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(Hypertension. 1996;28:341-346.)
© 1996 American Heart Association, Inc.

Articles

Neural Mechanism of Pressor Action of Nitric Oxide Synthase Inhibitor in Anesthetized Monkeys

Tomio Okamura; Kazuhide Ayajiki; Noboru Toda

the Department of Pharmacology, Shiga (Japan) University of Medical Science.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Intravenous injection of N^G-nitro-L-arginine (L-NA), a nitric oxide synthase inhibitor, elevated mean blood pressure by 29.0±4.9 mm Hg and decreased heart rate by 40.7±5.6 beats per minute in anesthetized Japanese monkeys (n=6), whereas N^G-nitro-D-arginine was without effect. After pretreatment with pentolinium, the magnitude of the pressure elevation by L-NA was significantly less than that after pretreatment with phentolamine. The reduced blood pressure by either of the pretreatment drugs was compensated to control levels by a continuous infusion of angiotensin II before L-NA administration. Isolated monkey distal mesenteric arteries (150 to 200 µm OD) without endothelium responded to nerve stimulation by nicotine with a contraction, which was abolished by prazosin alone or in combination with ,ß-methylene ATP. In the strips thus treated and contracted with prostaglandin F₂, nicotine caused a relaxation that L-NA abolished. L-NA but not N^G-nitro-D-arginine reversed the inhibition. Histochemical staining of NADPH diaphorase, considered to be identical to nitric oxide synthase in neuronal tissues, demonstrated that positively stained nerve fibers were consistently present in the adventitia of monkey distal mesenteric arteries and arterioles. These results strongly suggest that nitroxidergic vasodilator nerves innervate peripheral small arteries and arterioles in the monkey and that these nerves participate in the regulation of systemic blood pressure. High blood pressure caused by nitric oxide synthase inhibitors is associated with an elimination of nitroxidergic nerve function together with an impairment of the basal release of nitric oxide from the endothelium.

Key Words: nitric oxide • N^G-nitro-L-arginine • blood pressure • peripheral nerves • primates

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Evidence has accumulated that endogenous NO or its related substance, discovered to be an endothelium-derived relaxing factor, is a new intercellular signal-mediating molecule in the cardiovascular, immune, and central nervous systems.¹ We have histochemically demonstrated the presence of perivascular nerves containing NO synthase² and demonstrated the functional role of NO as a neurotransmitter of the vasodilator nerves in isolated dog cerebral³ and peripheral⁴ arteries. The nerve is called nitroxidergic.⁵ Numerous studies support the hypothesis that BP and vascular tone are regulated by endogenous NO synthesized from L-arginine, possibly in the endothelial cells, and the findings from our laboratory indicate that NO from the perivascular nerves is also involved. In fact, in anesthetized dogs, the roles of the nitroxidergic nerve in hypertension⁶ and cerebral vasoconstriction⁷ caused by L-NA, a specific NO synthase inhibitor, have been demonstrated. However, this may not be the case for the rat, because BP elevation caused by NO synthase inhibitors was not always suppressed by treatment with ganglionic blockers.⁸ Therefore, the significant role of neurogenic NO in BP regulation may vary among animal species. Results applicable to humans are more likely to be extrapolated from data obtained from monkeys than from other mammals.

We undertook the present study to examine whether elimination of neurogenic vasodilator control is involved in inducing the hypertension by L-NA administered to anesthetized Japanese monkeys. We also examined histochemical staining of NADPH diaphorase and isometric tension responses to nerve stimulation of isolated monkey distal mesenteric arteries and arterioles to clarify the presence and role of nitroxidergic nerves because our previous study included data on only proximal arteries.⁹ Responses to nerve stimulation were obtained by the addition of nicotine, which consistently produces vascular contractions and relaxations mediated by endogenous substances derived from nerves.¹⁰

	Methods

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Thirteen Japanese monkeys (Macaca fuscata) of both sexes weighing 6 to 10 kg were used for the study. All monkeys were fed standard chow and water ad libitum and were housed according to institutional guidelines at the Shiga University of Medical Science. These studies were approved by the Animal Rights Committee, Shiga University of Medical Science.

