ANP bioactivity in obese hypertensives.

ANP Bioactivity in Obese Hypertensives To the Editor: I write to comment on and to question features of the recent publication from Dessi-Fulgheri and colleagues that appeared in the February issue of Hypertension (Hypertension. 1999:33;658–662). The authors report that a bolus injection of ANP produces greater falls in blood pressure, greater increases in plasma cyclic GMP, and a greater suppression of plasma aldosterone that are all accompanied by increased natriuresis in obese subjects who have had a low-calorie diet for 4 days as compared with the response to ANP prior to calorie restriction. Several difficulties arise with this report. First, the dose employed is unclear. The abstract employs 0.6 mg/kg. In “Results,” a dose of 0.6 mg/kg is reported, and then in “Discussion,” 0.6 mg/kg reappears. This 1000-fold difference in dose should be of some concern. Notably, even 0.6 mg/kg (over 50 mg as a bolus) is a large dose and cannot be considered as ranking among “low doses” as these authors suggest. A bolus injection of this dose will produce pharmacological levels of plasma ANP never reproduced in health or in any pathophysiological state. Certainly such an injection will not result in “changes in circulating ANP confined within the normal range” as these authors claim. This information was well established by the mid-1980s when it became clear that the plasma half-life of human ANP was a little under 3 minutes. Early reports from our group indicated that a 100-mg bolus resulted in plasma ANP levels in excess of 2500 pmol/L at 1 minute after intravenous injection, with an exponential fall in levels over the first 10 minutes, and a return to basal values of plasma ANP after 30 minutes (Yandle et al. Life Sci. 1986; 38:1827–1833). This report has been repeatedly confirmed by other investigators over the last decade. Dessi-Fulgheri et al provide no measurements of plasma ANP prior to a stated peak level said to occur 30 minutes after peptide administration. This is quite implausible. It is notable that the protocol described in “Methods” states that plasma samples were taken at the time of ANP bolus (time 0) and 15, 30, 60, 90, and 120 minutes after ANP. However, only one time point is reported in the text. Furthermore, where other plasma variables are graphed (eg, Figure 2 shows plasma cyclic GMP concentration), the items depicted include 10, 20, and 30 minutes rather than 15 and 30 minutes. The achieved levels of plasma ANP throughout the course of this experiment (including the first 15 minutes) are crucial to interpretation of its physiological or pathophysiological significance. Why have plasma concentrations not been measured in the first few minutes after injection when it is obvious they will be at their peak, and why are levels not depicted for all time points when measurements are claimed to have been made? If these authors had wished to reproduce physiological or pathophysiological shifts in plasma ANP (which would be the appropriate approach to this experiment), then doses in the order of 2 or 3 ng/kg/minute (ie, in the order of 10 mg delivered over an hour to a 70 kg subject) would be appropriate (Richards et al. J Clin Endocrinol Metab. 1988;67:1134–1139; Richards et al. Hypertension. 1989;14:261–268). Finally, the biological effects of this 50-mg dose (assuming that the authors do mean 0.6 mg/kg) are implausibly small in terms of the natriuresis observed. A 100-mg bolus of ANP produces a several-fold rise in urinary excretion of sodium over the first 30 minutes after the injection in both normal volunteers and patients with hypertension, and some natriuretic effect is sustained out to at least 90 minutes post-injection (Richards et al. Lancet. 1985;I:545–549; Richards et al. Hypertension. 1985;7:812–817). The authors may have obscured some of the natriuretic effect by plotting data in 2 hour blocks; however, it is still notable that there is no significant natriuresis in the noncalorie restricted state, and this requires more explanation than is offered in the current paper. These questions challenge the plausibility of this report and cast doubt on its reliability as an indicator of physiological or pathophysiological events.