(Hypertension. 1995;25:162-165.)
© 1995 American Heart Association, Inc.
Articles |
Resetting Blood Pressure in Spontaneously Hypertensive Rats
The Role of Bradykinin
From the Genetic Physiology Unit, Department of Medicine, Austin Hospital, Heidelberg, Victoria, Australia.
Correspondence to Joseph B. O'Sullivan, Department of Medicine, University of Melbourne, Austin Hospital, Victoria 3084, Australia.
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Abstract |
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Abstract Brief angiotensin-converting enzyme (ACE) inhibition in young spontaneously hypertensive rats (SHR) causes a persistent reduction in blood pressure. Bradykinin accumulation may contribute to these long-term effects, and to test this hypothesis we studied the consequences of bradykinin B2 receptor antagonism during ACE inhibitor treatment in young SHR. Male SHR were treated from 6 to 10 weeks of age with water, ramipril (1 mg/kg per day), Hoe 140 (0.5 mg/kg per day), or both ramipril and Hoe 140. Systolic blood pressure and body weight were measured each week from 6 to 20 weeks of age. During treatment, Hoe 140 treatment resulted in lower blood pressures than in controls. Ramipril caused a larger fall in blood pressure over the same period. The ramipril plus Hoe 140 group had the lowest blood pressures of any group during treatment. After treatment, the blood pressure of Hoe 140–treated SHR was similar to that of untreated SHR. After ramipril, blood pressure rose but plateaued significantly below values in controls. In contrast, withdrawal of combined ramipril and Hoe 140 treatment caused a rapid rise of systolic blood pressure to levels significantly higher than in ramipril-treated SHR but less than in controls. The antihypertensive effects of Hoe 140 during the development of genetic hypertension may represent a direct effect of the drug or some alteration in the normal relation between bradykinin and blood pressure. The antagonism by Hoe 140 of the long-term blood pressure reduction after ramipril withdrawal indicates that the persistent effects of ACE inhibitors may in part be due to the accumulation of bradykinin during a critical stage of development.
Key Words: angiotensin-converting enzyme inhibitors • bradykinin • rats • hypertension, genetic
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Introduction |
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Angiotensin-converting enzyme (ACE) inhibitors are widely used in the treatment of hypertension. It has been demonstrated that ACE inhibitor treatment of young spontaneously hypertensive rats (SHR) produces a persistent suppression of blood pressure (BP) in the long term after treatment is withdrawn.1 2 3 4 In contrast, if adult SHR are treated with an ACE inhibitor, although BP is reduced over the treatment period, it returns to untreated levels once treatment is withdrawn.2
There is substantial evidence that the long-term suppression of BP seen in SHR after ACE inhibition in youth is at least in part due to inhibition of angiotensin II (Ang II) formation. Angiotensin receptor antagonists cause a persistent reduction in pressure,5 and long-term infusion of Ang II into ACE inhibitor–treated SHR restores BP to control levels.2 However, salt loading or aldosterone infusion during ACE inhibition, while further suppressing the renin-angiotensin system, attenuates the long-term antihypertensive effects,6 suggesting that Ang II itself may not explain all the effects of ACE inhibitors in young SHR.
Since ACE is also involved in the kallikrein-kinin system through its degradation of bradykinin, it has been proposed that BP suppression by ACE inhibitors may be due to an accumulation of bradykinin. Bradykinin can act through at least two receptors. A bradykinin type 2 (B2) receptor is thought to mediate most of the physiological functions of bradykinin,7 8 including vasodilation, effects on cardiovascular structure, and diuresis. A separate bradykinin type 1 (B1) receptor is believed to stimulate natriuresis9 and collagen synthesis and cell multiplication in human fibroblasts.10 Although numerous studies in vivo have investigated the short-term effects of bradykinin on BP in different experimental animal models, there is little evidence regarding the long-term actions of bradykinin, particularly in genetic hypertension. As it is possible that the persistent hypotensive effects of ACE inhibitors might in part result from accumulation of bradykinin, we studied the short- and long-term effects of blockade of the B2 receptor with Hoe 14011 12 during ACE inhibitor treatment of young SHR.
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Methods |
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Animals
Four-week-old male SHR were obtained from a colony maintained in the Genetic Physiology Unit, Austin Hospital, Melbourne, Australia. They were derived originally from National Institutes of Health SHR stock and are subject to regular tests with polymorphic markers to confirm their inbred status. All experiments were approved by the Austin Hospital Animal Welfare Committee.
