Jay I. Meltzer

ANGIOTENSIN II, NOREPINEPHRINE, AND RENAL TRANSPORT OF ELECTROLYTES AND WATER IN NORMAL MAN AND IN CIRRHOSIS WITH ASCITES*

In normal subjects, the rate of aldosterone secretion fluctuates widely according to the state of salt and water balance, but the pathways mediating this relationship are still to be identified. Hypersecretion of aldosterone occurs in malignant nephrosclerosis (2). Angiotensin, the pressor peptide released from plasma by renin, increases both the adrenal secretion (3) and the urinary excretion (4) of aldosterone in man. These observations support the suggestion (5) that a renaladrenal interaction might be involved in the normal regulation of sodium and potassium balance. By this mechanism, the kidney, perhaps sensitive to diminished arterial filling or ischemia, secretes renin, generating angiotensin, which then stimulates aldosterone secretion. Aldosterone, in turn, restores renal perfusion by promoting sodium and water retention. In malignant hypertension this mechanism may become deranged, leading to the coexistence of increased amounts of both angiotensin and aldosterone in the blood, a possibility that derives additional support from the earlier report (6) of increased blood angiotensin in these patients. On the other hand, since neither renin nor angiotensin has been conclusively demonstrated in normal human plasma, elaboration of these substances in malignant hypertension might be simply a consequence of severe renal damage. Our more recent work has investigated the possibility that this renal-adrenal interaction participates in normal homeostasis, as well as in the

Hepatic Uptake and Biliary Excretion of Indocyanine Green in the Dog.

Summary 1. Indocyanine green given intravenously to dogs is distributed in the plasma compartment and rapidly removed by the liver. 2. Biliary excretion of the dye is delayed, but an average of 97.3% of the administered dose is eventually recovered from the bile in apparently unaltered form. Indocyanine green does not appear in the urine. 3. Indocyanine green interferes with hepatic uptake of BSP from the plasma. 4. Absorption of indocyanine green from the bowel is minimal.

Metabolism of Sulfobromophthalein Sodium (BSP) in Dog and Man.

Summary During administration of a constant infusion of BSP in the dog and man, 3 chromatographically distinct metabolites were demonstrated in plasma and bile in addition to BSP itself. Part of the metabolic change involves conjugation of BSP or some BSP derivative with one or more amino acids. Some of the physiologic properties of BSP metabolites are described and discussed, particularly with reference to problems of BSP transport from plasma to bile.

Critique of Re-Analysis of the TROPHY Study

To the Editor: Two recent letters to the editor of The Journal of Clinical Hypertension suggested reevaluation of the Trial of Preventing Hypertension (TROPHY). Six years after publication, despite extensive valid criticism, it still holds interest for some hypertension specialists. Both letters suggest that the only problem with TROPHY was the artefact in measuring office blood pressure (BP) to diagnose clinical hypertension, and that reassessment of the visit-to-visit BP variation would solve it. As I pointed out in my critique, the problems are much deeper. The most serious was even highlighted by Dr Julius himself in a manuscript published midway into the study. His prospective analysis of the data predicted 5 possible scenarios “to guide analysis” and “ensure a priori objectivity of conclusions.” Each scenario was represented by a Kaplan-Meier graph of patient BPs after stopping 2 years of daily candesartan therapy. They were “Masking Hypertension,” “Eliminating Hypertension,” two forms of “Delaying Hypertension,” and “Slow Unmasking of Hypertension. As I previously concluded in, with the editors of the American Journal of Hypertension in agreement, only “Slow Unmasking” fitted the actual Kaplan-Meier curve of TROPHY. It is unfortunate that Dr Julius and coauthors never addressed the issues they raised in TROPHY, apparently wishing to forget their a priori analysis, performed only 2 years before. Independently, the basic BP data of TROPHY showed a return to control values within 9 months of stopping candesartan, leading Norman Kaplan in Uptodate to conclude “there is no evidence that transient antihypertensive therapy changes the course of prehypertension or hypertension.” Finally, the conclusions of TROPHY have no standing for two additional reasons: there were no events, and the gold standard for BP measurement, ambulatory BP monitoring, was not used. Both should be required before recommending new therapeutic ideas. Since the prevalence of “prehypertension” is 37% in US adults, any suggestion of drug treatment that could result in the medicalization of multi-millions of asymptomatic people should be done on solid evidence. Unfortunately, that is lacking in TROPHY.