In Vivo Experiment
Monkeys were anesthetized with ketamine (20 mg/kg IM) and sodium pentobarbital (10 mg/kg via a brachial vein). Supplemental doses (5 mg/kg) of sodium pentobarbital were given when necessary via a catheter inserted into the femoral vein. The monkeys were permitted to breathe spontaneously. Arterial systolic and diastolic BPs were monitored with a pressure transducer (MPU0.5, TMI Inc) and amplifier (AP641G, Nihon-Koden Kogyo Co) through a catheter inserted into the left or right brachial artery or the left femoral artery. The same artery was not used again for measurement. Heart rate was monitored by a cardiotachometer (AT610G, Nihon-Kohden Kogyo). Drugs were injected into the right femoral vein. D-NA or L-NA (10 mg/kg) was dissolved in saline (10 mL) and gradually injected for 2 minutes into the vein. L-NA studies were carried out three times in each monkey with a washout period of at least 3 weeks. During each recovery period, the monkeys were well cared for and released until the next series of experiments. No significant postoperative impairments, such as inflammatory symptoms, restriction of movement, and weight loss, were observed.

The monkeys were first treated with a bolus injection of 2 mg/kg pentolinium or phentolamine, followed by a continuous infusion of 0.2 mg/kg per minute. The order of treatments was randomized; the effectiveness of the ganglionic blocker was examined first in two of the six monkeys, that of the -blocker was examined first in two of the other monkeys, and the control experiment was done first in the remaining two. After reversal of the reflex decrease in heart rate by norepinephrine to tachycardia (for studies with pentolinium) or abolition of the pressor action of the amine (for studies with phentolamine) was determined, L-NA was administered. During the experimental period, Ang II (0.1 µg/kg per minute IV) was continuously infused by an infusion pump (model 22, Harvard Apparatus) to compensate the depressor action of pentolinium or phentolamine. The amounts of Ang II required to compensate the depressor actions of both pentolinium and phentolamine were almost the same, indicating that these blocking agents seemed to have no influence on the vasoconstrictor response unrelated to NO synthase blockade. Different results between male and female monkeys were not observed.

In Vitro Experiment
Monkeys were anesthetized with ketamine (20 mg/kg IM) and sodium thiopental (20 mg/kg IV) and killed by bleeding from the common carotid arteries. Within 30 minutes after death, the mesentery was rapidly removed, and the distal mesenteric arteries (150 to 200 µm OD) were carefully isolated and immediately used for tension experiments. The distal mesenteric regions including the arteries and arterioles (60 to 100 µm) were stored in the prefixed solution for histochemical study.

Tension Recording
Arteries were cut helically into strips approximately 20 mm long. The endothelium of the strips was mechanically removed by gentle rubbing with a cotton pellet. The specimens were fixed vertically between hooks in a 20-mL muscle bath containing a modified Ringer-Locke solution kept at 37±0.3°C and aerated with a mixture 95% O₂ and 5% CO₂. The hook anchoring the upper end of the strip was connected to the lever of a force-displacement transducer (AP621G, Nihon-Kohden Kogyo). Resting tension was adjusted to 0.5 g, which is optimal for inducing the maximal contraction.¹¹ The bathing medium contained (mmol/L) NaCl 120, KCl 5.4, CaCl₂ 2.2, MgCl₂ 1.0, NaHCO₃ 25.0, and dextrose 5.6, pH 7.35 to 7.42. Before the start of experiments, all preparations were allowed to equilibrate for 60 to 90 minutes in the bathing medium, during which time the bath solution was replaced every 10 to 15 minutes.

