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Stroke. 1997;28:1115-1122

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(Stroke. 1997;28:1115-1122.)
© 1997 American Heart Association, Inc.

Articles

Intra-arterial Nitrovasodilators Do Not Increase Cerebral Blood Flow in Angiographically Normal Territories of Arteriovenous Malformation Patients

Shailendra Joshi, MD; William L. Young, MD; John Pile-Spellman, MD; Patricia Fogarty-Mack, MD; Robert R. Sciacca, EngScD; Lotfi Hacein-Bey, MD; Hoang Duong, MD; Yvonne Vulliemoz, PhD; Noeleen Ostapkovich, REEG/EPT; Tara Jackson, BS

From the Departments of Anesthesiology (S.J., W.L.Y., P.F.-M., Y.V., N.O., T.J.), Neurological Surgery (W.L.Y., J.P.-S.), Radiology (W.L.Y., J.P.-S., L.H.-B., H.D.), Medicine (R.R.S.), and Pharmacology (Y.V.), College of Physicians and Surgeons, Columbia University, New York.

Correspondence to William L. Young, MD, P&S Box 46, Columbia University, College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032. E-mail WLY1{at}columbia.edu


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose The mechanism of adaptation to chronic cerebral hypotension in normal brain adjacent to cerebral arteriovenous malformations (AVMs) is unknown. To clarify these mechanisms, we performed cerebral blood flow (CBF) studies in structurally and functionally normal vascular territories during 53 distal cerebral angiographic procedures in 37 patients with AVMs.

Methods CBF was measured using the superselective intra-arterial 133Xe method before and after a 3-minute infusion of either verapamil (1 mg·min-1, n=23), acetylcholine (1.33 µg·kg-1·min-1, n=7), nitroprusside (0.5 µg·kg-1·min-1, n=16) or nitroglycerin (0.5 µg·kg-1·min-1, n=7).

Results Mean±SD systemic (76±13 mm Hg) and distal cerebral arterial (55±16 mm Hg; range, 20 to 97 mm Hg) pressures were not different among groups. Verapamil increased CBF (45±12 to 65±21 mL·100 g-1·min-1, P<.001). There was no effect of acetylcholine (no change [46±9 to 46±9 mL·100 g-1·min-1], NS) or nitroglycerin (36±14 to 36±13 mL·100 g-1·min-1, NS). Nitroprusside decreased CBF (40±12 to 31±11 mL·100 g-1·min-1, P<.001). The percent change in CBF after drug administration was proportional to cerebral arterial pressure for verapamil only (r=.57, P=.0051).

Conclusions When infused intra-arterially in clinically relevant doses in both hypotensive and normotensive normal vascular territories remote from an AVM nidus, calcium channel blockade caused vasodilation, but there was an absence of response to nitric oxide–mediated vasodilators. These data suggest that (1) the nitric oxide pathway probably is not involved in the adaptation to chronic cerebral hypotension in AVM patients and (2) if our findings in vessels remote from or contralateral to the AVM are applicable to vessels of patients with other forms of cerebrovascular disease, clinically relevant doses of intra-arterial nitrovasodilators may not be useful in the manipulation of cerebrovascular resistance.


Key Words: autoregulation • calcium channel blockers • cerebral blood flow • nitric oxide


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Patients with cerebral AVMs have a low-resistance fistulous connection between the arterial and venous circulation that results in a variable degree of hypotension in structurally and functionally normal vascular beds that are anatomically "removed" from the lesion.1 Despite variable degrees of cerebral arterial hypotension, CBF generally remains normal, and autoregulatory function in these beds, as assessed by manipulation of systemic arterial pressure, remains intact.2 3 We have shown previously that in angiographically normal vessels of AVM patients, cerebral vasodilation in response to papaverine, a potent vasodilator that works through a number of different mechanisms, is robust and a function of arterial pressure.4

Chronically hypotensive vascular beds adjacent to AVMs show an adaptive reduction in cerebral vascular tone that maintains cerebral blood flow.2 The hypothesis of this study is that such an adaptive reduction in cerebral arteriolar tone is mediated by NO. We therefore predicted that an adaptive activation of the NO pathway in chronically hypotensive arteriolar beds would lead to "desensitization" to exogenously administered NO. Such a desensitization would be the converse of sensitization to the NO-mediated vasodilation seen after NO synthetase inhibition.5 6 7 Hence, in chronically hypotensive vascular beds of AVM patients, NO-mediated vasodilation would be proportionally less effective when compared with vasodilation achieved by NO-independent agents. Therefore, NO-mediated agents (ACh, SNP, and NTG) would be less effective in causing vasodilation than a non–NO-dependent agent (verapamil) if the NO pathway was already participating in resetting (decreasing) background cerebrovascular tone. In the present study, we made the unexpected observation, however, that NO donation or generation from the luminal surface does not result in arteriolar vasodilation, even in angiographically normal vascular territories perfused at normal cerebral arterial pressures.


