Abstract Angiotensin II subtype 1 (AT1) receptor antagonists reduce mean arterial pressure in various experimental models of hypertension, including two-kidney, one clip (2K1C) renal hypertension. However, the regional hemodynamic mechanisms underlying the hypotensive effect of AT1 receptor antagonists in 2K1C rats under dynamic conditions have not been documented. Therefore, in the present study we determined the hemodynamic profile of the AT1 receptor antagonist CV-11974 in conscious 2K1C rats and sham-operated control rats. Approximately 4 weeks after clipping, rats underwent a further two-stage operation for implantation of Doppler flow probes on the contralateral (left) renal artery, superior mesenteric artery, and distal aorta as well as for the implantation of intravascular catheters. At least 24 hours after the last operation continuous recordings were made of mean arterial pressure; heart rate; and renal, mesenteric, and hindquarters flows and conductances (Doppler shift/mean arterial pressure) in response to three doses of CV-11974 (0.01, 0.1, and 1.0 mg/kg IV). CV-11974 caused a small hypotensive effect (decrease of approximately 15 mm Hg) in the sham group, but regional flows and vascular conductances did not change. By contrast, in 2K1C rats CV-11974 caused dose-dependent hypotension that was maximal (−19±6, −41±4, and −51±8 mm Hg, respectively) after 6 hours. These changes were associated with generalized vasodilatation (increased conductance) in all three vascular beds, although there were subtle differences with the different CV-11974 doses. The lowest dose of this compound tested (0.01 mg/kg, n=7) caused transient vasodilatation, and the intermediate dose (0.1 mg/kg, n=8) caused maximal vasodilatation in the mesenteric and hindquarters circulations (approximately 50% increase in conductances). A 10-fold higher dose of CV-11974 (1.0 mg/kg, n=7) produced sustained, hyperemic renal vasodilatation (approximately 30% and 70% increases in renal flow and conductance, respectively) in addition to mesenteric and hindquarters vasodilatation. Thus, CV-11974–induced hypotension was accompanied by widespread vasodilatation, although this was dose dependent only in the renal vascular bed. This study illustrates that AT1 receptor blockade causes vasodilatation in both renal and nonrenal circulations in 2K1C hypertension, contrasting with the relatively selective renal vasodilatation observed previously in spontaneously hypertensive rats. In addition, it was demonstrated that the maximal hypotension caused by CV-11974 occurred much later than the blockade of the cardiovascular effects of angiotensin II. This temporal disparity may imply that in addition to inhibition of tonic vasoconstriction maintained by circulating and/or tissue renin angiotensin systems, other mechanisms may also be involved in the antihypertensive effect of CV-11974.
The diverse cardiovascular actions of Ang II are generally considered to occur as a result of stimulation of AT1 receptors, which have a widespread peripheral and central distribution. Interestingly, AT1 receptor antagonists, such as losartan, have been shown consistently to lower MAP in SHR and renal hypertensive rats after peripheral administration.1 In addition, in other experimental models causing activation of the RAS, such as water deprivation, AT1 receptor antagonists also reduce MAP.2 3
However, the measurement of systemic blood pressure alone does not indicate where hemodynamic changes are occurring that contribute to the hypotensive effect. To this end, we have recently described the regional hemodynamic effects of the AT1 receptor antagonist CV-11974 in conscious SHR. We found that CV-11974 caused a relatively selective vasodilatation in the renal vascular bed that is likely to contribute to the antihypertensive effect of this compound.4 Since the SHR is generally considered to be a model exhibiting normal PRA, we were interested in examining the hemodynamic effects of CV-11974 in a high-renin–dependent model of hypertension. For this purpose we used 2K1C rats, at a time when they have elevated PRA, and continuously measured blood flow in the contralateral kidney together with mesenteric and hindquarters flows.
