(Hypertension. 1995;26:406-412.)
© 1995 American Heart Association, Inc.
Articles |
Stimulation of Endogenous Nitric Oxide Pathway by L-Arginine Reduces Declamp Mortality and Attenuates Hypertension Associated With Aortic Cross-Clamp–Induced Hindlimb Ischemia in Rats
From the Departments of Physiology (J.-S.J., L.G.D'A.) and Surgery (L.G.D'A.), The University of Michigan Medical School, Ann Arbor.
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Abstract |
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Abstract We tested the hypotheses that maintaining the activity of nitric oxide by L-arginine infusion would counteract the release of an endogenous nitric oxide synthase inhibitor, improve survival, and decrease intraoperative hypertension after infrarenal aortic cross-clamp surgery. Hindlimb ischemia was generated by infrarenal aortic cross-clamping and tying of the left femoral artery for 5 hours in rats with bilateral femoral and sciatic nerves cut. Mean blood pressure significantly increased during the 5-hour ischemic period in ischemic rats (no drug treatment). Baroreceptor function was inhibited in ischemic rats assessed by intravenous dose response to phenylephrine and nitroprusside after 5 hours of ischemia, suggesting baroreceptor resetting. In ischemic rats infused with L-arginine the intraoperative hypertension was prevented during the 5-hour period, suggesting that this hypertension may be mediated by nitric oxide inhibition. The rates of survival and arrhythmias 2 hours after declamping were 50% in ischemic rats and 100% in ischemic rats treated with N
-nitro-L-arginine (a nitric
oxide synthase inhibitor) 10 minutes before declamping. In
ischemic rats infused with L-arginine the survival
rate was significantly increased to 100% and the arrhythmic rate was
inhibited. We conclude that L-arginine prevents
hypertension during cross-clamping and decreases the mortality rate and
arrhythmias after declamping by maintaining nitric oxide
synthesis. These results suggest that humoral factors released from the
ischemic hindlimb may inhibit endogenous nitric
oxide production, thus contributing to intraoperative
hypertension, arrhythmias, and high mortality rate after aortic
cross-clamp surgery.
Key Words: nitric oxide • hypotension • baroreflex • arginine • nitro compounds • aneurysm • hypertension, intraoperative • hindlimb
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Introduction |
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Infrarenal aortic cross-clamp surgery has been shown to be associated with high mortality and hypotension after declamping,1 2 when many patients suffer acute myocardial ischemia3 and acute renal failure.4 During the cross-clamp period the ischemic hindlimb releases several factors, including inosine,5 hypoxanthine,5 adenosine,5 prostaglandin,6 and potentially other unknown factors. These metabolic products initially accumulate in the local tissue area and trigger the chemoreflex through the well-identified afferent neuronal pathway.7 A possibility that has not yet been ruled out is that some of these same local factors, on leaving the limb, return to the systemic circulation and contribute to the maintenance of the chemoreflex hypertension and high postclamp mortality rate.
The muscle chemoreflex elevates BP and heart rate in response to limb exercise.8 It is mediated through the accumulation of metabolic products that stimulate groups III and IV afferent fibers within the exercising limb.9 10 11 Other studies have demonstrated baroreceptor resetting to higher levels during exercise,12 13 but the factors or mechanisms causing this baroreceptor resetting remain undefined.
In a previous study we demonstrated a delayed-onset ischemic hypertension induced by infrarenal aortic cross-clamping in dogs.7 The systemic mean BP gradually increased after about 30 minutes of cross-clamping and could be maintained even though the ischemic blood, which might contain high concentrations of vasodilators such as adenosine, lactic acid, and prostaglandins, returned to the systemic circulation. This is a new model for induced ischemic hypertension and quite different from tourniquet-induced or low body compression–induced ischemia used by other investigators.14 In our model we cross-clamp the infrarenal aorta without blocking the venous return from the ischemic limb, so it is possible that humoral factors from the ischemic hindlimb return to the systemic circulation in the residual blood flow and contribute to the hypertension, baroreceptor resetting, and high mortality. The canine model is reproduced in the present study with the use of rats.
