-SP rats. In adult SH-SP rats NPY fails to enhance these responses. In this hypertensive model ageing seems to be associated with a loss of a modulatory role of renal NPY Y1 receptors. Since pressor responses to NE and ATP are higher in SH-SP animals, functional NPY-Y1 receptor downregulation might be an adaptive mechanism.
KEYWORDS Autonomic nervous system; Peptide hormones; Hypertension; Neurotransmitters; Receptors
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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The sympathetic nervous system controls blood pressure and renal function by releasing neurotransmitters from peripheral nerve endings. Norepinephrine (NE), adenosine-triphosphate (ATP) and neuropeptide Y (NPY) are released together and mediate their function by activation of
- and β-adrenoceptors, P2Y- and P2X-receptors and NPY-Y receptors [1–5]. Sympathetic overactivity seems to be closely related to essential hypertension [6,7]. Studies on experimental animals demonstrated that cutting renal nerves prevents or attenuates development of hypertension [7–9]. The main focus in the past was on studying the classical sympathetic neurotransmitter NE in development of hypertensive disease [3,10]. Accordingly, renal NE spillover is more pronounced in patients with essential [11] and renovascular hypertension [12]. Furthermore differences in sympathetic innervation, NE content within the synaptic vesicles, elimination of NE from the synaptic gap and regulation of NE release by presynaptic receptors were described for SHR [13,14].
However, since complete -adrenoceptor blockade does not prevent nerve stimulation-induced vasoconstrictions [1], the importance of focusing on nonadrenergic sympathetic neurotransmission by ATP and NPY is obvious. This is of particular interest since ATP acts as a potent vasoconstrictor in the kidney [1] and large amounts of ATP were released from synaptic nerve endings and renal cells [15,16]. In addition, NPY potentiates pressor responses induced by NE and ATP [1], NPY release is enhanced by sympathetic overactivity and high plasma levels of NPY are associated with the increased cardiovascular risk of patients with chronic renal failure [17].
The present study was performed to elucidate the role of sympathetic nonadrenergic neurotransmission by ATP and NPY in kidneys of hypertensive stroke-prone (SH-SP) rats. In addition, young and adult hypertensive animals were compared to investigate age-dependent changes of sympathetic nonadrenergic cotransmission during progression of hypertensive disease.
To test these hypotheses, renal sympathetic nerves were stimulated and pressor responses were analyzed. Nonadrenergic neurotransmission was studied by blocking the adrenergic component with the non-selective -adrenoceptor blocker phentolamine. Furthermore, low stimulation frequencies were chosen, since previous experiments could show, that the renal nerve stimulation induced rise in perfusion pressor was almost totally nonadrenergic at frequencies around 1 Hz [18]. ATP-P2 and NPY-Y1 receptor antagonists were used to demonstrate involvement of ATP and NPY as endogenous sympathetic neurotransmitters. By repetitive stimulations of renal sympathetic nerves, mechanisms were investigated that occur during sympathetic overactivity. To differentiate between presynaptic and postsynaptic alterations within the different rat populations, kidneys were stimulated by adding receptor agonists exogenously. Furthermore, quantitative real-time RT-PCR was performed to find out whether age-dependent changes in mRNA-expression level of NPY-Y1 receptors occur in hypertensive animals.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Male normotensive Wistar Kyoto rats (Charles River, Sulzfeld, Germany; 18–24 weeks/504 ± 49 g and 8–10 weeks/277 ± 18 g) and spontaneously hypertensive stroke-prone rats (SH-SP) (Max Delbrück Institut, Berlin; 18–24 weeks/300 ± 5 g and 8–10 weeks/215 ± 11 g) were used for the present study. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). Rats were anesthetized with sodium pentobarbital (60 mg/kg, intraperitoneally). The kidneys were isolated and perfused with Krebs–Henseleit solution according to a method described previously [1]. Bipolar platinum electrodes were placed around the renal arteries to stimulate the renal sympathetic nerves. Perfusion pressure was monitored continuously with a Statham P23 Db pressure transducer (Gould, Oxnard, CA) coupled to a Watanabe pen recorder (Graphtec, Tokyo, Japan).