Most previous studies testing AT1 receptor antagonists in renal hypertensive rats have only measured MAP in the conscious state1 5 6 or have determined renal hemodynamics at arbitrary time points with the use of microsphere injections in 2K1C rats.7 8 In the present study the regional hemodynamic effects of three CV-11974 doses in conscious 2K1C rats are described. This compound is a benzimidazole-7-carboxylic acid derivative and is the active metabolite of TCV-116 and has previously been shown to antagonize the actions of Ang II both in vitro and in vivo, leading to a reduction in MAP.6 9 10 11
Experimental procedures were approved by the Monash University Animal Ethics Committee and performed according to the National Health and Medical Research Council of Australia guidelines for animal experimentation.
To establish 2K1C hypertension, male Sprague-Dawley rats of approximately 5 weeks of age (150 to 200 g) were anesthetized with sodium methohexital (Brietal, Eli Lilly; 60 mg/kg IP, supplements as required). A U-shaped silver clip (0.2 mm ID) was placed on the right renal artery, following a flank incision, to cause partial renal occlusion. A sham control group of rats received similar surgical intervention except that the silver clip was not inserted. Systolic pressure was measured in both groups at weekly intervals with a tail-cuff pneumatic pulse transducer coupled to a sphygmomanometer preamplifier (Grass Instrument Co). Only rats with systolic pressure greater than 160 mm Hg were used. Approximately 4 to 5 weeks after clipping, both rat groups were anesthetized and had pulsed Doppler flow probes implanted for monitoring of contralateral (left) renal, mesenteric, and hindquarters blood flows, as described previously.12 13 At least 7 days later, under anesthesia, rats had catheters inserted into the right jugular vein for drug administration and another inserted into the distal aorta via the caudal artery for measurement of arterial blood pressure.
Experiments were begun in conscious rats at least 1 day after intravascular catheter implantation. Continuous recordings of blood pressure; heart rate; and mean and phasic renal, mesenteric, and hindquarters Doppler shift signals were made with a pulsed Doppler flowmeter (Crystal Biotech), and all variables were displayed on a Maclab-8 system (AD Instruments) interfaced with a Macintosh computer. The Doppler shift signal is used as a reliable index of blood flow.14 Regional vascular conductances were calculated by dividing the appropriate mean Doppler shift signal by MAP.
At the start of an experiment a plasma sample (0.2 mL) was collected from each rat for determination of PRA as described previously.15 Fifteen 2K1C rats and 10 sham-operated rats weighing 320 to 390 g were used in this study. Three CV-11974 doses (0.01, 0.1, and 1.0 mg/kg IV) were given to 2K1C and sham control rats, and the changes from baseline hemodynamic values were monitored for at least 24 hours. Separate groups of 2K1C rats received 0.01 mg/kg (n=7) and 0.1 mg/kg (n=8) CV-11974, and a 10-fold higher dose (1.0 mg/kg) was given to seven of these rats at least 24 hours after a lower dose of the compound. A dose of Ang II (25 to 50 ng) causing a pressor response of approximately 20 to 30 mm Hg was given before and approximately 30 minutes, 2, 6, and 24 hours after CV-11974 administration to test for functional blockade of the cardiovascular responses to Ang II.
At the end of experimentation rats were killed by anesthetic overdose, and the kidneys were removed and weighed.
The effects of CV-11974 relative to the predrug baseline in each group were assessed by one-way ANOVA with repeated measurements. Data from all cardiovascular variables are expressed as mean±group standard error, which was calculated from the equation , where EMS is the error mean square from the ANOVA, and n is the number of rats in each group. Additionally, the inhibitory effects of CV-11974 on maximal responses to Ang II were assessed in a similar manner. Data analysis was performed with a commercially available statistical package (clr anova), and all post hoc analysis was done with the Newman-Keuls test. A value of P<.05 was taken as significant.
Development of Hypertension in 2K1C Rats
Changes in systolic pressure over 4 weeks after the right renal artery was clipped are shown in Fig 1⇓. Basal systolic pressures did not differ before surgery between the two rat groups. Thereafter, systolic pressure increased progressively in 2K1C rats, whereas blood pressure remained unchanged in the sham control rats. Differences in systolic pressure between 2K1C rats and sham controls were evident after 2 weeks (Fig 1⇓).
