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(Hypertension. 1996;28:325-329.)
© 1996 American Heart Association, Inc.

Articles

Hypotensive Effect of a Newly Identified Peptide, Proadrenomedullin N-Terminal 20 Peptide

Tatsuo Shimosawa; Toshiro Fujita

the Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo 112, Japan.

Correspondence to Toshiro Fujita, MD, Fourth Department of Internal Medicine, University of Tokyo School of Medicine, 3-28-6 Mejirodai Bunkyo-ku, Tokyo, 112, Japan. E-mail fujita-dis@h.u-tokyo.ac.jp.

	Abstract

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Proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (AM), which are both derived from proadrenomedullin, exhibit marked hypotensive effects. We recently reported that PAMP but not AM reduced the release of norepinephrine from peripheral sympathetic nerve endings. Our present objective was to clarify the involvement of the sympathetic nervous system in the hypotensive action of PAMP and AM. Intravenous administration of PAMP (10, 20, and 50 nmol/kg) to conscious rats induced less reflex tachycardia (5±5, 10±5, and 14±6 beats per minute [bpm]) than that of AM in 0.1, 0.5, and 1.0 nmol/kg doses (5±8, 20±7, and 38±5 bpm, P<.01) although both agents showed similar hypotensive effects. We evaluated the effect of PAMP on blood pressure in pithed rats whose sympathetic nervous systems were abolished. In pithed rats, AM (-2±1, -7±1, and -10±3 mm Hg; NS, P<.05, and P<.01, respectively) but not PAMP evoked hypotension. In contrast, administration of PAMP (-3±1, -11±2, and -14±4 mm Hg; P<.05, P<.01, and P<.01, respectively) as well as adrenomedullin (-2±2, -10+3, and -15±4 mm Hg; NS, P<.01, and P<.01) significantly reduced blood pressure in electrically stimulated, pithed rats, which had reached almost the same levels as in conscious rats. In electrically stimulated, pithed rats, plasma norepinephrine level was reduced by PAMP but not by vehicle or AM. These findings suggest that the hypotensive effect of PAMP is mainly due to inhibition of peripheral sympathetic nerve activity.

Key Words: pithed rat • sympathetic nerve activity • norepinephrine

	Introduction

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Adrenomedullin is a hypotensive peptide that was originally isolated from pheochromocytoma cells.¹ The DNA sequence encoding the AM precursor, proadrenomedullin, has been identified in human as well as rat tissue.^{2 3} Cleavage at the signal peptide yields a propeptide that contains AM. The first paired basic amino acids in the propeptide are a representative site for proteolytic cleavage, which yields PAMP.^{2 3} Although tissue concentrations of PAMP are exceedingly high in the adrenal medulla, PAMP can also be detected in the plasma and other tissues, such as the right atrium, kidney, and brain.⁴ An mRNA of AM is reported to exist in both vascular smooth muscle and endothelial cells, which also suggests that PAMP exists in those tissues.^{5 6} This distribution of PAMP suggests that it has a physiological role in the control of the circulation.

AM is reported to decrease BP by inducing vasodilation and natriuresis.^{7 8 9} Recent studies have shown that AM causes vasodilation by elevating intracellular cAMP¹ and by activating NO synthase via elevation of intracellular calcium, thus increasing the production of NO to induce vasodilation.^{10 11 12} PAMP also reduces BP in the anesthetized rat¹³ by an unknown mechanism. In a previous study, PAMP but not AM reduced the overflow of NE from the peripheral sympathetic nerve endings of mesenteric arteries.¹⁴ Interestingly, the reduction of BP by PAMP was not associated with an increase in HR or cardiac output.¹⁵ Results suggest that PAMP may suppress peripheral sympathetic tone, which in turn decreases BP. However, numerous peripheral and central nervous structures are interconnected to control the circulation. In addition, several neurohormones besides NE participate in the regulation of the circulation.^{16 17 18} Thus, the hypothesis that PAMP evokes hypotension by reducing NE overflow requires direct examination.

To clarify the linkage between the ability of PAMP to reduce NE overflow at peripheral nerve endings and its hypotensive action, we investigated the effect of PAMP under conditions in which the overall sympathetic nerve activity was abolished by pithing and in which peripheral sympathetic activity was exogenously stimulated by electric stimulation through a pithing rod. These results were compared with those from conscious, unrestrained animals.

	Methods

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All procedures conformed with the guidelines for the care and handling of animals established by the US Department of Health and Human Services and published by the National Institutes of Health (NIH publication No. 85-23, revised 1985).