Most recently, we demonstrated in an in vitro study that the presence
of an endogenous NOS inhibitor from the
ischemic hindlimb can inhibit the NO-cGMP pathway and inhibit
the relaxation to acetylcholine in a vascular smooth muscle
preparation.15 This endogenous NO
inhibitor is likely a competitive inhibitor of
NOS because L-arginine can reverse the effect of the
endogenous NOS inhibitor.15 The
inhibition of the NO-cGMP pathway has been shown to facilitate
baroreceptor resetting during the onset of hypertension in rats treated
with N-nitro-L-arginine (an NOS
inhibitor).16 Thus, humoral factors from the
ischemic limb may contribute to the ischemic
hypertension by a direct action on vascular smooth muscle and/or by
facilitating baroreceptor resetting. To study the systemic effect of
ischemic plasma, we induced hindlimb ischemia in
bilateral femoral and sciatic denervated rats to eliminate the
contribution from the afferent neuronal pathway to the muscle
chemoreflex. We hypothesized that if these effects are mediated by
inhibition of the NO-cGMP pathway, they should be reversed by
L-arginine infusion. Likewise, the sensitivity of
baroreceptor function should be restored by L-arginine,
further indicating a role of NO in modulating the baroreceptor
sensitivity. If this pathway is to have potential clinical importance,
the L-arginine infusion should increase the survival rate
after cross-clamp surgery by maintaining NOS activity.
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Methods |
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General Protocol
Male Sprague-Dawley rats weighing approximately 250 to 300 g were used for the experiment. The entire experimental procedure conformed to the guidelines of the American Physiological Society and The University of Michigan Unit for Laboratory Animal Medicine. Each rat was anesthetized with pentobarbital (50 mg/kg IP) and maintained during the experimental period by urethane injection (50 mg IV in 0.1 mL isotonic saline) when necessary. The rat was placed on a temperature-controlled heated table, and rectal temperature was maintained at 37°C. The trachea was intubated to maintain a patent airway, and the right jugular vein was catheterized with two polyethylene (PE-50 and PE-10) tubes for infusion of an isotonic saline solution (0.01 mL/min) and drug injection, respectively. The left carotid artery was cannulated (PE-50) for continuous measurement of BP, which was displayed on an ink-writing oscillograph (RPS7C8A Polygraph, Grass Instruments); heart rate was obtained by tachographic conversion (Grass 7P4K) of the electrocardiographic signal, which was continuously monitored. The electrocardiogram was used for determination of the presence or absence of arrhythmias during the declamp period. A catheter (PE-120) was advanced into the bladder to let urine flow out during the experimental period. Bilateral femoral nerves were sectioned at the inguinal ring region, and bilateral sciatic nerves were sectioned through a posterior approach at their proximal end before aortic cross-clamping. The abdominal aorta was exposed by a longitudinal abdominal incision. The bilateral lumbar vessels were tied to decrease the influence of collateral circulation. After a stabilizing period hindlimb ischemia was induced by clamping of the left femoral artery and infrarenal aorta. The temperature in the hindlimb region of ischemic rats was maintained at 35°C (close to that in the control rats) by a separate temperature controller. Sham control rats had the same surgical manipulation and denervation of bilateral femoral and sciatic nerves but no cross-clamping. Ischemic rats were divided into three groups: 6 rats for ischemia alone, 7 rats for an L-NNA–treated group, and 7 rats for an L-arginine–infused group. Each group had 5 hours of ischemia followed by assessment of baroreceptor sensitivity by phenylephrine and nitroprusside. After phenylephrine and nitroprusside injection the clamps on the infrarenal aorta and left femoral artery were removed. The preparation procedure for the L-arginine infusion and L-NNA treatment is as follows.
L-NNA Pretreatment Group
In seven of the hindlimb ischemic rats, L-NNA (100
mg/kg IV) was given 10 minutes before declamping in an attempt to
prevent declamping hypotension and to study the effect of L-NNA
treatment on the survival rate 2 hours after declamping.