Basal Values for Cardiovascular Variables
Hemodynamic variables in the resting state in 2K1C and sham-operated rats are shown in Table 1⇓. The 2K1C rats had significantly higher resting MAP (P<.01) and PRA (P<.01) compared with sham controls. Regional flows were not significantly different between groups. Given the hypertension in the 2K1C rats, all vascular conductances were reduced; however, only the decrease in mesenteric conductance was significant (P<.05). Left and right kidney weights were similar in sham controls; however, in 2K1C rats the weight of the clipped (right) kidney was significantly less (P<.01) than weights of the left kidney and of both kidneys in the sham group.
Hemodynamic Effects of Ang II
Before CV-11974 administration, Ang II was given to both 2K1C rats and sham controls to cause a pressor response (20 to 30 mm Hg). Typically, 25 ng Ang II was used, although 50 ng Ang II was used in three rats and these responses were pooled. The Ang II–induced pressor response was accompanied by bradycardia and marked reductions in renal (approximately 45% to 50%) and mesenteric (approximately 50% to 60%) flows and variable increases in hindquarters flow (approximately 20% to 40%). Thus, there were pronounced reductions in renal (approximately 60%) and mesenteric (approximately 60% to 70%) conductances, with minimal change in hindquarters conductance (Figs 2⇓ and 3⇓). Similar hemodynamic responses to Ang II were observed in the sham-operated group (data not shown).
Ang II was tested at various times after CV-11974 administration (0.01 to 1.0 mg/kg). In 2K1C rats, 0.01 mg/kg CV-11974 markedly attenuated the effect of Ang II for several hours, although the Ang II response had virtually returned to control values 6 hours later (Fig 2⇑). With a 10-fold higher dose (0.1 mg/kg), CV-11974 abolished the effects of Ang II for 6 hours, but less than 24 hours, for all variables except the pressor response, which was slightly impaired at 24 hours (Fig 3⇑). Analogous results were obtained with 1.0 mg/kg CV-11974 in 2K1C rats and for all three doses of CV-11974 in sham-operated rats (data not shown).
Hemodynamic Effects of CV-11974
The effects of CV-11974 on regional flows and vascular conductances in the 2K1C hypertensive and sham control groups for the 0.1 mg/kg dose are shown in Figs 4⇓ and 5⇓ and for the 1.0 mg/kg dose in Figs 6⇓ and 7⇓. Additionally, the dose response relationship exhibited for the three CV-11974 doses in 2K1C rats for regional flows and conductances are shown in Figs 8⇓ and 9⇓.
In sham controls CV-11974 caused a small but significant hypotensive effect (maximum, approximately 15 mm Hg; P<.01), although regional flows (Figs 4⇑ and 6⇑) and conductances (Figs 5⇑ and 7⇑) did not change significantly with these doses. By contrast, in 2K1C rats 0.1 and 1.0 mg/kg CV-11974 caused progressive depressor responses that were maximal after 6 hours (−41±4 and −51±8 mm Hg, respectively). Whereas all regional flows tended to increase transiently, only the increase in mesenteric flow (1 to 5 minutes, maximum=19±9%, P<.05) after 0.1 mg/kg CV-11974 and the sustained increase in renal flow (1 minute to 4 hours, maximum=30±6%, P<.01) after 1.0 mg/kg CV-11974 were significant (Figs 4⇑ and 6⇑). Thus, given that flows were well maintained, vascular conductances were markedly increased at each site examined (Figs 5⇑ and 7⇑). Moreover, MAP was still significantly decreased 24 to 48 hours after CV-11974, and there were small increases in regional conductances, but these were not significant (Table 2⇓). Additionally, in some rats MAP was decreased for more than 2 days.