Animals were housed in groups of three to four per box in a temperature-controlled room (23° to 25°C) with a 12-hour day/night cycle. Food (Rat and Mouse Pellets, Norco) and water were administered ad libitum. Systolic BP and body weight were measured twice a week during the treatment phase between 6 and 10 weeks of age and once a week in the posttreatment phase until 20 weeks of age. BP was measured in conscious animals with a photoelectric tail-cuff pulse detection system (IITC Inc, Life Science Instrumentation). The sizes of the restraining cylinders and cuffs were matched to those of the growing animals. Before the experimental period, rats were conditioned to the restraining cylinders and BP measurement.
Drug Treatment
Four groups of male SHR were treated from 6 to 10 weeks of
age with one of the following: (1) water by gavage once a day (n=16),
(2) ramipril (1 mg/kg per day) by daily gavage (n=17), (3) Hoe 140 (0.5
mg/kg per day) delivered subcutaneously by osmotic minipumps (n=13), or
(4) ramipril (1 mg/kg per day) in combination with Hoe 140 (0.5 mg/kg
per day) (n=17). The dose and route of administration of Hoe 140 were
based on previously published studies.13 14 In a series of
pilot experiments, we confirmed previous observations15
that long-term treatment with Hoe 140 at 0.5 mg/kg per day inhibits the
short-term BP effects of bradykinin in control or ramipril-treated
rats.
Statistical Analysis
Longitudinal systolic BP and weight data were compared between
groups using repeated-measures analysis of variance (MANOVA,
SPSS/PC+).16 A probability value less than .05 was
accepted as statistically significant. Descriptive statistics
presented are mean±SEM.
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Results |
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Fig 1 shows the average weekly body weights for each of the four groups. Before and during treatment, all groups grew normally, and there were no significant differences (F3,59=0.53, P=.665). After treatment, there was increased variability in body weight and a tendency for the SHR that had received Hoe 140 or ramipril alone to be lighter than the other rats. However, the differences were not statistically significant (F3,59=2.44, P=.073), and the body weights of rats treated with both Hoe 140 and ramipril were almost identical to those of controls (Fig 1).
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), ramipril (1 mg/kg
per day) (
), Hoe 140 (0.5 mg/kg per day) (
), or ramipril (1
mg/kg per day) and Hoe 140 (0.5 mg/kg per day) (
). See text for
statistical comparisons.Average systolic BP values are shown in Fig 2. Control SHR showed a steady rise in pressure characteristic of the development phase of hypertension. Their average systolic BP from 6.5 to 10 weeks of age was 169 mm Hg. Hoe 140 treatment alone produced a slight but significant (F1,27=7.2, P=.012) fall in BP (average 6 to 10 weeks: 163 mm Hg) compared with controls (Fig 2). Ramipril decreased BP substantially (average 6 to 10 weeks: 143 mm Hg; F1,31=212, P<.0001) over the 4-week treatment period. The combination of ramipril and Hoe 140 treatment resulted in the lowest average pressures (average 6 to 10 weeks: 131 mm Hg) of all the groups, which were in particular significantly less than pressures in the ramipril-treated group (F1,32=39.8, P<.0001).
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After treatment was stopped, a different BP pattern emerged (Fig 2). All rats showed an increase in the 2 weeks after treatment, but the rate of rise varied significantly between groups (F6,118=5.2, P<.0001). Between 11 and 12 weeks of age, the systolic pressure of control animals rose on average by 6.5 mm Hg compared with a rise of 25.3 mm Hg in the rats that had been treated with both Hoe 140 and ramipril. The pressure increases in the ramipril (17.3 mm Hg) and Hoe 140 (15.4 mm Hg) groups were intermediate.
