Timolol plus acetazolamide: effect on formation of cerebrospinal fluid in cats and rats

Abstract

Administration iv of 50 mg X kg-1 acetazolamide (A) and 3 mg X kg-1 timolol (T) causes the formation of cerebrospinal fluid (f-CSF) to be reduced to 43.7% of the control rate compared with a reduction to 82.5% of control by T alone and to 52.6% of control by A alone. The effect of combined drugs is the same when A is combined with T initially, when A is added to T after studying T alone, or when T is added to A after studying A alone. In contrast, in rats f-CSF is not influenced by T, either alone or when in combination with A. The rate in rats is reduced to 55% of control by treatments with A or A and T. Decrease in formation of cerebrospinal fluid by A occurs through inhibition of carbonic anhydrase, but the means whereby T (a known blocker of beta-adrenergic receptors) causes a reduction in f-CSF is not established; it is known that it does not inhibit carbonic anhydrase. Control of f-CSF by the sympathetic nervous system is discussed.

Acetazolamide Mitigates Intracranial Pressure Spikes Without Affecting Functional Outcome After Experimental Hemorrhagic Stroke

“…The ability of acetazolamide to reduce CSF formation and ICP is well-documented across species [11, 12, 21, 22, 27]. Recently, a single, very large dose of acetazolamide (~ 800 mg/kg, ~ two to three times the scaled maximum daily dose recommended in humans [24, 33]) was shown to reduce ICP by as much as 85% for about 5 h in uninjured anesthetized rats [40].…”

“…Acetazolamide (Sigma, Oakville, ON; 50 mg/kg (~ 0.5 mL total volume) IP in 15% DMSO in saline, pH adjusted to 9 with NaOH to increase solubility [21], 2 mL/kg) or vehicle was given beginning 3 h after ICH. This dose of acetazolamide reduces CSF production to ~ 55% in Sprague-Dawley rats [11, 12] and is similarly effective in other species [11, 22]. This appears to be the maximal effect due to the presence of a subset of acetazolamide-insensitive carbonic anhydrases [23].…”

“…One possible method to safely reduce the total volume of intracranial contents is by diminishing cerebrospinal fluid (CSF) volume. Here, we tested whether the FDA-approved carbonic anhydrase inhibitor acetazolamide, well-known to decrease CSF production by altering bicarbonate transport in choroid plexus [11, 12], would attenuate ICP elevations after collagenase-induced ICH. This ICH model significantly raises ICP for at least several days [7, 13], whereas the other common ICH model, whole blood infusion, only modestly (30-min peak ICP < 15 mmHg) and transiently (~ 24 h) raises ICP [14].…”

Choroid plexus and the blood–cerebrospinal fluid barrier in disease

“…CSF secretion is influenced by the action of the autonomic nervous system. The capillaries and cuboidal epithelial cells are innervated by adrenergic nerve fibers arising from the superior cervical ganglia [46,47]. In addition, CP capillaries and cuboidal epithelial cells are also innervated by parasympathetic nerve fibers probably related to the glossopharyngeal and vagus nerves [48,49].…”

Development and functions of the choroid plexus–cerebrospinal fluid system

“…Finally, the anterior and posterior inferior cerebellar arteries, which originate from the basilar and vertebral arteries, supply the hindbrain ChP 1 . Blood flow and CSF secretion are thought to be regulated in part by sympathetic and parasympathetic innervation 1, 30–32 . Unlike the endothelium in the brain’s parenchyma, capillaries of the ChP are fenestrated.…”