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Cardiovascular Research 2000 45(2):463-469; doi:10.1016/S0008-6363(99)00279-5
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Copyright © 2000, European Society of Cardiology

Impaired potentiation by endothelin-1 and vasopressin of sympathetic contraction in tail artery from hypertensive rats

Angel Luis Garcìa-Villalón*, Luis Monge, Nuria Fernández, Miguel Angel Sánchez, Marìa Angeles Martìnez, Bernardino Gómez and Godofredo Diéguez

Departamento de Fisiologìa, Facultad de Medicina, Universidad Autónoma, 28029 Madrid, Spain

* Corresponding author. Tel.: +34-91-397-5424; fax: 34-91-397-5324 angeluis.villalon{at}uam.es

Received 17 June 1999; accepted 9 September 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: To analyse the effects of endothelin-1 and vasopressin on the sympathetic vasoconstriction during hypertension. Methods: Electrical field stimulation (4 Hz) was applied to isolated, 2 mm segments of the tail artery from spontaneously hypertensive (SHR) and normotensive Wistar–Kyoto (WKY) rats prepared for isometric tension recording. Results: The contraction to electrical stimulation was potentiated by endothelin-1 (10–10–10–8 M) in arteries from WKY but not from SHR, and by vasopressin (10–12–10–10 M) more markedly in arteries from WKY than from SHR. The potentiation by endothelin-1 was reduced more markedly by the antagonist of endothelin ETA receptors BQ-123 (10–5 M) than by the endothelin ETB receptor antagonist BQ-788 (10–5 M). The potentiation by vasopressin was reduced by the antagonist of vasopressin V1 receptors d(CH2)5Tyr(Me)AVP (10–7 M), but not by the vasopressin V2 receptor antagonist d(CH2)5D-Ile2, Ile4AVP (10–7 M). The blocker of L-type calcium channels verapamil (10–5 M) reduced the potentiation by both endothelin-1 and vasopressin in arteries from WKY rats, and increased the potentiation by vasopressin in arteries from SHR. Noradrenaline (10–8–10–4 M) contraction was not modified by endothelin-1 (3x10–9 M) or vasopressin (3x10–11 M), and contraction to endothelin-1 (10–9–10–7 M) and vasopressin (10–10–10–7 M) was lower in arteries from SHR than from WKY rats. Conclusions: (1) the potentiation by endothelin-1 and vasopressin of the sympathetic vasoconstriction, probably due to increased release of noradrenaline, is impaired during hypertension, and (2) this potentiation is mediated mainly by endothelin ETA receptors, and by vasopressin V1 receptors, in both WKY and SHR, and for both peptides it is mediated by L-type calcium channels in arteries from normotensive but not in those from hypertensive animals.

KEYWORDS Adrenergic (ant)agonists; Arteries, Ca-channel; Endothelins; Hypertension; Receptors


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Altered responsiveness of blood vessels to vasoactive agents is a common finding in human and experimental hypertension [1]. However, the characteristics of these alterations may differ, depending on the vasoactive agent, the type of hypertension and the vascular bed studied. The vasoconstriction to endothelin-1 may be elevated [2,3], reduced [4,5] or not modified [6] in hypertensive rats, and it may be increased in subcutaneous arteries from hypertensive patients [7]. The response to vasopressin during hypertension has been less studied, and there are reports showing that it may be increased in renal [8] and mesenteric [9] arteries of hypertensive rats.

Endothelin-1 and vasopressin are vasoconstrictor peptides which may be involved in pressure elevation during hypertension [10,11]. In addition to their direct constrictor effect on vascular smooth muscle, endothelin-1 [12,13] and vasopressin [14,15] may increase the response to stimulation of sympathetic vascular innervation, and this modulatory effect may be physiologically relevant for the regulation of blood pressure, as it is usually produced at low concentrations of these peptides. The potentiating effect of endothelin-1 on the sympathetic vascular response may be modified during hypertension as suggested by results obtained in rat mesenteric arteries from hypertensive rats [16,17]. The potentiating effect of vasopressin has not been studied during hypertension, to our knowledge.