Between 13 and 20 weeks of age, the control SHR showed a steady rise in BP although at a reduced rate compared with the period from 6 to 10 weeks (Fig 2). Over this period, the systolic BP of the Hoe 140–treated group was initially greater than that of the untreated SHR, but by 20 weeks the two were equivalent. Although lower during treatment, the posttreatment BP of ramipril plus Hoe 140–treated SHR (average: 195 mm Hg) was significantly greater than that in the rats that had received ramipril alone (F1,32=830, P<.0001). BP values in the ramipril plus Hoe 140–treated SHR were also significantly less than in SHR treated with Hoe 140 alone. SHR that had received ramipril showed little further rise in BP between 13 and 20 weeks of age (average: 173 mm Hg) and had BP levels significantly lower than all other groups (F3,59=400, P<.0001).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study provides evidence that the long-term reduction in systolic BP after ACE inhibition may be in part due to the actions of bradykinin. As we have demonstrated previously, SHR treated with an ACE inhibitor between 6 and 10 weeks of age showed a persistent reduction in systolic BP, but when Hoe 140 was combined with ACE inhibition, the long-term antihypertensive effects in the withdrawal phase were attenuated significantly. Presumably, the accumulation of bradykinin during ACE inhibition in young SHR in some way resets the BP track at a lower level, and blockade of the bradykinin B2 receptor prevents this component of the ACE inhibitor action.
If bradykinin is important in resetting BP, it does not account for all of the long-term effects, as the posttreatment BP of the ramipril plus Hoe 140 group was significantly lower than in control SHR, a shortfall that became more obvious toward the end of the study. During the last 7 weeks of the study, the systolic BP of ramipril-treated SHR averaged 34 mm Hg less than the BP of rats that had received Hoe 140. SHR treated with both Hoe 140 and ramipril had on average systolic pressures 22 mm Hg higher than those in ramipril-treated rats. One interpretation is that approximately 65% of the long-term effects of ACE inhibitors are due to bradykinin accumulation and the remainder due to inhibition of Ang II. However, without dose-dependence studies, it is not possible to determine the relative importance of bradykinin versus angiotensin. Nevertheless, we believe that both are important for the long-term effects of ACE inhibitors. Doubts raised by our previous experiments6 regarding the sole responsibility of angiotensin are strengthened by our present results. Despite the inhibition of Ang II formation during ramipril treatment, the posttreatment hypotensive effects were attenuated significantly by Hoe 140.
Although the exact mechanisms by which Hoe 140 affects the resetting of BP in the withdrawal period are not obvious, they cannot be related to reversal of the antihypertensive action of ramipril during treatment. In fact, we were surprised to find lower systolic pressure in young SHR treated with Hoe 140, and we believe that this is the first study of long-term Hoe 140 treatment during the development of genetic hypertension. The bradykinin B2 receptor is believed to mediate the vasodilator actions of bradykinin, and its blockade might have been expected to increase rather than decrease BP.17 Other investigators have reported a failure of Hoe 140 to reverse the antihypertensive effects of ACE inhibitors in older SHR.13 14 It has been suggested that the SHR may be a kinin-deficient strain,13 18 but this has not been observed when tissue levels have been measured,19 and it would not explain the depressor effects of Hoe 140 alone.
There are at least two possible explanations for the lower systolic BP in SHR receiving Hoe 140. Bradykinin may act differently in young SHR, and B2 receptor–mediated effects might contribute in some way, such as predominant vasoconstriction, to high BP. Alternatively, Hoe 140 itself may have caused the fall in BP. Acute dosage studies in anesthetized Sprague-Dawley rats have shown that intra-arterial infusion of Hoe 140 at a dose that is close to the rate infused subcutaneously in the present study had no significant effect on BP, although three times this dose resulted in a significant fall in systemic arterial pressure of approximately 30 mm Hg.20 It has been reported that a long-term, 4-week intraperitoneal infusion of Hoe 140 at approximately six times the dose we used does not alter tail-cuff pressure in female Wistar rats.21 However, results in other rat strains at different ages do not exclude strain- or age-specific effects of Hoe 140 in our studies. The depressor action of Hoe 140 may include intrinsic agonist activity at the B2 receptor or some receptor-independent cardiovascular action. However, most studies indicate that Hoe 140 has little agonist activity.11 17 22
These studies raise some interesting questions regarding bradykinin, Hoe 140, and systolic BP in young SHR. Nevertheless, they emphasize that events in youth can have long-term effects that may persist for the life of an animal.23 In the case of SHR, it appears that the pharmacological effects of ACE inhibitors can be explained by their actions on both bradykinin and angiotensin during a critical phase in development that affects, possibly through the kidney,24 the pathophysiological processes that lead to genetic hypertension.
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Acknowledgments |
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Dr Harrap was supported in this work as an R. Douglas Wright Fellow of the National Health and Medical Research Council of Australia. The authors are grateful to Hoechst AG, Frankfurt, Germany, for their generous donation of Hoe 140 and ramipril used in these studies.
Received July 20, 1994; first decision August 31, 1994; accepted October 12, 1994.
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