Attenuation of Genetic Hypertension After Short-term Vasopressin V1A Receptor Antagonism
Abstract Abnormalities of the vasopressin system are found in genetic hypertension. This study compares the delayed effects of a brief period of vasopressin V1A receptor blockade and angiotensin-converting enzyme inhibition in young female and male spontaneously hypertensive rats (SHR) on the development of hypertension in adult life. In a separate study, the role of vasopressin in the maintenance of blood pressure in adult SHR was assessed. Young SHR received either the nonpeptide vasopressin V1A receptor antagonist OPC-21268, the angiotensin-converting enzyme inhibitor ramipril, or vehicle from 6 to 10 weeks of age. During the treatment period, OPC-21268 and ramipril reduced systolic blood pressure compared with control SHR (P<.001). Blood pressure in male SHR 7 weeks after treatment withdrawal was 178±1 mm Hg in ramipril-treated, 184±1 mm Hg in OPC-21268–treated, and 200±2 mm Hg in control SHR (P<.001). Similar results were seen in female SHR, although both OPC-21268 and ramipril were less effective antihypertensive agents in female compared with male SHR. The sustained attenuation in blood pressure was not associated with significant cardiovascular structural changes (left ventricular–to–body weight ratio, renal weight–to–body weight ratio, mesenteric resistance artery media-to-lumen ratio). Results of vasopressin V1A receptor binding kinetics and plasma renin or aldosterone concentrations did not suggest a lasting effect of OPC-21268 on the vasopressin system or of ramipril on the renin-angiotensin system following treatment withdrawal. One week of OPC-21268 treatment in adult SHR had no effect on systolic blood pressure, indicating that vasopressin is not involved in the maintenance of blood pressure. In contrast, this study demonstrates the novel finding that brief vasopressin V1A blockade in young SHR attenuates the development of hypertension in adult SHR despite withdrawal of drug treatment. These results support a role for vasopressin in the development of hypertension.
Although the role of AVP in the pathophysiology of mineralocorticoid hypertension is well recognized,1 its contribution to the pathogenesis and maintenance of genetic hypertension remains controversial.2 3 The finding that hypertension develops in stroke-prone SHR crossbred with Brattleboro rats4 has long been a powerful argument against the importance of AVP, but the finding of AVP-like immunoreactivity indistinguishable from authentic AVP in peripheral tissues of the Brattleboro rat5 casts doubt on the validity of that argument. Earlier studies have investigated the role of AVP in the development of hypertension in the SHR using peptide AVP receptor antagonists. Treatment of young SHR with a mixed peptide V1/V2 receptor antagonist reduced blood pressure during treatment, but blood pressure rapidly returned to untreated levels within 2 weeks of treatment withdrawal.6 A similar study using a peptide V1 receptor antagonist had no effect on blood pressure in SHR.7
Such results contrast with the effect of ACE inhibition early in the development of hypertension, which prevents the full expression of hypertension in adult SHR.8 9 Such studies implicate Ang II as a hypertension-inducing factor, particularly since other classes of antihypertensive agents such as hydralazine, calcium antagonists, and β-blockers are less likely to cause persistent blood pressure reduction.10 The finding that blood pressure is not normalized but rather reset 20 to 30 mm Hg lower than in untreated SHR suggests that factors other than Ang II are involved in the pathogenesis of genetic hypertension.
In adult SHR with established hypertension, the role of AVP is unclear; there are reports that circulating vasopressin concentrations are increased and AVP receptor blockade lowers blood pressure as well as reports to the contrary.2 3
The development of nonpeptide AVP receptor antagonists has allowed the reassessment of the role of vasopressin in pathophysiological states. OPC-2126811 12 is a nonpeptide, orally active selective AVP V1A receptor antagonist that lowers blood pressure acutely in deoxycorticosterone acetate–salt hypertension,1 in Dahl salt-sensitive hypertension,13 and in the malignant phase of hypertension in the stroke-prone SHR.14 The purposes of this study were to compare the effect of a brief period of AVP V1A receptor blockade by OPC-21268 with ACE inhibition during the developmental phase of hypertension in young SHR and to assess the effect of withdrawal of treatment on blood pressure and cardiovascular structure in adult life. Sex differences in the efficacy of treatment were assessed because the pressor effects of AVP are greater in male than in female rats.15 In a separate study, the effect of chronic OPC-21268 treatment on blood pressure in adult SHR was examined.
