Delayed ventilatory response to CO2 after carbonic anhydrase inhibition with acetazolamide administration in the anesthetized rat.

Abstract

In order to estimate to what extent the stimulatory action of C02 on ventilation is mediated by the formation of H+, we studied effects on the temporal profile of ventilatory response to C02 of carbonic anhydrase (CA) inhibition with acetazolamide in the halothane anesthetized spontaneously breathing rat. Since hydration reaction of C02 yielding H + is delayed by CA inhibition, the time courses of changes in tidal volume (VT), respiratory frequency (f), and minute ventilation (VE) in response to a stepwise increase in end-tidal P~o2 (d PETCo2 15 mmHg) were compared before (control state) and after i.v. injection of acetazolamide (50 mg/kg) in the hyperoxic condition. In the control state, an increase in VT was significantly slower than that in f; and the mean response half-times (T, i2) for the increase in VT, f, and VE were 50.6, 18.1, and 31.0 s, respectively. After acetazolamide administration, responses to C02, especially f -response and consequently 1'E-response became much slower, and the T12 for VT, f, and VE were 67.9, 55.0, and 63.0 s, respectively. The delay in VT-response was not statistically significant. The magnitude of increase in VE in the steady state hypercapnic stimulation was almost the same before and after acetazolamide administration. The results suggest that a rapid increase in f during C02 inhalation occurs predominantly through an increase in H + produced by hydration of C02 with CA, whereas VT-response may occur without involvement of this process. The different time courses of VT-and f -responses and possible effects of molecular C02 and /or H + on the regulatory mechanism for ventilatory pattern were discussed.

Cellular mechanisms involved in CO2 and acid signaling in chemosensitive neurons

“…Indeed, the ventilatory response to hypercapnia is slowed in the presence of the CA inhibitor acetazolamide (67,360). However, in other studies respiratory drive was either decreased (7) or increased (67,68,359,402) by CA inhibitors.…”

Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression

“…Depending on blood flow-metabolism ratios the normal venous (and/or tissue)-arterial PCO 2 gradient can rise with total inhibition from 0.5-0.7 kPa (4-5 mmHg) to over 6.7 kPa (50 mmHg) [4,16,18]. In the brain, CO 2 retention in the vicinity of the central chemoreceptors will stimulate ventilation [19,20] enough to lower the Pa,CO 2 below normal and blunt the degree of tissue CO 2 retention. Red cell and tissue CA inhibition leads to a unique acidbase status in which arterial blood gases may not reflect the true systemic (tissue) acidotic situation.…”

“…In the brain, central chemoreceptor CA inhibition slows by 50% the rate of rise of ventilation to a hypercapnic challenge [19,20] by delaying the speed at which a new elevated PCO 2 reduces pH in the vicinity of the chemoreceptors. Although local chemoreceptor CA inhibition may also reduce baseline ventilation [25], this is rarely seen in vivo because any direct depression is overridden by the powerful opposing stimulant action of local retention of CO 2 from red cell and brain tissue CA inhibition [19,20,26] and the metabolic acidosis from renal CA inhibition.…”

“…Although local chemoreceptor CA inhibition may also reduce baseline ventilation [25], this is rarely seen in vivo because any direct depression is overridden by the powerful opposing stimulant action of local retention of CO 2 from red cell and brain tissue CA inhibition [19,20,26] and the metabolic acidosis from renal CA inhibition. With respect to the peripheral chemoreceptors, the findings are somewhat analogous.…”

Acetazolamide on the ventral medulla of the cat increases phrenic output and delays the ventilatory response to CO2.

“…The third objective was to determine whether localized inhibition of carbonic anhydrase in the RVLM would decrease the phrenic response to steady-state and step changes in CO2. Functional studies, which show that intravenous acetazolamide attenuates centrally mediated changes in ventilation in response to transient changes in CO2, indicate that carbonic anhydrase may play a role in the response of central chemoreceptors to transient changes in CO2 (Hanson, Nye & Torrance, 1981 a;Tojima, Kuriyama & Fukuda, 1988). Carbonic anhydrase has been localized to cells in the ventrolateral medulla (Ridderstrale & Hanson, 1985), in regions known to possess chemosensitivity (Schlaefke, See, Loescheke, 1970).…”