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Biomedical subjects

P B Molinoff

Publications and source records attributed to P B Molinoff.

At least 19 recordsLinked to original sources
PubMed1979

Fundamental difference between the molecular interactions of agonists and antagonists with the beta-adrenergic receptor.

Antagonist binding to the beta-adrenergic receptor is largely entropy driven, with only a small enthalpy component. The binding of agonists, on the other hand, is associated with a large decrease in enthalpy which permits a highly unfavourable decrease in entropy. The thermodynamic differences between the binding of agonists and antagonists may provide new insights into the molecular basis for hormone stimulation of adenylate cyclase activity.

Adenylyl Cyclases↗
PubMed1979

beta1- and beta2-Adrenergic receptors in rat cerebral cortex are independently regulated.

Repeated administration of the tricyclic antidepressant desmethylimipramine to adult rats for 10 days caused a 40% decrease in the density of beta1-adrenergic receptors in the cerebral cortex but had no effect on the density of beta2-adrenergic receptors. Conversely, destruction of noradrenergic neurons by administration of 6-hydroxydopamine to neonatal rats caused a 64% increase in the density of beta1-adrenergic receptors in adult cerebral cortex with no change in the density of beta2-adrenergic receptors. These results suggest that the beta-adrenergic receptors in rat cortex involved in neuronal function are primarily of the beta1 subtype.

Adrenergic beta-Agonists↗
PubMed1979

Effect of central catecholamine depletion on the osmotic and nonosmotic stimulation of vasopressin (antidiuretic hormone) in the rat.

The central nervous system (CNS) mechanism(s) for the release of antidiuretic hormone (ADH) by various stimuli is unknown. In this study, the role of CNS catecholamines in effecting ADH release was examined in conscious rats 10-14 d after the cerebroventricular injection of 6-hydroxydopamine (6-OHDA). This dose of 6-OHDA caused a 67% depletion of brain tissue norepinephrine and only 3% depletion of heart norepinephrine, as compared with controls, which were injected with the vehicle buffer alone. Either intravenous 3% saline (osmotic stimulus) or intraperitoneal hyperoncotic dextran (nonosmotic stimulus) was administered to water-diuresing rats through indwelling catheters. Neither of these maneuvers changed arterial pressure, pulse, or inulin clearance in control or 6-OHDA rats. The 3% saline caused similar increases in plasma osmolality (15 mosmol/kg H(2)O) in control and 6-OHDA rats. The control rats, however, increased urinary osmolality (Uosm) to 586 mosmol/kg H(2)O, whereas 6-OHDA rats increased Uosm only to 335 mosmol/kg H(2)O (P < 0.005). These changes in Uosm were accompanied by an increase in plasma ADH to 7.6 muIU/ml in control animals vs. 2.9 muIU/ml in 6-OHDA rats (P < 0.005). All waterdiuresing animals had undetectable plasma ADH levels. Dextran-induced hypovolemia caused similar decrements (- 10%) in blood volume in both control and 6-OHDA animals, neither of which had significant changes in plasma osmolality. This nonosmotic hypovolemic stimulus caused an increase in Uosm to 753 mosmol/kg H(2)O in control rats, whereas Uosm in 6-OHDA rats increased to only 358 mosmol/kg H(2)O (P < 0.001). At the same time, ADH levels also were significantly greater in Cont rats (2.4 muIU/ml) than in the 6-OHDA animals (0.69 muIU/ml; P < 0.05). These results therefore suggest that CNS catecholamines may play an important role in mediating ADH release in response to both osmotic and nonosmotic (hypovolemic) stimuli.

Animals↗
PubMed1979

Agonist-induced changes in beta adrenergic receptor density and receptor-mediated responsiveness in slices of rat cerebral cortex.

Incubation of slices of rat cerebral cortex with the beta adrenergic receptor agonist (-)-isoproterenol led to a 30 to 50% decrease in the number of binding sites for [125I]iodohydroxybenzylpindolol and to a 60 to 80% decrease in isoproterenol-stimulated cyclic AMP accumulation. The density of beta adrenergic receptors was also decreased following incubation with (-)-norepinephrine but not with (+)-isoproterenol or dopamine and the decrease in receptor density was blocked by co-incubation with the beta adrenergic receptor antagonist sotalol. The half-time for loss of receptors was approximately 3 min and recovery was observed during a 1 hr reincubation of tissue slices or following exposure to guanine nucleotides. A decrease in beta adrenergic receptor density was also observed following chronic treatment with desmethylimipramine which blocks norepinephrine reuptake and thus potentiates the effects of neurally released norepinephrine at adrenergic receptors. The loss of receptors induced in vitro could be reversed by reincubation or by exposure to guanine nucleotides. In contrast, the loss of receptors induced in vivo was not affected by these procedures.

