Other Autonomic Neurotransmitters

Both central and peripheral neurons generally contain more than one transmitter substance (see Chapter 12). The anatomical separation of the parasympathetic and sympathetic components of the ANS and the actions of ACh and NE provide the essential framework for studying autonomic function, but a host of other chemical messengers (e.g., purines, eicosanoids, NO, peptides) also modulate or mediate responses in the ANS. ATP and ACh can coexist in cholinergic vesicles; ATP, NPY, and catecholamines are found within storage granules of sympathetic nerves and the adrenal medulla. Many peptides are found in the adrenal medulla, nerve fibers, or ganglia of the ANS or in the structures that are innervated by the ANS, including the enkephalins, substance P and other tachykinins, somatostatin, gonadotropin-releasing hormone, cholecystokinin, calcitonin gene—related peptide, galanin, pituitary adenylyl cyclase-activating peptide, VIP, chromogranins, and NPY. Some of the orphan GPCRs discovered in the course of genome-sequencing projects may represent receptors for undiscovered peptides or other cotransmitters. The evidence for widespread transmitter function in the ANS is substantial for VIP and NPY. ATP and its metabolites may act postsynaptically and exert presynaptic modulatory effects on transmitter release via P2 receptors and receptors for adenosine. In addition to acting as a cotransmitter with NE, ATP may be a cotransmitter with ACh in certain postganglionic parasympathetic nerves, for example, in the urinary bladder. NPY is colocalized and coreleased with NE and ATP in most peripheral sympathetic nerves, especially those innervating blood vessels. Thus, NPY, together with NE and ATP, may be the third sympathetic cotransmitter. The functions of NPY include (1) direct postjunctional contractile effects; (2) potentiation of the contractile effects of the other sympathetic cotransmit-ters; and (3) inhibitory modulation of the nerve stimulation-induced release of all three sympathetic cotransmitters.

VIP and ACh coexist in peripheral autonomic neurons, and it seems likely that VIP is a parasympathetic cotransmitter in certain locations, such as the nerves regulating GI sphincters.

NANC TRANSMISSION BY PURINES Autonomic neurotransmission may be noradrenergic and noncholinergic (NANC). The existence of purinergic neurotransmission in the GI tract, genitourinary tract, and certain blood vessels is compelling; ATP fulfills the criteria for a neurotransmitter. Adenosine, generated from the released ATP by ectoenzymes and releasable nucleotidases, acts as a modulator, causing feedback inhibition of release of the transmitter. Purinergic receptors may be divided into the adenosine (P1) receptors and ATP receptors (P2X and P2Y receptors); both P1 and P2 receptors have various subtypes. Methylxanthines such as caffeine and theophylline preferentially block adenosine receptors (see Chapter 27). The P1 and P2Y receptors mediate their responses via G proteins; P2X receptors are a subfamily of ligand-gated ion channels.

ENDOTHELIUM-DERIVED FACTORS AND NITRIC OXIDE Intact endothelium is necessary to achieve vascular relaxation in response to ACh. This inner cellular layer of the blood vessel now is known to modulate autonomic and hormonal effects on the contractility of blood vessels. In response to a variety of vasoactive agents and even physical stimuli, the endothelial cells release a short-lived vasodilator called endothelium-derived relaxing factor (EDRF), now known to be NO. Products of inflammation and platelet aggregation (e.g., 5-HT, histamine, bradykinin, purines, thrombin) exert all or part of their actions by stimulating NO production. Endothelium-dependent relaxation is important in a variety of vascular beds, including the coronary circulation. Activation of receptors linked to the Gq-PLC-IP3 pathway on endothelial cells mobilizes stored Ca2+, activates endothelial NO synthase, and promotes NO production. NO diffuses to the underlying smooth muscle and induces relaxation of vascular smooth muscle by activating the soluble guanylyl cyclase, which increases cyclic GMP concentrations. Nitrate vasodilators used to lower blood pressure or to treat ischemic heart disease act as NO donors (see Chapter 31). NO also is released from certain nerves (nitrergic) innervating blood vessels and smooth muscles of the GI tract. NO has a negative inotropic action on the heart. Alterations in the production or action of NO may affect a number of conditions such as atherosclerosis and septic shock.

NO is synthesized from l-arginine and molecular oxygen by Ca2+-calmodulin-sensitive nitric oxide synthase (NOS). There are three known forms of this enzyme. One form (eNOS) is constitutive, residing in the endothelial cell and synthesizing NO over short periods in response to receptor-mediated increases in cellular Ca2+. A second form (nNOS) is responsible for the Ca2+-dependent NO synthesis in neurons. The third form of NOS (iNOS) is induced after activation of cells by cytokines and bacterial endotoxins. Once expressed, iNOS binds Ca2+ tightly, is independent of fluctuations in [Ca2+]i, and synthesizes NO for long periods of time. This inducible, high-output form is responsible for the toxic manifestations of NO. Glucocorticoids inhibit the expression of inducible, but not constitutive, forms of NOS in vascular endothelial cells. However, other endothe-lium-derived factors also may be involved in vasodilation and hyperpolarization of the smooth muscle cell. NOS inhibitors might have therapeutic benefit in septic shock and neurodegenerative diseases. Conversely, diminished production of NO by the endothelial cell layer in atherosclerotic coronary arteries may contribute to the risk of myocardial infarction.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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