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Trigeminovascular Fibers Increaseblood Flow in Cortical Gray

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Trigeminovascular Fibers Increaseblood Flow in Cortical Gray Proc. Natl. Acad. Sci. USA Vol. 86, pp. 1401-1405, February 1989 Neurobiology Trigeminovascular fibers increase blood flow in cortical gray matter by axon reflex-like mechanisms during acute severe hypertension or seizures (cerebrovascular circulation/axon reflex/hypertension/seizures/trigeminal nerve) DAMIANOS E. SAKAS*, MICHAEL A. MOSKOWITZ*t, ENOCH P. WEIt, HERMES A. KONTOSt, MICHIHISA KANO*, AND CHRISTOPHER S. OGILVY* *Neurosurgery and Neurology Services, Departments of Surgery and Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114; and tDepartment of Medicine, Medical College of Virginia, Richmond, VA 23298 Communicated by H. N. Munro, November 7, 1988 (receivedfor review September 1, 1988) ABSTRACT Cerebral blood flow was measured and com- niques as well as by Wallerian degeneration techniques (11) pared in 10 symmetrical brain regions following unilateral or by surgical lesioning combined with immunohistochemis- trigeminal ganglionectomy (n = 13), sham operation (n = 6), try (12, 13) or radioimmunoassay (14, 15). Fibers primarily or trigeminal root section (rhizotomy) (n = 8) in cats. Multiple from the ophthalmic division (7, 8) join sympathetic and determinations were obtained in anesthetized and paralyzed parasympathetic fibers within the cavernous plexus (11) from animals using radiolabeled mict-ospheres during (i) normocap- which they distribute to the ipsilateral internal carotid artery nia-normotension, (ii) hypercappia (5% C02/95% room air), and the circle of Willis. Trigeminovascular fibers are mainly (iii) angiotensin-induced acute severe hypertension (190 > unmyelinated (16), reside within the adventitial layer, trans- mean arterial blood pressure < 210 mmHg), or (iv) bicuculline- mit nociceptive information (17, 18), and contain substance P induced seizures. Flow was symmetrical in all brain regions at (12), neurokinin A (19), calcitonin gene-related peptide (13), rest and during increases induced by hypercapnia in the three and cholecystokinin 8 (20). groups. During severe hypertension or seizures, marked ele- In this report, we examined the possibility that sensory vations developed bilaterally (-93% and -130%, respec- axons participate in the regulation of cerebral blood flow tively). In ganglionectomized animals, increases due to hyper- based on knowledge that (i) substance P (21, 22), neurokinin tension or seizures were attenuated by 28-32% on the dener- A (23), and calcitonin gene-related peptide (13) are cere- vated side within cortical gray matter regions corresponding to brovasodilating molecules; (ii) peptides are released from pial the anterior, middle, and posterior cerebral arteries. Flow was vessels in vitro by depolarizing stimuli (24); and (iii) release symmetrical within all brain regions in sham-operated animals mediates vasodilation and/or increases in blood flow follow- and in the rhizotomy group, despite comparable increases in ing electrical stimulation of sensory nerves in other tissues regional cerebral blood flow induced by angiotensin. Hence, (25-27). Blood flow was examined during perturbations the trigeminal nerve mediates blood flow adaptations during previously shown to involve nonneurogenic (hypercapnia) severe hypertension and seizures. Furthermore, since trigem- and neurogenic mechanisms (at least in part). We conclude inal cell bodies and peripheral axons are destroyed or degen- that increases in brain blood flow during severe hypertension erate following ganglionectomy but not following rhizotomy, are not totally passive to the perfusion pressure. Further- local "axon reflex-like" mechanisms mediate these increases in more, increases in flow associated with generalized seizures cerebral blood flow. or hypertension are mediated in part by the trigeminal nerve via local "axon reflex-like" mechanisms involving neuropep- The neurogenic control of the cerebral circulation is complex tide release from perivascular nerve endings. and many aspects are poorly understood. Under resting conditions, the regulation of blood flow is controlled by the partial pressure of carbon dioxide in arterial blood, autoreg- MATERIALS AND METHODS ulation, metabolic and neurophysiological brain activity, and Sham and Lesioning Procedures. Male and female adult neurovascular influences (cf. ref. 1). Among the neurovas- mongrel cats (3.0-4.5 kg) were anesthetized with ketamine cular influences, the role of sympathetic activity has been hydrochloride (30 mg/kg, i.m.) and sodium pentobarbital most extensively studied (2-5). Sympathetic nerves influence (10-15 mg/kg, i.p.) and mechanically respirated with blood flow minimally under basal conditions, as evidenced by halothane anesthesia (0.5-2.0%) as needed. Animals were measurements during electrical stimulation (2, 3) or following subjected to unilateral trigeminalectomy as described (15). In chronic ablation (3) of the superior cervical ganglia. How- this procedure, trigeminal ganglia cell bodies are destroyed ever, during severe hypertension or seizures (4), sympathetic and perivascular fibers degenerate accordingly. Sham- nerves attenuate the expected increases in flow and, by so operated animals were subjected to craniectomy, exposure of doing, protect against the consequences of severe acute and the trigeminal ganglia, as well as an equivalent amount of chronic increases in perfusion pressure. Less consistent flow brain retraction as required for the ganglionectomy. patterns follow lesioning or stimulating parasympathetic The trigeminal root (that section between the ganglion and fibers (5, 6). the brainstem) was approached by a left suboccipital craniec- A third major pathway was recently defined innervating tomy, which extended laterally and superiorly without dam- cerebral blood vessels (7). Perivascular sensory axons pro- aging the sigmoid or transverse sinuses. The dura was cut jecting from the trigeminal ganglia were demonstrated by along the lateral edge of the craniectomy, and the cerebellum retrograde (7-9) and orthograde (10) axonal transport tech- Abbreviations: ACA, MCA, and PCA, anterior, middle, and poste- The publication costs of this article were defrayed in part by page charge rior cerebral arteries, respectively. payment. This article must therefore be hereby marked "advertisement" tTo whom reprint requests should be addressed at: Stroke Research in accordance with 18 U.S.C. §1734 solely to indicate this fact. Laboratory, Massachusetts General Hospital, Boston, MA 02114. 1401 Downloaded by guest on October 2, 2021 1402 Neurobiology: Sakas et al. Proc. Natl. Acad. Sci. USA 86 (1989) was gently retracted medially. A partial cerebellectomy window settings ('13Sn, 350-400; 103Ru, 450-550; 91Nb, 650- (removal of <20% of a single hemisphere) was necessary in 800; 46Sc, 830-1200 keV). Cerebral blood flow (ml per 100 g most instances to optimize root exposure for the rhizotomy. per min) was calculated as follows: Cb x 100 x RBF/Cr (Cb, The root was transected with microscissors. In this proce- counts g-l-min1 ofbrain samples; Cr, total cpm in reference dure, trigeminal ganglia cell bodies are preserved. The blood samples; RBF, arterial withdrawal rate). completeness of the ganglionectomy or rhizotomy was con- Experimental Procedures. Hypercapnia. Cerebral blood firmed by (i) the existence ofanesthesia to pin prick and touch flow measurements were made 10-15 min after the onset of in the trigeminal dermatome, and (ii) visual inspection of the breathing 5% CO2 in air. lesioned site at postmortem examination. Hypertension. Cerebral blood flow measurements were Cerebral Blood Flow. Measurements were made 8-25 days made -15 min after blood pressure was maintained at -200 after sham operation, trigeminal ganglionectomy, or rhizot, mmHg by intravenous infusion of angiotensin II (0.8-2.0 omy. Cerebral blood flow was measured with isotopically }.g kg- id labeled microspheres (113Sn, 103Ru, 95Nb, or 'Sc) (28) having Seizures. A bolus injection of (+)-bicuculline [1 mg kg-1 a diameter of 16.5 0.2 ,um. Animals were anesthetized with ml-l in 0.9% saline/acetone (4:1, vol/vol)] was used to sodium pentobarbital (30 mg/kg, i.p.; supplemented with 6.5 induce generalized seizures. Anesthesia was induced by mg/hr, i'.v.), intubated, paralyzed with gallamine triethiodide ketamine (30 mg/kg) and halothane (1-2%) and maintained (8-12 mg kg-l1hr-1) and respirated mechanically. The end with urethane (60 mg/kg) in animals paralyzed by gallamine. expiratory CO2 was monitored with an ET HL 200 CO2 Electroencephalogram activity was recorded on a Grass monitor (Instrumentation Laboratory, Lexington, MA) and model 7D polygraph. Mean arterial blood pressure was temperature was maintained at 370C-380C with a heating maintained below 150 mmHg by controlled hemorrhage. blanket. Arterial blood pressure was monitored by a trans- Blood flow measurements were obtained in the following ducer (Gould Inc., Oxnard, CA) and a Grass model 7D sequence: hypercapnia, normocapnia-normotension, fol- polygraph. Catheters placed in the vena cava, aortic arch, lowed by either severe hypertension or seizures. In some axillary artery, and left atrium were used for administering animals, a fourth measurement of blood flow was obtained drugs, obtaining reference blood samples, monitoring blood under resting conditions. pressure, and injecting microspheres, respectively. Micro- Paired Student's t test was used to calculate statistical spheres (3.3-8.2 x 105; 20-50 1uCi; 1 Ci = 37 GBq; in 4 ml of significance of differences in blood flow among the regions
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