BACKGROUND Vasodilator therapy may be associated with reflex counter-regulatory responses, and these responses may play a role in the development of tolerance to nitroglycerin (GTN). METHODS AND RESULTS Standing systolic blood pressure, body weight, urinary sodium, and hormonal responses to continuous (n = 10) and intermittent (n = 10) transdermal GTN administration were studied in normal volunteers. There was rapid attenuation of the hypotensive response to transdermal GTN therapy in the continuous but not in the intermittent therapy group. Significant weight gain and sodium retention occurred during continuous but not during intermittent GTN therapy. This was accompanied by a greater decrease in hematocrit in the continuous group, a finding that suggests that plasma volume expansion occurred during continuous GTN therapy. Continuous GTN therapy was associated with increases in plasma norepinephrine, atrial natriuretic peptide, arginine, vasopressin, and plasma renin activity. A different pattern of neurohormonal response was seen during intermittent therapy, with values tending to return to baseline levels after the nitrate-free interval. CONCLUSIONS Continuous transdermal GTN therapy leads to counter-regulatory responses associated with sodium retention and probable plasma volume expansion. By contrast, intermittent transdermal GTN therapy is associated with a different pattern of hormonal response, the lack of sodium retention and no evidence of plasma volume expansion. It is likely that these counter-regulatory responses play an important role in the attenuation of nitrate effects.

Although corticosteroids are effective in the treatment of hypercalciuria and hypercalcemia in chronic sarcoidosis, complications of their long-term use frequently limit therapy. We studied the efficacy of chloroquine in two patients with sarcoidosis who were unable to tolerate the dosage of corticosteroids required to control hypercalciuria and prevent the formation of renal stones. Over a three-year period, each patient received a 6-month and a 10-month course of oral chloroquine phosphate (500 mg per day) while continuing to receive corticosteroids at a fixed dose. Chloroquine therapy was associated with a significant reduction in levels of serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and urinary calcium. We observed a direct correlation between serum 1,25-(OH)2D levels and 24-hour urinary calcium excretion, supporting the hypothesis that excessive serum 1,25-(OH)2D is responsible for the hypercalciuria in sarcoidosis. Serum levels of 25-hydroxyvitamin D (25-(OH)D) did not change with therapy, suggesting that chloroquine may act by inhibiting the conversion of 25-(OH)D to 1,25-(OH)2D. Current dosage guidelines and ophthalmologic-surveillance techniques, which allow chloroquine to be administered with little risk of retinopathy, should permit an expanded role for this agent in the treatment of the calcium abnormalities of sarcoidosis.

On the basis of almost 15 years of experience with thiazide treatment in 346 patients with calcium stones, we believe that the following conclusions are justified: 1) Stone progression ceases in at least 90% of patients who take hydrochlorothiazide (50 mg, twice daily) on a regular basis. 2) A reduced dose of hydrochlorothiazide, i.e., 25 mg twice daily, appears to be effective in a significant proportion of patients. 3) Thiazides are effective in normocalciuric as well as hypercalciuric patients and in most patients with tubular ectasia (medullary sponge kidney). 4. Side effects necessitate discontinuation of thiazide treatment in approximately 7% of patients. The incidence and severity of side effects is reduced by initiating treatment with a small dose and by increasing the dose progressively until the full maintenance dose is achieved. A trial with a reduced dose is warranted in patients who are unable to tolerate the regular maintenance dose. 5) The therapeutic efficacy of thiazides in stone prevention cannot be accurately predicted by the degree of hypocalciuric response. Stone prevention may cease despite a minimal hypocalciuric response, whereas stone progression may occur when an adequate hypocalciuric response has taken place. 6) In addition to the hypocalciuric action, thiazides reduce urine oxalate excretion and increase urine zinc and (probably) magnesium; these effects probably contribute to the efficacy of this agent in stone prevention.

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