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Abstract

Since the UGDP findings, the use of sulphoylureas in ischaemic heart disease has been controversial. The UKPDS showed that first generation sulphonylureas can cause hypertension, but little is known about the mechanism of this.

We used the technique of head-out water immersion, as a method of inducing central volume expansion, to study the haemodynamic and renal effects of tolbutamide administration on non-diabetic individuals. The response to head-out water immersion for 4 hours was compared to the response on a non-immersion control day, in 8 non-diabetic (7 males and 1 female, ages 22-73 years, mean 40.4 years), on and off, a five day course of tolbutamide (250mg twice daily) with hourly blood pressure measurement together with blood and urine sampling. Ethical approval was obtained by the local ethics committee.

Results are given as mean±SEM, blood pressures are in mmHg, sodium excretions are in μmol min-1 and urine volumes are in mls.

As shown in the above table, water immersion produced a significant diuresis (p=0.002) and natriuresis (p<0.0001). Tolbutamide also produced a diuresis on the dry control days (p=0.008), however this diuretic effect was less marked when it was administered on a immersion day, where the diuresis failed to reach statistical significance, when compared to a dry control day on tolbutamide (p=0.065). There was a significant natriuresis with tolbutamide (p=0.044) and this natriuretic effect was enhanced on immersion (p=0.012). The largest differences in the mean systolic and diastolic blood pressures were between the readings taken on the control dry days, without the tolbutamide and the readings taken on the immersion days with tolbutamide, however these differences were not significant (systolic p=0.466, diastolic p=0.208).

off immersion, off tolbutamideon tolbutamide, off immersionoff tolbutamide, on immersionon tolbutamide, on immersion
sodium excretion126.9±14.7204.5±31.8250.1±12.4350.5±32.8
urine volume195.7±11.4241.7±9.7306.5±25.9375.1±22.6
systolic BP128.7±4.0130.9±9.1132.1±9.0135.7±8.1
diastolic BP76.7±8.778.3±3.678.8±3.981.5±2.8
off immersion, off tolbutamideon tolbutamide, off immersionoff tolbutamide, on immersionon tolbutamide, on immersion
sodium excretion126.9±14.7204.5±31.8250.1±12.4350.5±32.8
urine volume195.7±11.4241.7±9.7306.5±25.9375.1±22.6
systolic BP128.7±4.0130.9±9.1132.1±9.0135.7±8.1
diastolic BP76.7±8.778.3±3.678.8±3.981.5±2.8
off immersion, off tolbutamideon tolbutamide, off immersionoff tolbutamide, on immersionon tolbutamide, on immersion
sodium excretion126.9±14.7204.5±31.8250.1±12.4350.5±32.8
urine volume195.7±11.4241.7±9.7306.5±25.9375.1±22.6
systolic BP128.7±4.0130.9±9.1132.1±9.0135.7±8.1
diastolic BP76.7±8.778.3±3.678.8±3.981.5±2.8
off immersion, off tolbutamideon tolbutamide, off immersionoff tolbutamide, on immersionon tolbutamide, on immersion
sodium excretion126.9±14.7204.5±31.8250.1±12.4350.5±32.8
urine volume195.7±11.4241.7±9.7306.5±25.9375.1±22.6
systolic BP128.7±4.0130.9±9.1132.1±9.0135.7±8.1
diastolic BP76.7±8.778.3±3.678.8±3.981.5±2.8

This study suggests that short-term administration of tolbutamide results in a diuresis which is not significantly enhanced by volume expansion. It also results in a natriuresis, which is enhanced by volume expansion. This does not provide an explanation for the hypertension caused by first generation sulphonylureas. Further study is needed with tolbutamide administration over a longer term. We speculate that the natriuretic effect may be due to the actions of tolbutamide on the ascending loop on Henle.

tolbutamide, hypertension, immersion
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© American Journal of Hypertension, Ltd. 2001
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