Experimental procedures were approved by the Austin Hospital Animal Research Ethics Committee and performed according to the National Health and Medical Research Council of Australia guidelines for animal experimentation. OPC-21268 was a gift from the Otsuka Pharmaceutical Co Ltd. The selective AVP V1 receptor antagonist [1-(β-mercapto-β, β-cyclopentamethylene propionic acid), 7-sarcosine]AVP[d(CH2)5, sarcosine7]AVP was obtained from Auspep, Australia. AVP was purchased from Peninsula Laboratories Inc. Aprotinin, bacitracin, and Tris-HCl were obtained from Sigma Chemical Co. BSA was obtained from CSL Ltd. All other reagents were obtained from either BDH or Ajax Chemicals.
SHR and DRY rats were obtained from the Genetic Physiology Unit, Austin Hospital, Heidelberg, Australia. All SHR are regularly tested with polymorphic markers to confirm their inbred status. Rats were housed at 23°C to 25°C in a 12:12-hour light-dark cycle, with ad libitum food containing 0.4% to 0.6% NaCl (Norco) and water.
Blood Pressure Measurements
SBP was measured by the indirect tail-cuff technique (W&W recorder, model 8005) in preheated, lightly restrained rats. For direct intra-arterial MAP recording, rats underwent intraperitoneal injection of methohexitone sodium (0.4 mg/kg). A polyethylene cannula (PE-50) was inserted into the left carotid artery and exteriorized in the interscapular area. Rats were allowed to recover for 24 hours with free access to food and water. On the study day, conscious rats were weighed, and a blood pressure transducer (model DPT 3003-S, Peter von Berg) was calibrated and attached to the intra-arterial catheter. Transducer signals were preamplified before analog-to-digital conversion (MacLab/8TM, Analog Digital Instruments Pty, Ltd) for the recording and storage of data.
AVP V1A Receptor Binding Kinetics
Liver membranes were prepared, and the Bmax and apparent Kd of the V1A receptor were determined by use of the selective AVP V1 receptor antagonist [d(CH2)5, sarcosine7]AVP as previously described.11 16 17
Mesenteric Vessel Morphology
A mesenteric resistance artery biopsy was taken under intraperitoneal methohexitone sodium anesthesia. Resistance vessels of the first- or second-order branch of the superior mesenteric artery were dissected, and vessels ≈150 to 300 μm in external diameter were mounted in a microvascular myograph.1 Two mesenteric resistance arteries were assessed from each rat for lumen diameter, thickness of the media, and the media-to-lumen ratio.
Plasma AVP was extracted with acetone and ether and measured by radioimmunoassay (interassay and intra-assay coefficients of variation both <8%) with a specific rabbit AVP antiserum.18 Plasma osmolality was measured with a Wescor Vapor Pressure Osmometer 5100C. Membrane protein was measured by the method of Bradford with gamma globulin as standard.19 Plasma aldosterone was measured by Coat-A-Count direct radioimmunoassay, Diagnostic Products Co. Plasma renin activity was measured as described previously.20
Vasopressin V1A Blockade in Young SHR
Baseline SBP was measured in 5-week-old female (n=30) and male (n=28) SHR. Rats were randomized to one of three treatment groups and treated between the ages of 6 and 10 weeks with once-daily gavage of 5% arabic gum (vehicle), ramipril (1 mg/kg), or OPC-21268 (30 mg/kg). OPC-21268–treated rats also received OPC-21268 in their drinking water at a concentration adjusted according to weight and daily fluid intake to give a dose of 30 mg·kg−1·d−1 (based on data from unpublished metabolic studies). Rats therefore received a total daily OPC-21268 dose of 60 mg/kg. Treatment was withdrawn at the end of the 10th week of age, and the SBP was monitored for 7 to 8 weeks off treatment. At age 17 to 18 weeks, direct MAP was measured, the rats were decapitated, and trunk blood was collected for the measurement of plasma osmolality and plasma AVP. Kidneys were removed and weighed, and the left ventricle was dissected from the heart and weighed. Liver tissue was collected (n=5 to 7 per group) for AVP V1 receptor binding kinetics.
