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NEUROSURGICAL ANESTHESIA

Pial Arterial Response to Topical Verapamil in Acute Closed Cranial Windows in Rabbits

Roger Hartl, MD^*, Shailendra Joshi, MD, Sean Levine, MD, Mei Wang, MD, and Robert R. Sciacca, PhD

*Department of Neurosurgery, Weill Medical College, Cornell University, New York, New York; and Departments of Anesthesiology, Neurological Surgery, and Internal Medicine, College of Physicians and Surgeons, Columbia University, New York, New York

Address correspondence to Shailendra Joshi, MD, Department of Anesthesiology, P&S P Box 46, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, NY 10032. Address e-mail to sj121{at}columbia.edu. No reprints will be available.

	Abstract

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We have previously observed that intraarterial verapamil increases cerebral blood flow, whereas nitric oxide donors, such as nitroglycerin, do not. Clinically, both verapamil and nitroglycerin dilate large cerebral arteries. Therefore, we hypothesized that topical verapamil would dilate both the large proximal and the small distal cerebral arteries, whereas nitroglycerin would preferentially dilate only the large proximal arteries. We tested our hypothesis in acute cranial windows implanted in 10 New Zealand White rabbits. After predrug measurements, we superfused 4 increasing concentrations of verapamil or nitroglycerin (10^–8, 10^–6, 10^–4, and 10^–3 M) in the cranial windows for 5 min each. The maximum increase in diameter was expressed as a percentage change from predrug diameters. There was a 30-min period of rest between the two drug challenges. Topical verapamil increased the arterial diameter of the larger proximal arterioles (>60 µm) by 32% ± 18% and that of the smaller distal arterioles (<60 µm) by 62% ± 42%. A modest increase in arterial diameters of 11% ± 11% was observed after topical nitroglycerin that was significant only for the large-proximal arterioles. Within the 10^–8 to 10^–3 M range, topical verapamil, compared with nitroglycerin, proved to be a more potent cerebral vasodilator and had a more robust vasodilator effect on the distal small pial arteries.

	Introduction

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Intraarterial verapamil is a slow calcium channel blocking drug that augments cerebral blood flow (CBF) in humans and is also effective in relieving cerebral vasospasm (Fig. 1) (1–3). Direct measurements of human cerebral arterial resistance during intraarterial verapamil infusion suggest that verapamil dilates both the cerebral conductance and resistance arteries (4). Interestingly, human data suggest that intraarterial infusion of nitroglycerin does not augment CBF in normal cerebral arteries (2). In addition, IV administration of nitroglycerin decreases the middle cerebral artery (MCA) blood flow velocity but does not augment the CBF of healthy volunteers (5). This suggests that IV nitroglycerin dilates the large cerebral arteries, such as the MCA, but it may not dilate the distal resistance arterioles.

View larger version (18K): [in this window] [in a new window]   Figure 1. Bivariate line chart showing the effects of increasing concentrations of verapamil and (ver; )nitroglycerin (ntg; ) on the percentage increase in arterial diameters compared with predrug measurements. Data from all vessels were pooled (n = 80). Error bars indicate 1 se. *Significant difference from 10–8 M; #significant difference from 10–6 M; @significant difference between drugs.

Cranial window implants permit the measurement of vasodilator effects of drugs at multiple levels of the cerebral circulation. Topical administration of drugs within cranial windows has often been used to investigate the pharmacological effects of vasoactive drugs. Compared with IV or intraarterial administration, topical administration of drugs permits the investigation of pial arterial responses without the confounding systemic side effects of the drugs. Thus, topical administration is ideally suited for testing a wide range of molar concentrations. As reviewed by Iadecola (6), arterial size seems to affect the pharmacological response to drugs. However, the effect of arterial generation on arterial reactivity has not been reported (7). There is some evidence to suggest that certain characteristics of blood vessels, such as their innervation, may be a function of the arterial hierarchy (8–11).

