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(Hypertension. 1995;26:1138-1144.)
© 1995 American Heart Association, Inc.

Articles

Pressor and Reflex Sensitivity Is Altered in Spontaneously Hypertensive Rats Treated With Angiotensin-(1-7)

Ibrahim F. Benter; Debra I. Diz; Carlos M. Ferrario

From the Hypertension Center, The Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC; and the Division of Biomedical Sciences (I.F.B.), Southern College of Optometry, Memphis, Tenn.

Correspondence to Ibrahim F. Benter, PhD, Division of Biomedical Sciences, Southern College of Optometry, 1245 Madison Ave, Memphis, TN 38104.

	Abstract

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Abstract We have suggested that angiotensin-(1-7) [Ang-(1-7)] may oppose the pressor activity of angiotensin II (Ang II). This hypothesis was supported by the fact that long-term intravenous infusion of Ang-(1-7) transiently lowers blood pressure in spontaneously hypertensive rats (SHR). We now investigated whether the pressor sensitivity to bolus injections of either phenylephrine (PE) or Ang II was altered on day 12 of an Ang-(1-7) infusion when blood pressure in the SHR had returned to hypertensive levels. SHR (n=10) and WKY rats (n=8) were given Ang-(1-7) intravenously via osmotic minipumps at a dose of 24 µg/kg per hour for 2 weeks. On day 12 of the infusion, mean arterial pressure and heart rate in halothane-anesthetized rats were similar in Ang-(1-7)–treated SHR (142±6 mm Hg; 388±9 beats per minute) and those infused with vehicle (146±5 mm Hg; 392±13 beats per minute). Pressor responsiveness to PE in Ang-(1-7)–treated SHR was 22% less at a dose of 10 µg, while pressor responses to Ang II decreased by 20% and 25% at doses of 0.05 and 0.1 µg, respectively, compared with the vehicle-treated SHR (P<.05). There were no effects of the Ang-(1-7) infusion on pressor responses to Ang II or PE in WKY rats. In the SHR infused with Ang-(1-7), there was a 35% improvement in sensitivity of the reflex control of heart rate to levels not different from those in the untreated WKY rats (slope of the change in pulse interval versus the change in pressure increased from 0.34±0.03 to 0.46±0.01 ms/mm Hg). These data suggest that Ang-(1-7) may selectively activate antihypertensive mechanisms at the level of the vascular wall or the baroreflex.

Key Words: prostaglandins • nitric oxide • blood pressure • angiotensin II • baroreflex

	Introduction

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The primary characteristic of human essential hypertension is increased total peripheral resistance, and increased vascular reactivity is one of the factors that contribute to elevated vascular tone. Increased blood vessel reactivity to several vasoactive agents including adrenergic agonists and Ang II has been described in various vascular beds of hypertensive rats and human subjects.^{1 2 3} It has been suggested that the renin-angiotensin system contributes to development and maintenance of high peripheral resistance and increased vascular reactivity in human essential hypertension and animal models of hypertension.^{2 3 4 5 6} Ang II given at subpressor doses potentiates the vascular response of arteries to norepinephrine, clonidine, thrombin, histamine, and potassium,^{2 7 8} while ACE inhibitors can normalize the hyperreactivity of blood vessels to pressor agents in hypertensive animals and in patients with essential hypertension.^{2 3 9 10 11 12} Ang II also inhibits the baroreflex control of arterial pressure to augment actions of pressor agents.^{13 14}