*    Subjects and Methods
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 up arrowAbstract
 up arrowIntroduction
 *Subjects and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Patient Selection and Preparation
After institutional approval and informed consent were given, procedures were followed in accordance with institutional guidelines. The study was conducted during transfemoral cerebral angiographic procedures during the period from August 1994 through August 1996. Patients were undergoing either diagnostic superselective angiography or liquid polymer embolization (N-butyl cyanoacrylate) for the evaluation or treatment of AVMs. All patients were neurologically stable and at least 30 days removed from any clinical or radiographic evidence of cerebral hemorrhage. Patients who had undergone prior radiosurgery were excluded. A total of 53 single-dose studies were conducted on 37 AVM patients using four drugs: verapamil (23 studies, 14 patients), SNP (16 studies, 10 patients), NTG (7 studies, 6 patients), and ACh (7 studies, 7 patients). In addition, 1 patient undergoing presurgical evaluation who had a chronic seizure disorder from mesial temporal sclerosis with no demonstrable anatomic abnormalities of the cerebral circulation was investigated with SNP. Data from this patient were excluded from analysis. Only one drug was evaluated at each session, and sessions were separated by at least 4 to 6 weeks.

All patients received nimodipine (30 mg PO) as premedication. On arrival in the angiography suite, patients underwent standard anesthetic monitoring and received intravenous neuroleptic sedation (fentanyl, midazolam, droperidol) with supplemental propofol, titrated to render the patients comfortable but easily arousable for neurological testing.8

Microcatheter Placement
Under fluoroscopic guidance, a 7.0F coaxial catheter was placed in the cervical internal carotid or vertebral artery through a 7.5F femoral introducer sheath.9 An intracranial microcatheter, 1.5F at its distal tip (Magic, Balt), was passed through the coaxial catheter into a second or third division of one of the long circumferential cortical arteries, either the ACA, MCA, or PCA. The choice of vessel was determined by the interventional neuroradiologist during the course of the routine clinical imaging procedure. The microcatheter was positioned in a territory that fed structurally normal brain without angiographic evidence of any vascular abnormality; studied territories were normal on routine preoperative T1- and T2-weighted MRI studies. Since the vessel diameter at the tip of the microcatheter ranged between 1.5 and 3 mm, the microcatheter occupied 10% or less of the cross-sectional area of the vessel. Free flow of radiographic contrast was observed during fluoroscopy to verify the absence of any proximal obstruction to flow.

During the study, the microcatheter was sometimes placed contralateral to the AVM as part of the clinical investigation of collateral feeding pathways. To assess any influence of the AVM on vasodilator responses, we stratified the vessels investigated into two categories on the basis of angiography. The vessels were considered to be "isolated" from the AVM if they were contralateral to an AVM with unilateral feeding arteries. Conversely, the vessels were considered to be "nonisolated" when they were ipsilateral to the AVM or the AVM had bilateral feeding arteries. This dichotomy was introduced to control for any effect of proximity to the AVM nidus of a studied vascular territory.

Arterial Pressure Measurements
Systemic (femoral artery), coaxial (cervical internal carotid or vertebral artery), and intracerebral pressures were measured simultaneously with strain-gauge pressure transducers (Transpac, Abbott Critical Care) relative to the right atrium, displayed in real time on a monitor (Merlin, Hewlett-Packard), and digitally recorded with a MacLab system (AD Instruments). Mean pressure data were used as validated by Duckwiler et al.10 In addition, during distal advancement of the microcatheter, we verified that mean pressures in all three catheters (femoral, coaxial, and microcatheter) were similar as the microcatheter exited from the coaxial catheter in the cervical internal carotid or vertebral artery.