L-Arginine Infusion Group
Seven of the hindlimb ischemic rats were continuously
infused with L-arginine (120 mg/kg per hour) during
control, the 5 hours of ischemia, and the 2 hours of
declamping. This L-arginine dose has been demonstrated to
be without effect on the mean arterial BP of
Sprague-Dawley rats when continuously infused
intravenously for 1 week.17
L-Arginine was dissolved in 0.9% saline solution, and the
infusion rate was maintained at 0.01 mL/min. The control group received
a saline infusion at the same rate.
Baroreceptor Sensitivity
Baroreceptor sensitivity was assessed by intravenous
injections of phenylephrine (2, 5, 10, and 20 µg/kg) and
nitroprusside (2, 5, 10, and 20 µg/kg) after 5 hours of
ischemia. The injections of phenylephrine and
nitroprusside were done through PE-10 tubing with a Hamilton microliter
syringe. Sufficient time was allowed for baseline BP to be regained
between drug injections. The data of ischemia alone and
L-NNA–treated ischemic groups were pooled up to the time
when L-NNA was given and excluded one rat that had leaking of
phenylephrine solution from the junction of the PE-10
tubing and vessel wall.
Survival After Declamping
After evaluation of baroreceptor sensitivity the aorta and left
femoral arteries were declamped and BP, heart rate,
electrocardiogram, and survival time were continuously
monitored for an additional 2 hours in each group. Three of the control
rats were excluded from survival analysis because we did not
observe them long enough (2 hours) in the initial experiments in this
series.
Drugs
Nitroprusside was purchased from Abbott Laboratories;
L-phenylephrine HCl, L-arginine
hydrochloride, L-NNA, urethane, and sodium pentobarbital were purchased
from Sigma Chemical Co.
Statistics
Results are expressed as SEM for all observations. Multiple
comparison of means was accomplished by ANOVA followed by the
Newman-Keuls test when appropriate. Survival curve analysis was
generated by a computer program (SURVIVALTOOL for
STATVIEW). This program applies the Breslow-Gehan-Wilcoxon
test (a nonparametric test) to test for similarity between
the generated curves. If the group comparison showed a significant
difference, comparisons were made between curves for each treatment and
ischemia alone. The mortality and arrhythmic rates in 2 hours
of declamping were analyzed with Fisher's exact test and
unpaired t test. A probability value less than .05 was
considered statistically significant.
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Results |
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Survival
L-Arginine or L-NNA administration markedly altered survival after removal of the aortic cross-clamp. Fig 1A illustrates that the L-NNA dose sufficient to inhibit NOS reduced survival such that all rats in this treated group were dead by 70 minutes after declamping. By contrast, the ischemic group with no drugs had a 50% survival by 2 hours after declamping (Table 1). When L-arginine was infused throughout the experimental period, all the rats survived the full 2-hour test period. L-Arginine prevented mortality in the same rats when it reduced the occurrence of arrhythmias, as demonstrated in Table 1. Mean arterial BP at the onset of arrhythmia was 90±6 mm Hg for the ischemic group and 126±10 mm Hg for the L-NNA–treated group (Fig 2), indicating that a mechanism other than the decreasing of perfusion pressure caused arrhythmia.
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Hindlimb Ischemic Hypertension
L-Arginine infusion reduced the development of
hypertension during aortic cross-clamp, as demonstrated in Fig 3. Mean BP and heart rate of ischemic or control
rats were almost equal during the control period. In the
ischemic group, application of the aortic clamp significantly
increased systemic mean BP after 70, 80, 90, 120, and 150 minutes of
cross-clamping compared with mean BP of the control and
ischemic+L-arginine–infused groups. That is,
L-arginine infusion eliminated the increase in BP produced
by aortic cross-clamp. The ischemic group tended to have a
slightly higher heart rate than control rats during the hypertensive
period. This tachycardic effect, rather than a reflex bradycardia,
accompanied by hypertension indicates that baroreceptor sensitivity was
reduced during the 5 hours of the ischemic period. In the
L-arginine–infused rat group, heart rate tended to
increase compared with that in the ischemic and control
groups.
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P<.05, ischemic group vs
L-arginine–infused ischemic group.
