Ronald D. Robson

Antagonism by mianserin and classical α-adrenoceptor blocking drugs of some cardiovascular and behavioral effects of clonidine

Antagonism of pressor responses to sympathetic outflow stimulation and alpha-adrenoceptor agonists in pithed spontaneously hypertensive rats was used to estimate postsynaptic alpha-adrenoceptor blocking activity of mianserin, phentolamine, phenoxybenzamine, piperoxan and yohimbine. Estimation of presynaptic alpha-adrenoceptor blocking activity of these drugs was obtained by studying their ability to antagonize clonidine-induced suppression of positive chronotropic responses to sympathetic outflow stimulation. In this manner, evidence was obtained that mianserin causes selective presynaptic alpha-adrenoceptor blockade. Mianserin, piperoxan and yohimbine antagonized clonidine-induced avoidance blockade or hypotension in spontaneously hypertensive rats, but methysergide, phenoxybenzamine and phentolamine were ineffective. These results suggest that mianserin may antagonize the central effects of clonidine by blockade of noradrenergic presynaptic or autoreceptors and possibly explain the antidepressant effect of mianserin as due to indirect activation of central noradrenergic neurons.

Evidence for increased vagal tone and enhancement of baroreceptor reflex activity after xylazine (2-(2,6-dimethylphenylamino)-4-H-5,6-dihydro-1,3-thiazine) in anesthetized dogs

Abstract After an initial pressor response, xylazine (0.3 mg/kg, i.v.) caused a decrease in blood pressure, heart rate, responses to bilateral carotid artery occlusion in vagotomized and non-vagotomized dogs. Reflex bradycardia in response to norepinephrine was greater than control in non-vagotomized dogs even though the pressor effects were unchanged and heart rates were lower after drug. Responses to cardiac nerve stimulation were inhibited in non-vagotomized but not in vagotomized dogs after xylazine. The inhibition was abolished by subsequent vagotomy. These results suggest that xylazine causes an increase in vagal and baroreceptor activity which is probably centrally induced.

Dopaminergic mediation of the diuretic and natriuretic effects of ANF in the rat

Atrial natriuretic factor (ANF) increases sodium (Na+) and water excretion 8-10 fold on repeated administration to anesthetized rats. SCH-23390 (80 micrograms/kg i.v.) and R-sulpiride (80 micrograms/kg i.v.), selective antagonists of dopamine receptors in the renal vasculature, inhibited diuresis and natriuresis induced by AP III and dopamine. These findings suggest that ANF exerts its effects on renal Na+ and water handling via a dopaminergic mechanism; however, changes in intrarenal hemodynamics secondary to dopamine receptor blockade may attenuate the actions of ANF.

Oxaprotiline: Induction of central noradrenergic subsensitivity by its (+)-enantiomer

The effects of the tetracyclic antidepressant oxaprotiline and its two optically active enantiomers on the norepinephrine (NE) receptor coupled adenylate cyclase system were determined in slices of the rat cerebral cortex. While oxaprotiline does not change the response of the cyclic AMP generating system to NE after a single dose, chronic administration of the drug for 3 to 14 days down-regulates the receptor system. The noradrenergic subsensitivity is linked to a reduction in the Bmax value of beta-adrenergic receptors as assessed by (3H)-dihydroalprenolol binding without changes in the Kd value. The action of oxaprotiline on the NE receptor coupled adenylate cyclase system resides entirely in the (+)-enantiomer which is a potent inhibitor of the neuronal uptake of NE. The (-)-enantiomer of oxaprotiline which is a weak inhibitor of NE reuptake, failed, even in high doses, to modify the noradrenergic receptor system. Though not excluding co-regulatory factors in addition to NE, the studies support the view that an enhanced and persistent NE receptor interaction is one of the prerequisites for the in vivo down-regulation of central noradrenergic receptor function. The results also suggest that the therapeutic activity of oxaprotiline may reside in its (+)-enantiomer.

Effect of clonidine on responses to cardiac nerve stimulation as a function of impulse frequency and stimulus duration in vagotomized dogs

Abstract Using optimum voltage and variable periods of right cardiac nerve stimulation in vagotomized dogs, clonidine (30 μ/kg i.v.) reliably inhibited the tachycardia to 0.3 and 1 Hz, but antagonized only responses to brief periods of stimulation at impulse frequencies of 3 and 10 Hz. Clonidine extended the stimulus duration necessary to cause maximum tachycardia, particularly at the lower frequencies, and did not significantly depress the magnitude of response except at 0.3 Hz. The effect of clonidine on stimulus duration, which was apparently due to α-adrenoceptor activation since it was prevented by phentolamine, was not obtained with guanethidine (0.9 mg/kg i.v.), which caused good inhibition of the maximum tachycardia attainable at all selected frequencies.