Therefore, we hypothesized that the topical application of verapamil would increase pial arteriolar diameter independently of the arterial generation and size and, in contrast, that topical nitroglycerin would increase arterial diameter in way that was directly related to the size and inversely related to the arterial generation.

	Methods

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After approval by the Institution’s Animal Care and Use Committee, studies were performed on 10 New Zealand white rabbits (3–5 kg). We selected this species because they have a fairly large brain size to permit easy implantation of cranial windows (12). The animals were sedated with IM ketamine. IV access was achieved through an ear vein. Body temperature was kept constant by using a heating pad at 35°C–36°C. The animals were tracheotomized and mechanically ventilated by a small animal ventilator. Anesthesia was maintained by infusion of propofol 20–30 mg/h IV (100–200 µg · kg^–1 · min^–1). A femoral artery catheter allowed continuous monitoring of mean arterial blood pressure (MAP) and blood sampling when needed. The minute ventilation was aimed to maintain the arterial CO₂ partial pressure between 35 and 45 mm Hg. End-tidal CO₂ (ETco₂) and respiratory rates were continuously monitored (Novametrix 1260; Wallingford, CT). We administered an IV bolus of hydrocortisone (10 mg) to decrease systemic and local cranial inflammatory responses due to surgery. IV fluids were infused at 10 mL/h and consisted of lactated Ringer’s solution (7.5 mL/h), 5% dextrose (1.25 mL/h), and 5% albumin (1.25 mL/h). This regimen enabled us to maintain hemodynamic stability during the experiment.

Animals were placed prone in a stereotactic frame supporting the head and body. We used a modified version of the chronic cranial window previously described by Levasseur et al. (13). A trephination (diameter 8 mm) was prepared over the left cerebral hemisphere, the dura mater was reflected, and a custom-built metal chamber with inflow and outflow channels was inserted into the cranial defect. The chamber was covered with a glass disk that was held in place with dental cement. The pial surface was suffused with mock cerebrospinal fluid (CSF) at 0.1 mL/min, and the outflow was adjusted approximately 3–4 cm above the window. The mock CSF contained sodium 150 mM, potassium 3 mM, calcium 1.4 mM, magnesium 0.8 mM, phosphate 1.0 mM, and chloride 155 mM (Harvard Bioscience, Holliston, MA). The dead space of the window and the connectors was between 1.2 and 1.5 mL.

After surgery, we waited for 15 min for the preparation to stabilize before testing it for CO₂ response. According to initial ETco₂, the response to CO₂ was tested by inducing hypercapnia or hypocapnia by altering the respiratory rate to increase or decrease the ETco₂ by 10 mm Hg. In our model, there was an excellent correlation between ETco₂ and Paco₂ (ETco ₂ = 10.6 + 0.7 Paco₂; n = 35; r = 9; P < 0.0001). Therefore, we relied on ETco₂ measurements to adjust minute ventilation. The change in arterial diameters in response to the change in ETco ₂ was visually assessed on the video monitor. It corresponded to a 5%–10% change in measured diameters when assessed with videomicroscopy and imaging software, as described below. The ventilatory challenge was used only as a screening test before the preparation was subjected to topical drug challenges. All 10 preparations demonstrated a positive response to ventilation change. After testing for CO₂ reactivity, the ventilation was adjusted to maintain ETco ₂ of approximately 40 to 45 mm Hg, and the preparation was allowed to rest for approximately 30 min. The preparation was then subjected to topical drugs.