The purpose of the present study was to examine whether the potentiation of the sympathetic vasoconstriction produced by endothelin-1 and vasopressin in normotension is modified during hypertension, as well as to examine some mechanisms that may underly this potentiation. This study was performed in the tail artery, and the effects in arteries from spontaneously hypertensive rats (SHR) were compared to those in arteries from normotensive Wistar-Kyoto (WKY) rats. This artery has a dense sympathetic innervation [18], and the SHR is a strain of hypertensive rats that is widely used as a model of the established hypertension in humans [19,20].


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
Twenty three hypertensive (SHR) and 27 normotensive (WKY) male rats, 6 months old, were obtained from the Animal Facility of the Facultad de Medicina, Universidad Autónoma de Madrid. This investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. Rats were anaesthetised with diethyl ether and systolic arterial pressure was registered by cannulating the carotid artery and connecting the cannula to a pressure transducer (Letica, Barcelona, Spain) and this in turn to a recorder (Letica Polygraph 2006). The average systolic pressure of the animals was 172±7 and 108±19 mmHg for SHR and WKY rats, respectively. The rats were sacrificed by bleeding and the ventral caudal (tail) artery was dissected free and cut into cylindrical segments 2 mm in length. Each segment was prepared for isometric tension recording in a 4-ml organ bath at 37°C, containing modified Krebs-Henseleit solution with the following composition (millimolar): NaCl, 115; KCl, 4.6; KH2PO4, 1.2; MgSO4, 1.2; CaCl2, 2.5; NaHCO3, 25; glucose, 11.1. The solution was equilibrated with 95% oxygen and 5% carbon dioxide to give a pH of 7.3-7.4. Briefly, the method consists of passing two fine, stainless steel pins, 100 µm in diameter, through the lumen of the vascular segment. One pin is fixed to the organ bath wall, while the other is connected to a strain gauge for isometric tension recording, thus permitting the application of passive tension in a plane perpendicular to the long axis of the vascular cylinder. The recording system included a Universal Transducing Cell UC3 (Statham Instruments, Inc.), a Statham Microscale Accessory UL5 (Statham Instruments, Inc.) and a Beckman Type RS Recorder (model R-411, Beckman Instruments, Inc.). A previously determined resting passive tension of 0.75 g was applied to the vascular segments, and then they were allowed to equilibrate for 60–90 min.

Electrical field stimulation (4 Hz, 0.2 ms pulse duration, at a supramaximal voltage of 70 V, for 1 s) was applied to the arteries via two platinum electrodes placed either side of the artery and connected to a CS-14 stimulator (Cibertec). An interval of 10 min was imposed between stimulation periods to allow recovery of the response, and the stimulation was repeated in every case until the responses were reproducible during over 40 min under control conditions. The vascular response to electrical stimulation was recorded in the presence of tetrodotoxin (10–6 M) or phentolamine (10–6 M), to test whether the response is mediated by stimulation of perivascular nerve terminals, and activation of {alpha}-adrenoceptors, respectively.

The effects of endothelin–1 (10–10–10–8 M), the agonist of endothelin ETB receptors IRL-1620 (10–9–10–7 M), arginine-vasopressin (10–12–10–10 M) or the agonist of vasopressin V2 receptors desmopressin (10–8–10–6 M) on the arterial response to electrical field stimulation were analysed. Each of these substances was added cumulatively to the organ bath, and electrical stimulation was applied 10 min after adding each concentration of the substance. In each experiment, a vascular segment which received electrical stimulation but was not treated with any substance was used as a time control.

