1. Hypokalaemic periodic paralysis is characterized by attacks of muscle weakness. Glucose, insulin and an abnormal regulation of ATP-sensitive potassium channels may be involved in these attacks. We studied the effect of hyperglycaemia and of the potassium channel opener pinacidil on insulin release and muscle strength in patients with hypokalaemic periodic paralysis. 2. Insulin release was assessed on two occasions in four patients with hypokalaemic periodic paralysis and in eight matched control subjects, with and without treatment with 25 mg pinacidil orally, during a hyperglycaemic glucose clamp at a blood glucose level of 10 mmol/l, in a placebo-controlled, double-blind study. Muscle strength was measured in the hypokalaemic periodic paralysis patients before and during hyperglycaemia using a handheld dynamometer. 3. During the clamp, the mean glucose concentration (10-180 min) in control subjects was 9.9 +/- 0.07 and 10.0 +/- 0.03 mmol/l with and without pinacidil respectively, and in patients with hypokalaemic periodic paralysis was 10.0 +/- 0.04 and 10.1 +/- 0.06 mmol/l respectively (not significantly different). In both groups, the areas under the insulin curve from 0 to 10 min (first-phase insulin release) and from 30 to 180 min (second phase) were not different on the pinacidil study day compared with on the placebo day. The areas under the insulin curve of the first and second phases also did not differ between control subjects and patients with hypokalaemic periodic paralysis (with or without pinacidil). The M/I ratio, a measure of insulin sensitivity, was not different in the two groups. On the placebo day, baseline muscle strength in patients with hypokalaemic periodic paralysis was 165 +/- 16 N for the hip abductors and 168 +/- 19 N for the knee flexors. During the period of hyperglycaemia on the placebo day, muscle strength did not decrease in either muscle group. On the pinacidil study day, an increase in muscle strength was found only in the two hypokalaemic periodic paralysis patients with the lowest mean muscle strength (< 150 N) on the placebo day. The two hypokalaemic periodic paralysis patients with a mean muscle strength on the placebo day > 150 N showed no increase in muscle strength with pinacidil. 4. Insulin secretion and sensitivity were normal in patients with hypokalaemic periodic paralysis. Hyperglycaemia during hyperglycaemic clamping did not provoke paralytic attacks and did not result in a decrease in muscle strength. The potassium channel opener pinacidil had no effect on insulin secretion in hypokalaemic periodic paralysis patients or in normal subjects. Pinacidil may enhance muscle strength in those hypokalaemic periodic paralysis patients who suffer partial paralytic attacks.