Adrenergic beta-Agonists↗
PubMed1978

Presynaptic modulation of beta adrenergic receptors in rat cerebral cortex after treatment with antidepressants.

Treatment with desmethylimipramine (DMI), a tricyclic antidepressant, for 7 to 21 days resulted in a 35 to 45% decrease in the accumulation of adenosine cyclic 3':5'-monophosphate (cAMP) in response to a maximally effective concentration of (-)-isoproterenol (ISO) in rat cerebral cortical slices. The EC50 for ISO-stimulated cAMP accumulation was not affected by DMI administration. The diminution in responsiveness to catecholamines was accompanied by a 35 to 40% decrease in the density of beta adrenergic receptors as measured by the binding of [125I]iodohydroxybenzylpindolol. Decreases in ISO-sensitive cAMP accumulation and in beta adrenergic receptor density were temporally correlated, maximal decreases being observed within 5 to 7 days. Within 7 days after cessation of chronic DMI treatment ISO-stimulated cAMP accumulation and beta adrenergic receptor density returned to normal. The role of presynaptic nerve terminals in mediating these phenomena was also investigated. Treatment of newborn rats with 6--hydroxydopamine inhibited the development of noradrenergic nerve terminals in the cerebral cortex and blocked the effects of DMI on cortical cAMP accumulation and on beta adrenergic receptor density. The administration of the beta adrenergic receptor antagonist propranolol led to increases in maximal ISO-stimulated cAMP accumulations and beta adrenergic receptor density in the rat cerebral cortex. This increase was not affected by the simultaneous administration of propranolol and DMI. Thus, the effect of DMI appears to be mediated through an action of norepinephrine at beta adrenergic receptors. Chronic treatment with two other clinically effective antidepressants, pargyline and iprindole, led to effects similar to those observed with DMI administration. Pretreatment of neonates with 6-hydroxydopamine blocked the effect of iprindole on beta adrenergic receptors. Preincubation of cortical membranes with guanosinetriphosphate before determination of the density of beta adrenergic receptors had no effect on the decreased number of receptors had no effect on the decreased number of receptors seen in DMI-treated animals. These experiments suggest that antidepressants, acting presynaptically, increase the concentration of transmitter at noradrenergic synapses and induce a compensatory decrease in the density of beta adrenergic receptors.

Adenylyl Cyclases↗
PubMed1978

Adrenergic storage vesicles in rat heart: quantitation of membrane-bound and membrane-enclosed dopamine beta-hydroxylase.

Norepinephrine-containing storage particles in rat heart have been disrupted to determine their stability and to quantitate the amount of dopamine beta-hydroxylase (DBH) that exists in a soluble, membrane enclosed pool. Vesicles were relatively resistant to lysis by hypotonic shock or by up to five cycles of freezing and thawing. These procedures have been shown to release catecholamines from adrenal chromaffin granules readily. However, rat heart vesicles were sensitive to temperature and they could be lysed by mechanical disruption using a sonicator or a Polytron homogenizer. Increasing the force or duration of the disruption resulted in an increased release of norepinephrine and DBH into a supernatant fraction after high-speed centrifugation. Extrapolation of the data from such experiments gave an estimate for membrane-enclosed DBH of 37% of the total amount of enzyme activity. This estimate of the proportion of membrane-enclosed enzyme is considerably higher than those previously reported for membrane-enclosed DBH in sympathetic neurons.

Animals↗
PubMed1977

Ontogeny of beta-adrenergic receptors in rat cerebral cortex.

The ontogeny of beta-adrenergic receptors in rat cerebral cortex has been studied using [125I]iodohydroxybenzylpindolol as a ligand in an in vitro binding assay. The concentration of beta-adrenergic receptors was very low during the first week after birth. Between days 7 and 14 there was a rapid increase in the density of receptors. Adult levels were reached by the end of the second week. The affinities of 1-isoproterenol and iodohydroxybenzylpindolol for beta-adrenergic receptors did not vary with the age of the animal. Fluoride stimulated adenylate cyclase activity in the cerebral cortex was 40% of the adult level at birth and gradually increased to maximal levels over the next two weeks. On the other hand, catecholamine stimulated cyclic-3',5'-adenosine monophosphate accumulation was barely detectable during the first week after birth, but it increased rapidly to adult levels between days 7 and 14. The results suggest that it is the development of beta-adrenergic receptors that permits the expression of catecholamine sensitive adenylate cyclase activity. Norepinephrine stores in the cerebral cortex developed slowly reaching adult levels approximately two months after birth. There is therefore little correlation between the ontogeny of presynaptic adrenergic nerve terminals and the postsynaptic development of beta-adrenergic receptors.

Adenylyl Cyclases↗