My career has been in the field of cardiopulmonary physiology, specifically cardiopulmonary control. I began by studying the ventilatory response to carotid body stimulation caused by hypercapnic or hypoxic blood. I am still studying the carotid body, but the dependent variable has changed from the ventilatory response to neural activity. And the independent variable has changed from hypoxic blood to hypoxic solutions of various compositions. I am trying to define the role of acetylcholine. It is an essential excitatory neurotransmitter in the carotid body's transduction of hypoxia, hypercapnia, and acidosis into a neural signal. In addition to the use of pharmacological agents to block the release of acetylcholine or the cholinergic receptors, I am currently measuring the release of acetylcholine from the carotid body with HPLC. This measurement has never been made before to my knowledge; carotid body content has, but not release. I am also using immunocytochemical techniques to locate neuronal nicotinic and muscarinic receptors in the carotid body. Finally we have measured the impact of acetylcholine on dissociated glomus cells, the putative chemotransducing cell, with the use of patch clamp techniques and with the measurement of intracellular calcium. Experiments have shown that resting membrane potenial was reduced and intracellular calcium in these cells increased with the application of acetylcholine. This is a very exciting observation.

I have also studied the reflex effects of carotid body stimulation on static lung volumes, and during systemic hypoxia on pulmonary vascular resistance, and regional vascular resistances in the brain, heart, liver, kidney, spleen, stomach, large and small intestine, pancreas, adrenal glands, some skeletal muscles, and the eye. And I have two studies on the reflex response of ACTH and adrenal cortical hormones to hypoxic peripheral arterial chemoreceptor stimulation. Of greatest current interest is the spleen since it is the only organ besides the lung which shows an increase is vascular resistance in response to local hypoxia. I do not believe it is a much-studied organ. It might be helpful to do so in order, possibly, to gain some new insights into the much-studied hypoxic pulmonary vasoconstrictor response which is still something of a mystery.I have done a fair amount of work at the other end of the cardiopulmonary control system, on the principal muscle of respiration -- the diaphragm. I have tried to find out what the direct effect of various forms of acid-base imbalance were on the diaphragm. Mechanically it reduces the force of its twitch and tetanic contractions. But why? Most people used to say, "Oh it's a pH effect!" This does not say very much. In part the statement is true; but only in part. The accumulation of inorganic phosphate is also important, as is the effect on intracellular calcium. Curiously, we found that the greatest reduction in mechanical force came during compensated metabolic acidosis (low HCO3- + low PCO2 = normal pH). This condition in the resting diaphragm rendered the intracellular pH (measured with 31P NMR) normal or even a little alkaline. I have not worked in this field in some time. But I do not believe the answer to the question has been found. To do so would seem to have significant clinical relevance for patients who have chronic obstructive lung disease since they are frequently chronically hypercapnic, even though this is compensated. Several pieces of literature show that their diaphragmatic performance is compromised. It remains a question of considerable interest to me.

Environmental Health Sciences, carotid body, chemotransduction, cardiopulmonary control, acetylcholine, catecholamines, gene-based differences in ventilatory response to hypoxia and in morphology/function of the carotid body

1960-1961 Arno B. Luckhardt Fellow, University of Chicago

1962-1963 USPHS Fellow

1968-1973 Career Development Award

1981 Elected to Alpha Chapter of Delta Omega Public Health Society

1990 Elected Fellow of the Royal Academy of Medicine in Ireland

Journal Articles

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: 377-388, 2000

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: 485-494, 2000

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: 733-742, 2000.

Fitzgerald, R.S. Oxygen and carotid body chemotransduction: the cholinergic hypothesis -- a brief history and new evaluation. Frontiers review (invited). Respir. Physiol. 120: 89-104, 2000.

Fitzgerald, R.S., and M. Shirahata. Systemic responses elicited by stimulating the carotid body. Primary and secondary mechanisms. In: Carotid Body Chemoreceptors, edited by C. Gonzalez, New York, Springer-Verlag, 1997, pp. 171-191.