CBF Methodology
Our method of superselective 133Xe CBF measurement has been described previously.2 4 The method is conceptually and technically similar to the intracarotid technique.11 12 The difference between superselective and intracarotid injection of tracer is that with superselective injection, the distribution of tracer is anatomically discrete, and the arterial input pressure in the territory being perfused by the tracer injection can be precisely determined. Preliminary test-retest studies conducted with the superselective 133Xe injection technique using saline infusion (n=8) yielded a reproducibility of 8% to 10% (W.L.Y., unpublished observations, 1994). The reproducibility was determined by calculating the standard deviation of the test-retest difference divided by the mean CBF, multiplied by 100.

Briefly, the CBF probes are tungsten-collimated (30x20 mm), cadmium telluride scintillation detectors from a commercial CBF collection system (Carolina Medical). Two detectors were placed over the normal cortical vascular territory perfused by the pedicle to be injected with 133Xe. Placement of detectors was guided by contrast injection during fluoroscopy. A bolus of 133Xe in saline (1 to 2 mCi in 0.5 mL) was rapidly injected into the microcatheter as a compact bolus, and washout was recorded under stable physiological conditions for at least 1.5 minutes. The detector with higher peak washout activity was used for data analysis, since it was more likely to overlie the cortical region of interest. CBF was calculated using the initial slope method, using data collected between 20 and 80 seconds of tracer washout,2 which gives a value weighted toward gray matter.12 Washout curves were individually inspected for artifact and goodness of fit.

Mean systemic (femoral artery) and cerebral arterial pressures, as well as an arterial blood sample for determination of PaCO2 and hematocrit, were obtained concurrently with each CBF measurement. CVR was calculated as mean cerebral artery pressure divided by CBF.

Dose-Response Studies
A preliminary dose-response study was performed in 6 patients to determine the doses for SNP (Nitropress, Abbott Laboratories) and ACh (Miochol-E, Iolab Corporation). The doses for these drugs were chosen based on studies done in the peripheral and coronary vessels. From previous studies, we estimated that the volume of tissue to be infused was approximately 40 g.4 Our preliminary studies have shown that blood flow to such pedicles is {approx}40 mL·100 g-1·min-1 2 4 ; therefore, the perfusion rate was estimated at 16 mL·min-1. Studies in the peripheral and coronary circulation had demonstrated robust vasodilation at blood concentrations in the range of 10-5 to 10-7 mol/L for ACh and 10-7 to 10-8 mol/L for SNP.13 14 15 16 17 18 19 We calculated that these concentrations could be achieved by infusing ACh at 0.26, 2.6, and 26 µg·min-1 or SNP at 0.24, 0.48, and 2.4 µg·min-1. CBF, hemodynamic parameters, and arterial blood gases were determined at baseline and after a 3-minute infusion at each dose level. Each infusion was carried out as described in the following section.

Dose ranging studies were not carried out for verapamil (verapamil hydrochloride infusion, American Reagent Laboratories Inc) and NTG (American Reagent Laboratories Inc). Verapamil at 1 mg·min-1 and NTG at 0.5 µg·kg-1·min-1 are maximal intra-arterial doses used clinically to treat large-vessel vasospasm without causing bradycardia or systemic hypotension.

Single-Dose Studies
The protocol called for a baseline and a repeated CBF determination 3 minutes after the start of drug infusion. We used a rotating assignment for drug groups. Infusion doses were either verapamil 1 mg·min-1, SNP 0.5 µg·kg-1·min-1, ACh 1.33 µg·kg-1·min-1, or NTG 0.5 µg·kg-1·min-1. An infusion rate of 0.5 µg·kg-1·min-1 for SNP was chosen because this represented the maximal dose that could be administered without causing significant systemic hypotension during drug recirculation. The dose of 1.33 µg·kg-1·min-1 for ACh was chosen because it approached levels that might be expected to affect systemic vascular resistance during recirculation and far exceeded doses shown to be effective in the peripheral13 14 15 20 and coronary17 18 circulations.