According to a balanced randomization table, animals received superfusion of either nitroglycerin or verapamil. Escalating doses of each drug were used (10^–8, 10^–6, 10^–4, and 10^–3 M). Mock CSF and all solutions were warmed to 35°C–36°C in a water bath. For each drug concentration, the window was primed by infusion of the new drug concentration at 30 mL/h for 4 min. This was sufficient to clear the dead space volume of the system, which was estimated to be 1.2–1.5 mL. After the window dead space was cleared, the drug superfusion rate was decreased to 6 mL/h; this ensured a continuous gentle outflow from the window. For each concentration, the drug superfusion lasted for 5 min. Thus, the test for each concentration of drug took 10 min: 1 min to change the syringe, 4 min to prime the cranial window, and 5 min for the steady-state superfusion during which the imaging data were collected. Between the two drug challenges, the brain was superfused with artificial CSF for 30 min or until the arterial diameters returned to near-baseline values. Thus, the experiment lasted for a total of 2.5 h: 40 min for CO₂ response and recovery and 110 min for the 2 drug challenges, including 30 min of intervening rest. In theory, both ketamine and propofol have direct and indirect effects on CBF (14–16). The crossover study design and balanced randomization minimized the effects of time-related changes, if any, in preparation.

A custom-built Leitz epi-illumination microscope equipped with a Dage charge-coupled device camera was used for videomicroscopy. Video images were obtained during superfusion of mock CSF before drug superfusion and were then observed in real time and captured every 15 s. The images were magnified 150x and displayed in real time on a 12-in. high-resolution monitor. With this range of magnification, subtle changes (5%–10%) in arterial diameters can be tracked on the screen. In parallel, the images were stored on a Macintosh computer using Global Village imaging software. Eight vessels were selected in each cranial window for measuring arterial diameters. The vessels were chosen on the basis of their relationship to the main branches of the MCA. These main branches can be easily identified on the brain surface as one to three large vessels approximately 150 µm in diameter running from anterior-lateral to posterior-medial. Two main arterial segments were selected and named M-1. As the artery branched, subsequent generations of branching vessels were identified and named M-2, M-3, M-4, and so forth. Two arterial segments were identified for each of the 4 generations. Hence, the diameters of 8 arteries were measured in each window. Thus, in 10 animals, a total of 20 measurements were made for each of the 4 generations, i.e., a total of 80 arterial diameter measurements. Subsequently, these arteries were stratified as large (>60 µm) and small (<60 µm) vessels according to their diameters measured after CO₂ challenge. This dichotomy was based on the separation of arteriolar diameters in in vitro studies (7). The stratification based on size was secondary to the arterial generations; therefore, we assessed changes in diameters of 30 large (>60 µm at baseline) and 50 small (<60 µm at baseline) pial arteries.

Unless stated otherwise, all data are given as mean ± sd. Data were analyzed by repeated-measures analysis of variance for within-group comparisons. Between-group (nitroglycerin and verapamil) differences were compared by factorial analysis of variance. Post hoc testing for repeated measures was performed by a Bonferroni-Dunn test. Drug responses were judged by the percentage of change in arterial diameters from predrug measurements and log transformation of the diameters measuring relative changes.

	Results

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The mean weight of the 10 animals was 3.2 ± 0.9 kg. A positive response to changes in ventilation could be elicited in all preparations. MAP did not change significantly during the experiment. ETco ₂, respiratory rate, and core temperature remained comparable between the drugs and within the drug groups (Table 1).

There was a correlation between the arterial diameter recorded after recovery from the CO₂ challenge and the arterial generation (Table 2). No difference in predrug diameters was recorded before superfusion of nitroglycerin or verapamil. Main branch MCA vessels had a diameter of 149 ± 25 µm before nitroglycerin superfusion and 154 ± 41 µm before verapamil superfusion (Table 3). These diameters were comparable to the diameters recorded after the CO₂ challenge that are shown in Table 1. At baseline, small arteries (<60 µm; n = 50) had a mean diameter of 34 ± 15 µm before nitroglycerin and 32 ± 14 µm before verapamil, whereas large arteries (>60 µm; n = 30) had a baseline mean diameter of 129 ± 36 µm before nitroglycerin and 131 ± 47 µm before verapamil. It should be noted that there was a slight and statistically insignificant difference between the predrug diameters and baseline (posthypercapnia) measurements, in part because of randomized drug challenges.