Ang-(1-7) produces responses that are opposite to those of Ang II in both cell culture and whole-animal preparations.¹⁵ For instance, systemic injections of Ang-(1-7) into pithed rats produced a compound effect on arterial blood pressure that is characterized by an indomethacin-inhibitable long-lasting depressor component.¹⁶ Ang-(1-7) is a potent stimulator of prostaglandin release in neural and vascular cells,¹⁷ and chronic infusion of Ang-(1-7) increases urinary prostaglandin synthesis in hypertensive animals.¹⁸ Ang-(1-7) also elicits NO-dependent vasodilation in several preparations including coronary artery rings¹⁹ and isolated mesenteric or hindquarter vascular beds.²⁰ Ang-(1-7) also facilitates the baroreceptor reflex.^{21 22} Prostaglandins and NO can attenuate the vasoconstrictor effects of Ang II and -adrenergic agonists in various vascular beds.^{23 24 25} Thus, this study was undertaken to determine whether long-term intravenous infusion of Ang-(1-7) would alter vasoconstrictor responses to phenylephrine and Ang II and augment the baroreceptor reflex in the SHR.

	Methods

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Experiments were conducted in 13-week-old male SHR (n=12) and WKY rats (n=10) obtained from Charles River Laboratories Inc (Wilmington, Mass). Animals were placed in metabolic cages (Nalgene Plastic Metabolism Cages, Harvard Bioscience) within a room maintained at 22°C with a 12-hour dark-light cycle. Animals had free access to tap water and were fed a powdered standard rat chow that provided a daily intake of 17 mEq of K⁺ per 100 g of solid weight (Rodent Laboratory Chow 5001, Purina Mills Inc).

Rats were given a 2-week IV infusion of either vehicle (0.9% NaCl) or Ang-(1-7). Infusion was achieved by using osmotic minipumps (Alzet osmotic pump, model 2ML2, Alza) placed in the subcutaneous tissue. Rats were anesthetized with halothane (1% in a mixture of 95% O₂ and 5% CO₂), and pumps were inserted into the interscapular space through an incision at the back of the dorsum. One end of a PE-60 catheter was connected to the flow moderator, while the other end was introduced into the right jugular vein. Ang-(1-7) was infused at a rate of 24 micrograms/kilogram per hour, and the flow rate for Ang-(1-7) and vehicle was 5 µL/h. This rate of infusion was chosen because previous studies indicated that this dose of Ang II increased plasma levels of Ang II threefold to fivefold and moderately increased MAP,²⁶ and this dose of Ang-(1-7) caused a transient decrease in MAP and increased urinary prostaglandin excretion in SHR.¹⁸

Direct measurements of MAP and HR were obtained by insertion of a PE-50 catheter into a femoral artery 3 days before the procedure (on day 9). The arterial catheter was connected to a transducer (Spectramed TXXAD-R, Spectramed Inc), and variables were displayed on a multichannel polygraph (model 2000, Gould). Dose-response studies were performed on day 12 of infusion, when we previously showed that arterial pressures of control and treated animals were similar to preinfusion values. Ang II, phenylephrine, and 0.9% NaCl were administered via a catheter inserted into a femoral vein. Bolus injections of saline (vehicle), Ang II, or phenylephrine were spaced at 20-minute intervals. All drugs were dissolved in sterile 0.9% NaCl and given in a volume of 0.1 mL. A three-point dose-response curve was constructed in randomized dose sequences. At the end of the study, rats were euthanatized by pentobarbital overdose.

The data were analyzed to assess the baroreceptor reflex control of HR. The changes in MAP and HR in response to bolus injections of either Ang II or phenylephrine were determined. The transient changes in HR produced by the changes in MAP are an index of the component of the baroreflexes. Peak changes in HR in response to the increases in pressure were recorded. Pulse interval was calculated by the equation 60 000/HR (ms/beats per minute) and plotted against the change in pressure. The slope of the line expressing the HR/MAP, an index of reflex sensitivity, for each animal was determined, and the slopes were then averaged for each treatment group (Table 1). For graphic purposes, the mean±SEM of pressure and HR changes for each dose of phenylephrine or Ang II were plotted, and the best-fit regression line was drawn to illustrate the average slope.

