α-Adrenoceptor subclassification

Presynaptic α-autoreceptors

CATECHOLAMINES modulate a host of diverse responses in man. These responses are initiated by the interaction of catecholamines with discrete sites located on the plasma membrane of cells. Adrenergic receptors, like other hormone receptors, are responsible for the selective recognition and binding of specific molecular structures, in this case catecholamines such as epinephrine and related drugs. The demarcation between alpha-adrenergic and beta-adrenergic receptors has long been appreciated,1 as has the existence of beta-adrenergic receptor subtypes (beta1 and beta2).2 Recent advances in the understanding of alpha-adrenergic receptors have led to the appreciation of the existence of subtypes of . . .

Alpha-Adrenergic Receptor Subtypes

Effects on noradrenergic neurotransmission of five stereoisomers of yohimbine and of the closely related compound yohimbol were studied in strips of the pulmonary artery of the rabbit. In some experiments the tissue was preincubated with 3H-noradrenaline. Three effects were observed. Firstly, antagonism to the contractile effect of noradrenaline and of sympathetic nerve stimulation; the antagonism reflected competitive blockade of postsynaptic α-adrenoceptors. Secondly, an increase in the stimulation-evoked overflow of total tritium and 3H-noradrenaline; the increase appeared to be due to blockade of presynaptic α-adrenoceptors. Thirdly, an increase in the basal outflow of 3H-3,4-dihydrophenylglycol, presumably by impairment of the vesicular storage of 3H-noradrenaline. According to their relative potencies in eliciting these effects, the drugs could be divided into three groups. Rauwolscine, β-yohimbine and yohimbol preferentially blocked the presynaptic α-adrenoceptor; rauwolscine and β-yohimbine, like yohimbine, at low concentrations increased the contractile response to sympathetic nerve stimulation. Corynanthine preferentially blocked the postsynaptic α-adrenoceptor. Pseudoyohimbine and 3-epi-α-yohimbine were very weak antagonists at either receptor; they mainly accelerated the basal outflow of 3H-3,4-dihydroxyphenylglycol. From these results and those of a previous study it is concluded that, in a series of twelve α-adrenolytic drugs, rauwolscine shows the greatest preference for presynaptic and corynanthine the greatest preference for postsynaptic α-adrenoceptors. In view of the chemical similarity of the two compounds these opposite properties are striking. Corynanthine and rauwolscine might be useful tools for the subclassification of α-adrenoceptors.

Pre- and postsynaptic effects of yohimbine stereoisomers on noradrenergic transmission in the pulmonary artery of the rabbit.

Background: Older individuals experience physiologic changes in organ function related to aging or to specific disease processes. These changes can affect drug pharmacodynamics in older adults. Objective: The goal of this article was to review age-related changes in pharmacodynamics and their clinical relevance. Methods: PubMed and International Pharmaceutical Abstracts were searched (January 1980-June 2006) for the following combination of terms: pharmacodynamic and elderly, geriatric or aged. References cited in other reviews were also evaluated. The current review focused on age-related pharmacodynamic changes in agents affecting the central nervous system (CNS), cardiovascular, and endocrine functions. Results: Older adults frequently demonstrate an exaggerated response to CNS-active drugs. This is in part due to an underlying age-related decline in CNS function and in part due to increased pharmacodynamic sensitivity for some benzodiazepines, anesthetics, and opioids. The most important pharmacodynamic differences with age for cardiovascular agents are the decrease in effect for J3-adrenergic agents. This decline in response in vascular, cardiac, and pulmonary tissue may be due to a decrease in Gs protein interactions. Most studies indicate there is no decrease in cx-receptor sensitivity with age. Angiotensin-converting enzyme inhibitors do not show age-related differences in elderly patients. With the dihydropyridine calcium channel blockers, there was a slight increase in effect for older adults, but this was only for treatment-naive patients and was transient. Nondihydropyridines did not show an age- associated change in pharmacodynamic effect; however, in the elderly, there appeared to be a decrease in the PR interval prolongation normally seen with these agents. Studies of diuretics indicated that the changes in diuretic and natriuretic effects seen in the elderly were associated with pharmacokinetic changes and were not pharmacody- namic in nature. There was a lack of consistent evidence regarding whether sulfonylureas show age-related changes in pharmacodynamic effect. Conclusions: There is a general trend of greater pharmacodynamic sensitivity in the elderly; however, this is not universal, and these age-related changes must be investigated agent-by-agent until further research yields greater understanding of the molecular mechanisms underlying the aging process.

Pharmacodynamics in older adults: a review.

α2- and α2-vasular adrenoceptors in the dog

Prazosin and presynaptic alpha-receptors in the cardioaccelerator nerve of the dog

Trimazosin is a quinazoline antihypertensive agent structurally related to the selective alpha 1-adrenoceptor blocker prazosin. Trimazosin has been shown previously to have less affinity for alpha 1-adrenoceptors than prazosin. In the present study we compared the hypotensive potency and efficacy of the two agents, and their effects on pressor responses to phenylephrine in anesthetized dogs. We also determined the effect of trimazosin administered during a maximum hypotensive response to prazosin, and of sodium nitroprusside administered after trimazosin or prazosin. Compared with prazosin, trimazosin was a less potent but more efficacious hypotensive agent. At doses which caused equal or even greater hypotensive effects than those caused by prazosin, trimazosin caused less inhibition of pressor responses to phenylephrine. When administered during a maximum hypotensive response to prazosin, trimazosin caused an additional fall in pressure. These results clearly demonstrate an additional action of trimazosin beyond blockade of alpha 1-adrenoceptors. Both trimazosin and prazosin augmented the hypotensive effect of sodium nitroprusside, but only trimazosin enhanced its relaxant effect on isolated rat aorta. Thus we conclude that in addition to alpha 1-adrenoceptor blockade, another mechanism contributes to the hypotensive effect of trimazosin, and we speculate that elevation of cyclic GMP levels in vascular smooth muscle may be related to this additional mechanism.

The hypotensive effect of trimazosin is not caused solely by alpha 1-adrenoceptor blockade.

Effects of trimazosin and prazosin on blood pressure and on pressor responses to phenylephrine in rats.

Blockade of central alpha 2-adrenoceptors enhances the carotid occlusion response in dogs.

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