Figure 1 shows the change in arterial diameters after superfusion with verapamil and nitroglycerin. Table 3 shows the percentage of change from predrug arterial diameters in response to topical verapamil and nitroglycerin. The vessels have been classified by both generation (M-1 to M-4) and size (<60 and >60 µm). Collectively for all arterial measurements, superfusion of nitroglycerin even at the largest concentration of 10^–3 M caused no significant increase in arterial diameters (predrug 69 ± 50 µm, postdrug 76 ± 60 µm, n = 80). However, subgroup analysis revealed that there was a significant increase in M-1 and large arterial diameters (>60 µm) after exposure to 10^–4 and 10^–3 M nitroglycerin concentrations (Table 3).

In contrast to nitroglycerin, superfusion of verapamil resulted in a more profound concentration-dependent increase in arterial diameters (predrug 69 ± 57 µm; postdrug 96 ± 71 µm; n = 80; P < 0.001). Collectively, in the 10^–3 to 10^–8 M range, the concentration-dependent increase in pial arterial diameter was significantly larger for verapamil than nitroglycerin (P < 0.0001). As shown in Figure 2, predrug diameters were comparable before nitroglycerin and verapamil superfusion. Suffusion of 10^–3 M nitroglycerin resulted in a minimal increase in arterial diameters. However, a far more pronounced effect at all levels of the arterial tree was evident after 10^–3 M superfusion of verapamil. As shown in Table 3, topical verapamil caused a significant dose-dependent increase in arterial diameter across all arterial sizes. Smaller cerebral arterioles were more responsive to verapamil compared with the larger arterioles. At 10^–3 and 10^–4 M verapamil concentrations, compared with M-1, the M-3 arterioles demonstrated a more robust response to topical verapamil—e.g., 10^–3 M verapamil increased the M-1 diameter by 27% ± 19%, whereas the M-3 diameter increased by 60% ± 47% (n = 20 each; P < 0.0087).

View larger version (120K): [in this window] [in a new window]   Figure 2. Illustrative results showing the profound increase in arterial diameters at the largest concentration of verapamil (10–3 M) and the relatively modest response to topical nitroglycerin (10–3 M). A large branch of the middle cerebral artery (M-1) lies between lies between two veins from which the M-2 to M-4 branches can be traced to the periphery.

	Discussion

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There were two important results in this study. First, in the 10^–3 to 10^–8 M range, topical verapamil demonstrated a much more potent vasodilator effect on the pial arteriolar dilation than did topical nitroglycerin. Second, on the basis of arterial size and vessel generations, verapamil demonstrated a greater selectivity for smaller (<60 µm) cerebral arterioles and more distal generations (M-3 versus M-1). Furthermore, we observed only a modest effect of topical nitroglycerin that was significant only for the M-1 generation and arterioles >60 µm.

In most cranial window studies, pial arteriolar diameter measurements are made on a selected arteriole rather than on multiple vessels. In contrast, cranial window preparations allow the investigation of multiple arteriolar vessels with different diameters simultaneously. By using such a technique, Mchedlishvili (17) demonstrated that during seizures induced by strychnine or after an ischemic event, small pial arterioles (<100 µm) show a much more significant increase in diameter than larger arterioles. The advantage of multiple measurements is the elimination of bias to a particular arteriolar type. Hence, multiple measurements provide more precise information regarding the effect of the drug at different levels of cerebral microcirculation. The limitation of this approach is that the measurements of arteriolar diameters in different segments of the microcirculation may not be truly independent of each other. For example, relaxation of the proximal arteriole may increase the perfusion pressure in the distal arteriole and thus affect its radius. In theory, it could be argued that as long as the autoregulatory capacity of the downstream arterioles is intact, then changes in the downstream arteriolar tone should compensate for perfusion pressure changes due to alterations in tone of the upstream arteries.