Drugs were diluted in 0.9% saline solution and prepared in sterile fashion within 30 minutes before use. The SNP solution was protected from light after mixing. The syringe was allowed to saturate with NTG solution for 10 to 15 minutes. Fresh drug solution was transferred to the infusion apparatus immediately before use. The ACh preparation contained mannitol, and an equivalent amount of mannitol (Abbott Laboratories) was added to the saline solution for the baseline infusion (4 µg·kg-1·min-1). Target doses of drugs were achieved by varying the concentration, and the infusion rate was maintained at 1 mL·min-1. Any decreases in systemic arterial pressure during the first minute of drug infusion were treated with small doses of intravenous phenylephrine to prevent the confounding effects of appropriate autoregulatory vasodilation. This was necessary for the highest level of SNP infusion, during which there was a consistent 5% to 10% reduction in systemic arterial pressure, which was promptly restored with phenylephrine (20 to 40 µg) given intravenously before CBF measurement; such small systemic doses are devoid of cerebrovascular effects.2 3

Vasodilator Infusion and CBF Measurement
The protocol for single-dose studies (Fig 1Down) involved placement of external scintillation detectors. The position of the detectors relative to the microcatheter was confirmed by digital angiography. All infusions were delivered into the cerebral vessel by calibrated infusion pump (IVAC). After 3 minutes of saline solution infusion, baseline pressure recordings were made and 133Xe was injected into the microcatheter for CBF determination. Arterial blood samples from the femoral sheath introducer were taken immediately after tracer injection for PaCO2 and hematocrit determination. After 1.5 minutes of tracer washout, a 1-mL bolus of drug solution was given to clear the dead space of the microcatheter, and the drug infusion was begun. The drug was infused over the next 3 minutes, pressure measurements were then obtained, and 133Xe was injected to determine the CBF. Approximately 5 minutes elapsed between completion of the two CBF determinations.



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  		Figure 1. Sequence of events for single-dose studies. CBF #1 indicates baseline cerebral blood flow; CBF #2, after start of infusion of drug.

Data Analysis
Data are expressed as mean±SD for continuous variables and prevalence for discrete variables. Demographic data were analyzed by ANOVA (continuous variables) or {chi}2 (discrete variables). Measurements obtained at baseline and during infusion were analyzed by repeated measures ANOVA. Drug group was the between-group factor, and physiological values before and after drug infusion were the repeated measures. Linear regression was used to examine the relationship of cerebral arterial pressure and CBF responses to vasodilators.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 
Dose-Response Studies
Dose-response studies in 6 patients (2 men and 4 women) were undertaken during six procedures. All vessels investigated were remote from the AVMs and did not demonstrate any angiographic abnormalities. Three patients each received either ACh or SNP. There was no change in systemic blood pressure, PaCO2, or hematocrit after drug infusion. Incremental increases in SNP dose at 0.24, 0.48, and 2.4 µg·min-1 were undertaken in 2 patients. A third patient received only a single dose of SNP (10 µg·min-1). There was no apparent relationship between CBF changes and escalating doses of SNP (Fig 2ADown) or ACh (Fig 2BDown).



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  		Figure 2. Dose ranging studies. A, Dose ranging study with SNP. Patient 1 ({blacksquare}) and patient 2 ({circ}) received 0.24, 0.48, and 2.4 µg·min-1 SNP. Baseline data from one patient in this multiple-dose group was lost because of patient movement. Patient 3 ({blacktriangleup}) received a single dose of 10 µg·min-1 SNP. B, Dose ranging study with ACh. All 3 patients received three doses of ACh (0.26, 2.6, and 26 µg·min-1).

Single-Dose Studies
Results from 53 single-dose studies in 37 patients were available for analysis for the ACh, SNP, NTG, and verapamil groups. Fourteen patients were studied more than once on separate occasions. Different vascular territories were investigated during repeat studies in a given patient.

The patients in the four drug groups were comparable with regard to gender and age distribution (Table 1Down). Microcatheter placement for drug infusion was in the MCA in 40 cases, PCA in 8, and ACA in 5. Evidence of some passage of tracer through the AVM (termed a shunt spike21 ) was observed in 11 of the 53 total studies (despite a lack of angiographic shunting). There was no difference between drug groups for any physiological variables with respect to cerebral artery studied or the presence of a 133Xe shunt spike. The baseline femoral and cerebral arterial pressures, hematocrit, and PaCO2 were comparable among the groups and showed no change after drug infusion (Table 2Down).


