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(Stroke. 1995;26:682-687.)
© 1995 American Heart Association, Inc.

Articles

Effect of Nitric Oxide Synthase Inhibition on the Cerebral Vascular Response to Hypercapnia in Primates

Robert W. McPherson, MD; Jeffrey R. Kirsch, MD; Ramsis F. Ghaly, MD Richard J. Traystman, PhD

From the Department of Anesthesiology/Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Md; and Cook County Hospital, Chicago, Ill (R.F.G.).

Correspondence to Robert W. McPherson, MD, Meyer 8-138, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287.

	Abstract

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Background and Purpose The role of nitric oxide in cerebrovascular response to changes in PCO₂ is unclear. In the present study, we assessed responses at two levels of hypercapnia in a primate model before and after blockade of nitric oxide synthesis.

Methods We compared the effects of two levels of hypercapnia, defined as PCO₂ of 70 mm Hg (high-CO₂ group, n=5) and PCO₂ of 50 mm Hg (moderate-CO₂ group, n=6), on increases in regional cerebral blood flow (microspheres) before and after inhibition of nitric oxide synthase with N-nitro-L-arginine methyl ester (L-NAME; 60 mg · kg^-1) in isoflurane-anesthetized cynomolgus monkeys (1.0% end-tidal concentration).

Results Before L-NAME administration, hypercapnia increased flow in all regions (eg, forebrain: high-CO₂ group, 69±10 to 166±15 mL · min^-1 · 100 g^-1; moderate-CO₂ group, 49±7 to 93±15 mL · min^-1 · 100 g^-1) and decreased cerebral vascular resistance (high-CO₂, 1.1±0.1 to 0.4±0.1 mm Hg · mL^-1 · min · 100 g; moderate-CO₂, 1.4±0.1 to 0.7±0.1 mm Hg · mL^-1 · min · 100 g). During normocapnia, L-NAME decreased cerebral blood flow (high-CO₂, 37±9%; moderate-CO₂, 40±6%) and increased cerebral vascular resistance (high-CO₂, 93±33%; moderate-CO₂, 88±20%). After L-NAME, hypercapnia still increased blood flow in all regions (eg, forebrain: high-CO₂, 56±7 to 128±3 mL · min^-1 · 100 g^-1; moderate-CO₂, 36±5 to 57±8 mL · min^-1 · 100 g^-1) and decreased vascular resistance (high-CO₂, 1.5±0.1 to 0.6±0.1 mm Hg · mL^-1 · min · 100 g; moderate-CO₂, 2.0±0.3 to 1.2±0.1 mm Hg · mL^-1 · min · 100 g). In both groups L-NAME attenuated hypercapnia hyperemia by approximately 30% in cortex but not in other regions.

Conclusions Nitric oxide contributes to basal vascular tone but is not a major contributor to the mechanism of hypercapnia-induced cerebral vasodilation, except in cortex, in primates.

Key Words: cerebral blood flow • hypercapnia • nitric oxide • oxygen • monkeys

	Introduction

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Nitric oxide (NO) or an NO-containing compound has been implicated as an important mediator of cerebral vascular tone under a variety of anesthetic conditions.^{1 2 3} In addition, NO or an NO-containing compound appears to have an important function in endothelium-mediated cerebral vasodilation,^{4 5 6} dilation from local application of excitatory amino acids,⁷ and perivascular nerve stimulation.^{8 9} Recently, several studies have suggested that NO production contributes to the mechanism of cerebral vasodilation in response to changes in arterial carbon dioxide tension (PCO₂)^{10 11 12} and vasodilation of cerebral vessels due to extracellular acidosis¹³ but not in response to changes in arterial oxygen tension (PO₂).^{10 14 15} Many of the in vivo studies that have evaluated the role of NO in hypercapnic vasodilation have been performed in rodents,^{10 11 13} and therefore it is unclear whether NO plays a similar role in cerebrovascular responses to changes in PCO₂ in other species. For example, in preliminary studies in dogs,¹⁶ we demonstrated that inhibition of NO synthase (NOS) did not reduce the change in cerebrovascular resistance (CVR) that occurs during hypercapnia.