Drugs for this study were selected on the basis of their potential clinical usefulness in situations in which manipulation of cerebrovascular resistance and blood flow may be necessary. Topical calcium channel blockers have been shown to cause increases in the diameter of cerebral arteries (18,19). Our results are consistent with observations of other calcium channel-blocking drugs. For example, the response of pial arterioles to the vasodilating effect of the topically applied calcium antagonists nifedipine and nimodipine is more pronounced in small arterioles as compared with large arterioles, especially in those <70–100 µm (20,21). The arteriolar vasodilation observed after superfusion is comparable to the 50% dilation observed by Takayasu et al. (22) in isolated murine cerebral arterioles with a mean diameter of 52 µm.

However, the effect of nitroglycerin on cerebral circulation is not clearly understood. Simultaneous measurements of CBF by single photon emission tomography and transcranial Doppler flow velocity measurements suggest that during IV nitroglycerin infusion, the diameter of the MCA increases but that this does not increase CBF (5). This observation is supported by at least one other study that directly measured the increase in MCA diameter by using magnetic resonance imaging after nitroglycerin infusion (23). When nitroglycerin is directly infused into angiographically normal cerebral arteries of patients, it fails to increase CBF (2). However, in contrast to healthy volunteers, patients with significant cardiac disease undergoing angiography demonstrated a significant increase in blood flow after IV nitroglycerin (24). Taken together, these data suggest that nitroglycerin may not have a profound effect on the distal resistance arterioles; however, nitroglycerin can dilate large pial cerebral arteries such as the MCA.

Contrary to our hypothesis, we failed to observe a robust increase in large pial arterial diameters after topical nitroglycerin. Subgroup analysis of our data revealed that the increase in arterial diameters after topical nitroglycerin was significant only for the M-1 and the large pial arterioles. The relatively selective effect of nitroglycerin on large and small cerebral arterioles remains controversial. Inoue et al. (25) and Kawaguchi et al. (26) found a greater effect on small arterioles, whereas Ishiyama et al. (27) reported a greater effect on larger arterioles. In this study, even at the largest dose, the arterial diameters of M-1 and arteries >60 µm increased by approximately 10%. This effect is considerably less than that reported with topical nitroglycerin by other investigators (25–29). The relative lack of significant vasodilation after topical nitroglycerin could be due to the temperature difference between our study and those by other investigators. The core temperature in our study was 35°C, and the temperature of the superfused drugs was maintained between 35°C and 36°C, which was slightly less than that in the previously cited studies (37°C–38°C). The response to nitric oxide (NO)-dependent vasodilators can be temperature dependent (25,26). It is possible that a slightly lower temperature may have attenuated the response to nitroglycerin in our study.

Our results demonstrate that at an equimolar concentration, between 10^–8 and 10^–3 M, topical verapamil is a much more powerful vasodilator than nitroglycerin. Our group (2) previously reported the effect of superselective intraarterial injection of nitroglycerin and verapamil on CBF in structurally normal vascular territories of patients undergoing cerebral angiography. Using the xenon-133 technique, we found that at clinically tolerable doses, verapamil significantly increased CBF, whereas nitroglycerin and nitroprusside had no such effect. Despite the difference in administration of both drugs in these studies (intraarterial versus topical), the current experiments suggest that the effect of verapamil on CBF is due to a prominent vasodilatory effect in the cerebral microcirculation, particularly in the small arterioles. More recently, we (4) have developed a method for measuring segmental vascular resistance in human cerebral circulation in response to intraarterial drugs in vivo. Using this approach, we have observed that intraarterial verapamil decreases both proximal and distal cerebral arterial resistance. The differences between intraarterial and topical studies is that topical applications are relatively independent of drug kinetics and systemic side effects. Furthermore, during topical applications, the drugs are applied on the extraluminal surface. Thus, the intraarterial and topical studies complement each other. In case of verapamil, they seem to yield a similar result (4).

One of the more obvious clinical implications of this study could be the use of topical verapamil in treating cerebral vasospasm. Intrathecal NO donors have been used successfully in reversing cerebral vasospasm, but the results of these studies suggest that calcium channel blockade might be superior to the use of NO donors. However, the pathophysiology of cerebral vasospasm might be more complex, and these two drugs will need to be further evaluated in a vasospasm model.