A subgroup of male SHR from each treatment group (n=5 per group) underwent an additional experiment at age 14 weeks in which a mesenteric resistance artery biopsy was taken for morphological analysis.
Vasopressin V1A Blockade in Adult SHR
These studies assessed the role of AVP in the maintenance of blood pressure in established hypertension in adult SHR.
Group 1: Acute AVP V1A blockade in adult SHR. MAP was measured in conscious, adult (16-week-old), male SHR (n=20) and DRY rats (n=20) for 7 hours after oral OPC-21268 (30 mg/kg) (SHR, n=10; DRY, n=11) or vehicle (SHR, n=10; DRY, n=9).
Group 2: Chronic AVP V1A blockade in adult SHR. SBP was measured daily 1 hour after gavage in 16-week-old, male SHR (n=20) that received twice-daily gavage with OPC-21268 (30 mg/kg) (n=10) or vehicle (n=10) for 7 days. Treatment stopped on day 7, and SBP was measured for the next 5 days.
Group 3: Vasopressin V1A receptors in adult SHR. Male 16-week-old SHR (n=8) and DRY rats (n=8) were gavaged with vehicle (SHR, n=4; DRY, n=4) or OPC-21268 (30 mg/kg) (SHR, n=4; DRY, n=4) and killed 1 hour later. We have previously shown that AVP V1A receptor binding inhibition by oral OPC-21268 is maximal at 1 hour.9 Trunk blood was collected for the measurement of plasma osmolality and AVP concentrations. Liver membranes were prepared for the determination of the Bmax and apparent Kd of the V1A receptor.
The results are presented as mean±SEM. Longitudinal weight and SBP were compared between groups by ANOVA for repeated measures followed by post hoc analysis using ANOVA and Scheffé’s test when appropriate. The biochemical, cardiovascular-structure, and binding kinetic data were analyzed by ANOVA and Scheffé’s test. Significant differences were obtained when P<.05.
The general condition of all rats was good throughout the study period. One control female SHR was found dead at age 15 weeks and another at age 18 weeks.
Vasopressin V1A Blockade in Young SHR
Rats grew normally over the treatment period, with no deleterious effect of treatment on body weight (Fig 1a⇓, female; 1b, male SHR).
Systolic Blood Pressure
Treatment of young SHR between the ages of 6 and 10 weeks with OPC-21268 or ramipril attenuated the development of hypertension in adult life (Fig 2a⇓, female; 2b, male SHR). Over the treatment period between 6 and 10 weeks of age, the control SHR showed a steady increase in blood pressure characteristic of the developmental phase of hypertension. At age 10 weeks in both sexes, blood pressure was significantly lower in groups treated with OPC-21268 or ramipril than in control SHR (female: vehicle, 150±2; OPC-21268, 142±1; ramipril, 136±1 mm Hg, P<.001; male: vehicle, 187±2; OPC-21268, 159±2; ramipril, 148±2 mm Hg, P<.001). In both sexes, ramipril lowered blood pressure to a greater extent than OPC-21268 (female, P<.05; male, P<.01).
After withdrawal of treatment, SBP rose in all groups but did not reach the levels of control SHR in the groups treated with OPC-21268 or ramipril. Eight weeks after treatment withdrawal in female SHR, SBP was lower in groups previously treated with OPC-21268 or ramipril than in control SHR (female: vehicle, 194±1; OPC-21268, 183±1; ramipril, 176±1 mm Hg, P<.0001). Ramipril lowered blood pressure to a greater extent than OPC-21268 (P<.0001). Similarly, 7 weeks after treatment withdrawal in male SHR, SBP was lower in groups previously treated with OPC-21268 or ramipril than in control SHR (male: vehicle, 200±2; OPC-21268, 184±1; ramipril, 178±1 mm Hg, P<.001). Again, ramipril lowered blood pressure to a greater extent than OPC-21268 (P<.0001).