Isometric contractions and relaxations were displayed on an ink-writing oscillograph. The contractile response to 30 mmol/L K⁺ was first obtained, and the arterial strips were then washed three times with control media and left to stabilize for 40 to 50 minutes. Responses to nicotine were obtained under resting conditions or in the arterial strips partially precontracted with PGF₂ (4x10^-7 to 9x10^-7 mol/L), the contraction ranging between 20% and 35% of the contraction induced by 30 mmol/L K⁺. Relaxant responses to NO (acidified NaNO₂) were also obtained.¹² At the end of each experiment, papaverine (10^-4 mol/L) was applied to attain the maximal relaxation. Contractions and relaxations induced by the agents were presented as values relative to those induced by 30 mmol/L K⁺ or by 10^-4 mol/L papaverine, respectively. Responses to nicotine or NO (acidified NaNO₂) were obtained by direct addition of the drug to the bathing medium. In assessing the effects of blocking agents, we examined the responses to the agonist repeatedly until stabilization and then treated the artery strips with the blocking agents for approximately 30 minutes before the response to the agonist was obtained. Endothelium removal was verified by abolition or marked suppression of the relaxations caused by 10^-6 mol/L acetylcholine.

Histochemistry of NADPH Diaphorase
The staining method was described in a previous report.¹³ Briefly, distal portions of the monkey mesentery including arteries and arterioles were rapidly removed and fixed in ice-cold 0.1 mol/L PBS (pH 7.4) containing 0.3% glutaraldehyde and 4% paraformaldehyde and then postfixed overnight in 0.1 mol/L PBS with 4% paraformaldehyde followed by cryoprotection in 15% sucrose. The fixed tissues were cut into sections (20 µm thick) in a cryostat (Cryotom, Nakagawa Seisakusyo Co) and mounted onto gelatin/chrome-alum–coated glass slides. The sections were then rinsed in 0.1 mol/L PBS. NADPH diaphorase staining was performed by incubation of glass-mounted sections with 0.1 mol/L PBS, pH 8.0, containing 1 mmol/L NADPH (Kohjin Co), 2 mmol/L nitro blue tetrazolium (Sigma Chemical Co), and 0.3% Triton X-100 at 37°C. The incubation period (30 to 60 minutes) was determined by the intensity of the staining and was kept constant for all sections of the individual monkey. The reaction was terminated by washing the sections in 0.1 mol/L PBS. After several washes with distilled water, the sections were air-dried and cover-slipped with Xylene (Merck). Most of the serial sections were doubly stained with both NADPH diaphorase and eosin. A histochemical control experiment, in which NADPH was excluded from the reaction mixture, gave no positive staining. The sections were then examined and photographed under a light microscope (BH2, Olympus).

Statistics and Drugs
The results shown in the text and figures are expressed as mean±SE. Statistical analyses were made with Student's unpaired t test for two groups and Tukey's method after one-way ANOVA for more than three groups. L-NA and D-NA were from Peptide Institute Inc; L- and D-arginine and nicotine from Nacalai Tesque; phentolamine mesylate from CIBA-GEIGY; ,ß-methylene ATP and pentolinium from Sigma; PGF₂ from Japan Upjohn Co; norepinephrine hydrochloride and tetrodotoxin from Sankyo Pharmaceutical Co; and papaverine hydrochloride from Dainippon Pharmaceutical Co.

	Results

Top Abstract Introduction Methods Results Discussion References

 
BP Measurement
Intravenous injection of L-NA (10 mg/kg) elicited a slow elevation of BP in anesthetized monkeys (Fig 1). The pressure reached its peak value within 20 to 30 minutes, and hypertension persisted for 60 minutes or longer. Mean values of the increments in systolic and diastolic BPs are shown in the Table. Heart rate decreased inversely to the BP elevation. The induced hypertension and bradycardia were reversed by injection of L-arginine (500 mg/kg); the mean increase in BP by L-NA and decrease by L-arginine were 29.0±4.9 and 31.3±5.3 mm Hg, respectively (n=6). D-NA (10 mg/kg IV) did not alter systemic BP (Fig 1).

View larger version (8K): [in this window] [in a new window]   Figure 1. Effects of D-NA (10 mg/kg IV), L-NA (10 mg/kg IV), and L-arginine (500 mg/kg IV) on systemic blood pressure (top) and heart rate (bottom) in an anesthetized monkey.

