Liver carbonic anhydrase and urea synthesis. The effect of diuretics.

In isolated perfused rat liver, urea synthesis is rapid and reversibly inhibited not only by the well-known carbonic anhydrase inhibitors acetazolamide, methazolamide and ethoxzolamide, but also by diuretics, like xipamide, mefruside, chlortalidone, and chlorothiazide. Furosemide was without effect. Similar to findings with isolated perfused rat liver, acetazolamide inhibits urea synthesis from ammonium ions in normal and cirrhotic human liver slices. Inhibition of urea synthesis by xipamide and acetazolamide is accompanied by a 70% decrease of the cellular citrulline content and the tissue levels of 2-oxoglutarate and citrate, suggesting a block of urea synthesis at a step prior to citrulline formation. At a constant extracellular pH (7.4), inhibition of urea synthesis by xipamide, mefruside and acetazolamide was overcome by increasing the extracellular concentrations of HCO3- and CO2 to above twice the normal values. This shows that inhibition of urea synthesis by these diuretics is not due to an unspecific inhibition of one of the urea cycle enzymes but is due to an inhibition of mitochondrial carbonic anhydrase and therefore due to an impaired HCO3- provision for mitochondrial carbamoylphosphate synthesis. It is concluded that the activity of mitochondrial carbonic anhydrase is required for urea synthesis also in human liver and that several diuretics impair urea synthesis by inhibition of mitochondrial carbonic anhydrase. The pathophysiological significance of these data is discussed with respect to the development of diuretics-induced hyperammonemia and alkalosis in liver disease.

Carotid baroreceptor function in hypertensive patients.

Carotid baroreceptor function has been studied in twenty-five patients with essential hypertension and in ten normotensive control subjects of corresponding age. The carotid baroreceptors were stimulated by increasing the transmural pressure over the carotid arteries by the application of negative pressure in a box enclosing the neck. Stimulation elicited significant decreases in intra-arterial blood pressure, heart rate and cardiac index in both hypertensive and normotensive subjects. Both groups also showed a significant decrease in stroke index and a significant increase in total peripheral vascular resistance index. The response to carotid sinus stimulation did not differ significantly between the two groups. In fourteen of the hypertensive subjects, carotid baroreceptor function was studied after 4 months of saluretic therapy, mefruside, and in nine of these patients after additional treatment with a beta-receptor blocking drug, alprenolol, for another 4 months. Both mefruside and alprenolol induced a significant decrease in mean arterial blood pressure but the response to the carotid baroreceptor stimulation was not significantly altered. The findings indicate that the carotid baroreceptor is re-set to the actual blood pressure level, with little or no change in gain in hypertensive subjects both without and during hypotensive therapy.