2.1. Experimental protocol
The kidneys were perfused with drug-free Krebs–Henseleit solution at 37 °C with a constant flow rate of 4.2 ml/min g kidney weight. Kidney wet weights were calculated according to data of previously published experiments [3,19], showing that they correspond to approximately 0.5% of whole body weight. The perfusion solution was continuously gassed with carbogen (5% CO2/95% O2) and passed through a 0.45 µm filter before it reached the kidneys. Immediately after preparation, a priming stimulation of 5 Hz for 30 s (1 ms width, 40 V) and a bolus injection of KCl (60 mmol/L) was delivered to test the viability of the preparation followed by a stabilization period of 30 min. Phentolamine 1 µM was added to the perfusion solution 30 min after stabilization and 15 min before S1. This phentolamine concentration blocks, as previously demonstrated, maximal pressor responses to exogenous norepinephrine [1]. In experiments with two stimulations (S1 and S2; Figs. 2, 3 and 6
) renal nerve stimulations (RNS) at 1 Hz (30s, 1 ms width, 40 V) were applied at 6 min intervals. Suramin, BIBP and NPY were added 3 min after S1 to the perfusion solution by a perfusion apparatus (Braun, Melsungen, Germany) at a constant flow rate of 0.158 µl/min. In experiments with three repetitive stimulations (30 s, 1 ms width, 40 V), RNS were delivered with a 60 s interval (Figs. 4 and 5). In selected experiments the NPY-Y1 receptor antagonist BIBP 3226 was added 3 min before the repetitive RNS.
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The receptor agonists
,β-mATP and norepinephrine (NE) were added to the perfusion solution in a cumulative manner, expressed in a dose response curve (Fig. 7; Table 1). The time interval between applications of the different agonist concentrations was 2.5 min. The perfusion of drugs was stopped when the pressor responses had reached a maximum.
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2.2. Real-time RT-PCR analysis
Renal cortical tissue of two young (9 weeks) and two adult (22 weeks) SH-SP rats was homogenized in liquid nitrogen. RNA preparation was performed using Trizol reagent (Invitrogen/Germany). Following DNA digestion (Rnase free Dnase, Invitrogen, Germany) cDNA synthesis was performed with 3 µg of individual renal RNA extracts, 100 ng oligodT and 1 unit superscript reverse transcriptase (Invitrogen, Germany) according to the manufacturer's manual. The quality of the RNA was controlled using gel electrophoresis and PCR with GAPDH primer to exclude genomic DNA contamination. Specific primer pairs for rat NPY-Y1 (sense 5'-TGCGGCGTT CAAGGACAAGTATG-3', antisense 5'-GTAAGGGGCAGCCAGCAGACC-3'; product size: 273 bp) and the housekeeping gene glyceraldehyde 3-phosphate dehydrogenase (GAPDH) sense 5'-GGGCAAGGTCATCCCTGAGCTGAA-3', antisense 5'-GAGGTCCACCACCCTGTTGCTGTA-3'; product size 323 bp) were designed and synthesized by MWG Biotech (Germany). Real-time PCR was performed using a MJ Research Opticon (USA) cycler and a SYBR-Green PCR-Mix by Eurogentech (Belgium) The cycle profile was 3 min 94 °C then 40 times 30 s 94 °C, 30 s 65°, 30 s 72 °C. Data for NPY-Y1 and GAPDH was captured at 76 °C and 84 °C, respectively.
2.3. Calculations
All pressor responses were measured as the increase of perfusion pressure above basal perfusion pressure (
perfusion pressor=perfusion pressorstimulation–perfusion pressorbasal). Effects of drugs or repetitive RNS were expressed as a percentage of S1 (perfusion pressor S1 set to 100%).
