Medroxyprogesterone acetate with acetazolamide stimulates breathing in cats

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Abstract

Both medroxyprogesterone acetate (MPA) and acetazolamide (ACET) increase ventilation. Combined administration of these agents could result in an additional improvement of blood gases, for example in patients with chronic obstructive pulmonary diseases. The aim of this study in anaesthetized female (ovariohysterectomized, pre-treated with 17-β-estradiol) cats was to compare the effects on the CO2 response curve of MPA alone (4 μg kg−1, i.v.) with those after MPA followed by ACET (4 mg kg−1 i.v.). We performed dynamic end-tidal CO2 forcing and analysed the data with a two-compartment model comprising a fast peripheral and slow central compartment, characterized by CO2 sensitivities (Sp and Sc, respectively) and a single offset (the apnoeic threshold B). MPA reduced Sp from 0.22±0.09 (mean±S.D.) to 0.13±0.06 L min−1 kPa−1 (P<0.01) and Sc from 1.01±0.38 to 0.88±0.32 L min−1 kPa−1 (P<0.01). B decreased from 4.02±0.27 to 3.64±0.42 kPa (P<0.01). Subsequent administration of ACET reduced Sp and Sc further to 0.09±0.06 and to 0.70±0.49 L min−1 kPa−1 (P<0.01), respectively. The apnoeic threshold decreased further to 2.46±1.50 kPa (P<0.01). Because both treatments reduced ventilatory CO2 sensitivity, we conclude that a simulating effect on ventilation is due to a decrease in the apnoeic threshold. Combined administration of MPA and ACET may lead to larger increases in ventilation than treatment with either drugs alone.

Introduction

During human pregnancy and the luteal phase of the menstrual cycle ventilation is increased, for which the high plasma level of progesterone may be responsible (for review see Dempsey et al., 1988). Progesterone, or the synthetic progesterones medroxyprogesterone acetate (MPA) and chlormadinone acetate are sometimes used in hypoxic and hypercapnic patients with severe chronic obstructive pulmonary disease to stimulate ventilation and improve blood gas values (Skatrud et al., 1978, Skatrud and Dempsey, 1983, Vos et al., 1994).

In man, progesterone may increase ventilation by an effect on the hypothalamus and/or structures in the medulla oblongata (e.g. Skatrud et al., 1978, Zwillich et al., 1978, Dolly and Block, 1983, Pfaff and McEwen, 1983, Dempsey et al., 1988). A possible action on the peripheral chemoreceptors is indicated by the finding that during human pregnancy the hypoxic ventilatory response is increased (Moore et al., 1987). Progesterone may also influence the tone of upper airway muscles: in patients with obstructive sleep apnea, MPA was found to reduce the frequency of upper airway obstructions (Hensley et al., 1980, Popovic and White, 1998).

Data from animal studies also indicate that progesterone may stimulate breathing by an effect on peripheral and/or central sites (Bayliss et al., 1990, Bayliss et al., 1991, Favier et al., 1997). Guinea pigs, dogs and cats but not rats, goats, ponies and cows respond with an increased hypercapnic ventilatory response to progesterone administration (see Dempsey et al., 1988). Failure to show this response may be related to species or gender, or may be due to specific experimental circumstances such as level of arousal, pre-treatment with estradiol and dose (Brodeur et al., 1986, Dempsey et al., 1988, Tatsumi et al., 1991). An increase in hypoxic sensitivity by progesterone was reported in cat and rat (Hannhart et al., 1989, Favier et al., 1997).

A second agent used to improve blood gases in some hypercapnic and hypoxic patients with chronic obstructive pulmonary disease is the carbonic anhydrase inhibitor acetazolamide (ACET) (e.g. Skatrud and Dempsey, 1983, Vos et al., 1994). It is generally believed that this beneficial effect of ACET is due to a metabolic acidosis-induced increase in ventilatory drive. However, since carbonic anhydrase is present in many tissues and cells involved in the control of breathing, the respiratory effects of ACET may be much more complicated. For example, in a previous study in anaesthetized cats we showed that low-dose ACET (4 mg kg−1) causes a decrease in both the slope and X-intercept of the CO2 response curve (Wagenaar et al., 1996). A large dose of the agent (50 mg kg−1) totally abolishes the hypoxic ventilatory response (Teppema et al., 1988, Teppema et al., 1992).

Although MPA and ACET may act via different mechanisms, it is possible that (part of) their respiratory effects are due to an action on common structures, for example carotid bodies. It would be interesting, therefore, to compare the effects of a combined application with those of single treatments, and this was the aim of this study. In ovariohysterectomized, lightly anaesthetized female cats pre-treated with estradiol, we measured the effects of MPA and those of a subsequent administration of acetazolamide on the slope and intercept of the CO2 response curve. This enabled us to compare the effects of combined MPA+ACET administration with those of a single treatment with ACET as documented in a previous study (Wagenaar et al., 1996). To be able to separate the effects of MPA and ACET on the peripheral and central chemoreflex loops, we applied the dynamic end-tidal forcing technique and analysed the ventilatory data with a two-compartment model, comprising a fast peripheral and slow central component (De Goede et al., 1985).

Section snippets

Animals, surgery and measurements

The present experiments were performed in eight female cats (body weight 3.4–4.1 kg). The use of the animals was approved by the Ethical Committee for Animal Experiments of the Leiden University Medical Center.

An ovariohysterectomy was performed at least 1 month prior to the experiments. The animals were pre-medicated with 10 μg kg−1 17-β-estradiol (E2) (Sigma-Aldrich, Bornem, Belgium), dissolved in sesame oil (100 μg ml−1), twice daily subcutaneously during 3 days immediately prior to the

Results

One month after ovariohysterectomy in seven of eight cats, the mean plasma concentration of (E2) was 6.92±1.7 pg ml−1 (see also Hannhart et al., 1989). After E2-priming, the E2 concentration in these cats increased to a mean of 567.2±396.4 pg ml−1 (in one animal, E2 concentrations were not determined). Thirty-seven DEF runs were performed during the control situation, 33 after MPA administration and 24 after additional infusion of ACET. In Fig. 1 examples of three DEF-runs in one animal are

Discussion

In this study we found that in ovariohysterectomized cats pre-treated with 17-β-estradiol, 4 μg kg−1 MPA decreased the CO2-sensitivities of the peripheral (Sp) and central chemoreflex (Sc) loops with 41 and 13%, respectively. A subsequent administration of 4 mg kg−1 ACET caused a further reduction in carbon dioxide sensitivities (Sp 31% and Sc 20%). Both agents lowered the mean apneic threshold by 0.38 and 1.18 kPa, respectively.

Acknowledgements

We thank T.H. Arts (University of Nijmegen, Animal house) for performing the ovariohysterectomies in the cats, T.H. Blankenstein and Dr S.J. Dieleman (Univ Utrecht, Department of Herd Health and Reproduction) for determining the plasma levels of estrogen. This study was supported by a research grant from The Netherlands Astma Foundation.

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