The long-term objectives of my research have been to understand the hypoxic chemosensing mechanisms of the carotid body and to explore how the function of the carotid body is involved in physiology and pathophysiology of the cardiopulmonary and autonomic nervous systems. Many studies have suggested that carotid body function is closely correlated with common human diseases. For example, obstructive sleep apnea ia a major health problem in the United States. Approximately 4% of populations in any age groups are affected. Hypertension and other cardiovascular diseases are major consequences in this syndrom. The excitation of the carotid body during apnea is an immediate cause of nocturnal hypertension. At the same time, the excitation of the carotid body is essential to arouse these patients and to terminate apnea. In borderline cases of hypertension or in mild hypertensive subjects, the stimulation of the carotid body causes over-excitation of sympathetic nervous system. On the other hand, patients who have suffered near-fatal asthma attacks demonstrated a marked reduction in the function of the carotid body. Finally, in some rare diseases, such as the congenital hypoventilation syndrome and the sudden infant death syndrome, anatomical and biochemical abnormalities of the carotid body have been shown.

My hypothesis of chemoreception of the carotid body is that nicotinic ACh receptors in the carotid body is sensitive to oxygen tension. Hypoxia increases the sensitivity of the receptor to ACh and enhances the effect of ACh. Since ACh is an excitatory neurotransmitter in the carotid body, the sensitization of the receptor by hypoxia increases neural dischages in the sensory afferent nerves from the carotid body. My research team is investigating underlying mechanisms of hypoxic sensitivity of nicotinic receptors using multidiciplinary approaches with patch clamp, microfluorometric, immunocytochemical and molecular biological techniques.

Environmental Health Sciences, acetylcholine, carotid body, hypoxia, oxygen, nicotinic receptor, patch clamp, sleep apnea

Sponsor of Chung Long Chou, who received the Travel Award of Respiratory Neurobiology and Sleep in American Thoracic Society 1995.

Sponsor of Dr. Rodrogo Iturriaga, who received the Research Career Enhancement Award of the American Physiological Society for acquiring new techniques at my laboratory 1998.

1. Shirahata, M. Neurotransmission of the carotid body and anesthesia. J. Anesthesia, in press

2. Shirahata, M., T. Higashi, S. Hirasawa, S. Yamaguchi, R. S. Fitzgerald, and B. Lande. Excitation of Glomus Cells: Interaction between Voltage-gated K+ Channels and Cholinergic Receptors. In: Oxygen Sensing: Responses and Adaptaion to Hypoxia, edited by S. Lahiri, G.L. Semenza, and N. Prabhakar, New York, Marcel Dekker, 2002, in press.

3. Fitzgerald, R.S. H-Y. Wang, S. Hirasawa, and Shirahata, M. Neurotransmitter in the carotid body. In: Oxygen Sensing: Responses and Adaptaion to Hypoxia, edited by S. Lahiri, G.L. Semenza, and N. Prabhakar, New York, Marcel Dekker, 2002, in press.

4. Igarashi, A., S. Amagasa, H. Horikawa, and M. Shirahata. Vecuronium directly inhibits hypoxic neurotransmission of the rat carotid body. Anesth. Analg. 94:117-122, 2002.

5. Wang, H-Y.J., M. Shirahata, and R.S. Fitzgerald. L-dopa and high oxygen influence release of catecholamines from the cat carotid body. Adv. Exp. Med. Biol. 475:733-41, 2000.

6. Fitzgerald, R.S., M. Shirahata, and H-Y. J. Wang. Acetylcholine is released from in vitro cat carotid bodies during hypoxic stimulation. Adv. Exp. Med. Biol. 475:485-94, 2000.

7. Shirahata, M., Y. Ishizawa, M. Rudisill, J.S.K. Sham, B. Schofield, and R.S. Fitzgerald. Acetylcholine sensitivity of cat petrosal ganglion neurons. Adv. Exp. Med. Biol. 475:377-87, 2000.

8. Shirahata, M., and J.S.K. Sham. Roles of ion channels in carotid body chemotransmission. Jpn. J. Physiol. 49:213-228, 1999.

9. Fitzgerald, R.S., M. Shirahata, and H-Y. J. Wang. Acetylcholine release from cat carotid bodies. Brain Res. 841:53-61, 1999.

10. M. Shirahata, Y. Ishizawa, M. Rudissill, B. Schofield and R.S. Fitzgerald. Presence of nicotinic acetylcholine receptors in cat carotid body afferent system. Brain Res. 814:213-217, 1998.

11. Chou, C-L, B. Schofield, J.S.K. Sham, and M. Shirahata. Electrophysiological and immunocytological demonstration of cell-type specific responses to hypoxia in the adult cat carotid body. Brain Res.789:229-238, 1998.

12. Massari, V.J.,, M. Shirahata, T.A. Johnson, and, P.J. Gatti. Substance P immunoreactive terminals in the dorsolateral nucleus of the tractus solitarius: Roles in the baroreceptor reflex. Brain Res. 785:329-340, 1998.

13. M. Shirahata, R.S. Fitzgerald, and J.S.K. Sham. Acetylcholine increases intracellular calcium of arterial chemoreceptor cells from adult cats. J. Neurophysiol.78:2388-2395, 1997.

14. Fitzgerald, R.S., M. Shirahata, and T. Ide. Further cholinergic aspects of carotid body chemotransduction of hypoxia in the cat. J. Appl. Physiol. 82:819-827, 1997.

15. Ishizawa, Y., R.S. Fitzgerald, M. Shirahata, and B. Schofield. Localization of nicotinic acetylcholine receptors in cat carotid body and petrosal ganglion. Adv. Exp. Med. Biol. 410:253-6, 1996.

16. Shirahata, M., Y. Ishizawa, A. Igarashi, and R.S. Fitzgerald. Release of acetylcholine from cultured cat and pig glomus cells. Adv. Exp. Med. Biol. 410:233-237, 1996.

17. Shirahata, M., R.S. Fitzgerald, and J.S.K. Sham. Effect of acetylcholine on intracellular calcium of carotid body cells of adult cats. Adv. Exp. Med. Biol. 410:257-60, 1996.

18. Fitzgerald, R.S., M. Shirahata, and Y. Ishizawa. The pre-synaptic component of a cholinergic mechanism in the carotid body chemotransduction of hypoxia in the cat. Adv. Exp. Med. Biol. 410:245-52, 1996.

19. Fitzgerald, R.S., and M. Shirahata. Release of acetylcholine from the in vitro cat carotid body. Adv. Exp. Med. Biol. 410:227-232, 1996.

20. Chou, C-L, and M. Shirahata. Two types of potassium channels in carotid body cells of adult cats. Brain Res. 742:34-42, 1996.