The present physiological and neuropharmacological views and the essentials of the experimental results on the anatomical localization, functional and neuronal organization of the central respiratory mechanisms, classically expressed as the respiratory centers, in the brain stem were reviewed and discussed. The brain stem neural mechanism for central regulation of breathing is regarded as a complex neuronal mechanism consisting of several functional subsystems subserving different functions. One of its functions is the generation of respiratory rhythm. The subsystem for respiratory rhythm-generating mechanisms is located in the medullary reticular formation outside the DRG and VRG regions, which are thought to be premotor neuron pools. Rhythmic activity orginating in the medulla is dominant in terms of the spontaneity over other rhythmic activity in the pontine and spinal cord mechanisms. Evidences for heterogeneity of the functional properties of brain stem respiratory neurons have been demonstrated. Neuronal mechanisms involving respiratory neurons identified as members of the primary respiratory neuron population or neuronal networks consisting of different types of respiratory neurons located in the lateral region of the bulbar reticular formation may play important roles in the generation of respiratory rhythms. These aspects contribute to the understanding of the neurophysiological basis, providing important prerequisites for further neuropharmacological studies on neurotransmission within the neuronal network of the central respiratory mechanisms.
The great discovery by Furchgott of the relaxing factor released from the endothelium (EDRF) awakened us to the necessity to reevaluate the functional importance of endothelial cells that have been chemically or physically stimulated. EDRF was first demonstrated to be released by acetylcholine, substance P, bradykinin and calcium ionophore A23187; thereafter, many substances have been found to release EDRF. This factor is quite unstable, is not produced by cyclooxygenase, and is an activator of soluble guanylate cyclase that synthesizes cyclic GMP; its action is suppressed by antioxidants via the superoxide anions produced, potentiated by superoxide dismutase and abolished by methylene blue and oxyhemoglobin. Recently, the role of lipoxygenase products in the production of EDRF was evaluated with new 5-lipoxygenase inhibitors without antioxidant activity. During the last couple of years, the actions and chemical properties of EDRF were verified to be quite similar to those of nitric oxide (NO); therefore, the hypothesis of “EDRF=NO” is widely being accepted. NO is produced from L-arginine via catalysis by an enzyme that is activated by Ca2+. The enzyme activity is inhibited by L-monomethyl arginine and other L-arginine analogs. Chemical and physical stimulations increase intracellular Ca2+ in endothelial cells that seems to be associated with K+-channel opening and hyperpolarization. Current interests are directed to the possible roles of NO in the regulation of nerve function. There are evidences suggesting that NO modulates adrenergic nerve function in blood vessels and some brain cell functions regulated by cellular cyclic GMP. Particularly, NO may be a transmitter substance in non-adrenergic, non-cholinergic vasodilator nerves innervating the cerebral arteries. Future investigations will determine the physiological roles of EDRF or NO and its relationships to pathophysiology of vascular dysfunctions, such as vasospasm and those related to hypertension, diabetes, aging, etc., and the extended roles of NO in nerve function, inflammation, immune reactions, etc. would be clarified more extensively by accelerated progress in this field of research.