This study was designed to determine whether inhibition of NOS alters basal cerebral vascular tone and inhibits the cerebral vascular response to two levels of hypercapnia in primates. N-Nitro-L-arginine methyl ester (L-NAME) was used as an inhibitor of NOS. Cerebral oxygen consumption (CMRO₂) was measured to determine whether any change in basal cerebral vascular tone or alteration in cerebral vascular response to hypercapnia could be accounted for by alteration in brain metabolism.

	Materials and Methods

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This study was approved by the animal care and use committee at The Johns Hopkins Medical Institutions. Eleven male cynomolgus monkeys (3.5 to 5.5 kg) were sedated with intraperitoneal thiopental in increments of 25 mg · kg^-1 before induction of anesthesia by insufflation of isoflurane in oxygen. The total dose of thiopental was approximately 100 mg · kg^-1. After induction of anesthesia, a tracheostomy was performed, and the animal was mechanically ventilated to normocapnia with a Harvard small-animal ventilator. Oxygen was administered to maintain arterial PO₂ >90 mm Hg, and isoflurane was administered in the inspiratory limb of the ventilator circuit by an isoflurane vaporizer (Ohio Model TC-3). End-tidal isoflurane was monitored with an infrared analyzer designed for halogenated agents (Nellcor N-2500), and end-tidal isoflurane concentration was maintained at 1.0%. A single dose of pancuronium bromide (0.1 mg · kg^-1, IV bolus) was administered to minimize muscle contraction from electrocautery in all animals. A catheter was placed through the left thoracotomy into the left atrial appendage for radiolabeled microsphere injection. Bilateral brachial artery catheters were inserted and advanced into the aortic arch for measurement of mean arterial blood pressure (MABP), withdrawal of microsphere reference blood, and arterial blood sampling. A balloon-tipped catheter was placed retrograde through a femoral artery into the mid-thoracic aorta for use during the protocol in treating any decrease in MABP during hypercapnia. A femoral vein catheter was placed for rapid removal of blood to prevent increases in MABP after L-NAME administration.

The animal was turned prone, and a catheter was placed in the sagittal sinus for withdrawal of cerebral venous blood and measurement of sagittal sinus pressure. Arterial and sagittal sinus pressure transducers were referenced to the right atrium. Pressures were measured with Statham P23 Db transducers and recorded on a Gould-Brush polygraph. A thermistor was placed 3 mm into the parietal lobe through a burr hole, and temperature was maintained at 37.5±0.2°C with heating lamps. Arterial blood glucose level was measured with a Yellow Springs Glucose Analyzer (YSI model 2300). Glucose-containing solutions were administered in animals with serum glucose levels <60 mg · dL^-1. Arterial and sagittal sinus blood PO₂, PCO₂, and pH levels were measured at 37°C immediately after withdrawal using a Radiometer ABL3 analyzer. Oxygen saturation and hemoglobin were measured spectrophotometrically with a Radiometer hemoximeter OSM3. Arterial and cerebral venous oxygen contents were calculated from the measured oxygen saturation and hemoglobin concentration and corrected for dissolved oxygen. CMRO₂ was calculated by multiplying the arterial-to-cerebrovenous oxygen content difference by the forebrain cerebral blood flow (CBF). Cerebral perfusion pressure (CPP) was calculated as MABP-sagittal sinus pressure. CVR was calculated by dividing CPP by forebrain CBF. CBF was measured with radiolabeled microspheres (16±0.5 µm in diameter; Dupont-NEN Products) using the reference withdrawal method.¹⁷ Six radiolabels were used and injected in random sequence (¹⁵³Gd, ^114mIn, ¹¹³Sn, ¹⁰³Ru, ⁹⁵Nb, and ⁴⁶Sc). Regional blood flow was determined in the cortex (1 mmx10 mmx10 mm superficial slice), forebrain (cerebral hemispheres), caudate nucleus (as an example of a region of subcortical gray matter), periventricular white matter, hindbrain (brain stem and diencephalon), and cerebellum.