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. 475:377-387, 2000.

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.

Wang, H-Y, and R.S. Fitzgerald. Muscarinic receptors influence catecholamine release from the cat carotid body during hypoxia. Adv. Exp. Med. Biol. 45:48, 2001.

Wang, H-Y, and R.S. Fitzgerald. Muscarinic modulation of hypoxia-induced release of catecholamines from the cat carotid body. Brain Res. 927:122-137, 2001.

Hirasawa, S., D.B. Jacoby, C. Kobayashi, B. Schofield, R.S. Fitzgerald, and M. Shirahata. Expression and localization of neuronal nicotinic acetylcholine receptors in the cat chemosensory unit. Submitted to Amer. J. Physiol. Lung.

Yamaguchi, S., A. Balbir, B. Schofield, J. Coram, C. Tankersley, R.S. Fitzgerald, C.P. O’Donnell, and M. Shirahata. Structural and functional differences of the carotid body between DBA/2J and A/J strains of mice. J. Appl. Physiol. In Press.

Wang, H-Y, and R.S. Fitzgerald. Muscarinic modulation of hypoxia-induced release of catecholamines from the cat carotid body. Brain Res. 927: 122-137, 2002.

Fitzgerald, R.S., H-Y. J. Wang, S. Hirasawa, and M. Shirahata. Neurotransmitter relationships in the hypoxia-challenged cat carotid body. Adv. Exp. Med. Biol. 536:255-262, 2003.

Hirasawa, S., J. A. Mendoza, D.B. Jacoby, C. Kobayashi, R.S. Fitzgerald, B. Schofield, S. Chandrasagaran, and M. Shirahata. Diverse cholinergic receptors in the cat carotid body unit. Adv. Exp. Med. Biol. 536:313-320, 2003.

Fitzgerald, R.S., M. Shirahata, H-Y Jack Wang, A. Balbir, I. Chang. The impact of adenosine on the release of acetylcholine,dopamine, and norepinephrine from the cat carotid body Neurosc. Lett. 367: 304-308, 2004.

Fitzgerald, R.S., M. Shirahata, I. Chang, A. Balbir. L-arginine’s effect on the hypoxia-induced release of acetylcholine from the in vitro cat carotid body. Resp. Physiol. Neurobiol. In Press, 2005.

Fitzgerald, R.S., M. Shirahata, I. Chang. The effect of a nitric oxide donor, sodium nitroprusside, on the release of acetylcholine from the in vitro cat carotid body. Neurosc. Lett. In Press, 2005..

Abstracts:

Shirahata, M., R.S. Fitzgerald, and J.S.K. Sham. Roles of neuronal nicotinic acetylcholine receptors and K+ channels in the hypoxic excitation of glomus cells. FASEB J. 13: A1091, 1999.

Wang, H-Y. M. Shirahata, R.S. Fitzgerald. L-DOPA influences release jof catecholamines (Cas) from the stimulated cat carotid body (cb). FASEB J. 13: A1110, 1999.

Fitzgerald, R.S., M. Shirahata, H-Y. Wang. Acetylcholine (ACH) released from the cat carotid body (cb) during stimulation. FASEB J. 13: A1110, 1999.

Shirahata, M., and R.S. Fitzgerald. Acetylcholine-induced currents in cultured cat petrosal ganglion (PG) neurons. (ACh) is an excitatory neurotransmitter (NT) in the cat's carotid body (CB) chemotransduction of hypoxia. FASEB J. 14:A374, 1999.

Fitzgerald, R.S., H-Y. Wang, M. Shirahata. The role of M2 muscarinic receptors in the release of acetylcholine (Ach) from cat carotid body (cb) during hypoxia. FASEB J. 14: A392, 2000.

Shirahata, M. R.S. Fitzgerald, S. Yamaguchi, S. Hirasawa, and T. Higashi. Neuronal nicotinic AC receptors (nAChR) in cat glomus cells. FASEB J. 16:A149, 2001