Mean Arterial Blood Pressure
Direct MAP measurements in female SHR at 18 weeks and male SHR at 17 weeks confirmed that earlier treatment with OPC-21268 (female, P<.05; male, P<.05) or ramipril (female, P<.01; male, P<.05) reduced adult MAP compared with control SHR (Fig 3⇓, Table 1⇓).
Analysis of the relative fall in SBP in adult SHR off treatment for 7 to 8 weeks demonstrated that OPC-21268 was more effective in male SHR (male, 8% fall; female, 5.6% fall, P<.001) than was ramipril (male, 12.1% fall; female, 9.5% fall, P<.0001).
Although previous treatment with OPC-21268 or ramipril in young SHR lowered blood pressure into adulthood, this was not associated with a reduction in left ventricular–to–body weight ratio or an increase in renal weight–to–body weight ratio in either sex (Table 1⇑). The trend toward a reduction in media-to-lumen ratio 4 weeks after withdrawal of ramipril (Table 2⇓) did not reach statistical significance.
AVP Receptors and Hormonal Effects
No significant differences between the groups were observed for plasma vasopressin or plasma osmolality (Table 1⇑) after treatment had been stopped for 7 to 8 weeks. The binding kinetics of the AVP V1A receptor measured in female and male SHR 7 to 8 weeks after OPC-21268 withdrawal were unchanged (data not shown), indicating no persistent effect of OPC-21268 at the AVP receptor. Similarly, previous ramipril had no effect on plasma renin activity or plasma aldosterone in male SHR (Table 1⇑), indicating no persistent suppression of the renin-angiotensin system after withdrawal of treatment.
Vasopressin V1A Blockade in Adult SHR
Group 1: Acute AVP V1A Blockade in Adult SHR
Baseline body weights were similar in all rats (SHR, 346±7 g, n=20; DRY, 330±13 g, n=20). The SHR were hypertensive (MAP, 180±5 mm Hg, n=20) compared with DRY rats (MAP, 134±3 mm Hg, n=20) (P<.01), and oral OPC-21268 (30 mg/kg) significantly lowered MAP in the SHR alone (P<.01) (Fig 4a⇓). The average maximal fall in MAP in the OPC-21268–treated SHR was 26±3 mm Hg, and the average time to the maximal effect was 2.1±0.4 hours. After 3 to 4 hours, all rats tended to fall asleep, and in the SHR, whether treated or untreated, sleep was associated with a nonsignificant further fall in blood pressure.
Group 2: Chronic AVP V1A Blockade in Adult SHR
Baseline SBP in the SHR was 206±2 mm Hg (n=20). Chronic oral OPC-21268 had no significant effect on SBP (Fig 4b⇑) or on body weight compared with vehicle (day 1: OPC-21268, 330±7 g; vehicle, 305±8 g; day 7: OPC-21268, 320±7 g; vehicle, 309±12 g; day 12: OPC-21268, 345±6 g; vehicle, 331±7 g).
Group 3: Vasopressin AVP V1A Receptors in Adult SHR
Table 3⇓ shows the acute effect of orally administered OPC-21268 (30 mg/kg) on Bmax and Kd of V1 binding sites in rat liver membranes in SHR and DRY rats. Basal Bmax was significantly higher in DRY rats than in SHR (P<.05). Oral OPC-21268 significantly increased the apparent Kd (P<.01) of the liver V1 receptor in both SHR and DRY rats, with no effect on liver Bmax, indicating that OPC-21268 acts as a competitive inhibitor at the AVP V1 receptor. There were no significant differences in plasma AVP concentrations or plasma osmolality between the SHR and DRY rats and no effect of OPC-21268 compared with vehicle on either parameter in either group (Table 3⇓).