Baseline data were obtained during normocapnia after 1 hour of anesthesia. CO₂ was then introduced into the inspiratory limb of the ventilator, and a second set of data was obtained 10 minutes after end-tidal CO₂ had reached a plateau. At the end of the hypercapnic measurement (moderate-CO₂ group, PCO₂ of 50 mm Hg; high-CO₂ group, PCO₂ of 70 mm Hg), supplemental CO₂ was discontinued, and a third set of data was obtained 15 minutes after the end-tidal CO₂ tension had returned to baseline.¹⁸ L-NAME (60 mg · kg^-1) was then administered intravenously over 10 minutes, during which time blood was removed to prevent increases in MABP. We have found that this dose of L-NAME is necessary to reliably reduce cortical NOS activity by >90%.¹⁹ In the high-CO₂ group (n=5), a fourth set of data was obtained 20 minutes after the end of L-NAME administration during normocapnia; in the moderate-CO₂ group (n=6), the fourth set of data was obtained during normocapnia 60 minutes after the end of L-NAME administration. CO₂ was again introduced into the inspiratory limb of the ventilator, and a fifth set of data was obtained 10 minutes after end-tidal CO₂ had reached a plateau in both groups.

Values are expressed as mean±SEM. ANOVA for within (time) subjects design was used to compare regional CBF, blood gas levels, and hemodynamic variables during the measurement periods. The Student-Newman-Keuls test was used to correct for multiple comparisons. Because standard deviation increased with the mean value, a logarithmic transformation was performed on regional CBF and CVR data before data analysis. A paired t test was used to determine whether the changes in CBF and CVR that occurred with hypercapnia were different before and after administration of L-NAME. P.05 was considered significant.

	Results

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Table 1 demonstrates physiological variables in high- and moderate-CO₂ group animals during the study. MABP and CPP did not change throughout the study in both groups, although after L-NAME administration, MABP and CPP were slightly higher in the high-CO₂ group (P<.05). Hypercapnia increased sagittal sinus pressure before and after L-NAME in both groups (P<.05). Both groups required hemorrhage of approximately 15 mL · kg^-1 to prevent increased CPP after L-NAME, and reinfusion of blood was required during hypercapnia to keep CPP constant. Arterial oxygen content and PO₂ were unchanged during the two episodes of hypercapnia and were not altered by L-NAME administration in either group. A similar degree of hypercapnia (PCO₂ of 70 mm Hg in the high-CO₂ group; PCO₂ of 50 mm Hg in the moderate-CO₂ group) with an associated decrease in pH was achieved before and after L-NAME.

View this table: [in this window] [in a new window]   Table 1. Hemodynamic and Blood Gas Data During Normocapnia and Hypercapnia Before and After L-NAME Administration

Before L-NAME administration (Table 2), hypercapnia increased blood flow in both groups in the cerebellum, hindbrain, caudate nucleus, forebrain, and cortex but not in white matter. L-NAME decreased flow in the cerebellum (high-CO₂ group, 32±8%; moderate-CO₂ group, 45±6%), hindbrain (high-CO₂, 37±5%; moderate-CO₂, 36±7%), caudate nucleus (high-CO₂, 25±5%; moderate-CO₂, 16±8%), forebrain (high-CO₂, 37±9%; moderate-CO₂, 40±7%), and cortex (high-CO₂, 26±8%; moderate-CO₂, 27±5%) compared with the immediately preceding pre–L-NAME normocapnic value (normocapnia before L-NAME versus normocapnia after L-NAME). After L-NAME, blood flow was increased by hypercapnia in the cerebellum, hindbrain, caudate nucleus, forebrain, and cortex in both groups. The cerebral cortex was the only region that demonstrated an attenuation in hypercapnic vasodilation after L-NAME administration (Fig 1).