We also tested 2K1C rats with a lower dose of CV-11974 (0.01 mg/kg) to match more closely the hypotensive effect of this compound in SHR.4 For comparative purposes these data were plotted together with data from the other CV-11974 doses in 2K1C rats in Figs 8⇑ and 9⇑. Interestingly, CV-11974 (0.01 mg/kg) evoked significant increases in renal (3 to 20 minutes, maximum=29±8%, P<.01), mesenteric (5 to 10 minutes, maximum=14±3%, P<.05), and hindquarters (60 to 120 minutes, maximum=17±6%, P<.01) flows, although hypotension was not evident until 90 minutes to 6 hours (maximum=−19±6 mm Hg, P<.01) (Fig 8⇑). Renal (5 to 20 minutes, maximum=28±12%, P<.05) and mesenteric (10 minutes, 12±2%, P<.05) conductances transiently increased, and hindquarters conductance increased from 90 minutes to 6 hours (maximum=25±8%, P<.01) (Fig 9⇑). Clearly, CV-11974 caused dose-related increases in renal conductance, although the increases in conductances in the mesenteric and hindquarters circulations were maximal after the intermediate dose of CV-11974 (Fig 9⇑).
In the present study we have shown that the AT1 receptor antagonist CV-11974 caused dose-related hypotension and peripheral vasodilatation in conscious renal hypertensive rats. To our knowledge this is the first study to document the regional hemodynamic effects of an AT1 receptor antagonist under dynamic conditions in conscious 2K1C rats.
As expected and in accordance with other studies,16 17 18 19 2K1C rats had higher basal MAP, and PRA was approximately sevenfold higher compared with sham rats. Our studies were performed approximately 4 to 6 weeks after clipping during the acute phase of renal hypertension (phase 1), during which elevations in PRA are maximal.18 19 20 21 The stimulus for the marked increase in renin release, which can be detected within 1 to 2 days after clipping,22 is thought to be underperfusion of the clipped kidney.18 19 21 23
In the present study we monitored renal hemodynamics in the nonclipped kidney continuously with Doppler flowmetry to measure renal flow in the left (contralateral) kidney of 2K1C rats and their normotensive sham-operated counterparts. We found that contralateral renal flow was in fact slightly but not significantly increased in the hypertensive group, in the face of an activated RAS and thus increased MAP. Previous studies have demonstrated similar findings in the nonclipped kidney, which, because of the elevated systemic blood pressure, have resulted in increased renal vascular resistance.23 We found that the reduction in resting renal conductance in 2K1C rats failed to reach significance compared with control rats. In any case, a generalized state of activation of the RAS can be inferred from the uniform decreases in vascular conductances because the mesenteric and hindquarters conductances were also reduced, indicative of vasoconstriction in the resting state. However, it must be realized that we have not measured actual volume flow; therefore, any between-group comparison must be viewed in this light.
The reasons why contralateral renal flow is well maintained during this renin-dependent hypertensive phase are not completely understood but may involve alterations in autoregulatory mechanisms and pressure natriuresis23 and also humoral vasodilator factors that oppose the effects of Ang II.18 19 In this context, it has recently been suggested that renal perfusion in the nonclipped kidney is largely maintained by the vasodilator influence of nitric oxide.8
The dependence of hypertension in 2K1C rats on the RAS is well accepted, given that inhibitors of the RAS will reverse raised MAP acutely or will prevent the development of renal hypertension.1 18 19 21 23 In the present study the effects of CV-11974 are consistent with this concept because the AT1 receptor antagonist produced dose-dependent hypotension in 2K1C rats that was not as apparent in normotensive rats. Nevertheless, there was a small hypotensive effect in the normotensive group, as is sometimes reported for AT1 receptor antagonists.1 The two highest doses of CV-11974 tested (0.1 and 1.0 mg/kg IV) abolished the cardiovascular effects of Ang II over 6 hours, similar to data obtained previously in conscious normotensive rats.10 The Ang II dose used (25 ng) was larger than that used in analogous studies in conscious SHR,4 which probably reflects a reduced sensitivity to exogenously administered Ang II in the activated RAS model and/or enhanced sensitivity in the SHR model. CV-11974 at these doses caused marked, abrupt falls in MAP (approximately 40 to 50 mm Hg) that were considerably larger than those observed previously in SHR (approximately 25 mm Hg).4 These data are consistent with the effects of the parent compound, TCV-116, which was also found to be more efficacious in 2K1C rats compared with SHR.6 Therefore, to make additional hemodynamic comparisons with SHR, we gave a 10-fold lower dose (0.01 mg/kg) of CV-11974 to 2K1C rats to evoke a smaller hypotensive effect.