The effect of endothelin-1 on the response to electrical stimulation was studied in arteries in the presence of BQ-123 (10–5 M) and BQ-788 (10–5 M), antagonists of endothelin ETA and ETB receptors, respectively, and the effect of vasopressin on the response to electrical stimulation was studied in arteries in the presence of d(CH2)5Tyr(Me)AVP (10–7 M) and d(CH2)5 D-Ile2, Ile4 AVP (10–7 M), antagonists of vasopressin V1 and V2 receptors, respectively. The effect of both endothelin-1 and vasopressin was studied in arteries in the presence of the blocker of calcium channels verapamil (10–5 M). After obtaining a reproducible, control response to electrical stimulation, an antagonist was added to the organ bath, and after 20 min incubation electrical stimulation was applied; then endothelin-1 or vasopressin was also added and electrical stimulation was again applied to the arteries in the presence of both the antagonist and endothelin-1 or vasopressin.

To examine the site of action, prejunctional or postjunctional, of endothelin-1 and vasopressin on the arterial response to electrical stimulation, cumulative concentration–response curves to noradrenaline (10–8–10–4 M) were performed in control conditions and in arteries treated with a single concentration of endothelin-1 (3x10–9 M) or vasopressin (3x10–11 M), these substances being incubated during 10 min before testing noradrenaline.

To determine the direct contractile effect of endothelin-1 (10–9–10–7 M) and vasopressin (10–10–10–7 M), cumulative concentration–response curves to these peptides were also performed in non-treated arteries.

The values of the contraction to endothelin-1, vasopressin and noradrenaline are shown in absolute values, and the effect of endothelin-1 or vasopressin on the response to electrical stimulation, as percentage increments over the control response. These data are expressed as means±SEM. EC50 values for the concentration–response curves for endothelin-1, vasopressin and noradrenaline were calculated as the concentration producing 50% of the maximal effect by geometric interpolation, and are expressed as pD2 (–log EC50). Data were evaluated by a analysis of variance applied to each group of data, followed by a Dunnet's test to compare each experimental condition with its control. P<0.05 was considered significant.

Drugs used were: (–) arterenol, bitartrate salt (noradrenaline), phentolamine hydrochloride, tetrodotoxin (Fugu poison), verapamil hydrochloride, [Arg8]-vasopressin acetate; [deamino-Cys1, D-Arg8]-vasopressin (desmopressin) acetate; the V1 antagonist (b-Mercapto-b, b -cyclopenta- methylenepropionyl1, O-Me-Tyr2, Arg8)-vasopressin [d(CH2)5Tyr(Me)AVP], from Sigma; cyclo (D-a-aspartyl-L-prolyl-D-valyl-L-leucyl-D-tryptophyl, peptide free base (BQ-123); N-(N-(N-(2,6-dimethyl-1-piperidinyl) carbonyl) -4-methyl-L-leucyl)-1-(methoxycarbonyl)-D-tryptophyl) D-norleucine monosodium (BQ-788), and endothelin-1 (8.21), N-Suc-(Glu9, Ala11,15), peptide free base (IRL-1620), from Research Biochemicals International; endothelin-1 (human, porcine) and the V2 antagonist d(CH2)5 D-Ile2, Ile4, Arg8 vasopressin, from Peninsula Laboratories All drugs were dissolved in distilled water and further diluted in isotonic NaCl.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Response to electrical field stimulation
Electrical stimulation (4 Hz) produced contraction of the vascular segments, which was similar in arteries from SHR (0.65±0.026 g) and from WKY (0.60±0.022 g) rats. This contraction was markedly reduced (95–97%) by tetrodotoxin or phentolamine. In time control experiments, a small progressive reduction of the response (4–5%) was observed throughout the duration of the experiments (~1 h).

3.2 Effects of endothelin-1 and vasopressin on the response to electrical field stimulation.
The concentrations of endothelin-1 (10–10–3x10–9 M in WKY and 10–10–10–8 M in SHR) and vasopressin (10–12–3x10–11 M in WKY and 10–12–10–10 M in SHR) used in this protocol did not produce contraction of the arteries or produced a contraction that was lower than 25% of the response to electrical stimulation. We consider that this small contraction should not affect greatly the response to electrical stimulation [21].