View this table: [in this window] [in a new window]   Table 2. Regional Cerebral Blood Flow in Moderate-CO2 and High-CO2 Groups Before and After L-NAME Administration

View larger version (32K): [in this window] [in a new window]   Figure 1. Bar graph shows hypercapnic cerebral blood flow response in percent increase from the normocapnic values in the high-CO2 (n=5) and moderate-CO2 (n=6) groups before and after administration of N-nitro-L-arginine methyl ester (L-NAME; 60 mg · kg-1). Values are mean±SEM. - indicates pre–L-NAME value; +, post–L-NAME value; *, P.05 vs pre–L-NAME value.

Before L-NAME administration, CVR decreased with hypercapnia and returned to baseline values with the return to normocapnia in both groups (Fig 2). Administration of L-NAME resulted in substantially increased cerebrovascular tone in both groups. After administration of L-NAME, the absolute decrease in CVR with hypercapnia (CVR_normocapnia-CVR_hypercapnia) was similar to that observed before L-NAME ([in mm Hg · mL^-1 · min · 100 g] high-CO₂ group: pre–L-NAME, 0.6±0.1; post–L-NAME, 0.9±0.2; moderate-CO₂ group: pre–L-NAME, 0.8±0.1; post–L-NAME, 0.9±0.2). Baseline CMRO₂ was similar between groups and was not changed by hypercapnia or L-NAME in either group, indicating an appropriate and stable plane of general anesthesia.

View larger version (34K): [in this window] [in a new window]   Figure 2. Bar graphs show cerebral vascular resistance (CVR) and cerebral oxygen consumption (CMRO2) during normocapnia (N) and hypercapnia (H) before (Pre) and after (Post) administration of N-nitro-L-arginine methyl ester (L-NAME; 60 mg · kg-1). Values are mean±SEM. * indicates P.05 hypercapnic value vs first normocapnic value for either before or after L-NAME; +, P.05 for corresponding pre–L-NAME value within the same group (eg, hypercapnic CVR before vs after L-NAME).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
We found that inhibition of NOS activity decreased CBF and increased CVR under basal conditions in isoflurane-anesthetized primates. Although inhibition of NOS slightly decreased the maximal CBF during hypercapnia and decreased the hypercapnic CBF response in cortex, the absolute decrease in CVR during hypercapnia was similar before and after L-NAME administration. Our data suggest that although NO, or an NO-containing compound, is an important mediator of basal cerebrovascular tone, it is not a major mediator of hypercapnia-induced cerebral vasodilation in primates, except perhaps in cortex.

We chose a dose of L-NAME that would inhibit brain NOS activity by >90% in these primates. In dogs we previously found that 40 mg · kg^-1 was required to meet this goal.²⁰ In one monkey (not included in this study), we found that 40 mg · kg^-1 L-NAME suppressed NOS activity to approximately 20% of baseline. Therefore, in the animals in this study, we used a larger dose of L-NAME to completely suppress enzyme activity. Subsequent determination of NOS activity in monkeys that received 60 mg · kg^-1 indicated >90% suppression of NOS activity.¹⁹ This finding was not surprising to us because we have also found differences in other species in sensitivity for inhibition of NOS activity by L-NAME. For example, 10 mg · kg^-1 L-NAME inhibits NOS activity by >90% in cats,²¹ whereas 50 mg · kg^-1 L-NAME is required in piglets for the same degree of inhibition.¹⁵

The increase in cerebrovascular tone observed in this study after inhibition of NOS is consistent with that seen in several other studies. For example, in pentobarbital-anesthetized rats¹ and piglets,³ N^G-monomethyl-L-arginine significantly reduced CBF. Likewise, a reduction in CBF was observed after NOS inhibition with N^G-nitro-L-arginine in chloralose- and urethane-anesthetized cats.²² Consistent with the effect of NOS inhibition on CBF is the finding that topically applied N^G-monomethyl-L-arginine produced concentration-related constriction of pial vessels that was greatest in larger vessels.² The source for NO production may be endothelium, perivascular neurons, astrocytes, or cortical neurons.^{7 23 24 25 26 27}