2.4. Drugs and vehicles
The Krebs–Henseleit solution had the following composition (mM): NaCl 118, KCl 4.7, CaCl2 2.5, MgSO4 0.45, NAHCO3 25, KH2PO4 1.03, D-(+)-glucose 11.1, Na2EDTA 0.067 and ascorbic acid 0.07 (Sigma, Germany). The following drugs were employed: neuropeptide Y (Bachem, Germany), phentolamine mesylate (Aventis, Switzerland) ,β-methylene Adenosin-5'-triphosphate (,β-mATP), (±)-norepinephrine HCl, BIBP 3226 (kindly donated by Thomae, Germany) and suramin hexasodium salt (Bayer, Germany). Drugs were dissolved in distilled water before being diluted with Krebs–Henseleit solution. NPY was dissolved in sodium phosphate buffer (0.1 M, pH 7.2).
2.5. Statistical analysis
All data were expressed as mean ± S.E.M. Differences between RNS and dose–response curves were analyzed by two-factorial ANOVA for repeated measurements and unpaired Student's t-test modified according to Bonferroni. Probability levels of P<0.05 were considered statistically significant. The number of experiments indicates the number of individual kidneys.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Kidneys of adult and young normotensive WKY and hypertensive SH-SP rats were isolated and perfused. The perfusion rate was adjusted to the body weight. Kidneys of young and adult WKY were perfused with 5.8 ± 0.4 ml/min and 10.6 ± 1.0 ml/min, kidneys of young and adult SH-SP with 4.5 ± 0.2 ml/min and 6.3 ± 0.1 ml/min, respectively. Basal perfusion pressor was recorded in n=4 animals each group. Basal perfusion pressor was 43 ± 9 mmHg and 39 ± 8 mmHg in young and adult WKY and 47 ± 10 mmHg and 62 ± 12 mmHg in young and adult SH-SP rats.
3.1. Renal nerve stimulation-induced pressor responses in isolated perfused kidneys from WKY and SH-SP
Renal nerve stimulation (RNS) at 1 Hz evoked contractions, which were not blocked by the non selective -adrenoceptor antagonist phentolamine (1 µM) in WKY and SH-SP (Fig. 1). The RNS-induced phentolamine-resistant pressor responses were not significantly different in kidneys of young WKY (8–10 weeks) and adult (18–24 weeks) SH-SP rats. In contrast, phentolamine-resistant pressor responses to RNS were significantly greater in young (8–10) SH-SP (Fig. 1) to those in adult SH-SP (18–24 weeks) and age matched WKY rats. Phentolamine-resistant pressor responses were almost completely abolished by the non selective P2 receptor antagonist suramin (100 µM) (Fig. 2). Pressor responses in S1 and S2 were identical, when no further drug was added before S2. This was tested for WKY and SH-SP rats (data not shown).
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3.2. Role of NPY in phentolamine-resistant pressor responses
To test whether endogenous NPY plays a role in RNS-induced phentolamine-resistant pressor responses in kidneys of hypertensive rats, the NPY-Y1 receptor blocker BIBP 3226 (1 µM) was added to the perfusion solution before S2 (Fig. 3). In this set of experiments, BIBP 3226 (1 µM) significantly reduced phentolamine-resistant pressor responses in WKY, but not in adult SH-SP (18–24 weeks) rats (Fig. 3). Compared to adult SH-SP, BIBP 3226 (1 µM) significantly decreased the phentolamine-resistant pressor responses in young SH-SP (8–10 weeks) rats.
Phentolamine-resistant pressor responses to RNS (1 Hz) were delivered in short time intervals of 60 s. In WKY and young SH-SP a progressive increase in pressor responses could be observed (Fig. 4). In contrast, such increase was not observed in adult SH-SP (18–24 weeks) rats. The progressive rise of pressor responses to three repetitive RNS at 1 Hz with 60 s interval was prevented by the NPY-Y1 receptor antagonist BIBP 3226 (1 µM) (Fig. 5).
When the NPY(1–36) peptide (0.1 µM) was applied exogenously before S2 (Fig. 6) it potentiated the RNS-induced phentolamine-resistant pressor responses in WKY, young SH-SP (8–10 weeks) but not in adult SH-SP (18–24 weeks) rats. No significant difference was detected in young (8–10 weeks) compared to adult normotensive WKY (18–24 weeks) (Fig. 6) rats.