Baroreceptor Sensitivity
The effects of intravenous phenylephrine
and nitroprusside on BP and heart rate are presented in Table 2. The absolute change in BP in response to
phenylephrine was similar in all three groups. However, at
a phenylephrine dose of 5 µg/kg, the percent increase in
BP as shown in Fig 4 was significantly reduced in
ischemic rats compared with control and
L-arginine–infused ischemic rats. In contrast
to the effect of phenylephrine, the absolute change of mean
BP at 5 µg/kg nitroprusside and the percent mean BP decrease at 5 and
10 µg/kg nitroprusside were significantly less compared with control
rats (Table 2 and Fig 5).
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Baroreceptor sensitivity (beats per millimeter of mercury per minute; Table 3) was significantly reduced in ischemic and L-arginine–infused ischemic rats compared with control rats when assessed with phenylephrine (2, 5, and 10 µg/kg). Although L-arginine infusion did not fully restore baroreceptor sensitivity, it did tend to improve it compared with ischemic rats. As shown in Fig 6, the stimulus-response curve of the baroreceptor tended to be shifted to the right in ischemic rats compared with control rats.
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Discussion |
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The most scientifically compelling and potentially clinically important observation in this study is that L-arginine increases survival and prevents hypertension during aortic cross-clamping. This is presumably by its know action of stimulating NOS, but other beneficial effects of L-arginine cannot be ruled out. L-Arginine infusion at a dose similar to the dose of 120 mg/kg per hour that we used has been shown to stimulate NOS18 but did not reduce BP during 1 week of continuous infusion in Sprague-Dawley rats.17 The complementary observation was also made that L-NNA (an NOS inhibitor) decreases survival after aortic cross-clamping, presumably in this case by inhibiting NOS. Derivatives of L-arginine, including L-NNA and NG-monomethyl-L-arginine, have been demonstrated previously to inhibit NOS.18 19 20 These complementary observations are indirect evidence that NO, by some as yet undefined mechanism, may be playing an important role in the survival of these rats after removal of the aortic cross-clamp.
L-NNA is a potent NOS inhibitor and may increase the afterload of the heart by increasing total peripheral resistance, causing vasoconstriction in the coronary artery,21 and increasing the washout of humoral factors from the ischemic hindlimb by increasing perfusion pressure. The initial drop in BP during declamping is more predominant in the L-NNA–treated group, so the possibility that NO synthesis contributes to the initial declamping hypotension can be ruled out. Furthermore, we will argue that it is reasonable to conclude that L-arginine significantly improved survival rate and inhibited hypertension during the cross-clamp period by the specific effect of L-arginine stimulating NOS. Previous studies have shown that L-arginine attenuated the hypertension in Dahl/Rapp salt-sensitive rats18 and rats treated with long-term NG-nitro-L-arginine methyl ester.17 22 The authors concluded that these rats have a functional impairment of NOS.17 18 22 In contrast to these hypertensive models, L-arginine has no effect on the development of hypertension in stroke-prone spontaneously hypertensive rats23 or on the mean arterial BP of spontaneously hypertensive rats18 and deoxycorticosterone acetate–salt hypertensive rats.24 L-Arginine fully reversed the hypertensive response during the cross-clamp period in the present study. This suggests that at least part of the hypertension during clamping is due to NOS inhibition, perhaps in response to the release from the hindlimbs of an endogenous NOS inhibitor such as asymmetrical dimethylarginine.25 26
If ischemic hindlimbs were releasing an NOS inhibitor that contributed to the morbidity in this model, then one would predict that the use of an exogenous NOS inhibitor would further decrease survival. The survival rate of rats treated with an L-NNA dose known to inhibit NOS was significantly decreased. A higher percentage of arrhythmias developed in the L-NNA–treated ischemic group than in the ischemic group. These arrhythmias are not likely a result of inadequate perfusion pressure because the onset of arrhythmia occurred at mean arterial BP values above 126 and 90 mm Hg, respectively. An endogenous NOS inhibitor released from the ischemic hindlimb may contribute to the development of arrhythmia in our study by effectively producing coronary vasoconstriction with ischemia, leading to arrhythmia. Other possible factors causing high mortality and morbidity rates in our model may include pulmonary edema and multiple organ failure. It has been suggested that the inhibition of NOS by an exogenous NOS inhibitor caused severe impairment of cardiac function, reduction of cardiac output, and vasoconstriction in multiple organs.27 Very recently, a study reported that the pulmonary vein from newborn lambs was capable of endothelium-dependent constriction in response to L-NNA and pulmonary arteries showed no effect in response to this NOS inhibitor.28 A severe vasoconstrictive effect in response to either an endogenous or exogenous NOS inhibitor that acts preferentially in pulmonary veins may cause pulmonary edema and hypoxia and subsequently cause increased arrhythmias and mortality.
