Inhibition of renal carbonic anhydrase for stimulation of ventilation – an obsolete indication?

Die Blockade der Carboanhydrase oder in differenzierter Weise die Hemmung einzelner Isoenzyme führt zu einer signifikanten metabolischen Azidose durch renalen Bicarbonatverlust. Der dadurch entstehende Anstieg des arteriellen pCO2 verursacht über zentrale und periphere Chemorezeptoren eine Atemstimulation. Diese kann als Prophylaxe der Höhenkrankheit, in begrenztem Maße therapeutisch beim Schlaf-Apnoe-Syndrom, und bei entsprechender Indikation therapeutisch bei chronisch obstruktiven Lungenerkrankungen ausgenützt werden. Obwohl bescheiden in der Wirkung scheint dieser therapeutische Weg bei der Behandlung von einigen Patienten offen. Die Indikation muss aber ensprechend eng gesteckt werden.

Reduced proximal reabsorption resets tubuloglomerular feedback in euvolemic rats

Inhibition of renal carbonic anhydrase reduces proximal reabsorption and activates tubuloglomerular feedback (TGF). The TGF response is saturable, with highest gain focused near the natural flow rate. Therefore, any large change imposed on ambient tubular flow should reduce the TGF response to subequent flow perturbations. However, TGF tends to align with ambient flow regardless of the rate of ambient flow, suggesting that TGF resets to accommodate changes in flow while maintaining feedback efficiency. We used micropuncture and videometric flow velocitometry to test for TGF resetting in free-flowing nephrons during systemic infusion of the carbonic anhydrase inhibitor benzolamide (BNZ, 5 mg ⋅ kg−1 ⋅ h−1) in euvolemic rats. Late proximal flow (VLP) and the fractional compensation (C) of TGF for perturbations in VLP were assessed repeatedly before and during BNZ. Early on, BNZ reduced C, consistent with TGF saturation. Over the next 45–60 min, VLP increased gradually by ∼5 nl/min as C recovered to pre-BNZ levels. BNZ also increased VLP by ∼5 nl/min when TGF was rendered inoperative by intratubular wax block, but this increase occurred rapidly. These data demonstrate rightward resetting of TGF during reduced proximal reabsorption.

Renal acid-base physiology in marine teleost, the long-horned sculpin (Myoxocephalus octodecimspinosus)

We have sought to define urinary acid-base excretion in the marine teleost using the long-horned sculpin, Myoxocephalus octodecimspinosus. Urine flow (1.7 ml.h-1.kg-1) is relatively high, and glomerular filtration rate is very low (2.9 ml.h-1.kg-1). The urine-to-plasma ratio of inulin is 2. Renal clearance of p-aminohippurate is very high (108 ml.h-1.kg-1); phosphate and divalent cations are also secreted. In this framework we found urinary pH to average 6.6, but infusion of acid or alkali elicited a pH range of 6.1-7.8. Untreated fish may also have alkaline urine; so it is not surprising that precipitates of calcium or magnesium phosphate are sometimes found in bladder. These are of fine sandy quality and never cause blockage. Infusion of buffer (imidazole) increased the concentration of titratable acid 11-fold and output 2.5-fold. Carbonic anhydrase inhibitors had no effect on any urinary component, and histochemical studies revealed that cytoplasm and membranes did not yield the specific cobalt stain for the enzyme. An alkaline load (NaHCO3) is rapidly dissipated by gill excretion, mediated in part by carbonic anhydrase. An acid load (HCl) is rapidly dissipated by gill excretion, not dependent on carbonic anhydrase, and some renal excretion. Comparison and contrast of the low rates of HCO3- reabsorption in the marine teleost (and elasmobranch) with those of mammals suggest strongly that renal carbonic anhydrase evolved in connection with these high reabsorptive rates beginning in freshwater fish and continuing through amphibia and birds.