Sympathetic nervous system moves toward center stage in cardiovascular medicine: from Thomas Willis to resistant hypertension.

n 1664, the first anatomically correct depiction of the sympathetic nervous system came from Thomas Willis and his circle of London anatomists, 1 included in The Anatomy of the Brain and Nerves, 1664 (Figure 1). This, the first work dedicated completely to the nervous system, also described the arterial loops at the base of the brain, which we now know as the Circle of Willis. 1 Christopher Wren, an anatomist member of the group, was the principal illustrator 1 before being asked by the City Fathers to turn his talents to town planning, architecture , and cathedral building after the 1666 Great Fire of London. Almost 2 centuries later, subsequent microscopic examination demonstrated that blood vessel walls were densely inner-vated, leading Stelling in 1840 2 to correctly conclude that these vasomotor fibers were in fact sympathetic nerves that were carried from the central nervous system to the blood vessels. In the mid-19th century, celebrated European physiolo-gists, including Brown-Sequard, Waller, and Bernard, 2 built on these observations, demonstrating vasoconstriction with electrical stimulation of the cut nerves and vasodilatation on nerve section, which indicated that the sympathetic fibers exerted a tonic, vasoconstrictor influence. The pressor nerves had gained recognition. Identification of the sympathetic neurotransmitter proved to be difficult. Claims for epinephrine 3,4 and the hypothetical sympathins I and E confused the picture. Ulf von Euler compared bioassay responses of epinephrine, norepinephrine, and dihydroxy norephedrine with those of cattle splenic nerve extract, by testing blood pressure (BP) responses in the anes-thetized cat and contractile responses in the isolated pregnant rabbit uterus, to definitively demonstrate the primary transmitter to be norepinephrine. 5 This discovery provided the theoretical knowledge for the development of pharmacological antagonists of the sympathetic nervous system, subsequently used as antihypertensive drugs, and quickly led to the application of neurochemical methods, initially the measurement of norepinephrine excretion in urine, 6 in efforts to quantify sympathetic nervous system activity in humans. The publication of the first sensitive and specific plasma cat-echolamine assay by Engelman et al 7 was a milestone in the field. For a time, plasma norepinephrine measurements were the principal method for the investigation of sympathetic neu-ral mechanisms in clinical medicine. Plasma norepinephrine measurements, although providing a useful guide to sympathetic nervous system function, have substantial limitations. The principal one was that this or in fact any other global index of sympathetic nervous function provides no information on the regional patterning …