The ionic mechanism underlying the chronotropic effect of epinephrine on the rabbit sinoatrial (S-A) node has been studied. Epinephrine (5.5 X 10(-6) M) increased the spontaneous rate from 206 +/- 25 min-1 to 242 +/- 39 min-1. The effect of epinephrine was reproducible on repetitive applications. Voltage clamp experiments using the two microelectrode technique revealed the following changes in the membrane current: epinephrine (5.5 X 10(-7) M) increased the limiting conductance for the slow inward current (is) by approximately 30% and the potassium current (ik) by about 10%, keeping the kinetics of is and ik constant. From the holding potential of -70 mV the activation of is was observed on step depolarization positive to -60 or -55 mV in both control and epinephrine solution. The hyperpolarization-activated current (ih) was also increased by about 20% at -70 mV, and its time course was slightly accelerated. Participation of is for the chronotropic effect of epinephrine was strongly suggested by the findings that is was partially available positive to -60 mV and that epinephrine could not increase the slope of diastolic depolarization when is was blocked by D 600.

We measured serum urate in 3,258 Japanese outpatients. Five of them had persistent hypouricemia. Three also had microhematuria. Four of the five patients were proven to have renal uricosuria with hypouricemia, but otherwise normal tubular function. When tested with both pyrazinamide and benzbromarone, 1 patient had a presecretory reabsorption defect, 2 had postabsorption defects, and 1 an enhanced renal tubular secretion of urate. These results suggest that persistent hypouricemia in outpatients is of very low incidence, is usually caused by an isolated metabolic error of urate transport, and is not related to drug ingestion or systemic disease.

Hypertension is a common complication in patients with gout and/or hyperuricemia. Besides, hyperuricemia is a risk factor of gout as well as ischemic heart disease in hypertensive patients. Moreover, the risk of gout is modified by antihypertensive drugs. However, it remains unclear how antihypertensive agents affect uric acid metabolism. In the present study, we investigated the uric acid metabolism in treated hypertensive patients to find out whether any of them would influence serum levels of uric acid. 751 hypertensive patients (313 men and 438 women) under antihypertensive treatment were selected. Blood pressure (BP), serum uric acid (SUA) and serum creatinine (Scr) were measured and evaluated statistically. In patients treated with diuretics, beta-blockers and/or alpha-1 blockers SUA levels were significantly higher than in patients who were not taking these drugs. Besides, the estimated glomerular filtration rate (eGFR) in patients treated with diuretics, beta-blockers and/or alpha-1 blockers was negatively correlated with SUA level. There were gender differences in the effects of beta-blockers and alpha-1 blockers. Multiple regression analysis indicated that both diuretics and beta-blockers significantly contributed to hyperuricemia in patients with medication for hypertension. Diuretics, beta-blockers and alpha-1 blockers reduced glomerular filtration rate and raised SUA levels. Calcium channel blockers, ACE inhibitors and angiotensin receptor blockers, including losartan, did not increase SUA levels.

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