3.3. Pressor responses to exogenous ,β-mATP and norepinephrine
A concentration-dependent increase in perfusion pressor could be induced by the P2X1/3 selective receptor agonist ,β-mATP (Table 1) and by NE (Fig. 7). In adult hypertensive SH-SP rats the change in perfusion pressor by exogenously applied ,β-mATP and NE was well preserved (Fig. 7; Table 1); and even higher than in normotensive animals.
3.4. NPY-Y1 receptor expression in young and adult hypertensive rats
Real-time RT-PCR analysis revealed do differences in NPY-Y1 mRNA expression in adult compared to young SH-SP rats (Fig. 8). To ensure that comparable mRNA amounts were used for all groups, real-time RT-PCR analysis has been also performed for the housekeeping gene GAPDH (Fig. 8).
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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The present study was conducted to analyze sympathetic nonadrenergic neurotransmission in hypertensive stroke-prone (SH-SP) rats compared to normotensive animals (WKY-rats). Moreover, adult and young hypertensive animals were used to investigate the potential role of aging on sympathetic nonadrenergic cotransmission during the progression of hypertensive disease.
4.1. Sympathetic nerves and renovascular resistance
In the presence of the non-selective -adrenoceptor antagonist phentolamine, RNS still elicited pressor responses. These -adrenoceptor blockade-resistant pressor responses were almost completely abolished by the non-selective P2-receptor antagonist suramin and thus reflect purinergic phentolamine-resistant pressor responses due to neuronally released ATP [20]. Against our expectation, the RNS-induced purinergic pressor responses were by no means greater in adult hypertensive SH-SP rats than in normotensive rats arguing against a role of nonadrenergic neurotransmission in hypertension. Another study, however, demonstrated on small mesenteric resistance vessels, greater -adrenoceptor blockade-resistant vasoconstrictions in SHR compared to WKY [21]. There are various parameters such as type of vascular bed, gender, species and age of the studied animal which certainly influences the observed pressure response in SHR animals in each individual study.
To test whether nonadrenergic neurotransmission might subject to age related changes, as seen in adrenergic neurotransmission [13,22] and to test whether nonadrenergic neurotransmission might play a role in young hypertensive subjects we further utilized young SH-SP rats and compared them with adult SH-SP animals in the present study. The purinergic phentolamine-resistant pressor responses were significantly increased in young (8–10 weeks) hypertensive SH-SP rats, compared to those observed in adult hypertensive SH-SP and normotensive adult WKY rats. No such difference was found in young compared to adult WKY rats. Blood pressure young (8–10 weeks) SH-SP rats is already elevated [23] but has not yet reached the maximal levels. Thus, the present study suggests that a renal nonadrenergic component may play a role in the developmental stage of hypertension in this strain. The reason for the small response of adult hypertensive animals might reflect either a reduced synaptic transmitter release of NPY and ATP or a lack of postsynaptic receptor function in adult hypertensive animals. The possibility that the release of sympathetic transmitters might decrease when the studied animal grows older has been postulated by some authors [3,22,24].
To answer the question why the nonadrenergic pressor responses attenuate in aged hypertensive animals further experiments have been performed using various agonists and antagonists.
4.2. Does NPY enhance sympathetic neurotransmission in adult hypertensive rats?
Previous studies have shown that NPY is a key modulator of renovascular resistance [1,21]. Though the NPY-Y1 receptor blocker BIBP 3226 significantly reduced the purinergic -adrenoceptor blockade-resistant pressor response in WKY, it was without any effect in adult SH-SP animals in the present study. In contrast to adult SH-SP, BIBP reduced purinergic pressor responses in young SH-SP rats. When renal nerves were stimulated repetitively to mimic a situation of enhanced sympathetic drive, pressor responses in normotensive and young hypertensive animals were not stable but increased from stimulation period to stimulation period. This potentiating effect is mediated by endogenously released NPY since it was blocked by BIBP [18]. As expected, this potentiating effect of NPY was not observed in adult SH-SP rats and indicates a markedly disturbed modulatory function of NPY in these animals.