Protocol 1: Response of BP and HR in Unanesthetized, Unrestrained Rats
A total of 12 male Sprague-Dawley rats (250 to 300 g; Charles River Japan, Atsugi, Japan) were used in this study. Twenty-four hours before the experiments, the rats were anesthetized with ether and both the left carotid artery and jugular vein were cannulated with PE-50 polyethylene tubing tapered at the tip. Both catheters were tunneled subcutaneously to the back of the neck, filled with heparinized saline (200 U/mL), and plugged with stainless steel pins. The incisions were closed with sutures. After the surgical procedure, the rats were placed in a cage that permitted free movement for at least 3 hours to acclimate them to the new environment. MAP and HR were recorded with a pressure transducer (model TP-200T, Nihon ) that was connected to a thermal array recorder (model WS-641 G, Nihon Kohden). The peptides AM (0.1, 0.5, and 1 nmol/kg) and PAMP (10, 20, and 50 nmol/kg, both from Peptide Institute Inc) or vehicle (0.1 mL saline) were injected as an intravenous bolus into the jugular vein in a serial dosing manner. Each injection was administered 15 minutes after MAP had returned to basal level. The nadir values of the decreases in MAP and the peak values of increases in HR were considered to be the responses to each peptide dose.

Protocol 2: Depressor Response in the Pithed Rat
A total of 29 male Sprague-Dawley rats (250 to 300 g; Charles River Japan, Atsugi, Japan) were anesthetized with ether and the surgical procedures and cannula implants were done as described above. Following the tracheal cannulation, the animals were pithed by inserting a steel rod (outer diameter, 16 mm) that was covered with enamel except at its end (5 mm) through the orbit and foramen magnum and into the spinal column to its sacral end. The animals were then placed on a ventilator (SN-480-7, Shinano) and respired artificially through the tracheal cannula by 1 mL/100 g body weight of stroke volume (60 strokes·min^-1). Both vagal nerves were cut. MAP and HR were recorded as described before. Body temperature was maintained at 39°C by a thermostatically controlled heating table. The peptides AM and PAMP (at doses identical to those in protocol 1) and vehicle were injected into the jugular vein as a bolus from 10 minutes after pithing and at 7-minute intervals thereafter. As in protocol 1, the nadir values of the decreases in MAP and the peak values of the decreases in HR were considered to be the responses to each peptide dose.

The effects of AM (n=6) and PAMP (n=7) were also evaluated in electrically stimulated pithed rats, in which MAP and HR were maintained at the same level as in conscious rat. A steel rod inserted behind the skull and between the vertebral column and the skin served as the indifferent electrode. For these studies the pithing rod was inserted and its end placed at the level of the 7th to 10th thoracic vertebrae. Electrical stimulation (30 V, 0.5 Hz, 1 millisecond for 30 minutes delivered from an electrical stimulator [SEN3301, Nihon Kohden]) was generated between the pithing rod and the indifferent electrode¹⁹ subsequent to a 1 mg/kg intravenous injection of (+)-tubocurarine (Sigma Chemical Co). MAP and HR were monitored as described above. AM, PAMP, or vehicle was administered intravenously as a bolus 3 minutes after the electrical stimulation began. A 7-minute interval elapsed between peptide injections.

Protocol 3: Measurement of NE Levels
A total of 17 male Sprague-Dawley rats (250 to 300 g; Charles River Japan, Atsugi, Japan) were used, cannulated, and pithed as described above. A volume of 2 mL of arterial blood was drawn for baseline determinations of NE levels 5 minutes after pithing. After collecting the sample, 2 mL of whole blood collected from two Sprague-Dawley rats were transfused into the pithed rats. Seven minutes after electrical stimulation, a second sample for measuring NE was drawn and blood was transfused as described above. Seven minutes after collecting the second blood sample, 0.1 mL saline (n=5), PAMP (50 nmol/kg in 0.1 mL saline; n=7) or AM (1 nmol/kg in 0.1 mL saline; n=5) were injected intravenously, and a third sample of arterial blood was drawn 5 minutes after injection. The NE level was determined by the trihydroxyindole method after high-performance liquid chromatography separation as previously reported.²⁰ With this method, NE levels of 5.88 fmol/mL to 58.82 pmol/mL (1 to 10 000 pg/mL) can be accurately measured, a range that includes the plasma NE concentration within 200.00 fmol/mL to 10.00 pmol/mL.

Statistics
All results are given as means±SEM. Data were analyzed by ANOVA. Repeated measurements or multiple comparisons of MAP and HR changes in response to AM or PAMP were analyzed by Scheffe's method. To compare results between experimental methods, data were analyzed with a two-way ANOVA and subsequent multiple comparisons by Scheffe's or Dunnett's method. A level of P<.05 was defined as statistically significant.