Another effect of NOS inhibitors that may cause a higher mortality rate in our model is a direct increase in sympathetic nerve activity with a vasoconstriction that is independent of the direct peripheral vasoconstrictive effect of decreased NO.29 This direct sympathetic stimulation effect of an NOS inhibitor can lead to severe vasoconstriction in multiple organs and tissues, including coronary and renal arteries. If this is the case, one may speculate that infusion of vasoconstrictors such as norepinephrine would also lead to cardiac arrhythmias and mortality in this model.
Baroreceptor function was reset to a higher pressure level after 5
hours of cross-clamping. Studies have suggested that resetting of the
baroreceptor can be mediated by the angiotensin II receptor
in the central nervous system,30 involvement of the
electrogenic sodium pump,31
prostaglandin,32 or NO.16 A
recent study demonstrated NOS activity in the carotid
sinus,33 suggesting a possible local role of NO synthesis
in regulating baroreceptor sensitivity. However, L-arginine
did not significantly restore the sensitivity of baroreceptors,
suggesting that the resetting of the baroreceptor during hindlimb
ischemia in our study may be due to other factors as discussed
above. L-Arginine, which acts as the substrate for NOS,
increased heart rate during the 5-hour ischemic period in the
present study. This presumably tachycardic effect of
L-arginine supports our view that NOS stimulation
contributes to the antihypertensive (vasodilative) effect and the
increase in survival. Other effects of L-arginine, however,
may contribute to the antihypertensive effect of
L-arginine.34 For instance, the
metabolic product of L-arginine, agmatine,
may have an antihypertensive effect by acting on central
2 receptors.34 However, if the protective
effect of L-arginine is mediated by factors other than
stimulation of NOS, for example, by a central 2 receptor
effect, L-arginine would tend to decrease both mean
arterial BP and heart rate simultaneously, as
suggested by studies that showed central 2
receptor–mediated hypotensive and bradycardic
effects.35 36 This was not seen in the present
studies.
The L-arginine–infused group had an increased
heart rate during the cross-clamping period. Thus, another explanation
for the protective effect of L-arginine may be through the
maintenance of a higher cardiac output. This tachycardic effect
of L-arginine is not consistent with other reports
which showed that L-arginine has no effect on mean
arterial BP and heart rate in Sprague-Dawley rats
at these doses.17 Our interpretation for this is that the
tachycardic effect of L-arginine is a baroreceptor reflex
tachycardia caused by reversal of the effect of an
endogenous NOS inhibitor during a steady-state
high BP. This hypothesis is further supported by the observation that
L-arginine infusion caused a tachycardic effect in
N-nitro-L-arginine–treated
rats.17
The exact identities of the humoral factors involved in ischemic hypertension and the high mortality rate are currently unclear. Recent studies have suggested a factor in plasma capable of NOS inhibition.25 37 The endogenous NO synthesis inhibitor asymmetrical dimethylarginine may be involved in our observation. In certain diseases, including muscular dystrophy, the urinary asymmetrical dimethylarginine concentration is increased.25 26 We speculate that during muscle ischemia the asymmetrical dimethylarginine concentration is increased and contributes to the ischemic hypertension and high mortality rate because of localized vasoconstriction and ischemia in the myocardium and kidney, with acute respiratory distress attributable to pulmonary vasoconstriction.28
Previous investigators used a variety of pharmacological approaches to prevent declamp hypotension, including intravenous infusion of vasoconstrictor38 and fluid supplement.39 40 These manipulations increase or maintain systemic BP, but they also may increase the washout of humoral factors from the ischemic hindlimb after declamping. If an endogenous NO-cGMP inhibitor were released, it could cause peripheral vasoconstriction involving the coronary and renal circulations and increase the mortality rate. In clinical studies it has been shown that patients have a high mortality rate after cross-clamp surgery3 4 ; this high mortality rate tends to be the consequence of acute myocardial infarction and acute renal failure. Although we did not assess cardiac and renal functions in the current study, a previous study from our laboratory has demonstrated the elevation of renal vascular resistance and total peripheral resistance without a change in cardiac output and plasma renin activity during cross-clamping in a canine model.7 An NOS inhibitor released from the ischemic hindlimb after cross-clamp surgery may have the same effect as an exogenous NOS inhibitor in constricting vessels in the heart21 and kidney41 and impairing the function of both organs, thereby contributing to mortality.