In our study, L-NAME caused a substantial decrease in CBF in both groups and therefore alteration in cerebral vascular tone. Under these conditions it is difficult to make comparisons for the absolute change in CBF before and after L-NAME administration because there is a large change in vascular tone, reflected by the large difference in CVR. For example, there may be different amounts of flow-mediated dilation with different vascular tones.²⁸ Therefore, we chose to compare pre– and post–L-NAME values, during hypercapnia, as the absolute change in CVR. Using this analysis, there was no difference in response to hypercapnia between values before and after L-NAME in either group. Regional hypercapnic CBF response also was not different before and after L-NAME, except for a modest decrease in cortex response. Others have also demonstrated a greater sensitivity of cortex regarding the effect of NOS inhibition on regional CBF response to hypercapnia.²⁹ The modest decrease in hypercapnic CBF response in cortex after L-NAME in the present study may partially account for the observed reduced CBF response to hypercapnia in studies using laser-Doppler flowmetry to measure CBF. These studies are unable to measure the effect of L-NAME on hypercapnia-induced changes in regional CVR and may overestimate the role of NO in hypercapnia-induced cerebral vasodilation. We conclude that, in primates, if alteration in baseline cerebral vascular tone is taken into account, there is little support for a major role of NO in the mechanism of hypercapnic cerebral vasodilation, except perhaps for in the cortex.

A preliminary report in primates suggests that intra-arterial administration of N^G-monomethyl-L-arginine completely blocked the CBF response to hypercapnia.³⁰ However, this study is difficult to compare with ours because the isoflurane concentration, the method of measurement of CBF, the time of hypercapnic response after N^G-monomethyl-L-arginine, the degree of NOS inhibition, and the control of other important physiological variables (eg, CPP, PO₂, brain temperature) are not indicated.

It is possible that in our study L-NAME did not attenuate the cerebral vascular effect of hypercapnia because of incomplete inhibition of NOS. This is unlikely, since we have demonstrated >90% inhibition of NOS with this dose of L-NAME in monkeys during the time course that was used in this study in the high-CO₂ group.¹⁹ Our results differ from a recent study in rats by Iadecola and Zhang³¹ using laser-Doppler flowmetry, which showed that the attenuation of hypercapnic vasodilation is increased over time after administration of a blocker of NOS and is dependent on the level of hypercapnia. We found a similar level of vasodilation with a delay of either 20 or 60 minutes after administration of L-NAME. Likewise, in dogs L-NAME did not attenuate the cerebral vascular effect of hypercapnia in any region other than cortex at a dose of 40 mg · kg^-1, which also inhibits NOS by >90%.¹⁶ To the contrary, none of the studies that demonstrate attenuated cerebral vascular response to hypercapnia after administration of an NOS inhibitor documented the degree of inhibition of NOS with the dose of inhibitor used. Therefore, it is not possible to determine whether the difference between studies is due to a difference in degree of NOS inhibition.

It is not likely that the general lack of effect of L-NAME on hypercapnic CBF response is due to insufficient time for L-NAME to inhibit NOS: we have found that this dose of L-NAME produced >90% inhibition of NOS in primates over the same time course as in these experiments.¹⁹ In addition, a similar degree of normocapnic flow decrease by L-NAME was seen in both groups despite a longer delay for CBF measurement in the moderate-CO₂ group. We found a decrease in normocapnic flow after L-NAME that was similar to that found by Iadecola and Xu in rats³² ; however, they found a 78% decrease in hypercapnic flow after L-NAME, whereas we found residual hypercapnic flow of 60% (high-CO₂ group) and 48% (moderate-CO₂ group). In the present study, only cortex demonstrated a modest decrease in percent change in CBF after administration of L-NAME. This effect of L-NAME was not observed in other gray matter regions (eg, caudate) and is therefore of questionable significance.

It is possible that the time course for inhibition of NOS activity in brain as a whole is different than that required to inhibit the cerebral vascular response to hypercapnia. Our measurement of brain NOS activity is the total activity from neurons, astrocytes, and endothelium. Therefore, our measurement of brain NOS activity may misrepresent NOS activity from any one source (eg, endothelium) that constitutes total brain NOS activity. If this were the case, it would be possible that, even with >90% inhibition of brain NOS activity, hypercapnia could increase CBF by a mechanism that involved only stimulation of endothelium NOS. This is an unlikely scenario because the timing for measurement of hypercapnic response in our study was similar to timing used in other studies^{10 12} that demonstrated marked attenuation of the CBF response to hypercapnia after administration of an NOS inhibitor.

