The National High Blood Pressure Education Program presents the complete Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Like its predecessors, the purpose is to provide an evidence-based approach to the prevention and management of hypertension. The key messages of this report are these: in those older than age 50, systolic blood pressure (BP) of greater than 140 mm Hg is a more important cardiovascular disease (CVD) risk factor than diastolic BP; beginning at 115/75 mm Hg, CVD risk doubles for each increment of 20/10 mm Hg; those who are normotensive at 55 years of age will have a 90% lifetime risk of developing hypertension; prehypertensive individuals (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg) require health-promoting lifestyle modifications to prevent the progressive rise in blood pressure and CVD; for uncomplicated hypertension, thiazide diuretic should be used in drug treatment for most, either alone or combined with drugs from other classes; this report delineates specific high-risk conditions that are compelling indications for the use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers); two or more antihypertensive medications will be required to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg) for patients with diabetes and chronic kidney disease; for patients whose BP is more than 20 mm Hg above the systolic BP goal or more than 10 mm Hg above the diastolic BP goal, initiation of therapy using two agents, one of which usually will be a thiazide diuretic, should be considered; regardless of therapy or care, hypertension will be controlled only if patients are motivated to stay on their treatment plan. Positive experiences, trust in the clinician, and empathy improve patient motivation and satisfaction. This report serves as a guide, and the committee continues to recognize that the responsible physician's judgment remains paramount.

Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

### A. Overview

Extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface receptors termed purine receptors. In this review particular emphasis is placed on the discrepancy between the

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Receptors for Purines and Pyrimidines

The ascending monoamine pathways in the rat brain are demonstrated by the pile up of fluorescent material occurring in the axons after various types of lesions. The anatomy of the pathways is outlined in drawings of frontal sections of the brain and the origin and termination of several pathways is determined by studying the anterograde and retrograde degeneration occurring after well localised lesions. It is possible to separate the ascending NA pathways into a dorsal and a ventral bundle of axons. The dorsal bundle innervates the cortex and the hippocampus and the ventral bundle supplies NA nerve terminals to the medulla, the pons, the mesencephalon and the diencephalon. The dorsal bundle is found to originate in the locus coeruleus. Lesions of this nucleus abolish the nerve terminals in all cortical areas and in several other areas of the brain indicating a unique role for the locus coeruleus in influencing the activity of the entire brain. The 5-HT pathways have a distribution similar to the ventral NA pathyway. The course of the nigro-striatal and the meso-limbic DA pathways is presented in detail.

Stereotaxic mapping of the monoamine pathways in the rat brain.

Regulatory T cells (T regs ) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate T reg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic T regs . We determined that short-chain fatty acids, gut microbiota–derived bacterial fermentation products, regulate the size and function of the colonic T reg pool and protect against colitis in a Ffar2 -dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.

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The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis

From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites

: A methodological description gives detailed instructions for the preparation, freeze-drying, histochemical treatment, and sectioning of tissues for fluorescence microscopy of catecholamines, 5-hydroxytryptamine and their immediate precursors. (Author)

A detailed methodological description of the fluorescence method for the cellular demonstration of biogenic monoamines

Four adenosine receptor subtypes of the family of G protein-coupled receptors, designated A1, A2A, A2B and A3 are currently known. In this study all human subtypes were stably transfected into Chinese hamster ovary (CHO) cells in order to be able to study their pharmacological profile in an identical cellular background utilizing radioligand binding studies (A1, A2A, A3) or adenylyl cyclase activity assays (A2B). The A1 subtype showed the typical pharmacological profile with 2-chloro-N6-cyclopentyladenosine (CCPA) as the agonist with the highest affinity and a marked stereoselectivity for the N6-phenylisopropyladenosine (PIA) diastereomers. In competition with antagonist radioligand biphasic curves were observed for agonists. In the presence of GTP all receptors were converted to a single low affinity state indicating functional coupling to endogenous G proteins. For A2A adenosine receptors CGS 21680 (2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadeno sine) and N-ethylcarboxamidoadenosine (NECA) were found to be the most potent agonists followed by R- and S-PIA with minor stereoselectivity. The relative potencies of agonists for the A2B adenosine receptor could only be tested by measurement of receptor-stimulated adenylyl cyclase activity. NECA was the most potent agonist with an EC50-value of 2.3 microM whereas all other compounds tested were active at concentrations in the high micromolar range. Inhibition of NECA-stimulated adenylyl cyclase identified xanthine amino congener (XAC; 8-[4-[[[[(2-aminoethyl)amino]-carbonyl]methyl]oxy]phenyl]-1,3-dipropylxa nthine) as the most potent antagonist at this receptor subtype. The A3 receptor was characterized utilizing the nonselective agonist [3H]NECA. The N6-benzyl substituted derivatives of adenosine-5'-N-methyluronamide (MECA) turned out to be the most potent agonists. The notion of xanthine-insensitivity of the A3 receptor should be dropped at least for the human receptor as xanthines with submicromolar affinity were found. Overall, the pharmacological characteristics of the human receptors are similar to other species with some species-specific characteristics. In this study we present for the first time the comparative pharmacology of all known human adenosine receptor subtypes. The CHO cells with stably transfected adenosine receptors provide an identical cellular background for such a pharmacological characterization. These cells are valuable systems for further characterization of specific receptor subtypes and for the development of new ligands.

Comparative pharmacology of human adenosine receptor subtypes – characterization of stably transfected receptors in CHO cells

Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids

Autonomic nerves, mast cells, and amine receptors in human brain vessels. A histochemical and pharmacological study.

Summary— The pineal gland of the rat has been studied using a highly specific and sensitive fluorescence microscopical method for the cellular localization of certain biogenic monoamines, in combination with fluorimetric determinations of 5-hydroxytryptamine (5-HT) levels under normal and experimental conditions. Exceptionally large amounts of 5-HT have been found in the gland. This amine is located partly in the parenchymal cells and partly in the pineal sympathetic nerves. There is strong evidence to support the view that the sympathetic nerves are noradrenergic, but take up 5-HT from the parenchymal cells into their terminal portions, which run within the gland. A unique feature thus exists in the sympathetic nerves of the rat's pineal in that they contain two different monoamines.



The experiments have shown that half of the pineal 5-HT is located in the sympathetic nerves, and that the rest is stored in the parenchyma. A small portion of this parenchymal pool is dependent on an intact innervation and is lost on denervation. After the injection of noradrenaline, the fluorescence of the pineal nerves changes to show the characteristics of a catecholamine. Half of the pineal 5-HT is then depleted, showing that the neuronal 5-HT is replaced by the administered noradrenaline. No change can be registered in pineal 5-HT levels 22 hours after the administration of α-methyl-m-tyrosine. However, metaraminol causes a pronounced depletion of pineal 5-HT. A reaccumulation of the 5-HT fluorescence in the pineal nerves can be brought about by the injection of nialamide to reserpinized animals, as it occurs in the cerebral nerves containing 5-HT.

Christer Owman

Papers

A detailed methodological description of the fluorescence method for the cellular demonstration of biogenic monoamines

Comparative pharmacology of human adenosine receptor subtypes – characterization of stably transfected receptors in CHO cells

Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids

Autonomic nerves, mast cells, and amine receptors in human brain vessels. A histochemical and pharmacological study.

Studies on 5-hydroxytryptamine stores in pineal gland of rat.