The most striking finding in the present study was that in parallel with the hypotension, CV-11974 caused generalized vasodilatation in all three vascular beds examined although the resultant vasodilatation was dose dependent only in the renal vascular bed. This can clearly be seen by the fact that the CV-11974–induced increases in mesenteric and hindquarters conductances were maximal after the intermediate dose (0.1 mg/kg), whereas renal conductance increased further with the 10-fold higher CV-11974 dose.
The mechanisms underlying these hemodynamic differences can be inferred by examination of the actual blood flows in the three regions. With the two highest CV-11974 doses tested (0.1 and 1.0 mg/kg) flows in the mesenteric and hindquarters circulations were well maintained and even transiently increased (eg, mesenteric flow over the first 5 minutes following 0.1 mg/kg) in the face of marked, rapid hypotension that resulted in pronounced vasodilatation. By contrast, the highest CV-11974 dose remarkably caused hyperemic renal vasodilatation because renal flow increased above basal levels for several hours despite an even greater hypotensive response. Thus, renal vasodilatation was substantially higher than that produced in the other two vascular beds (ie, increases in renal conductance versus mesenteric/hindquarters conductances of approximately 70% and 50%, respectively).
It is also possible that part of the hemodynamic change after CV-11974 occurred as a result of an autoregulatory mechanism in response to the fall in MAP, although this cannot be ascertained directly. Nevertheless, it is conceivable that superimposed on the direct inhibition of Ang II–mediated vasoconstriction, a component of the increased vascular conductances after CV-11974 was autoregulatory in nature and so secondary to the initial hypotensive effect. This may be more relevant in the renal vasculature because the kidney is well recognized as a strongly autoregulating organ.
Interestingly, the hemodynamic profile of CV-11974 in 2K1C rats was quite different to that previously seen in SHR at the same doses4 ; this is likely to reflect the different levels of tonic vasoconstriction maintained by Ang II in the two experimental models. The SHR model is considered to have normal PRA, although it is well documented that vasoconstrictor tone in the kidney is enhanced by Ang II.24 25 26 27 Indeed, we previously found that basal renal conductance was decreased significantly in SHR compared with Wistar-Kyoto rats; however, basal mesenteric and hindquarters conductance values were similar between the two strains. Accordingly, CV-11974 (0.1 mg/kg) caused hyperemic vasodilatation that was confined to the renal compartment, further supporting the pivotal role of the kidney in the antihypertensive action of CV-11974 in SHR.4 In 2K1C rats, however, widespread tonic vasoconstriction was evident by the uniform decreases in vascular conductances with respect to sham controls, which presumably reflected higher plasma renin levels in this model. As a consequence, the magnitude as well as the sites of vasodilatation in 2K1C rats were increased compared with SHR, leading to substantial vasodilatation in all three vascular beds examined. Moreover, hypotension persisted for several days, in contrast to the effect of CV-11974 in SHR, although the reason for this is not immediately obvious.
However, given that CV-11974 selectively increased renal flow and conductance in SHR but with only modest hypotension,4 it was of interest to determine whether a similar selective effect of CV-11974 could be observed only in the renal compartment of 2K1C rats. Therefore, we also tested a 10-fold lower dose of the antagonist to match more closely the degree of hypotension seen in SHR. At this dose (0.01 mg/kg) CV-11974 markedly increased both renal and mesenteric flows to the same extent in their respective regions, as seen with the higher doses of the compound, which is consistent with the marked attenuation of the effect of Ang II. Thereafter, renal and mesenteric vasodilatation rapidly waned before the development of any significant hypotension (>90 minutes). Thus, it was not possible to produce a renal-selective profile in 2K1C rats, although it was difficult to match exactly the time course of hypotension in the two models because of the delayed hypotension in the 2K1C rats, presumably offset initially by an increase in cardiac output.28 Nevertheless, in water-deprived Brattleboro rats, which also exhibit an activated RAS, losartan and its metabolite EXP 3174 both caused hypotension of similar magnitudes and time courses to that seen in SHR but with widespread vasodilatation.2 3 Therefore, those data further support the idea that high-renin–state models, unlike SHR, exhibit generalized vasodilatation in response to AT1 receptor antagonists.