Another potential confounding factor in our study was the use of L-NAME as the inhibitor of NOS, since it has been demonstrated to also have antimuscarinic effects at high concentrations.³³ This is probably not an important factor, since other more potent muscarinic-receptor antagonists do not alter the cerebral vascular response to hypercapnia.³⁴ Furthermore, Pelligrino et al¹⁰ also used L-NAME in their studies and demonstrated substantial attenuation of the CBF response to hypercapnia in rats.

Other laboratories have demonstrated that NO may be an important mediator of vasodilation during moderate levels of hypercapnia but not at extreme levels of hypercapnia.³⁵ Although it is possible that inhibition of NOS may have attenuated the cerebral vascular response to a lesser level of hypercapnia than that achieved in the moderate-CO₂ group, this is an unlikely explanation for our data; other investigators have raised PCO₂ to a higher level (70 to 80 mm Hg, Pelligrino et al¹⁰ ; 68 mm Hg, Wang et al¹² ) during hypercapnia and still demonstrated significant attenuation of the hypercapnic CBF response. In addition, Iadecola et al³⁶ demonstrated that NOS inhibition was most effective in inhibiting the CBF hypercapnia response at PCO₂ of 60 mm Hg and that there was attenuation of the response at PCO₂ from 40 to 80 mm Hg. At PCO₂ levels above 80 mm Hg, there was no attenuation of the response. In the moderate-CO₂ group, the maximal PCO₂ value was only 50 mm Hg. Therefore, we expected to find profound inhibition of hypercapnic reactivity after L-NAME administration if NO was an important mediator of hypercapnic CBF hyperemia in primates.

Isoflurane was used for the anesthesia in this study because it is a clinically relevant anesthetic and its use is associated with hemodynamic stability. In addition, we demonstrated that response to both hypocapnia and hypercapnia is retained with anesthetic concentrations comparable to those used in the present study.³⁷ A possible confounding problem with the use of isoflurane as the basal anesthetic is that it, like the other inhalational anesthetics, appears to increase CBF via a mechanism involving stimulation of NOS.^{20 38} However, we do not believe that the use of isoflurane in our study accounts for the preserved response to hypercapnia; several other studies that demonstrate attenuation of the cerebral vascular response to hypercapnia after NOS inhibition also used an inhalational anesthetic technique (halothane). Halothane, like isoflurane, increases CBF throughout the brain by a mechanism that can be prevented by administration of L-NAME and that therefore presumably involves stimulation of NOS activity.²⁰

Another potential explanation for the differences in our data and the previous studies in rats, which demonstrate a significant dependence of CO₂ blood flow response on NOS,^{10 11 12} is the possibility that rats may have a greater dependence on NO for control of CBF. Although higher brain levels of NOS would not necessarily prove a higher level of basal function, it would support the hypothesis that rats have a higher basal NOS tone than primates. No study has yet evaluated this possibility.

In conclusion, we found that NO contributed to basal cerebral vascular tone in primates. Hypercapnic CBF response was retained in all areas of isoflurane-anesthetized monkeys after inhibition of NOS, although there is a decrease in hypercapnic CBF response in cerebral cortex compared with the baseline response. Because absolute change in CVR with hypercapnia was not affected by L-NAME, we conclude that NO is not a major contributor to the mechanism of hypercapnia-induced vasodilation in primates.

	Acknowledgments

 
This study was supported in part by US Public Health Service National Institutes of Health grants GM-46764 and NS-20020. We wish to thank Renee Tankersley for assistance in the preparation of this manuscript and the technicians of the Anesthesiology/Critical Care Medicine Laboratory for technical assistance.

Received September 20, 1993; revision received November 28, 1994; accepted December 29, 1994.

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