View this table: [in this window] [in a new window]   Table 1. Effect of Ang-(1-7) Infusion on the Mean of the Slope of the Change in Pulse Interval vs the Change in Pressure in Response to Ang II and Phenylephrine in SHR and WKY Rats

Statistical Analysis
All values are expressed as mean±SEM. ANOVA was performed, followed by Duncan's multiple range test to determine which mean values differed from control mean values (SAS Institute). The criterion for statistical significance was P<.05. Unpaired t tests were used to compare the two groups.

Drugs
Ang-(1-7) and Ang II were obtained from Bachem Bioscience Inc. Phenylephrine was obtained from Sigma Chemical Co.

	Results

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SHR and WKY rats received an infusion of either vehicle or Ang-(1-7) at a rate of 24 micrograms per kilogram per hour for 2 weeks. At the end of the study, baseline MAP and HR did not differ between the Ang-(1-7)–treated and control SHR (Table 2).

View this table: [in this window] [in a new window]   Table 2. Effect of 12-Day Infusion of Ang-(1-7) on the Basal MAP and HR in SHR and WKY Rats

Effect of Intravenous Infusion of Ang-(1-7) on Pressor and HR Response
As shown in Fig 1A and 1B, Ang-(1-7) infusion significantly attenuated the pressor response to injections of the highest dose of phenylephrine in SHR (P<.05) but not in WKY controls. The fall in HR observed in response to the increased blood pressure due to injections of phenylephrine was significantly greater, as shown by the increase in pulse interval, at all doses in the treated SHR compared with the control group; there was no difference between treated or control WKY rats (Fig 2A and 2B). The pressor response to Ang II injections was also attenuated in Ang-(1-7)–treated SHR compared with vehicle-treated SHR controls at the highest doses (Fig 1D). In contrast, the Ang-(1-7) infusion did not cause a change in pressor sensitivity to Ang II in WKY rats (Fig 1C). The bradycardic response due to elevation of blood pressure of Ang II injections differed between treated and control groups only at the highest dose in the SHR (Fig 2C and 2D).

View larger version (20K): [in this window] [in a new window]   Figure 1. Graphs show change in MAP in WKY rats (A and C) and SHR (B and D) in response to intravenous injections of Ang II and phenylephrine. Open squares indicate vehicle-treated animals; filled squares, Ang-(1-7)–treated animals. Values are mean±SE. *P<.05, values comparing Ang-(1-7)–treated with vehicle-treated animals.

View larger version (20K): [in this window] [in a new window]   Figure 2. Graphs show change in pulse interval in WKY rats (A and C) and SHR (B and D) in response to injections of Ang II and phenylephrine. Open squares indicate vehicle-treated animals; filled squares, Ang-(1-7)–treated animals. Values are mean±SE. *P<.05, values comparing Ang-(1-7)–treated with vehicle-treated animals.

Effect of Intravenous Infusion of Ang-(1-7) on the Baroreceptor Reflex
As shown in Table 1 and Fig 3A and 3B, the mean of the slope of individual regression lines for pulse interval versus MAP generated from response to phenylephrine for each animal was significantly lower in SHR versus WKY rats, as previously reported by others.^{27 28} In SHR infused with Ang-(1-7), there was a 35% improvement in sensitivity of the reflex control of HR (from 0.34±0.03 to 0.46±0.01 ms/mm Hg) to levels not different from those in the untreated WKY rats. In contrast, although there was a trend for a higher slope of the phenylephrine reflex in the WKY rats infused with Ang-(1-7), the change was not statistically significant (Table 1, P>.05).

View larger version (24K): [in this window] [in a new window]   Figure 3. Graphs show change in pulse interval in WKY rats (A and C) and SHR (B and D) in response to change in MAP. Lines represent best-fit regression line through the mean±SE of the pressure and HR values. Open squares indicate vehicle-treated animals; filled squares, Ang-(1-7)–treated animals. Values are mean±SE. *P<.05, values comparing Ang-(1-7)–treated with vehicle-treated animals.