View this table: [in this window] [in a new window]   Table 1. Effects of NG-Nitro-L-Arginine (10 mg/kg IV) on Systolic and Diastolic Blood Pressures and Heart Rate in Anesthetized Monkeys Treated with Pentolinium and Phentolamine

Treatment with pentolinium in doses (2 mg/kg bolus injection plus 0.2 mg/kg per minute infusion) sufficient to reverse to tachycardia the reflex bradycardia caused by a pressor dose of norepinephrine (3 µg/kg) significantly inhibited the pressor effect of L-NA compared with that under control conditions in the same monkeys (Fig 2). Changes in heart rate caused by norepinephrine before and after treatment with pentolinium were -20.5±5.2 and +25.1±4.2 beats per minute, respectively. The decrease in BP by pentolinium was compensated by continuous, intravenous infusion of Ang II (0.1 µg/kg per minute). Treatment with phentolamine in a dose (2 mg/kg) sufficient to lower systemic BP to a level almost identical to that caused by pentolinium markedly depressed the pressor response to norepinephrine. The induced hypotension was compensated by the infusion of Ang II. L-NA elevated systolic, mean, and diastolic pressures in the presence of phentolamine to a similar extent, as it had done under control conditions (Fig 3, Table).

View larger version (11K): [in this window] [in a new window]   Figure 2. Effects of L-NA (10 mg/kg IV) on systemic blood pressure (BP, top) and heart rate (HR, bottom) in an anesthetized monkey treated with pentolinium (2 mg/kg IV and successive infusion at 0.2 mg/kg per minute). Hypotension caused by pentolinium was compensated by infusion of Ang II (0.1 µg/kg per minute IV). NE indicates norepinephrine (3 µg/kg IV bolus).

View larger version (40K): [in this window] [in a new window]   Figure 3. Effects of L-NA (10 mg/kg IV) on mean blood pressure in control monkeys (left) and modifications by treatment with pentolinium (PTN, 2 mg/kg IV and successive infusion at 0.2 mg/kg per minute) and phentolamine (PHA, 2 mg/kg IV and successive infusion at 0.2 mg/kg per minute) of increments of mean blood pressure (MBP) induced by L-NA (right). Hypotension caused by the treatment drugs was compensated by infusion of Ang II (0.1 µg/kg per minute IV). Cont. indicates control. For statistical analysis, Student's paired t test (left) and Tukey's method after one way ANOVA (right) were used.

Tension Responses of Isolated Small Arteries to Nerve Stimulation
Monkey distal mesenteric arteries denuded of endothelium responded to 10^-4 mol/L nicotine with contractions that were abolished by treatment with 10^-5 mol/L prazosin; the mean value of the contractions in control conditions was 12.6±2.8% (n=6) relative to the contractions caused by 30 mmol/L K⁺ (1116±309 mg). In the strips partially contracted with PGF₂, the nicotine-induced contraction was reversed to a relaxation with prazosin alone or in combination with 10^-6 mol/L ,ß-methylene ATP. Treatment with 10^-6 mol/L L-NA abolished or reduced the nicotine-induced relaxation to a slight contraction, whereas this treatment did not influence the response to NO (acidified NaNO₂). L-Arginine (3x10^-4 mol/L) reversed the inhibitory effect of the NO synthase inhibitor. Quantitative data are shown in Fig 4. D-Arginine did not restore the relaxation (n=3). Typical recordings are demonstrated in Fig 5. The relaxations caused by nicotine were not influenced by 10^-6 mol/L indomethacin (n=4) or 10^-7 mol/L atropine (n=3) or timolol (n=3) but were abolished by 10^-5 mol/L hexamethonium (n=4).

View larger version (31K): [in this window] [in a new window]   Figure 4. Modification by L-NA (10-6 mol/L) and L-NA plus L-arginine (L-Arg., 3x10-4 mol/L) of the responses to nicotine (top) and acidified NaNO2 (NO, bottom) of monkey distal mesenteric arteries denuded of endothelium and partially contracted with PGF2 (n=6). Strips were treated with 10-5 mol/L prazosin or prazosin plus 10-6 mol/L ,ß-methylene ATP to abolish the contractile response. Relaxations induced by 10-4 mol/L papaverine were taken as 100%. aP<0.01, significantly different from control (C); bP<0.01, significantly different from L-NA plus L-arginine (Tukey's method). Vertical bars represent SEM.