In conclusion, our results suggest that there are significant differences in the pial arterial response to topical verapamil and nitroglycerin in the 10^–3 to 10^–8 M range. Compared with nitroglycerin, topical verapamil results in a more profound increase in arteriolar diameters that is more significant for the small distal arterioles.

Thanks are due to the following staff members of the College of Physicians and Surgeons of Columbia University: Jodi Wagman and Sulli J. Popilskis, DMV (Institute of Comparative Medicine).

	Footnotes

 
Supported in part by National Institutes of Health Grant K08 00698 and the Irving Clinical Research Career Award (SJ).

Accepted for publication September 22, 2004.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Joshi S, Young WL, Pile-Spellman J, et al. Manipulation of cerebrovascular resistance during internal carotid artery occlusion by intraarterial verapamil. Anesth Analg 1997;85:753–9.[Abstract]
2. Joshi S, Young WL, Pile-Spellman J, et al. Intra-arterial nitrovasodilators do not increase cerebral blood flow in angiographically normal territories of arteriovenous malformation patients. Stroke 1997;28:1115–22.[Abstract/Free Full Text]
3. Feng L, Fitzsimmons BF, Young WL, et al. Intraarterially administered verapamil as adjunct therapy for cerebral vasospasm: safety and 2-year experience. AJNR Am J Neuroradiol 2002;23:1284–90.[Abstract/Free Full Text]
4. Joshi S, Meyers P, Pile-Spellman J, et al. Intracarotid verapamil decreases both proximal and distal human cerebrovascular resistance. Anesthesiology 2004;100:774–81.[Web of Science][Medline]
5. Dahl A, Russell D, Nyberg-Hansen R, Rootwelt K. Effect of nitroglycerin on cerebral circulation measured by transcranial Doppler and SPECT. Stroke 1989;20:1733–6.[Abstract/Free Full Text]
6. Iadecola C. The role of nitric oxide in cerebrovascular regulation and stroke. In: Mathie RT, Griffith TM, eds. The haemodynamic effects of nitric oxide. London: Imperial College Press, 1999:207–53.
7. Faraci FM. Role of endothelium-derived relaxing factor in cerebral circulation: large arteries vs. microcirculation. Am J Physiol 1991;261:H1038–42.
8. Fahrenkrug J, Hannibal J, Tams J, et al. Immunohistochemical localization of the VIP1 receptor (VPAC1R) in rat cerebral blood vessels: relation to PACAP and VIP containing nerves. J Cereb Blood Flow Metab 2000;20:1205–14.[Web of Science][Medline]
9. Shimizu T, Koto A, Suzuki N, et al. Occurrence and distribution of substance P receptors in the cerebral blood vessels of the rat. Brain Res 1999;830:372–8.[Web of Science][Medline]
10. Badaut J, Moro V, Seylaz J, et al. Distribution of muscarinic receptors on the endothelium of cortical vessels in the rat brain. Brain Res 1997;778:25–33.[Web of Science][Medline]
11. Zhang QJ, Hara H, Kobayashi S. Distribution patterns of sensory innervation from the trigeminal ganglion to cerebral arteries in rabbits studied by wheat germ agglutinin-conjugated horseradish peroxidase anterograde tracing. Neurosurgery 1993;32:993–9; discussion 9.[Web of Science][Medline]
12. Edvinsson L, MacKenzie ET, McCulloch J. The blood vessel wall: endothelial and smooth muscle cells. In: Edvinsson L, ed. Cerebral blood flow and metabolism. New York: Raven Press, 1993:40–56.
13. Levasseur JE, Wei EP, Raper AJ, et al. Detailed description of a cranial window technique for acute and chronic experiments. Stroke 1975;6:308–17.[Abstract/Free Full Text]
