4 ATP and nitric oxide
Learning objective 4: Identify the role of ATP and nitric oxide in smooth-muscle relaxation and blood-vessel dilation.
In addition to NE, E, and ACh, the neurotransmitters ATP and NO (nitric oxide) can play important roles in the ANS. [ASIDE: ANS terminals also release many active neuropeptides, but those ANS actions are not yet targets of pharmaceutical interventions, and we do not amplify on them here.]
NO, nitric oxide, is a hydrophobic gas (like CO, carbon monoxide) that diffuses readily from one cell to the next. It relaxes vascular smooth muscle. NO is synthesized inside cells by nitric-oxide synthase (NOS) in response to Ca2+/calmodulin following cytosolic Ca2+ rises. The diffusible NO gas stimulates guanylyl cyclase inside cells. This enzyme related to adenylyl cyclase generates cyclic-GMP (cGMP), which activates protein kinases that promote smooth muscle relaxation increasing blood flow. Fig. 3 illustrates two possible sources of NO. In the male and female genitalia, NOS seems to be in the vari- cosities of the postganglionic nerve fibers, and so NO synthesis is increased by the same presynaptic Ca2+ rise that also mediates exocytosis of vesicles of ACh. The NO potentiates blood flow during sexual arousal. Viagra and other erectile dysfunction drugs act by prolonging the lifetime of cGMP (stopping its breakdown by a PDE) and hence promoting vascular smooth muscle relaxation. In the cardiac coronary circulation, NOS is in the endothelial cells that line the blood vessels. Calcium rises through ACh acting on endothelial M3 receptors. NO then diffuses to the blood vessel smooth muscle to allow vasodilation and enhance coronary blood flow. Some nitro drugs that release NO, such as nitroglycerine, are used clinically to improve coronary circulation.
ATP is obligatorily co-packaged and co-released with NE, E, and ACh as the polyvalent anion that counters the positive charge of these neurotransmitters inside the synaptic vesicles and chromaffin granules. It is co-released during exocytosis as a cotransmitter. The released extracellular ATP can activate purinergic receptors that are ligand-gated non-selective cation channels. Activation of such purinergic receptors initiates contraction of smooth muscle in arterioles and in the vas deferens.