View larger version (9K): [in this window] [in a new window]   Figure 5. Responses to nicotine (N, 10-4 mol/L) and acidified NaNO2 (NO) before and after treatment with L-NA (10-6 mol/L) and L-NA plus L-arginine (3x10-4 mol/L) in a monkey distal mesenteric arterial strip treated with 10-5 mol/L prazosin and partially contracted with PGF2. PA indicates 10-4 mol/L papaverine, which produced the maximal relaxation. NO concentrations are expressed as -log [mol/L].

Histochemical Study
Perivascular nerve fibers containing NADPH diaphorase were observed in cryostat sections of the distal mesenteric arteries and arterioles obtained from monkeys. There were abundant positively stained bundles and fibers in the adventitia (Fig 6).

View larger version (84K): [in this window] [in a new window]   Figure 6. Histochemical demonstration of perivascular nerves containing NADPH diaphorase in a cryostat section of monkey mesenteric arteriole. Positively stained nerve bundles (arrows) and fibers (arrowheads) are clearly seen in the adventitia and vicinity of the arteriole. Bar=50 µm.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Systemic administration of NO synthase inhibitors elevates BP^{14 15} and decreases organ blood flow,¹⁶ indicating that endogenous NO plays an important role in the regulation of BP and local blood flow. Since the lipophilic radical was primarily discovered to be an endothelium-derived relaxing factor (EDRF),¹⁷ the hemodynamic actions of NO synthase inhibitors are considered to have resulted from an inhibition of the basal release of endothelium-derived NO. However, it has recently been recognized that NO derived from perivascular nerves also plays an important role in the control of vascular tone in vivo. For instance, intracisternal administration of L-NA produced constriction of the basilar artery in anesthetized dogs; the constriction was markedly inhibited by treatment with hexamethonium, a ganglionic blocking agent, but was augmented by phentolamine. This suggests that under resting conditions, neurogenic NO rather than EDRF is strongly involved in the regulation of basilar arterial tone and that the neurogenic vasodilation counteracts the vasoconstriction caused by noradrenergic nerve activation.⁷ Furthermore, in anesthetized dogs,⁶ hypertension caused by intravenous administration of the NO synthase inhibitor was markedly suppressed by treatment with the ganglionic blocker, indicating that high BP elicited by NO synthase inhibitors is not solely due to an abolition of the basal release of EDRF.

These findings suggest that neurogenic NO is involved in the regulation of arterial and arteriolar tone in the dog. However, this may not be the case in the rat, as it has been reported that ganglionic blockers fail to suppress the elevation of BP induced by acute administration of NO synthase inhibitors.⁸ The discrepancy between our data and those of other researchers seems to be due to the difference in animal species used. In rats, a main neurotransmitter of the vasodilator nerve in the peripheral tissues may be different from NO, since impairment of the vascular actions of calcitonin gene–related peptide is reported to abolish the neurogenic dilatation in rat mesenteric arterioles.¹⁸ In addition, a recent study reported an elevation of BP in endothelium-derived NO synthase knockout mice in which NO synthase inhibitors did not raise BP.¹⁹ Therefore, it is likely that the neurotransmitter of vasodilator nerves that innervates the arterioles and is responsible for vasodilatation may be different among animal species.