In arteries from WKY rats, endothelin-1 and vasopressin increased in a concentration-dependent way the contraction to electrical stimulation. However, in arteries from SHR, endothelin-1 did not modify significantly the contraction to electrical stimulation, and vasopressin produced an increase of this contraction which was significant only at the highest concentration studied (10–10 M) (Fig. 1).


Figure 1
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  		Fig. 1 Upper panels: effects of endothelin-1 on the contraction to electrical stimulation (4 Hz at supramaximal voltaje) in tail arteries from WKY and SHR rats, in the absence (control) and in the presence of BQ-123 (10–5 M) or BQ-788 (10–5 M). Lower panels: effects of vasopressin on the contraction to electrical stimulation (4 Hz at supramaximal voltaje) in tail arteries from WKY and SHR rats, in the absence (control) and in the presence of d(CH2)5Tyr(Me)AVP (10–7 M), or d(CH2)5 D-Ile2, Ile4 AVP (10–7 M). Points are means±SEM. In each case, data are average from 6–7 animals. *, *, Significantly different from the potentiation by endothelin-1 or vasopressin in the absence of antagonist (*P<0.05, *P<0.01).

 
In arteries from WKY rats, BQ-123 (10–5 M) abolished (P<0.01) and BQ-788 (10–5 M) partially reduced (P<0.01) the potentiation produced by endothelin-1 of the contraction to electrical stimulation. In arteries from SHR, endothelin-1 in the presence of BQ-123 or BQ-788 did not modify significantly the contraction to electrical stimulation, as occurred in control conditions (Fig. 1). The agonist of endothelin ETB receptors IRL-1620 (10–9–10–7 M), did not modify the contraction to electrical stimulation (not shown).

In arteries from both SHR and WKY rats, the antagonist of vasopressin V1 receptors d(CH2)5Tyr(Me)AVP (10–7 M) abolished (P<0.01), and the antagonist of vasopressin V2 receptors d(CH2)5 D-Ile2, Ile4 AVP (10–7 M) did not modify significantly, the potentiation produced by vasopressin of the contraction to electrical stimulation (Fig. 1). Desmopressin potentiated the contraction to electrical stimulation in arteries from both WKY and SHR rats but only at very high concentrations (3x10–7–10–6 M) (not shown).

The antagonist of calcium channels verapamil (10–5 M) reduced the contraction to electrical stimulation more (P<0.01) in arteries from SHR (69±3% reduction) than in those from WKY (53±3% reduction) rats. In the presence of this calcium antagonist, the potentiating effect of both endothelin-1 and vasopressin on the response to electrical stimulation in arteries from WKY rats was reduced (P<0.01), whereas the observed potentiating effect of vasopressin in arteries from SHR was increased (P<0.05). In the presence of verapamil, endothelin-1 did not modify the response of arteries from SHR to electrical stimulation, as occurred in control arteries (Fig. 2).


Figure 2
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  		Fig. 2 Effects of endothelin-1 and vasopressin on the contraction to electrical stimulation (4 Hz at supramaximal voltaje) in tail arteries from WKY and SHR rats, in the absence (control) and in the presence of verapamil (10–5 M). Points are means±SEM. In each case, data are average from 6–7 animals. *, *, Significantly different from the control (*P<0.05, *P<0.01).

 
3.3 Contraction to noradrenaline
Noradrenaline (10–8–10–4 M) produced a concentration-dependent contraction which was not significantly different in arteries from SHR (maximal effect=2.8±0.21 g, pD2=6.18±0.13) and WKY (maximal effect=2.5±0.22 g, pD2=6.26±0.07) rats. A single concentration of endothelin-1 (3x10–9 M) or vasopressin (3x10–11 M), which produced clear potentiation of the response to electrical stimulation, did not modify significantly the response to noradrenaline in arteries from SHR and WKY rats (Fig. 3).


