Manipulation of cerebrovascular tone, either directly or indirectly, is an important component of anesthetic and peri-operative care in patients at risk for neurologic injury. This project has the general aim to better characterize the control mechanisms for maintenance of human cerebrovascular tone in health and disease. Such knowledge would greatly facilitate strategies aimed at protecting the brain from permanent damage. In addition to answering mechanistic questions, the proposed studies will also be useful in the development of protocols for acute pharmacologic manipulation of cerebrovascular resistance during anesthesia and surgery in cases where cerebral arterial access is available. This is timely because there is an increasingly frequent use of endovascular surgery for a wide variety of cerebrovascular diseases. It is believed that cerebral blood flow (CBF) is regulated by three main mechanisms: nitric oxide (NO) (predominantly via cGMP), prostaglandins (predominantly via cAMP) and ATP-sensitive K+ channels. This project addresses two specific questions: (1) To what extend does NO influence resting human cerebrovascular tone? (2) What is the relative importance of neuronal versus endothelial nitric oxide synthase (NOS) in influencing resting vascular tone? Our primary hypothesis is that in humans, enothelially-generated NO is a major regulatory influence. Parallel in-vivo (in humans and non-human primates) and in-vitro experiments will be done. In-vivo studies will employ intracarotid infusion of drugs. Intracarotid infusion enables assessment of cerebrovascular effects of a drug in relative isolation from its systemic side-effects. The clinical research will be conducted during cerebral angiography of functionally and angiographically normal cerebral hemispheres. Animal experiments, in baboons, will be conducted in parallel with the clinical research. In vitro studies will be undertaken on intracranial vessels harvested at autopsy from baboons. This parallel model of human and primate is a unique and powerful approach for exploring he full dose-response range of various agonists and antagonists as well as allowing design of optimal protocols utilizing a limited supply of clinical subjects. In addition, in-vitro studies will provide the insight into molecular and cellular mechanisms that regulate cerebrovascular tone. If endothelial-NO is a major determinant of human cerebrovascular tone, neuroprotection using neuronal NOS inhibitors should not compromise tissue perfusion, and intra-arterial NO donors may be useful in manipulation of cerebral perfusion in ischemic brain injury.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Clinical Investigator Award (CIA) (K08)
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Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Joshi, Shailendra; Meyers, Phillip M; Ornstein, Eugene (2008) Intracarotid delivery of drugs: the potential and the pitfalls. Anesthesiology 109:543-64
Joshi, Shailendra; Wang, Mei; Etu, Joshua J et al. (2008) Transient cerebral hypoperfusion enhances intraarterial carmustine deposition into brain tissue. J Neurooncol 86:123-32
Wang, Mei; Etu, Joshua; Joshi, Shailendra (2007) Enhanced disruption of the blood brain barrier by intracarotid mannitol injection during transient cerebral hypoperfusion in rabbits. J Neurosurg Anesthesiol 19:249-56
Joshi, Shailendra; Emala, Charles W; Pile-Spellman, John (2007) Intra-arterial drug delivery: a concise review. J Neurosurg Anesthesiol 19:111-9
Joshi, Shailendra; Ornstein, Eugene; Bruce, Jeffrey N (2007) Targeting the brain: rationalizing the novel methods of drug delivery to the central nervous system. Neurocrit Care 6:200-12
Wang, Mei; Joshi, Shailendra (2007) Electrocerebral silence after intracarotid propofol injection is a function of transit time. Anesth Analg 104:1498-503, table of contents
Reif, Roberto; Wang, Mei; Joshi, Shailendra et al. (2007) Optical method for real-time monitoring of drug concentrations facilitates the development of novel methods for drug delivery to brain tissue. J Biomed Opt 12:034036
Lavine, Sean D; Wang, Mei; Etu, Joshua J et al. (2007) Augmentation of cerebral blood flow and reversal of endothelin-1-induced vasospasm: a comparison of intracarotid nicardipine and verapamil. Neurosurgery 60:742-8;discussion 748-9
Bandola, David M; Joshi, Shailendra (2006) Prone View with Mayfield head frames. Anesth Analg 102:1298-9
Joshi, Shailendra; Wang, Mei; Etu, Joshua J et al. (2006) Bolus configuration affects dose requirements of intracarotid propofol for electroencephalographic silence. Anesth Analg 102:1816-22

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