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with the dose of isoprenaline which increased heart rate by 25 beats min-'. 4 The dose/response curves of both isoprenaline/HR and metoprolol/HR were significantly shifted to the right in IDDM-patients with hypoglycaemia unawareness compared with controls and IDDM-patients with hypoglycaemia awareness (P < 0.05). 5 Reduced sensitivity of isoprenaline stimulation has also been shown before, whereas reduced sensitivity of a blocking agent has not earlier been shown. 6 These findings support the hypothesis of reduced ,-adrenergic sensitivity as one pathophysiological component in hypoglycaemia unawareness.

The present study was undertaken to decide whether the bound fractions and/or total concentrations of catecholamines were determinative for the variability of biologically active concentrations in human plasma. The binding and concentrations of noradrenaline (NA) and adrenalin (Adr) were determined in acute phase plasma after major hip surgery in five subjects. The bound fractions before surgery were 23.0% and 18.4% for NA and Adr, respectively. The binding of catecholamines increased in the post-operative period. Five days after surgery the binding of NA and Adr was 30.9% and 24.0%, respectively. The surgical trauma induced an acute phase reaction in plasma with a decrease of albumin (HSA) concentrations whereas the concentrations of alpha-1 acid glycoprotein (AAG) increased. The catecholamine concentrations showed a considerable inter- and intraindividual variability. However, the present work shows that the variability of the biologically active catecholamine concentrations is mainly dependent on the total plasma concentrations and not the plasma protein binding.

The transport of cGMP out of cells is energy requiring and has characteristics compatible with an ATP-energised anion pump. In the present study a model with inside-out vesicles from human erythrocytes was employed for further characterisation of the cGMP transporter. The uptake of leukotriene C(4) (LTC(4)), a substrate for multidrug resistance protein (MRP), was concentration-dependently inhibited by the leukotriene antagonist MK571 (IC(50)=110+/-20 nM), but cGMP was unable to inhibit LTC(4) uptake. Oxidised glutathione (GSSG) and glutathione S-conjugates caused a concentration-dependent inhibition of [(3)H]cGMP uptake with IC(50) of 2200+/-700 microM for GSSG, 410+/-210 microM for S-(p-nitrobenzyl)glutathione and 37+/-16 microM for S-decylglutathione, respectively. Antioxidants such as reduced glutathione and dithiothreitol did not influence transport for concentrations up to 100 microM, but both inhibited cGMP uptake with approx. 25% at 1 mM. The cGMP pump was sensitive to temperature without activity below 20 degrees C. The transport of cGMP was dependent on pH with maximal activity between pH 8.0 and 8.5. Calcium caused a concentration-dependent inhibition with IC(50) of 43+/-12 microM. Magnesium gave a marked activation in the range between 1 and 20 mM with maximum effect at 10 mM. The other divalent cations, Mn(2+) and Co(2+), were unable to substitute Mg(2+), but caused some activation at 1 mM. EDTA and EGTA stimulated cGMP transport concentration-dependently with 50% and 100% above control at 100 microM, respectively. The present study shows that the cGMP pump has properties compatible with an organic anion transport ATPase, without affinity for the MRP substrate LTC(4). However, the blockade of the cGMP transporter by glutathione S-conjugates suggests it is one of several GS-X pumps.

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