Several other studies have tested the renal hemodynamic function of Ang II receptor antagonists in 2K1C rats, although the simultaneous measurement of nonrenal regions is less often performed. With the use of clearance studies in anesthetized 2K1C rats, it was found that saralasin infusions significantly increased renal flow, glomerular filtration rate, and excretory function in the nonclipped but not the clipped kidney.29 Other researchers7 8 have performed single microsphere determinations in untreated or losartan-treated 2K1C rats. Losartan lowered MAP and caused small (nonsignificant) increases in renal flow and reductions in renal resistance in the nonclipped kidney compared with untreated animals. However, conflicting data were reported for the clipped kidney, as losartan was reported to cause either a marked increase in renal flow and decreased resistance8 or no change in renal flow.7 Additionally, losartan decreased resistance in intestinal tissues,7 consistent with the present study. In any case, these studies further support the role of the RAS in the maintenance of tone in nonclipped kidneys and are consistent with the effects of ACE inhibitors in 2K1C rats.7 30
Surprisingly, few studies have examined the regional hemodynamic effects of ACE inhibitors in 2K1C rats. ACE inhibitors have been shown to improve (nonclipped) renal function in anesthetized30 and conscious7 2K1C rats. Additionally, single time-point microsphere determinations revealed that enalapril and losartan decreased local vascular resistances in intestinal and adrenal tissues.7 In one study the effects of captopril on intact renal, mesenteric, and hindquarters flows (with the use of electromagnetic flow probes) in conscious 2K1C rats were reported, although simultaneous measurements were not made and only data 10 minutes after captopril administration were presented.31 Nevertheless, it was found that captopril (1 mg/kg) increased renal flow and decreased renal and mesenteric but not hindquarters resistances. However, dose-related or time-course effects were not examined.31 In another model of the activated RAS, ie, water-deprived Brattleboro rats, ACE inhibitors generally caused vasodilatation in renal, mesenteric, and hindquarters vascular beds,32 and essentially similar widespread vasodilatation occurred after administration of AT1 receptor antagonists in the same model.2 3 Thus, in the limited number of studies performed, it would appear that ACE inhibitors and AT1 receptor antagonists exert similar hemodynamic profiles in high-renin states.
However, in the present study it is difficult to attribute the hemodynamic effect of CV-11974 in 2K1C hypertension solely to the inhibition of circulating Ang II. The two highest CV-11974 doses used inhibited the cardiovascular effects of exogenously administered Ang II for at least 6 hours and would most likely have had a similar effect on endogenous Ang II in the high-renin–state model. Indeed, these CV-11974 doses are orders of magnitude above the Ki value (0.64 nmol/L) of this compound at vascular AT1 receptors.33 But as previously mentioned, CV-11974 caused dose-dependent renal vasodilatation, which would argue against a progressive inhibition of vascular tone maintained by Ang II, especially because analogous dose-related increases in conductances did not occur in the mesenteric or hindquarters vascular beds. Therefore, it is conceivable that inhibition of the local RAS in the kidney also contributed to the hyperemic vasodilatation seen with the highest dose. Consistent with this concept, previous studies have reported that in 2K1C rats both vascular renin and Ang II levels in aortic and mesenteric tissues are markedly increased.20 34 However, it would have to be argued that there is a greater upregulation of the renal RAS in the contralateral kidney, although expression of the renin gene was in fact decreased at this site.22 Alternatively, greater access to renal (compared with nonrenal) sites may only be possible at the highest CV-11974 dose, or as discussed previously, an autoregulatory component may contribute to the greater renal vasodilatation observed.