To extrapolate the data obtained from animal studies to humans, it is important to determine different mechanisms of action in primate and subprimate mammals. The present study clearly reveals an involvement of neurogenic NO in BP regulation in the monkey, as previously observed in the dog, as pentolinium in a ganglionic blocking dose significantly inhibited the pressor response to L-NA, whereas phentolamine had no effect. Since the inhibition by pentolinium of the L-NA action was observed in the monkeys, in which BP was maintained by the continuous infusion of Ang II at a level almost identical to that before administration of the ganglionic blocker, the influence of a BP fall on the L-NA action was excluded. In addition, a failure by the -adrenoceptor antagonist to inhibit the pressor response to L-NA suggests that the L-NA–induced pressor response is not mainly associated with an activation of the sympathetic nervous system, in contrast to the studies in rats.^{20 21} Our previous studies on isolated canine peripheral arteries have demonstrated that L-NA does not affect the action of norepinephrine and the amine release from adrenergic nerves but augments the contraction caused by perivascular nerve stimulation.²² Similar findings were obtained in the proximal portion of monkey mesenteric arteries.⁹ In addition, intravenous injection of NO synthase inhibitors is expected to reach the nerve terminals located in the adventitia, as intraluminal application of the inhibitors selectively potentiated the pressor responses to nerve stimulation in isolated, perfused mesenteric arterial segments of the dog.²³ Therefore, the hypertensive action of L-NA in the monkey seems mainly to be associated with inhibition of the synthesis of neurogenic NO but not with potentiation of sympathetic nerve function. On the other hand, the ganglionic blocking agent did not abolish the pressor action of L-NA, indicating that the action resistant to ganglionic blockade is mediated by a basal release of NO from extraneuronal tissues, possibly the endothelium.

In monkey distal mesenteric arterial strips without endothelium, contractions caused by nicotine were markedly suppressed or abolished by prazosin, suggesting the involvement of the ₁-adrenoceptor subtype that is stimulated by neurogenic norepinephrine. In some strips in which the response was not completely abolished by prazosin, the remaining response was abolished by ,ß-methylene ATP, which desensitizes the excitatory response mediated by P_2x-purinoceptors.²⁴ The contraction caused by nicotine seems to be associated with activation of adrenergic nerves and to a lesser extent purinergic ones. Under blockade of the ₁-adrenoceptor alone or in combination with the P_2x-purinoceptor, the arterial strips responded to nicotine with a relaxation that was selectively inhibited by the NO synthase inhibitor, the response being restored by L-arginine. These results suggest an important role of the nitroxidergic nerve in regulating the tone of small mesenteric arteries and arterioles. The vasodilator nerve seems to functionally counteract the vasoconstrictor nerve. Demonstration of perivascular nerves containing NADPH diaphorase in the small arteries and arterioles supports the idea of nitroxidergic innervation, because diaphorase is considered to be identical to NO synthase in tissues of neural origin.²⁵ Similar findings have been obtained by functional and histochemical studies on dog cerebral, retinal, temporal, mesenteric, saphenous, and renal arteries and monkey cerebral, temporal, proximal mesenteric, and renal arteries.^{2 13 26 27 28} Nicotine stimulates the release of nitroxy compounds from endothelium-denuded cerebral²⁹ and temporal²² arteries and increases the content of cyclic GMP in the tissues,⁴ the effects of which are abolished by NO synthase inhibitors. Therefore, NO appears to act as a neurotransmitter in vasodilator nerves, innervating the monkey distal mesenteric artery and arteriole, which may be an important determinant of vascular resistance.

In summary, the elimination of nitroxidergic neural function may be involved in the mechanism underlying the elevation of systemic BP by the NO synthase inhibitor in the monkey, as seen in the dog.⁶ The neural factor involved in the overall effect of the inhibitor is less in the monkey (approximately 42%, the amount depressed by ganglionic blockade) than in the dog (approximately 68%). However, the results so far obtained clearly indicate that NO derived from perivascular nerves as well as non-neuronal tissues mediates reduced vascular resistance in the monkey. Further study is required to verify our hypothesis that it is possible to extrapolate the findings obtained with anesthetized Japanese monkeys to humans.

	Selected Abbreviations and Acronyms

 

Ang II = angiotensin II BP = blood pressure D-NA = NG-nitro-D-arginine L-NA = NG-nitro-L-arginine NO = nitric oxide PBS = phosphate-buffered saline PGF2 = prostaglandin F2

	Acknowledgments

 
This work was supported in part by the Uehara Memorial Foundation and Takeda Medical Research Foundation. The authors thank Kazuhide Yoshida for excellent technical assistance.

	Footnotes

 
Reprint requests to Dr Noboru Toda, Department of Pharmacology, Shiga University of Medical Science, Seta, Ohtsu, Shiga 520-21, Japan. E-mail okamura@bellebsd.shiga-med.ac.jp.

Received December 19, 1995; first decision February 2, 1996; accepted May 13, 1996.

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