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  		Table 1. Patient Profile


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  		Table 2. Effect of Drug Infusion on Systemic and Cerebral Hemodynamics

CBF and CVR were comparable at baseline. After drug infusion, CBF and CVR showed a significant change within and among groups (Table 2Up). Infusion of verapamil increased CBF from 45±12 to 65±21 mL·100 g-1·min-1 (P<.001) and decreased CVR from 1.3±0.6 to 0.9±0.3 mm Hg·mL-1·100 g-1·min-1 (P<.001). The percent change in CBF was directly proportional to the cerebral arterial pressure (y=-27+1.5x, r=.57, P=.0051). This is shown in Fig 3ADown. For purposes of comparison, data from a previous study of papaverine using a similar protocol4 are shown in Fig 3BDown.



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  		Figure 3. Vasodilatory response to superselective intra-arterial infusion of non–NO-mediated (squares) and NO-mediated (circles) vasodilators. A, Verapamil (1 mg·min-1, n=23); B, papaverine (7 mg·min-1, n=10 [data taken from a previous study4 ]); C, SNP (0.5 µg·kg-1·min-1, n=16); D, NTG (0.5 µg·kg-1·min-1, n=7); and E, ACh (1.33 µg·kg-1·min-1, n=7). Percent change in CBF after vasodilator is plotted as a function of baseline cerebral arterial pressure. {square} and {circ} indicate nonisolated vessels; {blacksquare} and {bullet}, isolated vessels. {bigtriangleup} (isolated vessel) in C represents the patient without intracranial AVM.

Mean blood pressure was comparable before and after SNP infusion (Table 2Up). SNP infusion decreased CBF by 21%. As shown in Fig 3CUp, the percent change in CBF was unrelated to the baseline cerebral arterial pressure (y=.214x-10.12, r=.19, P=.46). Infusion of NTG or ACh did not affect CBF and did not alter any of the physiological variables (Table 2Up). There was no clear relationship between the change in CBF and the cerebral arterial pressure, as shown in Fig 3DUp and 3EUp.

Effect of the Presence of an AVM on Vascular Responses
Nine studies were performed in vascular territories considered to be "isolated" from the AVM. The percent change in CBF after vasodilator infusion was not different in the isolated and the nonisolated vessels, as shown in Fig 3AUp through 3E. Therefore, anatomic proximity to the AVM itself did not affect cerebrovascular responses. Data from the patient with mesial temporal sclerosis, while not included in the main analysis, are plotted in Fig 3CUp. In this patient, SNP infusion into the PCA had little effect on CBF or other physiological variables.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
This study is to our knowledge the first to measure vascular responses to superselective infusions of vasoactive drugs that act through NO generation in the intact cerebral circulation in human subjects. We found that in angiographically normal vessels of AVM patients, intra-arterial infusion of three agents presumed to work through an NO-mediated pathway (SNP, NTG, and ACh) did not increase CBF. This lack of vasodilation occurred despite (1) doses of SNP that were sufficient to transiently decrease systemic vascular resistance during recirculation and (2) doses of all agents high enough to elicit vasodilation in human studies of other vascular beds or in animal studies of the cerebral circulation. Verapamil, our positive control drug, increased CBF, and as predicted by current theories of cerebral autoregulation, the increase in CBF was proportional to the baseline cerebral arterial pressure.22 Our results with verapamil were similar to but less robust than data obtained with another NO-independent vasodilator, papaverine.4

The sometimes profound degree of cerebral arterial hypotension observed in normal territories in patients harboring cerebral AVMs1 is usually well compensated. CBF is usually maintained, and autoregulatory function and vascular reactivity are evident in these beds when assessed by manipulation of systemic arterial pressure2 3 or PaCO2.23 The lower limit of cerebral autoregulation appears to be shifted to the left, ie, to a lower pressure than normal. Therefore, flow is maintained at a normal level in the presence of reduced perfusion pressure.2 24 The mechanism for such an adaptive decrease in resting cerebrovascular tone remains unknown. However, if NO were involved in the adaptive decrease in resting CVR, one might expect to see a relationship between baseline cerebral arterial pressure and vasodilator response; at least there should be a difference between verapamil and NO-mediated agents in the relationship between vasodilator response as a function of baseline cerebral arterial pressure. In our study, however, there was no relationship between baseline cerebral arterial pressure and the response of the arteriolar bed to infusion of NO-mediated vasodilators. In contrast, there was a positive correlation between vasodilator response to verapamil and baseline cerebral arterial pressure, similar to our previously reported results for papaverine.4