Activation of receptors by agonists generally promotes a ‘down-regulation’ phenomenon, while inhibition of a receptor by antagonists or denervation produces an ‘up-regulation’ [25]. Real-time RT-PCR analysis however did not reveal a difference in NPY-Y1 receptor mRNA expression in young compared to adult SH-SP rats. This functional ‘down-regulation’ does not necessary imply less mRNA or protein expression. Posttranslational modifications like phosphorylation or receptor internalisation might be involved here. NPY plasma levels are high in spontaneously hypertensive rats [24] and in hypertensive patients [17]. In addition, NPY-immunoreactivity analyzed in plasma, superior mesenteric artery, adrenal medulla, coelic ganglia and kidney demonstrates that NPY levels markedly differ depending which tissue, age and hypertension status is used [24]. For that reason, it is plausible that due to a constant high NPY release, NPY might loose its potentiating effects as a result of functional NPY receptor ‘down-regulation’. To prove that the ineffectiveness of the NPY-Y1 receptor blocker BIBP in adult SH-SP is due to reduced postsynaptic response to NPY and not due to reduced synaptic release, the kidneys were perfused with the NPY receptor agonist NPY(1–36). Exogenous NPY(1–36) potentiated RNS-induced pressor response by more than 200% in WKY. Similar effects effect were observed in other cardiovascular tissues including the kidney [1,5,24,26,27]. However, in adult hypertensive animals the perfusion of NPY failed to potentiate RNS-induced pressor responses. And again, in young hypertensive SH-SP rats the potentiating effect of NPY was still well preserved. This suggests a reduction of postsynaptic NPY-Y1 receptor function in rats with long time hypertension. Why NPY was without an effect in our study with adult SH-SP kidneys in contrast to experiments conducted by Zukowska-Grojec et al. [24] on mesenteric arteries is unclear. Differences in hypertensive rat strains (SHR vs. SH-SP) and differences in the studied tissue type, however, have to be considered. In addition, the actual study analyzed the potentiating effect of NPY rather than the vasoconstrictive effect of NPY itself.
4.3. Preserved P2X-receptor and -adrenoceptor function in adult hypertensive rats
The question arises whether in parallel to NPY the effect of other sympathetic transmitters in the kidney like ATP and NE is altered in young compared to adult hypertensive subjects. To analyze this, ,β-mATP was perfused exogenously. This stable ATP analogue was used since it effectively activates P2X1 receptors [20]. Immunohistochemical and radioligand binding studies have shown that the P2X1 receptor subtype is the P2 receptor subtype of resistance vessels in rat kidneys [28]. In contrast to exogenously perfused NPY, ,β-mATP increased the renovascular resistance in adult hypertensive rats. Moreover, the increase in hypertensive rats was even significantly higher than in normotensive animals. In line with this, NE induced pressor responses were also higher in adult hypertensive SH-SP as compared to normotensive rats. This indicates intact postsynaptic P2-receptor and -adrenoceptor function in adult hypertensive animals. The mechanism of the increase in purinergic and adrenergic pressor response remains unclear but might reflect a general vascular hyperreactivity of the hypertensive SH-SP rats. In accordance with that, a nonspecific increase in media thickness, media to lumen ratio and response to NE has been observed in SH-SP by Rizzoni et al. [29].
In summary the presented data suggest that the progression of hypertensive disease in the SH-SP rat model is associated with a significant change in nonadrenergic neurotransmission. While in kidneys of young hypertensive rats the transmitter NPY is able to modulate purinergic vascular responses, this mechanism is lost in animals with long time hypertension.
One could speculate that the vascular hyperreactivity to NE and its cotransmitter ATP in the development of hypertension forces the organism to downregulate other components of the sympathetic nervous system like NPY. This loss of NPY modulation might disable the sympathetic nervous system to fine-regulate the renovascular resistance in hypertensive disease.
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Acknowledgements |
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The study was supported by the Deutsche Forschungsgemeinschaft (Ru 401/5-7). The excellent technical assistance of Petra Stunz and Bettina Priesch is greatly acknowledged.
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Notes |
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Time for primary review 8 days
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References |
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