Support for the importance of the tissue RAS may also be assumed from the temporal disparity observed between the inhibition of Ang II–evoked cardiovascular responses and the hypotensive effect of the AT1 receptor antagonist. That is, all CV-11974 doses immediately abolished Ang II responses; however, maximal hypotension was not achieved until 6 hours later. This discrepancy has been noted previously1 4 6 and has been attributed to more time being needed for the compound to inhibit the RAS in the vasculature rather than the circulating RAS. However, with the lowest CV-11974 dose, maximal hypotension occurred at a time (6 hours) when Ang II responsiveness had almost returned to control (predrug) levels and there was minimal vasodilatation in the renal and mesenteric vascular beds, although hindquarters conductance was increased. This finding would in fact argue against a time-dependent blockade of the tissue RAS, because under these conditions it would be difficult to reconcile a greater blockade of Ang II in the tissue, as opposed to the plasma, compartment. Conceivably, CV-11974–induced vasodilatation in the clipped kidney itself, as noted with losartan,8 may also play a role under these conditions. However, it is more likely that other mechanisms may also play a role in AT1 receptor–induced hypotension. Consistent with this notion, CV-11974 increased hindquarters conductance at each dose, which is at variance with the lack of vasoconstrictor activity demonstrated for exogenous Ang II in this vascular bed (cf, renal and mesenteric vasoconstriction). Indeed, this feature has been noted previously for losartan and EXP 3174 in water-deprived Brattleboro rats, in which it was postulated that these compounds may inhibit prejunctional AT1 receptors in the hindquarters (and perhaps other regions) and therefore suppress Ang II–induced facilitation of neurally mediated vasoconstriction.3 Alternatively, Ang II may potentiate the vasoconstrictor actions of norepinephrine at the postjunctional vascular level. Whatever the explanation, it would have to be argued that these Ang II effects occur at concentrations below those required to cause direct vasoconstriction in order for CV-11974 to lower MAP in the face of virtually normal Ang II responses. In any case, it is likely that there would be a complex interplay between direct and indirect actions of Ang II in plasma and tissue compartments.
In conclusion, the AT1 receptor antagonist CV-11974 (0.01 to 1.0 mg/kg) caused hypotension associated with generalized vasodilatation in 2K1C rats that was dose dependent in nature in the renal but not mesenteric or hindquarters vasculature. Although the hemodynamic profile of CV-11974 differed compared with that obtained in SHR (ie, renoselective),4 these findings revealed heightened vasodilatation in the nonclipped kidney, relative to the other circulations, when larger doses of CV-11974 (1.0 mg/kg) were given to 2K1C rats. Importantly, there was a clear separation between hypotension and blockade of cardiovascular effects to Ang II after CV-11974, suggesting that other mechanisms, in addition to blockade of the circulating/tissue RAS, may be involved in the antihypertensive effect of CV-11974. Finally, this study illustrates the importance of the RAS in both renal and nonrenal circulations in 2K1C hypertension and the hemodynamic outcome after the short-term administration of an AT1 receptor antagonist.
Selected Abbreviations and Acronyms
|2K1C||=||two-kidney, one clip|
|Ang II||=||angiotensin II|
|AT1||=||angiotensin II subtype 1|
|MAP||=||mean arterial pressure|
|PRA||=||plasma renin activity|
|SHR||=||spontaneously hypertensive rat(s)|
These studies were supported by grants from the National Health and Medical Research Council of Australia, William Buckland Foundation (Australia), and the Monash University Research Initiatives Fund. We would like to thank Dr Minoru Hirata (Takeda Chemical Industries Ltd, Japan) for the gift of CV-11974.
Reprint requests to Dr R.E. Widdop, Department of Pharmacology, Monash University, Clayton, Victoria 3168, Australia.
Presented previously at a satellite symposium of the 15th Meeting of the International Society of Hypertension, Melbourne, Australia, March 19, 1994 (Blood Pressure. 1994;3[suppl 5]:15-20).
- Received June 6, 1995.
- Revision received July 28, 1995.
- Accepted August 21, 1995.
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