Characterization of alpha-adrenoceptors in the nucleus reticularis gigantocellularis involved in the cardiovascular depressant effects of guanabenz in the rat.

The participation of alpha-adrenoceptors in the nucleus reticularis gigantocellularis in the hypotensive, negative inotropic and chronotropic effects induced by guanabenz, was examined in rats anesthetized with pentobarbital sodium (40 mg/kg, i.p.). Pretreatment with alpha-adrenoceptor antagonists yohimbine (10 micrograms), phentolamine (2.5 micrograms) and phenoxybenzamine (20 micrograms), which were injected bilaterally into the nucleus reticularis gigantocellularis, significantly antagonized the cardiovascular suppressant effects normally produced by systemic administration of guanabenz (10 micrograms/kg, i.v.). Pretreatment with prazosin (0.25 microgram) did not affect the vasodepressive, but significantly attenuated the bradycardic actions of guanabenz. The general trend of "antagonization potency" shown by the alpha-adrenergic blockers, against the cardiovascular effects of guanabenz, was in the order: yohimbine greater than phentolamine greater than phenoxybenzamine greater than prazosin. It is concluded that while the alpha 2-adrenoceptors in the nucleus reticularis gigantocellularis are more critically involved in the antihypertensive actions of guanabenz, the possibility exists that alpha 1-adrenoceptors may also participate, in part.

Participation of nucleus reticularis gigantocellularis in guanabenz-promoted hypotension, decrease in cardiac contractility and bradycardia in rats.

The possible participation of the nucleus reticularis gigantocellularis in the hypotension, decrease in cardiac contractility and bradycardia induced by guanabenz was examined in rats that were anesthetized with pentobarbital sodium (40 mg/kg, i.p.). Guanabenz (10 micrograms/kg, i.v.) elicited an initial, transient hypertension, accompanied by an increase in cardiac contractility, followed by a significant and sustained hypotension, as well as decrease in the force and rate of cardiac contraction. In rats receiving bilateral focal electrolytic lesions of the nucleus reticularis gigantocellularis, the same injection produced only the initial transient responses, without the subsequent depressant effects. Microinjection of guanabenz directly into the ventro-medial portion of the nucleus reticularis gigantocellularis, at an ineffective systemic concentration (500 ng), produced significant and prolonged reduction in arterial pressure, cardiac contractility and heart rhythm. On the other hand, local application of the same concentration (500 ng) of guanabenz into the lateral portion of the same nucleus produced only minor hypotension and bradycardia, with no decrease in cardiac contractility. It is concluded that the nucleus reticularis gigantocellularis is at least one of the central sites through which guanabenz may produce its cardiovascular suppressant effects.

Pulmonary edema as a cause for fulminant death following microinjection of kainic acid into the rat medulla oblongata.

The present study confirmed histopathologically the suggestion that pulmonary edema may underlie the fulminant death following microinjection of kainic acid into many medullary sites in rats anesthetized with pentobarbital sodium. We also observed a sustained elevation in systemic arterial pressure, cardiac contractility and heart rate before the animal succumbed to kainate neurotoxicity. It is suggested that the increased systemic hydrostatic pressure may retrogradely promote pulmonary hypertension that precipitates pulmonary edema.

Concomitant hypotensive and antinociceptive effects of guanabenz in conscious rats: involvement of nucleus reticularis gigantocellularis.

Subcutaneous administration of guanabenz (1, 2, 5, or 8 mg/kg) in conscious Sprague-Dawley rats exerted concomitant suppressive actions on systolic pressure (tail-cuff sphygmomanometric measurement) and pain responses (hot-plate algesio-metric assay) that varied both in degree (antinociception much greater than hypotension) and response pattern. Furthermore, both depressive effects were appreciably attenuated by bilateral lesions of the nucleus reticularis gigantocellularis in the medulla oblongata. It is speculated that separate subpopulations of neurons within this reticular nucleus may be involved in the expression of hypotension and antinociception by this amino-guanidine derivative.