Modification by antihypertensive drugs of reflex circulatory responses induced by vertical tilting or bilateral carotid occlusion

Abstract Bilateral carotid artery occlusion (BCO) caused a significant increase in blood pressure and heart rate in Dialurethane anesthetized dogs, while vertical tilting caused an increase in heart rate with no significant change in blood pressure. Mecamylamine, bretylium, bethanidine and dibenamine (each at 10 mg/kg, i.v.) markedly reduced the positive chronotropic effects of both BCO and vertical tilting, reduced the pressor response to BCO and resulted in an inability to maintain blood pressure when the dogs were tilted to a vertical position. Hydralazine decreased blood pressure at 0.5 and 1.0 mg/kg, i.v., but only the higher dose caused severe inhibition of the tilt reflex. Bethanidine or guanethidine given chronically produced a biphasic response to tilting, first a decrease in blood pressure then an overshoot above control levels, while responses to BCO were minimally depressed. Clonidine given either acutely or chronically had no effect on the responses to tilting but inhibited those to BCO. Reserpine in small doses given chronically also selectively depressed the carotid occlusion reflex. Oral doses of drug given chronically were selected to cause essentially equal reductions on blood pressure of renal hypertensive dogs. Thus, a high incidence of clinical orthostatic hypotension appears associated with those antihypertensive agents which depress reflex changes induced by both procedures, whereas unimportant postural circulatory changes may be anticipated for drugs which selectively depress the carotid occlusion reflex.

CGS 7525A, A new, centrally active alpha2 adrenoceptor antagonist

CGS 7525A, a new tetracyclic compound, was evaluated for alpha 2 adrenoceptor antagonism in receptor binding assays and in behavioral and electrophysiological tests. 3H-Clonidine, but not 3H-prazosin, binding was potently inhibited in vitro by CGS 7525A. In vivo, CGS 7525A attenuated the suppressant action of clonidine on phenylquinone-induced writhing and on locus coeruleus neuronal firing rate. Mianserin was nearly equipotent with CGS 7525A in the 3H-clonidine binding assay, but considerably less potent in the measures of alpha 2 adrenoceptor antagonism in vivo. Both CGS 7525A and mianserin displaced 3H-spiroperidol binding from frontal cortex 5-HT2 binding sites. Although yohimbine resembled CGS 7525A in most respects, its activity at 5-HT2 binding sites was relatively low, CGS 7525A was not associated with any appreciable blockade of norepinephrine or serotonin uptake in vitro. Thus, CGS 7525A appears to be a promising new pharmacological tool for investigating the behavioral function of brain alpha 2 adrenoceptors.

Effects of clonidine on baroreceptor function in anesthetized dogs

The effects of clonidine (15-30 mug/kg i.v.) on carotid sinus and other baroreceptors were investigated in anesthetized dogs. In 14 control dogs, right carotid sinus pressure was controlled by retrograde perfusion through the common carotid artery at constant flow with femoral arterial blood. Graded reductions in heart rate and blood pressure induced by graded increases in carotid sinus pressure were prevented, whereas reflex bradycardias associated with norepinephrine pressor activity were potentiated by clonidine. Norepinephrine-induced bradycardia, although reduced, still persisted after chronic bilateral sinusectomy and these responses were also potentiated by clonidine. In contrast, clonidine did not potentiate reflex bradycardia in dogs 20 days after aortic stripping. In intact dogs, clonidine inhibited the response to bilateral carotid artery occlusion and to carotid sinus nerve stimulation. These studies suggest that clonidine can inhibit carotid sinus baroreceptor function and simultaneously potentiate other, presumably aortic, baroreceptor activity.

Pharmacological alterations of vagally induced tachycardia in anesthetized dogs

Abstract Frequency-dependent tachycardia was obtained during vagal stimulation in anesnthetized, atropine-treated (1 mg/kg, i.v.) dogs. Vagally induced tachycardia was enhanced in both magnitude and duration by desipramine, whereas the magntide of tachycardia in response to cardioaccelerator nerve stimulation was not markedly enhanced. Vagal tachycardia was not inhibited by guanethidine (1 mg/kg, i.v.) but was markedly reduced after ganglion blockade by chlorisondamine (2 mg/kg, i.v.) or hexamethionium (10 mg/kg, i.v.). β-Receptor blockade by 1-oxprenolol (0.25 mg/kg, i.v.) totally blockade the response. Reserpine pretreatment decreased cardiac responses to sympathetic nerve stimulation to a greater degree than to vagal stimulation. From these results, it is suggested that the vagally induced tachycardia may be explained by acetylcholine (Ach)-mediated release of catecholamine from stores other than those susceptible to sympathetic nerve stimulation and these stores may reside in chromaffin tissue.

Elevated arterial cyclic AMP levels during the development of spontaneous hypertension in rats

Vascular cyclic AMP alterations were studied during the initiation of vascular hypertrophy and hyperplasia in spontaneously hypertensive rats (SHR). The onset of hypertension at 6 weeks of age coexisted with a three-fold elevation in the aortic content and concentration of cyclic AMP, whereas aortic DNA and protein contents were identical to those of WKY controls. A similar cyclic AMP elevation was present in 12-week-old SHR when vascular hypertrophy and hyperplasia were already established. These experiments suggest the participation of cyclic AMP in the process of hypertensive vascular growth.