14. Lei H, Grinberg O, Nwaigwe CI, et al. The effects of ketamine-xylazine anesthesia on cerebral blood flow and oxygenation observed using nuclear magnetic resonance perfusion imaging and electron paramagnetic resonance oximetry. Brain Res 2001;913:174–9.[Web of Science][Medline]
15. Bjorkman S, Akeson J, Nilsson F, et al. Ketamine and midazolam decrease cerebral blood flow and consequently their own rate of transport to the brain: an application of mass balance pharmacokinetics with a changing regional blood flow. J Pharmacokinet Biopharm 1992;20:637–52.[Web of Science][Medline]
16. Veselis RA, Reinsel RA, Feshchenko VA, et al. A neuroanatomical construct for the amnesic effects of propofol. Anesthesiology 2002;97:329–37.[Web of Science][Medline]
17. Mchedlishvili G. Regulation providing an adequate blood supply to cerebral tissue. In: Bevan JA, ed. Arterial behavior and blood circulation in the brain. New York: Consultants Bureau, 1986:96–175.
18. Altura BM, Altura BT, Gebrewold A. Differential effects of the calcium antagonist, verapamil, on lumen sizes of terminal arterioles and muscular venules in the rat mesenteric, pial and skeletal muscle microvasculatures. Br J Pharmacol 1980;70:351–3.[Web of Science][Medline]
19. Leblanc R, Feindel W, Yamamoto L, et al. Reversal of acute experimental cerebral vasospasm by calcium antagonism with verapamil. Can J Neurol Sci 1984;11:42–7.[Web of Science][Medline]
20. Brandt L, Ljunggren B, Andersson KE, et al. Effects of topical application of a calcium antagonist (nifedipine) on feline cortical pial microvasculature under normal conditions and in focal ischemia. J Cereb Blood Flow Metab 1983;3:44–50.[Web of Science][Medline]
21. Tanaka K, Gotoh F, Muramatsu F, et al. Effects of nimodipine (Bay e 9736) on cerebral circulation in cats. Arzneimittelforschung 1980;30:1494–7.[Medline]
22. Takayasu M, Bassett JE, Dacey RG Jr. Effects of calcium antagonists on intracerebral penetrating arterioles in rats. J Neurosurg 1988;69:104–9.[Web of Science][Medline]
23. Niehaus L, Gottschalk S, Weber U. Effect of drug-induced vasodilatation of basal brain arteries with nitroglycerin on blood flow velocity and volume flow in the middle cerebral artery. Ultraschall Med 1998;19:225–9.[Web of Science][Medline]
24. Gusev AT, Lebedeva OI, Galiautdinov GS, et al. Effect of nitroglycerine on cerebral blood flow and central hemodynamics in patients with chronic heart failure. Kardiologiia 1984;24:49–52.
25. Inoue S, Kawaguchi M, Kurehara K, et al. Effect of mild hypothermia on nicorandil-induced vasodilation of pial arterioles in cats. Crit Care Med 2001;29:2162–8.[Web of Science][Medline]
26. Kawaguchi M, Ishimura N, Kurehara K, et al. Mild hypothermia can attenuate nitroglycerin-induced vasodilation of pial arterioles in the cat. Anesth Analg 1998;86:546–51.[Abstract]
27. Ishiyama T, Dohi S, Iida H, et al. Mechanisms of vasodilation of cerebral vessels induced by the potassium channel opener nicorandil in canine in vivo experiments. Stroke 1994;25:1644–50.[Abstract]
28. Mayhan WG, Didion SP. Acute effects of ethanol on responses of cerebral arterioles. Stroke 1995;26:2097–101; discussion 102.
29. Mayhan WG. Endothelium-dependent responses of cerebral arterioles to adenosine 5'-diphosphate. J Vasc Res 1992;29:353–8.[Web of Science][Medline]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Hartl, R. Articles by Sciacca, R. R. Search for Related Content PubMed PubMed Citation Articles by Hartl, R. Articles by Sciacca, R. R. Related Collections Neuroanesthesia Pharmacology