Effects of inhibitors of enzymatic and cellular pH-regulating systems on central sympathetic chemosensitivity

Abstract

Previous studies in cats using isolated NaCl-CO2 perfusion of the lower brainstem demonstrated an intrinsic chemosensitivity of sympathoexcitatory bulbospinal neurones within the rostroventrolateral medulla (RVLM). In the present experiments, the effects of inhibitors of enzymatic and cellular systems, known to be involved in pH regulation, were investigated. Isolated perfusion of the lower brainstem with CO2-enriched solutions was performed and preganglionic sympathetic nerve activity (SNA) was recorded. Drugs were locally injected into the left RVLM with glass micropipettes. Perfusion of the RVLM with CO2-enriched solutions over a period of 15 s induced a marked increase in SNA. The magnitude of absolute changes in SNA during perfusion depended on the level of basal SNA before perfusion. Microinjections of 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and acetazolamide (ACZ) induced a marked rise in basal SNA, whereas diethylpyrocarbonate (DEPC) and ethylisopropylamiloride (EIPA) had no significant effect on basal SNA. After application of DIDS and DEPC, the peak change in SNA due to perfusion of the RVLM with CO2-enriched solutions was slightly diminished. Furthermore, neither ACZ nor EIPA produced any significant influence on the slope, peak change and time course of the increase in SNA compared with control perfusions. We conclude that the enzymatic and cellular carrier systems tested in this study are not or only slightly involved in central sympathetic chemosensitivity.

Selective inhibition of the Na + /H + exchanger type 3 activates CO 2 /H + -sensitive medullary neurones

“…As Na + -dependent Cl -/HCO 3 -seems to play a minor role in the ventrolateral medulla [23,24] either NHE3 itself or further unknown mechanisms could account for this effect. The NHE1 inhibitor EIPA also failed to induce hypercapnic-like nerve fibre activity originating from ventrolateral neurones of the cat [14]. This finding indirectly supports the role of NHE3 as one major NHE subtype within ventrolateral neurones.…”

“…In fact, regulation of pH i in VLNcs or nucleus tractus solitarius neurones differs from that of neurones within non-chemosensitive brain areas [23,24] as they do not counteract a moderate (∆pH i <0.2 units) intracellular acidosis due to hypercapnia (pCO 2 elevated to 80-100 mmHg) or withdrawal of CO 2 /HCO 3 -amiloride, but not by 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS), pointing to a major contribution of Na + /H + exchange (NHE), while (Na + -dependent) Cl -/HCO 3 -antiport appears to be less involved. Previous in vivo studies show that inhibition of NHE by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) fails to activate respiration [14], and amiloride stimulates breathing frequency only at high (>1 mol/l) concentrations [30]. However, the inhibitory properties of amiloride or EIPA strongly depend on the subtype of NHE that is expressed.…”

A Novel Inhibitor of the Na+/ H+ Exchanger Type 3 Activates the Central Respiratory CO2 Response and Lowers the Apneic Threshold

“…Microinjections of 100 M ethyl-isopropyl-amiloride (EIPA) into the ventrolateral medulla did not add to preganglionic sympathetic nerve activation elicited by hypercapnic brainstem perfusion in the cat (26). Likewise, cisternal infusion of amiloride between 10 Ϫ5 and 10 Ϫ2 M failed to change the CO 2 sensitivity of pulmonary ventilation in anesthetized rabbits (27,28).…”

Human G protein β3 subunit variant does not alter hypercarbic or hypoxic ventilatory response

“…Whilst there are some clues that NHE is not causally involved in the functioning of central chemosensitivity (König et al ., 1995), inhibition of NHE3 acidifies and activates neurones in the medulla oblongata (Wiemann et al ., 1999). However, only 50% of all subjects with essential hypertension show enhanced NHE activation (Rosskopf et al ., 1993; Siffert et al ., 1995).…”