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R R Ruffolo

Publications and source records attributed to R R Ruffolo.

At least 217 records · Page 12Linked to original sources
PubMed1981

Postsynaptic alpha adrenergic receptor subtypes differentiated by yohimbine in tissues from the rat. Existence of alpha-2 adrenergic receptors in rat aorta.

The selective alpha-2 adrenergic receptor antagonist, yohimbine, was used to differentiate postsynaptic alpha-adrenergic receptors in five peripheral tissues of the rat. Three distinct postsynaptic receptor subtypes were observed based on the affinity of the receptors for yohimbine. Receptors with high affinity for yohimbine were detected in the aorta, whereas low affinity receptors were observed in the vas deferens. The affinity for yohimbine in these two tissues differed by over 50-fold. Receptors with intermediate affinity for yohimbine were found in the portal vein, spleen and bladder. The Schild plot for yohimbine in the bladder suggests that blockade of alpha receptors in this tissue is not competitive or that there exists more than one type of alpha-adrenergic receptor present. Comparison of the dissociation constant of yohimbine in the aorta with dissociation constants obtained from the literature for this compound in a variety of tissues containing alpha-1 or alpha-2 adrenergic receptors indicates that the postsynaptic alpha adrenergic receptor in the aorta is of the alpha-2 type. Conversely, the postsynaptic alpha adrenergic receptor in the portal vein appears to be alpha-1. The differences in postsynaptic alpha appears to be alpha-1. The differences in postsynaptic alpha adrenergic receptors in these two vascular tissues may reflect the marked differences in adrenergic innervation and the possible relative lack of neuroeffector junctional alpha adrenergic receptors in the rat aorta.

Animals↗
PubMed1981

Alpha and beta adrenergic effects of the stereoisomers of dobutamine.

Dobutamine and its stereoisomers were evaluated for alpha and beta adrenergic activities in vitro. The racemate and the (--)-isomer were found to be potent partial agonists of alpha adrenergic receptors in rat aorta. The (+)-isomer lacked alpha agonist activity. The affinities of (+/-)-, (+)- and (--)-dobutamine for the alpha adrenergic receptor were high (--log KB values of 7.01, 7.02 and 7.07, respectively) and not significantly different from one another. These data indicate that (+)- and (--)- dobutamine bind equally to the alpha adrenergic receptor, however, subsequent to binding, only the (--)-isomer is capable of activating the receptor and eliciting an alpha adrenergic response. The (+)-isomer, which has the same affinity as the (--)-isomer but which lacks agonist activity, is a potent competitive alpha blocker. Both stereoisomers of dobutamine were agonists of beta adrenergic receptors of cat papillary muscle and right atria. In contrast to the alpha adrenergic effects, the more potent isomer at the beta adrenergic receptor was (+)- dobutamine. The isomeric activity ratio for the stereoisomers of dobutamine was approximately 1 log unit in favor of the (+)-isomer with respect to both inotropic and chronotropic responses. Dose-response curves to the racemate were always situated between the stereoisomers, approximately 2-fold to the right of (+)-dobutamine. These results indicate that the stereochemical requirements of alpha and beta adrenergic receptors are opposite for the stereoisomers of dobutamine with the alpha receptor favoring the (--)-isomer and the beta receptor favoring the (+)-isomer.

Animals↗
PubMed1980

Computerized graphic methods for determining dissociation constants of agonists, partial agonists, and competitive antagonists in isolated smooth muscle preparations.

Computer programs have been written that calculate dissociation constants for agonists, partial agonists, and competitive antagonists from data generated in isolated smooth muscle preparations. The data are analyzed according to standard procedures and are presented in graphical form with the aid of an inexpensive digital plotter. The digital plotter coupled with a computer markedly decreases the time required to perform these fundamental analyses and also reduces the chance for error and experimenter bias.

Animals↗
PubMed1980

Receptor interactions of imidazolines. IV. Structural requirements for alpha adrenergic receptor occupation and receptor activation by clonidine and a series of structural analogs in rat aorta.

Clonidine and a series of nine halogen and alkyl-substituted structural analogs were evaluated for alpha adrenergic receptor agonist activity in rat aorta. Phenylephrine was included for comparison. All the imidazolines were partial agonists with respect to phenylephrine due to the fact that they only weakly activated the receptor. Whereas phenylephrine requires approximately 0.2% receptor occupancy to produce a response 20% of maximum, the imidazolines required from 25 to 100% receptor occupancy to produce the same response. Although clonidine and its structural analogs are from 125 to 500 times weaker activators of the alpha adrenergic receptor than phenylephrine, they have from 2 to 60 times higher affinity for the receptor than phenylephrine. The results support our previous conclusions that a dichotomy exists between the factors that direct receptor occupation and receptor activation since the structural requirements for each of these parameters differ.

Adrenergic alpha-Agonists↗
PubMed1980

Receptor interactrions of imidazolines. VI. Significance of carbon bridge separating phenyl and imidazoline rings of tolazoline-like alpha adrenergic imidazolines.

