Visual cycle and its metabolic support in gecko photoreceptors.

Photoreceptors of nocturnal geckos are transmuted cones that acquired rod morphological and physiological properties but retained cone-type phototransduction proteins. We have used microspectrophotometry and microfluorometry of solitary isolated green-sensitive photoreceptors of Tokay gecko to study the initial stages of the visual cycle within these cells. These stages are the photolysis of the visual pigment, the reduction of all-trans retinal to all-trans retinol, and the clearance of all-trans retinol from the outer segment (OS) into the interphotoreceptor space. We show that the rates of decay of metaproducts (all-trans retinal release) and retinal-to-retinol reduction are intermediate between those of typical rods and cones. Clearance of retinol from the OS proceeds at a rate that is typical of rods and is greatly accelerated by exposure to interphotoreceptor retinoid-binding protein, IRBP. The rate of retinal release from metaproducts is independent of the position within the OS, while its conversion to retinol is strongly spatially non-uniform, being the fastest at the OS base and slowest at the tip. This spatial gradient of retinol production is abolished by dialysis of saponin-permeabilized OSs with exogenous NADPH or substrates for its production by the hexose monophosphate pathway (NADP+glucose-6-phosphate or 6-phosphogluconate, glucose-6-phosphate alone). Following dialysis by these agents, retinol production is accelerated by several-fold compared to the fastest rates observed in intact cells in standard Ringer solution. We propose that the speed of retinol production is set by the availability of NADPH which in turn depends on ATP supply within the outer segment. We also suggest that principal source of this ATP is from mitochondria located within the ellipsoid region of the inner segment.

Measurement of thermal contribution to photoreceptor sensitivity.

Activation of a visual pigment molecule to initiate phototransduction requires a minimum energy, Ea, that need not be wholly derived from a photon, but may be supplemented by heat. Theory predicts that absorbance at very long wavelengths declines with the fraction of molecules that have a sufficient complement of thermal energy, and that Ea is inversely related to the wavelength of maximum absorbance (lambda(max)) of the pigment. Consistent with the first of these predictions, warming increases relative visual sensitivity to long wavelengths. Here we measure this effect in amphibian photoreceptors with different pigments to estimate Ea (refs 2, 5-7) and test experimentally the predictions of an inverse relation between Ea and lambda(max). For rods and 'red' cones in the adult frog retina, we find no significant difference in Ea between the two pigments involved, although their lambda(max) values are very different. We also determined Ea for the rhodopsin in toad retinal rods--spectrally similar to frog rhodopsin but differing in amino-acid sequence--and found that it was significantly higher. In addition, we estimated Ea for two pigments whose lambda(max) difference was due only to a chromophore difference (A1 and A2 pigment, in adult and larval frog cones). Here Ea for A2 was lower than for A1. Our results refute the idea of a necessary relation between lambda(max) and Ea, but show that the A1 --> A2 chromophore substitution decreases Ea.

Exceptional pharmacokinetics of trivalent chromium during occupational exposure to chromium lignosulfonate dust.

The excretion of chromium in the urine of workers exposed to chromium lignosulfonate was studied. The chromium in the dust was in the trivalent (III) oxidation state, and 30% of the particles were less than 5 micron in diameter. Chromium (III) lignosulfonate dust was rapidly absorbed, and a peak of urinary excretion was seen immediately after exposure. No appreciable accumulation of chromium occurred over 3 d, as evaluated by comparison with preshift urinary chromium concentrations. The addition of ethylenediaminetetra-acetate to the urine of exposed persons greatly enhanced the capacity of chromium to traverse a dialysis membrane; the same effect was seen with chromium (III) chloride. It is concluded that chromium (III) lignosulfonate yields chromium (III), which acts pharmacokinetically like water-soluble hexavalent chromium compounds.

Treatment of hypertension successively with a diuretic, clonidine or a beta-blocking agent and hydralazine.

The present study was carried out in an homogenous group of 49 untreated hypertensive patients, all aged 45 years. Diastolic blood pressure was equal to or greater than 110 mmHg in successive measurements; eleven patients were classified as WHO group II, and the others as WHO group I. An initial placebo period of 3 weeks was followed by cyclothiazide medication with a good response in 6 patients. The remaining patients were given either clonidine or practolol, and by adjustment of the dose a good response was obtained in 31 patients. In these cases the treatment was exchanged after 6 weeks. The antihypertensive effect of relatively small doses of clonidine was equal to that of practolol. Since completion of the study practolol has been withdrawn because of the emergence of long term toxic effects. In 12 cases, hydralazine had to be added to obtain a satisfactory response. Mild side-effects were common, especially at the beginning of clonidine treatment, but they did not necessitate discontinuation of treatment. Further comparative studies of clonidine and beta-blockers should be carried out and more experience with the combination of clonidine and vasodilators in the treatment of hypertension is necessary.

The use of clonidine and practolol in the treatment of hypertension.

The antihypertensive effects of clonidine hydrochloride and practolol were compared in 42 men, aged 45 years, who had not received any antihypertensive therapy before, except one patient. The diastolic blood pressures were at least 110 mmHg on two successive visits to the health centre before their selection to the trial. One half of them were classified into the WHO group 1 and the other half into group 2. There was no statistical difference in the systolic and diastolic blood pressures between clonidine and practolol group at the end of placebo period. The study started with a three-week placebo period. Thereafter, 20 patients were given clonidine 0.225 mg and twenty-two practolol 200 mg daily. The next control was carried out after three weeks. The dosage was kept unchanged or increased according to the antihypertensive response. After three weeks, clonidine and practolol dosages were checked again, and 25 mg of chlorothiazide were added to the treatment in 15 clonidine cases and in 18 practolol cases. After the next three-week period, the same regimen was continued on most patients for 6-9 weeks. The daily dosage of clonidine varied from 0.225 to 0.900 (mean 0.394) mg and that of practolol from 200 to 600 (mean 382) mg. Both regimens resulted, when individually adjusted, in a mean systolic blood pressure level of less than 150 mmHg and diastolic pressures less than or equal to 100 mmHg. Hydrochlorothiazide potentiated the blood pressure effect almost equally in both regimens. The blood pressure reduction was statistically significant (p less than 0.05) both in the clonidine and practolol group. There was no significant difference of the mean blood pressures after the active drug therapy between these two groups. A moderate reduction of pulse rate was observed in both main groups, but it was not related to the antihypertensive efficacy. Side-effects were mild. Dryness of the mouth and sedation were more common in patients receiving clonidine. No oculocutaneous or other "immunological" manifestation were seen during the 15-18 weeks' practolol therapy.