The results of this study provide evidence that the vasopressin system is involved in the development of genetic hypertension. Short-term treatment with the nonpeptide AVP V1A receptor antagonist OPC-21268 in young SHR during the developmental phase of hypertension led to persistent lowering of blood pressure into adulthood despite withdrawal of treatment. As with ACE inhibition during the developmental phase, OPC-21268 did not reduce blood pressure to normotensive levels but rather reset SBP at a significantly lower level compared with control SHR. These novel results have been shown in both male and female SHR. In contrast, AVP is unlikely to play a major role in the maintenance of hypertension, since chronic AVP V1A receptor blockade did not lower blood pressure in adult male SHR with established hypertension.
Although many studies on ACE inhibition and the development of genetic hypertension exist in the literature, few articles have as yet addressed similar questions concerning the role of AVP. Sladek et al7 showed that chronic AVP blockade with a peptide V1 receptor antagonist, d(CH2)5-d-Tyr(Me)AVP, from 4 to 13 weeks had no effect on blood pressure, whereas a mixed peptide V1/V2 receptor antagonist, d(CH2)5-d-Tyr(Me)VAVP, from 4 to 18 weeks reduced blood pressure, albeit short term.6 It is difficult to explain the latter, since blockade of a putative vasodilator V2-like receptor might be expected to increase peripheral resistance and attenuate the effect of V1 antagonism. Differences in affinity of the antagonists for their receptor, accessibility of the antagonists to the putative site of action, or the timing of the intervention may explain the differences between results with peptide and nonpeptide AVP receptor antagonists. More recently, male SHR of an unspecified age were treated for 10 weeks with high-dose oral OPC-21268 (200 mg·kg−1·d−1).21 Rats were hypertensive at the start of treatment (140 mm Hg), and OPC-21268 appeared to lower final SBP by 20 mm Hg compared with control SHR. This effect was not significant, possibly due to small numbers, but may reflect, as with ACE inhibition, that there is a certain critical phase during which treatment must be started to produce significant and lasting effects on blood pressure.22 Further studies will be required to answer this important question.
The mechanism responsible for the persistent antihypertensive effects of OPC-21268 and ramipril after treatment withdrawal remains unclear. The AVP V1 binding kinetics results do not indicate any lasting effects of OPC-21268 at the V1A receptor after treatment withdrawal. Persistent ACE inhibition after ramipril withdrawal is also unlikely, as indicated by unchanged plasma renin activity and aldosterone concentrations. Furthermore, if persistent tissue ACE inhibition were responsible for the fall in blood pressure, reversal of structural hypertrophy would also be expected. The lack of regression of cardiovascular hypertrophy despite the fall in blood pressure is not unexpected, considering that the rats had received no treatment for at least 7 weeks. It is well known that whereas ACE inhibition causes regression of cardiovascular hypertrophy during treatment, the benefits appear to be reversed once treatment stops. In male SHR treated with perindopril between ages 6 and 10 weeks, no change in cardiac-to–body weight ratio or in media-to-lumen ratio was present at 25 weeks, although differences had been present at 10 weeks of age when the rats were on treatment.9
Although our data suggest that improvement in structural hypertrophy in the heart or the resistance vessels is not necessary for blood pressure reduction, the corollary may be true, ie, that lack of structural improvement is due to the lack of normalization of blood pressure. It is also possible that the blood pressure reduction per se during the developmental phase may be responsible for the persistent lowering of blood pressure in the adult rat. Since this effect has not been seen with antihypertensive agents other than the ACE inhibitors and now with AVP V1A receptor blockade, it is more likely that treatment has interfered with a specific mechanism such as Ang II or AVP. Since neither OPC-21268 nor ramipril normalized blood pressure, neither the AVP nor the renin-angiotensin system can be implicated as the sole mediators of the development of hypertension in the SHR; studies currently under way address whether the combination of an ACE inhibitor and AVP receptor blockade during development will normalize adult blood pressure in the SHR. It has previously been shown that the combination of OPC-21268 and the ACE inhibitor captopril in male Dahl salt-sensitive rats was not additive in terms of blood pressure reduction, although each individual treatment attenuated hypertension.13 On the other hand, in female Dahl salt-sensitive rats, neither treatment alone was effective, whereas the combination prevented an increase in blood pressure. The relevance of these results to the present study is uncertain, considering the difference in the hypertensive model and the treatment regimens used.