	Results

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Protocol 1: Response of BP and HR in Unanesthetized, Unrestrained Rats
Changes in MAP and HR in conscious rats are summarized in Table 1. Baseline MAP and HR did not differ among the three groups. Both AM (in 0.1, 0.5, and 1 nmol/kg doses) and PAMP (in 10, 20, and 50 nmol/kg doses) decreased MAP in a dose-dependent fashion (AM: -1±3, -6±6, -20±5 mm Hg, respectively; PAMP: -2±4, -10±7, -25±5 mm Hg, respectively; Fig 1a). The increase in HR was significantly smaller in PAMP-treated rats (5±5, 10±5, 14±6 bpm, respectively, n=6) than AM-treated rats (5±8, 20±7, 38±5 bpm, respectively, n=6; Fig 1b).

View this table: [in this window] [in a new window]   Table 1. Changes in MAP and HR in Conscious, Pithed, and Electrically Stimulated (ES), Pithed Rats

View larger version (31K): [in this window] [in a new window]   Figure 1. BP and HR response to AM and PAMP. AM in doses of 0.1, 0.5, and 1 nmol/kg and PAMP in 10, 20, and 50 nmol/kg doses were intravenously injected, and changes in MAP and HR were plotted. a, Decrease in MAP by AM (closed squares) or PAMP (closed circles). b, Increase in HR by AM (closed squares) or PAMP (closed circles). Note that reflex tachycardia was smaller with PAMP than AM. P<.01 by ANOVA and Scheffe's method.

Protocol 2: Depressor Response in the Pithed Rat
Absolute values of MAP and HR are summarized in Table 1. In pithed rats baseline MAP and HR did not differ among the three groups. AM (n=6) at 0.1, 0.5, and 1 nmol/kg doses decreased MAP (-2±1, -7±1, and -10±3 mm Hg, respectively), whereas PAMP (n=7) at 10, 20, and 50 nmol/kg doses had no significant effect on MAP (-0±2, -1±2, and -2±4 mm Hg, respectively; Fig 2a). HR was not significantly changed by any dose of AM (0±2, 0±3, and 0±1 bpm, respectively) or PAMP (0±3, 0±3, and 0±3 bpm, respectively).

View larger version (28K): [in this window] [in a new window]   Figure 2. Hypotensive effect of AM and PAMP in electrically unstimulated and stimulated, pithed rats. AM in 0.1, 0.5, and 1 nmol/kg doses and PAMP in 10, 20, and 50 nmol/kg doses were injected intravenously, and decreases in MAP were plotted. a, PAMP did not reduce MAP in electrically unstimulated, pithed rats (closed triangles), whereas AM reduced MAP (closed squares). b, PAMP (open triangles) and AM (open squares) each reduced MAP in electrically stimulated, pithed rats. *P<.05, P<.01 by ANOVA and repeated measurements. Comparisons between different experimental methods were analyzed by ANOVA and Scheffe's method.

Electrical stimulation through the pithing rod elevated both MAP and HR to almost the same levels as those in conscious rats measured in protocol 1 (Table 1). The responses to electrical stimulation were completely abolished by 1 mg/kg hexamethonium (Sigma), which suggests that this pressor response reflects peripheral sympathetic stimulation (n=3; MAP: 53±6 to 50±6 mm Hg; HR: 255±20 to 260±15 bpm).

In the electrically stimulated and pithed rat, PAMP (n=7) in 10, 20, and 50 nmol/kg doses evoked a depressor response in a dose-dependent fashion (-3±1, -11±2, and -14±4 mm Hg, respectively; Fig 2b). A result that contrasts to the findings in unstimulated, pithed rats (Fig 2a), AM in doses of 0.1, 0.5, and 1 nmol/kg also decreased MAP in electrically stimulated pithed rat (-2±2, -10±3, and -15±4 mm Hg, respectively). This hypotensive effect was comparable to that in unstimulated, pithed rats and the hypotensive effect of PAMP in electrically stimulated rats. While HR did not change significantly in response to any AM dose (0±0, 0±2, and 0±3 bpm, respectively), it decreased significantly in response to PAMP in a dose-dependent fashion (-5±5 -10±3, and -20±4 bpm, respectively).

Protocol 3: NE Levels
Plasma NE levels after pithing did not differ among control, PAMP, and AM groups (Table 2). After electrical stimulation, the NE level significantly increased in all three groups. Although AM injection reduced MAP as it had in protocol 2, the mean plasma NE level after electrical stimulation was similar to that of the control group. In contrast to the AM group, plasma NE levels were significantly decreased after PAMP injection and were lower than for the control or AM group (Table 2).