Figure 3
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  		Fig. 3 Contraction to noradrenaline of tail arteries from WKY (left) or SHR (right) rats, in the absence (control) and in the presence of endothelin-1 (3x10–9 M) or vasopressin (3x10–11 M). Points are means±SEM. In each case, data are average from 6–7 animals.

 
3.4 Contraction to endothelin-1 and vasopressin
Endothelin-1 (10–9–10–7 M) and vasopressin (10–10–10–7 M) produced concentration-dependent contractions of arteries from both SHR and WKY rats, but the maximal effect was lower in arteries from SHR both for endothelin-1 (1.0±0.1 vs. 1.6±0.12 g, P<0.01) and vasopressin (1.6±0.1 vs. 2.0±0.1 g, P<0.05); the pD2 values were not significantly different in the arteries from the two types of rats both for endothelin-1 (7.77±0.02 vs. 7.85±0.07) and vasopressin (8.90±0.24 vs. 9.28±0.08). These results are summarised in Fig. 4.


Figure 4
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  		Fig. 4 Contraction to endothelin-1 (left) and vasopressin (right) of tail arteries from WKY or SHR rats. Points are means±SEM. In each case, data are average from 6–7 animals. *, *, Significantly different between arteries from WKY and SHR (*P<0.05, *P<0.01).

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
The present study suggests that endothelin-1 and vasopressin may modulate the vascular response to sympathetic stimulation, and that this modulation may be impaired during hypertension.

The results of the present study indicate that during normotension, both endothelin-1 and vasopressin potentiate the vasoconstriction to stimulation of perivascular sympathetic nerve endings, which confirm previous studies from our laboratory [13,15], and agree with those described by others [12]. In our experimental preparation, this potentiation may be due to the fact that these peptides enhance the release of noradrenaline by acting on perivascular sympathetic nerves at the prejunctional level. This hypothesis is based on the finding that the contraction to electrical stimulation was abolished by tetrodotoxin or phentolamine, indicating that this response is mediated by release of noradrenaline from sympathetic nerves, and that the contraction to electrical stimulation but not to exogenous noradrenaline was increased by endothelin-1 or vasopressin. Our results also suggest that the potentiation by endothelin-1 is mediated by endothelin receptors of the ETA rather than of the ETB subtype, because this effect was reduced more markedly by the ETA receptor antagonist BQ-123 than by the ETB receptor antagonist BQ-788, and moreover the ETB receptor agonist IRL-1620 did not reproduce the potentiating effects of endothelin-1 at any concentration used. Likewise, the potentiating effect of vasopressin may be mediated mainly by vasopressin V1 receptors, because this effect was reduced by a V1 receptor antagonist but was not affected by a V2 receptor antagonist; also the V2 receptor agonist desmopressin increased the sympathetic response only at very high concentrations, this effect being probably non specific. In relation to the effect of endothelin-1, both inhibitory and facilitatory prejunctional endothelin receptors have been described previously in the rat tail artery, respectively reducing and increasing the release of noradrenaline from perivascular sympathetic nerve endings [22]. These inhibitory receptors may be of the ETB subtype, but the nature of the facilitatory endothelin receptors was undecided in that study [22] because this response was antagonised similarly by BQ-123 and BQ-788. Our results in the presence of IRL-1620 or BQ-788 do not suggest, however, the presence of prejunctional inhibitory endothelin ETB receptors. This discrepancy between ours and that study [22] may be due to methodological differences. Particularly, in that study [22] greater stimulation frequency (8 vs. 4 Hz) and train duration (3 min vs. 1 s) were used, compared with our study, this may produce greater neurotransmitter release that may be differently affected by prejunctional inhibition. Regarding vasopressin, there are no studies in literature, to our knowledge, describing prejunctional vasopressin receptors in perivascular nerve endings.