On the basis of animal studies, nitrovasodilators25 26 27 28 and ACh29 30 31 are considered to be cerebral vasodilators. Although it has been suggested that both ACh32 33 and nitrovasodilators34 cause vasodilation by mechanisms that do not involve NO, these results are controversial.35 We infused doses of ACh ({approx}90 µg·min-1) and nitrovasodilators ({approx}35 µg·min-1) that were large enough to increase blood flow in human forearm13 14 15 20 36 37 and the coronary circulation.17 18 38 39 We estimate that superselective infusion of SNP at 0.5 µg·kg-1·min-1 in the cerebral arteries resulted in a blood concentration that was at least an order of magnitude higher than intra-arterial concentrations reported to be effective in vasodilating human brachial13 14 37 40 and coronary39 41 arteries (Fig 4Down).



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  		Figure 4. Human responses to SNP in the peripheral, coronary, and cerebral circulations. Dose-response data are pooled from studies of intra-arterial administration of SNP in brachial ({bullet})13 14 37 40 or coronary arteries ({square})39 41 compared with the findings of the present study in the cerebral circulation ({blacktriangleup}). Change in organ blood flow after SNP administration, expressed as percent change from the baseline values, is shown as a function of the concentration of SNP in arterial blood in micrograms per milliliter. Mean values are given; variance is not shown for the sake of clarity. Blood concentrations were estimated by dividing the dose of SNP in micrograms per minute by the baseline organ blood flow in milliliters per minute.

We observed a decrease in CBF after administration of SNP, which does not fit any of the current theories of NO action on the cerebral circulation. In sedated human subjects, intravenous SNP can minimally decrease the CBF.42 Henriksen et al43 observed that intravenous nitroprusside, sufficient to cause a reduction of 15 mm Hg in systemic blood pressure, did not affect CBF. Cessation of SNP infusion, however, resulted in a 13% increase in CBF. The decrease in CBF in the present study is unlikely to be due to the intravenous phenylephrine (20 to 40 µg) that was needed to maintain systemic blood pressure. Cerebral vessels are relatively insensitive to {alpha}-adrenergic agonists, particularly phenylephrine.44 In animal experiments and in human studies, intravenous phenylephrine is used to increase systemic blood pressure without adversely affecting the CBF.2 3 45 46

Most of the data regarding NO-mediated cerebral vasodilation has been obtained from studies that involve either in vitro large-vessel preparations47 or abluminal application with cranial window preparations.48 49 One would think that any effect of the blood-brain barrier to restrict access to vascular smooth muscle might be more evident from application of drugs from the abluminal rather than the luminal surface.

Failure of NO-mediated vasodilators to augment CBF is unlikely to be due to endothelial dysfunction or a decrease in endothelial NO synthase activity in our study sample. Endothelial removal results in supersensitivity to SNP50 and vasoconstriction to ACh.17 Similarly, pharmacological inhibition of NO synthase activity results in supersensitivity to SNP in the cerebral,5 systemic,6 and coronary7 circulations. Clinically and radiographically, we had no reason to suspect any endothelial injury in our patients. It may be that in the human cerebral circulation, there is something unique about NO-mediated vasodilators given from the luminal side of the vessel. For example, there could exist some biophysical restriction to NO furnished from the luminal side of the arterioles that prevents it from reaching the "receptor" guanylate cyclase in vascular smooth muscle.

The following speculations can be offered as lines of further inquiry: (1) Patients harboring a cerebral AVM, compared with those with an otherwise normal cerebral circulation, have a complete loss of NO responsiveness in cerebral arteriolar vessels. We regard this explanation to be highly unlikely because of the wide range of cerebral pressures observed and locations of the vascular beds studied, which were remote from the AVM in many cases; furthermore, this was not supported by our study of the one patient without an AVM. (2) Responses to intraluminal administration of NO-mediated vasodilators (or NO) in cerebral circulation are species dependent, even between humans and subhuman primates.51 (3) There are counterregulatory mechanisms, as proposed by Gardiner et al5 but as yet unknown, that cause a paradoxical decrease in CBF with intraluminal instillation of NO donors in the human cerebral circulation.