The reflex hypertension in our current model demonstrates that hindlimb
ischemia activates a reflex increase in systemic BP in
bilateral femoral and sciatic denervated rats, suggesting that humoral
factors gradually released from the hindlimb may contribute to the
above effects. However, the possibility of residual afferent fibers in
the psoas muscle and skin of hindlimb and other areas cannot be ruled
out in this study. Other investigators have suggested the muscle
chemoreflex as activating sympathetic nerve activity,14
thus increasing mean BP. An increase in plasma
norepinephrine concentration during the hindlimb
ischemic period has been reported.14 This high
norepinephrine concentration may cause receptors to
downregulate42 and attenuate the pressor effect to
phenylephrine (at a low dose) in ischemic rats in
our observation. A previous study has shown that high concentrations of
norepinephrine can decrease the 1 receptor
mRNA level in vascular smooth muscle.43 The
L-arginine–infused ischemic rats had an
improved vasoconstrictive effect in response to
phenylephrine. This improvement may involve these secondary
effects of NO. It has been demonstrated that endogenous NO
can modulate the vasoconstriction response to
norepinephrine in vascular smooth muscle.44
L-Arginine infusion maintains the activity of NO, and this
NO synthesis inhibits norepinephrine release from
sympathetic nerve terminals45 and attenuates the vascular
constrictive response to endogenous
norepinephrine release stimulated by electrical
stimulation44 ; thus, L-arginine may prevent
the downregulation of receptors.
The vasodilative effect in response to nitroprusside (5 and 10 µg/kg) was significantly inhibited in ischemic rats. This observation is consistent with our in vitro observation.15 Nitroprusside mediates the relaxation of vascular smooth muscle through NO release and through the NO-cGMP pathway to relax vascular smooth muscle.46 The less vasodilative effect in response to nitroprusside in ischemic rats suggests that the ultimate impairment may also involve guanylate cyclase in vascular smooth muscle.
In summary, our results suggest that the release of a humoral factor or factors, perhaps from the hindlimb, may directly contribute to the hypertension observed during skeletal muscle ischemia. This factor may act by inhibiting the NO-cGMP vasodilator mechanism and by resetting baroreceptors to a higher level. The current clinical interventions to prevent cross-clamp hypertension and declamping hypotension may require reconsideration of this potentially important physiological role of NOS in the maintenance of declamp survival rate. L-Arginine maintains the activity of NOS, prevents ischemic hypertension, and reduces mortality after declamping. Thus, L-arginine should be considered as a candidate for safe and effective intervention in patients undergoing aortic cross-clamp surgery or suffering from the chronic ischemia of intermittent claudication.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a Grant-in-Aid from the American Heart Association, Michigan Affiliate (35GS945). We are grateful to Steven E. Whitesall and Mary C. Lloyd for their assistance in this project and the National Defense Medical Center, Taiwan, ROC, for the fellowship support of Jong-Shiaw Jin. We thank Dr R. Clinton Webb for his scientific and editorial counsel.
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Footnotes |
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Reprint requests to L.G. D'Alecy, DMD, PhD, The University of Michigan Medical School, Department of Physiology, 7799 Medical Science Building II, 1301 E Catherine St, Ann Arbor, MI 48109-0622. Email lgdalecy@umich.edu.
Received February 9, 1995; first decision March 16, 1995; accepted May 24, 1995.
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