View this table: [in this window] [in a new window]   Table 2. Effect of PAMP and AM on Plasma NE Levels in Pithed Rats

	Discussion

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Kitamura et al¹ discovered the novel hypotensive peptide AM in pheochromocytoma tissue extract, isolated a cDNA clone of the AM precursor from the pheochromocytoma cDNA library, and determined its nucleotide sequence.² Its precursor, preproadrenomedullin, consists of 185 amino acids that include both the AM sequence and a unique 20-residue sequence in the N-terminal region, a peptide named PAMP.^{2 3 4} Both AM and PAMP possess hypotensive activity.^{7 13} While AM is known to be a potent vasodilator that acts by elevating intracellular cAMP and increasing NO,^{1 8 10 11 12} the hypotensive mechanism of PAMP is not fully known. In a previous study with isolated rat mesenteric arteries, we showed that PAMP inhibits NE overflow,¹⁴ which is thought to be the hypotensive mechanism of PAMP, but that precise relationship has not been clarified.

Recent studies on local neuromodulating hormones derived from nerve terminals as well as endothelium and/or vascular smooth muscle cells have revealed that NE and several other factors, such as NO, endothelin, neuropeptide Y, calcitonin-gene related peptide, and others are important for BP regulation.^{16 17 18} Thus, there is a possibility that PAMP action to reduce in vitro NE release is not necessarily related to its hypotensive effect. Moreover, numerous peripheral and central nervous system structures are interconnected to control the circulation. Thus, the vasomotor center activates efferent pathways that innervate sympathetic ganglia, which in turn exert an effect on BP regulation. In this study, the hypotension evoked by PAMP was accompanied with less reflex tachycardia than that evoked by AM in the conscious, unrestrained rat. To elucidate whether PAMP induced hypotension by reducing sympathetic tone, we investigated the PAMP effect in the pithed rat, a model in which the sympathetic nervous system has been destroyed.

In pithed rats, AM but not PAMP evoked hypotension. These results indicate that an interaction between PAMP and sympathetic nerve activity plays a role in the hypotensive effect of PAMP but not of AM. In the present study, plasma NE levels were significantly elevated by electrical stimulation, suggesting that peripheral sympathetic tone was exogenously activated by electrical stimulation in pithed rats. In response to electrical stimulation, while both AM and PAMP evoked hypotension, plasma NE levels were decreased only in the PAMP group. Moreover, a small but significant decrease in HR was also observed in the PAMP-treated group. These data suggest that PAMP induces its hypotensive action by inhibiting peripheral sympathetic nerve activity, results and a notion that are consistent with previous data.^{7 8 14 21}

The hypotensive effect of AM is 50 times more potent than that of PAMP. In this study, we did not examine the effect of higher AM doses on sympathetic nerve activity. However, in our previous report, we examined the effects of identical AM and PAMP concentrations on NE overflow and showed that only PAMP decreased NE overflow.¹⁴ All these data suggest that the hypotensive mechanism of AM is partly due to a vasodilator action and that of PAMP is a reduced NE release from sympathetic nerve endings.

It has been reported that the plasma AM level is elevated in patients with congestive heart failure or in those with hypertension.^{22 23 24} AM levels are also higher in patients with renal dysfunction.^{23 24} AM is a vasodilator⁸ as well as a potent natriuretic and diuretic peptide.^{22 12} These observations suggest that AM has a compensatory function to offset further development of renal dysfunction and congestive heart failure and thus may be useful in treating patients with cardiorenal dysfunction. The mRNA level of AM is reported to be increased in ventricular smooth muscle from patients with failing hearts.²² As mentioned, PAMP and AM are both derived from the same precursor peptide. Thus, PAMP may also be increased in patients with congestive heart failure or hypertension, and it may have a compensatory role in these disorders.

In conclusion, although PAMP and AM are derived from the same peptide and show a hypotensive action, the mechanisms of their hypotensive effects differ. The hypotensive action of PAMP may be mainly due to inhibition of sympathetic neural transmission at nerve endings rather than a direct, vasodilator action on vascular smooth muscle, which is the main hypotensive mechanism of AM.

	Selected Abbreviations and Acronyms

 

AM = adrenomedullin BP = blood pressure bpm = beats per minute HR = heart rate MAP = mean arterial pressure NE = norepinephrine PAMP = proadrenomedullin N-terminal 20 peptide

Received December 1, 1995; first decision December 26, 1995; accepted May 21, 1996.

	References

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