The slope of the reflex control of HR in response to bolus injections of Ang II was less than that observed with phenylephrine in both SHR and WKY rats (Table 1). This is consistent with the inhibitory effects of Ang II on reflex control of HR.^{13 14 22} SHR treated with Ang-(1-7) showed an improvement in the slope of the reflex generated by Ang II (Table 1 and Fig 3C and 3D). In addition, there was an increase in reflex sensitivity in WKY rats treated with Ang-(1-7) when Ang II is used as the test agent, suggesting that Ang-(1-7) is reversing the effects of Ang II to suppress the reflex.

	Discussion

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Systemic administration of Ang-(1-7) attenuated the pressor effectiveness of the highest doses of exogenously administered phenylephrine and Ang II in hypertensive but not normotensive rats. This finding is in contrast to previous observations with Ang II infusions that potentiate -adrenergic receptor–mediated pressor responses. More important, however, Ang-(1-7) infusion substantially reversed the inhibitory effects of Ang II on the reflex control of HR in both SHR and WKY rats, improving the impaired slope of the reflex control of HR as determined with phenylephrine in SHR.

It has been suggested that increased vascular reactivity to vasoactive hormones contributes to the development and maintenance of high blood pressure in essential hypertension.^{1 3 5} Aalkjær et al²⁹ showed that blood vessels from essential hypertensive patients showed greater responses to norepinephrine compared with control subjects. Ang II is one of the vasoactive peptides that have significant regulatory effects on vascular reactivity. Subthreshold concentrations of Ang II increase contractile response of arteries to norepinephrine, clonidine, thrombin, histamine, and potassium.^{2 8}

Vascular hyperreactivity is present in the SHR,⁶ and both losartan and ACE inhibition can attenuate hypertension and suppress vascular hyperreactivity.^{30 31} Similarly, long-term administration of lisinopril decreases pressor responses to norepinephrine in normal renin essential hypertensive patients.³ However, the mechanism by which ACE inhibitors reduce vascular reactivity is not clear. A recent study showed that the reduction of the phenylephrine-induced tone by losartan was enhanced by perindoprilat, suggesting that the ACE inhibitor attenuated phenylephrine-induced tone not only by inhibition of Ang II production but probably also through other mechanisms.²

Ang-(1-7), similar to losartan and ACE inhibitors, may function to oppose the actions of Ang II.¹⁵ We suggested that Ang-(1-7) may contribute to the antihypertensive effects produced by ACE inhibitors because circulating levels of Ang-(1-7) increase 25- to 50-fold during ACE inhibition.³² A long-term infusion of Ang-(1-7) mimics the hemodynamic effects of ACE inhibition.¹⁸ Moreover, long-term infusion of Ang-(1-7) in SHR produces significant increases in urinary PGE₂ and 6-ketoprostaglandin F₁ accompanied by diuresis, natriuresis, and a decrease in blood pressure.¹⁸ A more recent study clearly demonstrated the opposing actions of Ang-(1-7) in a genetic model of hypertension that is associated with heightened activity of the brain angiotensin system. In this study, endogenous neutralization of Ang-(1-7), by administration of a specific Ang-(1-7) antibody, caused further elevation of arterial pressure, whereas blood pressure fell after central administration of a monoclonal Ang II antibody.³³

Ang-(1-7) is a potent stimulator of prostaglandin release in neural and vascular cells,¹⁷ and systemic administration of Ang-(1-7) produces a compound pressor-depressor effect with a predominant depressor component in intact pithed Sprague-Dawley rats.¹⁶ Indomethacin can inhibit most of the depressor component. It is well established that prostaglandins are involved in the regulation of blood pressure by exerting local modulatory actions within vascular beds and that abnormal levels of prostaglandins may contribute to the development of genetic hypertension.^{5 17 34} In the SHR, basal levels of PGE₂ and PGI₂ are reduced in smooth muscle cells, and the release of PGI₂ in response to Ang-(1-7) is markedly attenuated.¹⁷ In addition, it has been shown that both PGE₂ and PGI₂ can attenuate the vasoconstrictor effects of Ang II and -adrenergic agonists in several vascular beds.^{24 25} Since Ang-(1-7), under conditions similar to the present study, increased urinary prostaglandin synthesis in the SHR and produced a prostaglandin-dependent vasodilatory effect acutely,¹⁸ it is possible that prostaglandins may have contributed to the decrease in vascular reactivity observed in this study at the highest doses of the vasoconstrictor agents.