Our data suggest that clinically relevant doses of intra-arterial nitrovasodilators may not be useful in the manipulation of CVR. For example, in a rat model of MCA occlusion, intracarotid SNP (50 µg·kg-1 for 1 hour) improved outcome after ischemic injury, which suggests a beneficial vasodilator effect of NO in this setting.52 However, such large doses are not feasible without incurring systemic hypotension or concomitant massive vasopressor support. Therefore, pharmacological NO donation with currently used nitrovasodilators in the early phases of an acute ischemic insult may not offer a clinical strategy for intervention in brain injury. Notwithstanding, further studies are warranted to develop techniques for the manipulation of CVR, both at the conductance and resistance level.

In summary, in structurally and functionally normal cerebrovascular territories of patients harboring AVMs, pharmacological arteriolar vasodilation by intraluminal administration of drugs that act through NO pathways is absent, but vasodilation to non–NO-mediated agents is robust and related to baseline cerebral arterial pressure.


*    Selected Abbreviations and Acronyms
 
ACA = anterior cerebral artery
ACh = acetylcholine
AVM = arteriovenous malformation
CBF = cerebral blood flow
CVR = cerebrovascular resistance
MCA = middle cerebral artery
NO = nitric oxide
NTG = nitroglycerin
PCA = posterior cerebral artery
SNP = sodium nitroprusside


*    Acknowledgments
 
This work was supported in part by National Institutes of Health grants RO1 NS27713 and RO1 NS34949 and in part by a Clinical Scholar Grant from the International Anesthesia Research Society (Dr Young). The authors wish to thank the neuroradiology technology staff and Kathleen Connaire, RN, Noeleen Moohan, RN, Steven M. Marshall, BS, and Gene Mack, BS, for additional technical assistance. The following members of the Columbia University AVM Study Project also contributed to portions of this work: Meng C. Vang, MD; Bennett M. Stein, MD; J.P. Mohr, MD; Randolph S. Marshall, MD; Ronald M. Lazar, PhD; Christian Koennecke, MD, and Henning Mast, MD.

Received January 13, 1997; accepted March 31, 1997.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Fogarty-Mack P, Pile-Spellman J, Hacein-Bey L, Osipov A, DeMeritt J, Jackson EC, Young WL. The effect of arteriovenous malformations on the distribution of intracerebral arterial pressures. AJNR Am J Neuroradiol. 1996;17:1443-1449.[Abstract]
  2. Young WL, Pile-Spellman J, Prohovnik I, Kader A, Stein BM, for the Columbia University AVM Study Project. Evidence for adaptive autoregulatory displacement in hypotensive cortical territories adjacent to arteriovenous malformations. Neurosurgery. 1994;34:601-611.[Medline] [Order article via Infotrieve]
  3. Young WL, Kader A, Prohovnik I, Ornstein E, Fleischer LH, Ostapkovich N, Jackson LD, Stein BM. Pressure autoregulation is intact after arteriovenous malformation resection. Neurosurgery. 1993;32:491-497.[Medline] [Order article via Infotrieve]
  4. Fogarty-Mack P, Pile-Spellman J, Hacein-Bey L, Ostapkovich N, Joshi S, Vulliemoz Y, Young WL. Superselective intraarterial papaverine administration: effect on regional cerebral blood flow in patients with arteriovenous malformations. J Neurosurg. 1996;85:395-402.[Medline] [Order article via Infotrieve]
  5. Gardiner SM, Kemp PA, Bennett T. Effects of NG-nitro-L-arginine methyl ester responses to acetylcholine, 5'-N-ethylcarboxomidoadenosine or salbutamol in conscious rats. Br J Pharmacol. 1991;103:1725-1732.[Medline] [Order article via Infotrieve]
  6. Moncada S, Rees DD, Schulz R, Palmer RMJ. Development and mechanism of a specific supersensitivity to nitrovasodilators after inhibition of vascular nitric oxide synthesis in vivo. Proc Natl Acad Sci U S A. 1991;88:2166-2170.[Abstract/Free Full Text]
  7. Garcia JL, Fernandez N, Garcia-Villalon AL, Monge L, Gomez B, Dieguez G. Effects of nitric oxide synthesis inhibition on the goat coronary circulation under basal conditions and after vasodilator stimulation. Br J Pharmacol. 1992;106:563-567.[Medline] [Order article via Infotrieve]
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