Our results also suggest that there is a sex difference in the efficacy of OPC-21268 and ramipril. Ramipril lowered blood pressure to a greater extent than OPC-21268 in both sexes, and both OPC-21268 and ramipril were more effective antihypertensive agents in male than in female SHR. The pressor response to AVP is greater in male than in female rats,15 and it has recently been shown that sex-specific differences in G protein signaling exist in kidneys from hypertensive rats.23 These observations certainly deserve further study and may have important clinical implications for treatment of human hypertension.
It is not clear how AVP V1 blockade with OPC-21268 during the developmental phase of hypertension leads to persistent reduction in blood pressure after treatment withdrawal. OPC-21268 may act directly at the vascular V1 receptor to antagonize the action of circulating or local AVP. During the development of hypertension, AVP may contribute to increased renovascular resistance24 through AVP-induced vasoconstriction in the vasa recta of the renal medulla.25 It is possible that antagonism by OPC-21268 could improve medullary blood flow, prevent the rise in renovascular resistance, and attenuate subsequent hypertension. OPC-21268 antagonizes AVP-induced vasoconstriction in rat mesenteric resistance arteries,1 26 but to date, its effects in the renal vasculature are unknown. Alternatively, OPC-21268 may act centrally to reduce AVP-mediated increased sympathetic outflow, which is thought to contribute to the development of hypertension.27 28 It is not clear whether central AVP V1 receptors29 are accessible to orally administered OPC-21268, which could, however, act at the circumventricular organs, which lack a blood-brain barrier.
In established hypertension, AVP does not play a major role in the maintenance of blood pressure in the SHR, since chronic treatment with OPC-21268 failed to lower blood pressure. On the other hand, the finding in this and other studies14 that an acute dose of OPC-21268 will lower blood pressure in established hypertension illustrates the point that the initial responses to blockade of homeostatic systems may not predict the long-term responses. Since binding kinetic studies confirmed that OPC-21268 was blocking the AVP V1 receptor, the lack of effect of 1 week of treatment may reflect the vascular structural changes and their importance in the maintenance of hypertension. Like other pressor agents, AVP is a growth factor,30 and since OPC-21268 antagonizes the action of AVP in vascular smooth muscle cells,31 32 it is possible that a longer period of OPC-21268 treatment may regress cardiovascular hypertrophy.
In summary, this study provides support for the importance of AVP in the development of genetic hypertension. Since AVP V1 receptor antagonism during the developmental phase of hypertension using the nonpeptide OPC-21268 attenuated but did not normalize blood pressure in the adult, it is likely that AVP is only one of a number of factors involved in the pathogenesis of genetic hypertension. The importance of Ang II in the development of genetic hypertension was confirmed, because ramipril treatment in young SHR also led to resetting of blood pressure in adulthood. In contrast, AVP does not play a major role in the maintenance of hypertension in the adult SHR, when nonspecific structural effects are perhaps more relevant. This work adds to our understanding of the pathogenesis of hypertension and may lead to the development of new treatment strategies.
Selected Abbreviations and Acronyms
|Ang II||=||angiotensin II|
|ANOVA||=||analysis of variance|
|Bmax||=||maximal binding site density|
|propionic acid), 7-sarcosine]AVP|
|MAP||=||mean arterial pressure|
|SBP||=||systolic blood pressure|
|SHR||=||spontaneously hypertensive rats|
This work was supported by grants from the Austin Hospital Medical Research Foundation and the National Health and Medical Research Council of Australia.
- Received May 15, 1995.
- Revision received July 5, 1995.
- Accepted August 7, 1995.
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