Ang-(1-7) also produces vasodilation by releasing NO in several vascular beds. Osei et al²⁰ found that Ang-(1-7) produces significant vasodilation in the isolated mesenteric and hindquarter vascular beds of the cat and that this vasodilatory effect was partially blocked by inhibition of NO synthase. In addition, it was shown that Ang-(1-7) produces vasodilation of coronary arteries through an NO-dependent system.¹⁹ These findings suggest that NO released by Ang-(1-7) may have contributed to the observed changes in vascular reactivity. This hypothesis is supported by the observation that incubation of aortic ring segments with NO donors decreases sensitivity to both G protein–linked agonists and direct G protein stimulation.²³ Studies have shown that decreased synthesis of NO by the endothelium also contributes to hyperreactivity of vasculature to pressor agents.^{35 36} The basal formation of NO is reduced in the SHR,³⁷ and N^G-monomethyl-L-arginine increases vasoconstrictor responses to norepinephrine more in WKY rats than in the SHR.^{23 38} Nakamura et al¹⁰ showed that in the forearm arterial beds of healthy volunteers, N^G-monomethyl-L-arginine can block an augmentation of blood flow induced by ACE inhibitors. Moreover, the depressor component of the response produced by systemic injection of Ang-(1-7) was significantly attenuated in two-kidney, one clip hypertensive dogs treated long term with an inhibitor of NO synthase.^{39 40}

SHR are known to have impaired baroreflex function, which can be reversed with converting-enzyme inhibition or AT₁ blockade.^{27 28} Ang II also inhibits reflex control of HR after intravenous administration, reducing the reflex sensitivity approximately 50%.^{13 14} In this study, we observed impaired reflex sensitivity as determined with phenylephrine in SHR and its improvement after a 12-day infusion of Ang-(1-7). The Ang-(1-7) infusion also increased the slope of reflex control of HR in both WKY rats and SHR when Ang II was used to generate the reflex relationship. The magnitude of the improvement was substantial and is similar to that observed with converting-enzyme inhibition. Taken together, these data suggest that the effects of Ang-(1-7) to improve the reflex in the SHR may relate to antagonism of endogenous Ang II. In addition, activation of prostaglandins is also known to improve baroreceptor reflex sensitivity.^{41 42}

In summary, the modest attenuation of the pressor response to Ang II and phenylephrine and the greater improvements in baroreceptor reflex function observed in response to long-term Ang-(1-7) infusions in SHR could be due to activation of local vascular antihypertensive mechanisms. Whatever the mechanism, these findings suggest that Ang-(1-7) may work as an inhibitor of the actions of vasoactive peptides such as Ang II and adrenergic stimulants. The recovery of the blood pressure toward hypertensive levels seen in our previous study,¹⁸ despite persistent reductions in vascular reactivity and/or reflex function as described here, may reflect either differences in the time course of the recovery process or activation of alternate pressor mechanisms.

	Selected Abbreviations and Acronyms

 

ACE = angiotensin-converting enzyme Ang-(1-7) = angiotensin-(1-7) Ang II = angiotensin II HR = heart rate MAP = mean arterial pressure NO = nitric oxide PGE2 = prostaglandin E2 PGI2 = prostacyclin SHR = spontaneously hypertensive rat(s) WKY = Wistar-Kyoto

	Acknowledgments

 
This work was supported in part by grants HL-38535, HL-51952, and HL-52006 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. Debra I. Diz held an Established Investigatorship from the American Heart Association during the course of this work.

Received June 19, 1995; first decision August 18, 1995; accepted September 10, 1995.

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