The pharmacological significance of the carbon bridge separating the imidazoline and phenyl rings of tolazoline-like alpha adrenergic imidazolines has been investigated. Extending the carbon bridge to two carbon atoms, or deleting the carbon bridge, lowers affinity of the imidazolines for the alpha receptor and markedly decreases or abolishes efficacy (i.e., agonist activity), suggesting that a single carbon atome optimallyu separates the phenyl and imidazoline rings. Although one carbon is optimal for alpha adrenergic activity, this particular atom does not appear to be essential since nitrogen may substitute for carbon with no marked or consistent changes observed in affinity or efficacy. Hydroxylation of the carbon bridge decreases affinity for the receptor approximately 10-fold but does not alter efficacy, whereas a similar substitution made in the norepinephrine-series of phenethylamines markedly increases affinity (Patil et al., 1974). With both the imidazolines and phenethylamines, this carbon atom may stereoselectively influence binding to the receptor. These results suggest that the carbon atom bridging the phenyl and imidazoline rings of tolazoline-like imidazolines serves only to provide optimal separation between these rings and does not contribute directly to the binding process. It is proposed that alpha adrenergic imidazolines interact differently with the alpha adrenergic receptor than the norepinephrine-like phenethylamines.

Adrenergic alpha-Agonists↗
PubMed1980

Receptor interactions of imidazolines. V. clonidine differentiates postsynaptic alpha adrenergic receptor subtypes in tissues from the rat.

The alpha-adrenergic effects of clonidine were studied in five tissues of the rat. Postsynaptic alpha adrenergic receptors in these tissues may be divided into three distinct classes based on affinity of the receptors for clonidine. High affinity receptors are located in the aorta and low affinity receptors in the vas deferens. Receptors with intermediate affinity are found in the portal vein, spleen and bladder. The bladder may also contain, to a small extent, a population of receptors similar to those found in the vas deferens which may mediate a different response. Available data suggest that the alpha adrenergic receptor of the rat aorta with high affinity for clonidine may be of the alpha-2 type but located postsynaptically in this tissue.

Animals↗
PubMed1979

Kinetics of alpha-adrenoreceptor blockade by phentolamine in the normal and denervated rabbit aorta and rat vas deferens.

The rates of onset and offset of alpha-adrenoreceptor blockade by phentolamine (5 X 10(-7) M) have been studied on the normal and denervated rabbit aorta and rat vas deferens. Removal of the adventitia with its accompanying sympathetic nerve component results in an approximately threefold increase in the rate of onset of alpha-adrenoreceptor blockade by phentolamine in the rabbit aorta. The rate of offset of blockade by the antagonist on the aorta is likewise faster after the adventitia has been removed (approximately threefold faster for loss of 90% of the antagonist from the region of the receptors). This effect is not likely to be attributed to the absence of sympathetic nerve terminals since surgical denervation of the rat vas deferens has no effect on the kinetics of receptor blockade in this densely innervated organ. These data suggest that the adventitia of the rabbit aorta may serve as a diffusion barrier which limits the antagonist's access to, and efflux from, the region of the receptors. The dissociation constant of phentolamine (calculated from the equilibrium dose ratio) on the alpha-adrenoreceptor is unaltered by denervation in either tissue and is identical in both tissues. It is suggested that alpha-adrenoreceptors in the rabbit aorta and rat vas deferens are of a single type and are not significantly affected, with respect to antagonist affinity, by denervation.

Animals↗
PubMed1978

Kinetics of blockade of different receptors by chlorpromazine in rabbit stomach strips.

The kinetics of receptor blockade by chlorpromazine (5 X 10(-8) M) were studied on fundic strips from the rabbit stomach. Onset of blockade by chlorpromazine proceeds at nearly identical rates when carbamylcholine and histamine are the agonists (t1/2 = approximately 5 min) while occurring more slowly against phenylephrine (t1/2 = 41 min). Similarly, offset of blockade by chlorpromazine is faster against carbamycholine and histamine (t1/2 = 83 and 34 min, respectively) than against phenylephrine (t1/2 = 385 min). The pA2 values of chlorpromazine on the alpha-adrenergic, muscarinic and histaminic (H1) receptors are 8.96, 7.17, and 7.90, respectively. No correlation exists between the kinetics of blockade and the affinity of chlorpromazine for the receptors. It is suggested, therefore, that alpha-adrenoreceptors in the rabbit stomach are less accessible to chlorpromazine, or distributed differently within the tissue, than either the muscarinic or histaminic receptors.

Adrenergic alpha-Antagonists↗
PubMed1978

Synapse turnover: a mechanism for acquiring synaptic specificity.

Neurons are generated in chick retina that are able to form synapses with striated muscle cells for only a brief period during embryonic development. The ability to form synapses is lost with a half-life of 21 hr. Retina neuron-myotube synapses form rapidly but soon are terminated. Chick embryo spinal cord neurons also form synapses with muscle cells for only a limited time during development, but these synapses are long lived. These results show that different classes of synapses turn over at different rates and suggest that part of the specificity of synaptic circuits may be acquired during development by a process of selection based on synapse termination rates.

Age Factors↗