Moreover, the possible increment in the release of noradrenaline from perivascular nerves, and thus the potentiation of the sympathetic contraction by endothelin-1 and vasopressin, may be mediated by calcium entry in perivascular nerve endings, because this phenomenon was abolished by verapamil, which is an antagonist of calcium channels of the L-type. The potentiating effects of endothelin-1 in rabbit ear artery [13] and of vasopressin in rat mesenteric [23] or rabbit ear [15] arteries have been shown to be dependent on extracellular calcium entry, although in these studies it is suggested that the effects of endothelin-1 and vasopressin may be postjunctional.

Comparing the results obtained in the arteries from normotensive and hypertensive rats, it may be suggested that during hypertension the effects of both endothelin-1 and vasopressin on the sympathetic vascular response are reduced, as both the potentiation by endothelin-1 and vasopressin, and the direct vascular contraction to these peptides, were lower in arteries from hypertensive than in those from normotensive rats. This impaired response may be specific for these peptides, because the vascular response to exogenous noradrenaline was not different in the arteries from both strains of rats. Our results with endothelin-1 may partially agree with those of Tabuchi et al. [16] in rat mesenteric arteries, who found impaired prejunctional and postjunctional effects of endothelin-1 in hypertensive rats. In these arteries, however, endothelin-1 may cause prejunctional inhibition and postjunctional facilitation of the sympathetic responses, which is different from what found in our study in the rat tail artery.

The differences found by us between normo and hypertensive rats regarding the potentiating effects of endothelin-1 and vasopressin may be due to the involvement of different types of calcium channels. In arteries from normotensive rats, calcium channels of the L type may mediate the potentiating effect of both endothelin-1 and vasopressin, because this phenomenon was reduced by verapamil, whereas in arteries from hypertensive rats endothelin-1 did not affect the response to nerve stimulation, and verapamil did not reduce but increased the potentiation by vasopressin. Thus, it may be suggested that in hypertension, as compared with normotension, the participation of L-type calcium channels in the potentiating effects of endothelin-1 and vasopressin may be reduced. It may be hypothesised that during hypertension endothelin-1 and vasopressin may have a lower ability to activate this type of calcium channels, due to impairment of the channel itself, of the endothelin and vasopressin receptors (e.g. diminished ETA or V1 receptor expression), or of mechanisms connecting the receptors with the channel. It is difficult to understand why verapamil increased the potentiating effect of vasopressin in arteries from SHR. We may speculate that, as the response to electrical stimulation is lower in the presence of this calcium antagonist, it is more easily potentiated by vasopressin, although a direct effect of verapamil on the V1 receptor can not be excluded.

Endothelin-1 and vasopressin potentiatied the contraction to sympathetic stimulation at low, subthreshold concentrations, these effects may therefore be relevant to the regulation of arterial pressure and to the pathophysiology of hypertension. The impaired potentiating effect found in arteries from hypertensive animals may be an adaptive phenomenon to the elevated arterial pressure. In some models of hypertension, such as the DOCA-salt hypertensive rat, in which the content of endothelin-1 in the vascular wall is elevated [24], the reduced responsiveness to this peptide has been explained as a downregulation phenomenon, due to prolonged exposure of the receptor to elevated concentrations of the agonist [5]. Although the SHR model of hypertension may not show increased content of endothelin-1 in the vascular wall [24], release of this peptide may be increased in some particular vascular beds, such as mesenteric arteries of SHR [25]. Plasma levels of vasopressin may be increased in hypertensive rats [26], which may contribute to the reduced response to this peptide.

In summary, the results of the present study suggest that the potentiating effect of endothelin-1 and vasopressin on the vascular response to sympathetic stimulation may be impaired during hypertension. This phenomenon may be an adaptive response of the vascular wall to the hypertensive status.

Time for primary review 34 days.


   Acknowledgements
 
The authors are grateful to Mrs. M.E. Martìnez and H. Fernández-Lomana for technical assistance. This work was supported, in part, by FIS (N° 96/0474), CICYT (N° PM95-0032) and CAM (N° AE00236/95).


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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