There is growing evidence from epidemiological and animal studies that low- level exposure to lead may result in increased blood pressure, a major risk factor in the development of cardiovascular, cerebrovascular and renovascular disease. Several observations indicate that lead-associated hypertension arises from enhanced vascular responsiveness to catecholamines, mediated in part by lead-induced elevation in intracellular calcium. Using established human protocols that measure the pressor response to infused norepinephrine, we will investigate whether a reduction in soft tissue lead burden by EDTA chelation can reduce the vascular responsiveness of subjects with occupational lead exposure. From both a physiologic and public health standpoint, black adults appear particularly susceptible to the hypertensive effects of lead, and constitute a key target group for initial subject selection. In our group's recent cross-sectional study of San Francisco bus drivers, a strong relationship between lead and blood pressure was found exclusively in black subjects. Other studies have found black hypertensives to have an elevated pressor response to infused catecholamines, and to have higher intracellular stores of calcium, the same mechanisms experimentally implicated in lead's blood pressure effects. It therefore seems plausible that race and lead may interact to enhance the blood pressure response to endogenous catecholamines. Across all age groups, black Americans have higher blood lead concentrations than do whites, and the contribution of occupational and environmental lead exposure to the high prevalence of hypertension among blacks may be substantial. Our experimental design examines a mechanistic role of lead in hypertension and explores a potential therapeutic intervention. Asymptomatic black men with blood lead concentrations between 25 and 80 ug/dl, indicative of occupational lead exposure, will be recruited as subjects from the California State Lead Registry, California's Toxic-Info Center, and the large referral network at the University of California-San Francisco's Occupational Medicine Program. Fourteen non-medicated subjects with diastolic blood pressure between 85 and 105 mmHg on two consecutive screenings, indicative of borderline to moderate hypertension, will be admitted to the UCSF General Clinical Research Center and stabilized for 48 hours on a fixed sodium diet (160 mEq/d). In each of 2 intervention cycles, subjects will receive a stepped-dose infusion of norepinephrine (NE) (known to generate a linear blood pressure response), immediately before and after an experimental intervention, and the slope of the dose- response lines will be calculated. In one cycle the intervention will consist of a 48 hour lead chelation with i.v. EDTA, in the other matched i.v. placebo. The order of the 2 cycles will be assigned in a double blinded, balanced manner. For each subject, the change in slope between the pre- and post-intervention NE infusion, a measure of the change in pressor sensitivity, will be compared between the chelation and placebo cycles. In a secondary analysis, linear regression will relate the change in slope to the change in blood lead concentration. If results indicate that reduction in lead burden by EDTA chelation is associated with decline in pressor sensitivity, the first human experimental evidence of a lead-blood pressure relationship will be established. To explore the specificity or generalizability of these results, further investigations supported by the SERCA Award will apply this low-cost model to the study of 1) non-black subjects, 2) subjects with lower blood lead concentrations (e.g., less than 25 ug/dl), or 3) sub- groups in which positive trends are found. Pilot data will be generated examining the utility of lead chelation as an anti-hypertensive intervention, and by extension, the value of primary prevention of low to moderate lead exposure.
