Comparison of peripheral and central nervous system sympatholytic actions of prazosin using the cat nictitating membrane.

Prazosin is a highly selective alpha 1-adrenoceptor antagonist that decreases blood pressure by actions on both the peripheral and central (CNS) divisions of the nervous system. The present investigation was undertaken in an attempt to characterize the relative contribution of these two sympatholytic sites of action. Submaximal contractions of the nictitating membranes were evoked by electrical stimulation of the preganglionic cervical sympathetic nerve trunk and by stimulation of the posterior hypothalamus in anesthetized cats. In initial control experiments, phenoxybenzamine (0.1-3.0 mg/kg i.v.) produced an equivalent depression of evoked nictitating membrane responses from both peripheral and CNS sites of activation which suggests only a peripheral blocking action as well as functional equivalence of the intensity of CNS and peripheral nerve stimulation. In contrast, prazosin (3-300 micrograms/kg i.v.) caused a differential dose-related depression of the evoked responses with ED50s of 81.5 micrograms/kg (peripheral stimulation) and 12.5 micrograms/kg (CNS stimulation) respectively; P less than 0.05. Pretreatment with rauwolscine (500 micrograms/kg i.v.) totally prevented the differential CNS sympatho-inhibition produced by prazosin. These results indicate that, although both CNS and peripheral sites of drug action are manifest, the ED50 for prazosin-induced CNS sympatho-inhibition is approximately 6-fold less than that required for direct alpha 1-adrenoceptor blockade at the end organ. In addition, prazosin produces CNS sympatho-inhibition indirectly by means of an alpha 2-adrenoceptor mechanism.

Laser-induced glaucoma in rabbits.

Argon laser energy was applied to the trabecular meshwork of pigmented rabbits in an attempt to develop an animal model of 'glaucoma'. Laser energy was varied to determine the optimal level needed to produce sustained ocular hypertension. An initial response of ocular hypertension followed by hypotension was observed in all of the animals tested. Approximately half of the laser-treated rabbits developed a secondary buphthalmus and sustained ocular hypertension. In these animals outflow facility was decreased by approximately 60%. Histologic examination at 4- and 8 weeks after laser treatment demonstrated a wound-healing response resulting in closure of the intertrabecular spaces and obstruction of outflow to injected carbon particles. Optic nerve cupping and a loss of ganglion cells were also observed. Topical application of L-timolol (0.5%), pilocarpine (2.0%) and forskolin (1.0%) were found to be effective in decreasing intraocular pressure in the laser-treated, hypertensive eye with no significant effect in control non-laser-treated eyes, suggesting that this model can be a useful tool for screening potential antiglaucoma medications.

Analysis of CNS sympatho-inhibition produced by guanabenz.

The effects of guanabenz on several autonomic systems were observed in vagotomized, anesthetized cats with the aim of determining, in a quantitative sense, the degree to which guanabenz produces a clonidine-like central nervous system action. Guanabenz given as a single dose (50 micrograms/kg i.v.) produced a transient hypertension associated with a more sustained bradycardia and depression of centrally (hypothalamic) evoked electrodermal responses (EDR). Increasing cumulative doses of guanabenz (3-1000 micrograms/kg i.v.) also resulted in a dose-related depression of EDR amplitude, transient hypertension followed by hypotension, sustained bradycardia, and mydriasis. All responses were antagonized by pretreatment with yohimbine (0.5 mg/kg i.v.). The ED50 for depression of the centrally evoked EDR was in the range of 50-100 micrograms/kg i.v. in the non-pretreated preparations. Guanabenz (100 micrograms/kg i.v.) was shown to be devoid of significant ganglionic blocking properties. These experiments suggest that guanabenz acts like clonidine in the CNS and that an alpha 2-adrenergic inhibitory mechanism is involved in its myriad of central autonomic effects.

Effect of clonidine and chlorpromazine on centrally evoked electrodermal responses and their interaction with yohimbine.

Both clonidine and chlorpromazine reduced the amplitude of electrodermal responses (EDR) evoked by stimulation of the hypothalamus at a constant submaximal frequency (10-16 Hz). The ED50 for clonidine was approximately 5 mug/kg and that for chlorpromazine was about 1 mg/kg. Yohimbine pretreatment (0.5 mg/kg, i.v.) antagonized the effects of clonidine but did not alter the effectiveness of clorpromazine in inhibiting these responses. Yohimbine alone was without effect on these sympathetic-cholinergic responses. These results suggest that clonidine and chlorpromazine deress central sympathetic reactivity by different mechanisms.

Studies on the site of action of clonidine utilizing a sympathetic-cholinergic system.

Clonidine (30 mug/kg, i.v.) reduced centrally evoked electrodermal responses (EDR) following stimulation of reactive loci in the hypothalamus and medulla. The responses were most depressed following low frequency stimulation. Similar results were observed on the EDR evoked by stimulation of the cervical cord in the spinal cat. Little effect was seen following peripheral nerve stimulation. These results demonstrate that clonidine depresses the reactivity of this sympathetic-cholinergic system at all central levels including the cervical cord.

The electrodermal response as a model for central sympathetic reactivity: the action of clonidine.

Electrodermal responses (EDR) were evoked centrally by stimulation of reactive loci in the posterior hypothalamus and peripherally by stimulation of the distal portion of the sectioned median or ulnar nerve. Moderate doses of clonidine (3-30 mug/kg, i.v.) reduced the amplitude of the centrally evoked EDR while having no effect on the peripherally evoked responses. This central action of clonidine occurred concomitantly with the clonidine-induced bradycardia and hypotension. Administration of clonidine shifted the centrally evoked EDR frequency-response curve to the right in a dose related manner at 3, 10 and 30 mu/kg, i.v. 1 mug/kg was without effect on these responses. This central depressant action of clonidine was partially reversed following administration of yohimbine (0.5-1.0 mug/kg, i.v.). These results suggest that clonidine inhibits central reactivity in this sympathetic-cholinergic system in a manner analogous to its action on other sympathetic systems, and that a central adrenergic inhibitory mechanism may be involved.

Brainstem loci for activation of electrodermal response in the cat.

Brainstem loci from which electrodermal responses could be elicited were systematically explored by direct-stimulation techniques in chloralose-anesthetized and decerebrate cats. Reactive sites of the greatest amplitude were found to extend from the rostral border of the posterior hypothalamus, through the ventrolateral reticular formation of the pons and the medulla, to the cervical cord. Stimulation of these sites elicited stable, reproducible electrodermal responses of 10-30 mV in amplitude. In addition, it was found that stimulation of the ventrolateral extent of the lower brainstem evoked similar responses in the decerebrate preparation. Electrodermal responses could not be elicited from the dorsal medulla, the posterior commissure, or the midline region. The electrodermal response could be elicited from an apparently hypothalamus through the ventrolateral brainstem.