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P A Insel

Publications and source records attributed to P A Insel.

At least 163 records · Page 9Linked to original sources
PubMed1986

Expression of beta-adrenergic receptors in synchronous and asynchronous S49 lymphoma cells. II. Relationship between receptor number and response.

We have used two experimental approaches--receptor inactivation with an irreversible antagonist and changes in receptor expression during passage of cells through the cell cycle--to explore the relationship between beta-adrenergic receptor number and response in intact S49 lymphoma cells. beta-Receptors in asynchronous cultures of S49 cells were blocked to varying degrees with the irreversible antagonist bromoacetylalprenololmenthane (BAAM). Blockade by BAAM was noncompetitive and did not alter the affinity of receptors for the agonist isoproterenol. Intracellular accumulation of cAMP in response to 1 microM isoproterenol was proportional to receptor number both at times of initial and maximal accumulation. In contrast, when intracellular accumulation of cAMP in response to isoproterenol was measured in synchronized cultures of S49 cells (obtained by centrifugal elutriation), a notably different relationship was observed. Cells were least responsive, that is, receptors appeared "uncoupled," during S phase of the cell cycle. This attenuation of response was not due to alterations of receptor number, receptor affinity for agonist, or expression of the catalytic unit of adenylate cyclase. Use of the antibiotic mycophenolic acid, a selective inhibitor of the synthesis of GTP, elicited response patterns in asynchronous cells similar to those seen in synchronized cells. These results confirm that wild-type S49 cells do not possess spare receptors. In addition to the importance of total receptor number in determining maximal response to isoproterenol, receptors may show differential efficacy in promoting cAMP accumulation as cells traverse the cell cycle. Changes in cellular levels or utilization of GTP during the cell cycle may serve to regulate the coupling of receptors to the stimulation of adenylate cyclase.

Adenylyl Cyclases↗
PubMed1986

Agonist-mediated regulation of alpha 1- and beta 2-adrenergic receptor metabolism in a muscle cell line, BC3H-1.

We have compared the metabolism of alpha 1- and beta 2-adrenergic receptors which are both expressed in BC3H-1 muscle cells. During growth of the cells to confluence, the number of alpha 1-receptors per mg of membrane protein increases, whereas that of the beta 2-receptors remains constant. Experiments using cycloheximide and irreversible alpha 1- and beta 2-receptor antagonists, phenoxybenzamine and N-[2-hydroxy-3-(1-naphthoxy)-propyl]-N'-bromoacetylethylenediamine , respectively, yield disparate turnover rates (t1/2) for the two receptors: alpha 1 congruent to 25 hr, beta 2 congruent to 200 hr. These experiments suggest that synthesis of beta 2-receptors virtually ceases in confluent cells. Maximally effective doses of agonists down-regulated both receptor types 80-90% and enhanced the rates of loss of both receptors (t1/2 = 1-5 hr). The rates of down-regulation were not affected by cycloheximide, implying that agonists enhance receptor clearance rather than decrease receptor appearance. The rank orders of potencies of agonists for promoting receptor down-regulation were those characteristic of alpha 1- and beta 2-receptors. However, concentrations of agonists that resulted in down-regulation of each receptor subtype were 10- to 100-fold lower than those required for occupancy of receptors as assessed in radioligand binding studies. Receptor recovery following removal of agonists was blocked by cycloheximide and was much faster than the recovery that followed treatment of cells with irreversible antagonists. Therefore, protein synthesis (but perhaps not receptor synthesis per se) appears necessary for recovery from down-regulation. In addition, the rates of recovery of alpha 1- and beta 2-receptor-mediated functions (phosphatidylinositol turnover and cyclic AMP synthesis, respectively) following receptor down-regulation or irreversible blockade parallel the rates of receptor recovery. These data indicate that basal metabolism of alpha 1- and beta 2-receptors in BC3H-1 cells is substantially different, but that agonist-mediated changes in metabolism of the two receptor subtypes are similar. Thus, common mechanisms appear to mediate the regulation by agonists of alpha 1- and beta 2-receptors in these cells.

Animals↗
PubMed1986

Expression of fibrinogen receptors during activation and subsequent desensitization of human platelets by epinephrine.

Epinephrine causes platelet aggregation and secretion by interacting with alpha 2-adrenergic receptors on the platelet surface. Platelet aggregation requires the binding of fibrinogen to a specific receptor on the membrane glycoprotein IIb-IIIa complex. Although the IIb-IIIa complex is identifiable on the surface of resting platelets, the fibrinogen receptor is expressed only after platelet activation. The current studies were designed to examine the effect of occupancy of platelet alpha 2-adrenergic receptors by epinephrine on the expression of fibrinogen receptors and on the aggregation of platelets. The ability of epinephrine to induce the expression of fibrinogen receptors was studied under two different conditions: acute stimulation (less than 1 min) and prolonged stimulation (50 to 90 min), the latter of which is associated with a reduction or "desensitization" of the platelet aggregation response. Expression of the fibrinogen receptor was monitored with 125I-fibrinogen as well as with 125I-PAC-1 (PAC-1), a monoclonal antibody that binds to the glycoprotein IIb-IIIa complex only after platelets are activated. Epinephrine caused an immediate increase in PAC-1 and fibrinogen binding that was dependent on occupancy of the alpha 2-receptor by epinephrine and on the presence of extracellular free Ca (KCa = 30 mumol/L). By itself, 1 mmol/L Mg was unable to support induction of the fibrinogen receptor by epinephrine. However, it did decrease the Ca requirement by about two orders of magnitude. Prolonged stimulation of unstirred platelets by epinephrine led to a 70% decrease in the aggregation response when the platelets were subsequently stirred. Despite their decreased aggregation response, desensitized platelets bound PAC-1 and fibrinogen normally, indicating that the loss of aggregation was not due simply to a decrease in fibrinogen receptor expression. Although desensitization was not affected by pretreatment of the platelets with aspirin, it was partially prevented when extracellular Ca was chelated by EDTA during the long incubation with epinephrine. These studies demonstrate that once platelet alpha 2-adrenergic receptors are occupied by epinephrine, extracellular Ca is involved in initiating the aggregation response by supporting the induction of the fibrinogen receptor and the binding of fibrinogen. Furthermore. Ca-dependent reactions subsequent to fibrinogen binding may be necessary for maximal platelet aggregation and are impaired when platelets become desensitized to epinephrine.

Antibodies, Monoclonal↗
PubMed1985

Externalization of beta-adrenergic receptors promoted by myocardial ischemia.

beta-Adrenergic receptors were identified in two fractions of guinea pig myocardium: a purified sarcolemmal fraction and a light vesicle (presumably intracellular) fraction. In the light vesicle fraction, which contained approximately 25 percent of the myocardial receptors under control conditions, the receptors appeared to be segregated from the stimulatory guanine nucleotide binding and catalytic components of adenylate cyclase. During myocardial ischemia, beta-adrenergic receptors were redistributed from the intracellular vesicles to the sarcolemmal fraction, where isoproterenol-stimulated adenylate cyclase activity was increased. These findings should facilitate further studies on cellular and molecular mechanisms that regulate adrenergic receptor traffic in the myocardium and may explain the rapid enhancement in adrenergic receptor expression that occurs with myocardial ischemia.

5'-Nucleotidase↗
PubMed1985

Genetic analysis of beta-adrenergic receptor internalization and down-regulation.

We have used wild-type and variants of the T-lymphoma cell line S49 to explore internalization and down-regulation of adenylate cyclase-linked beta-adrenergic receptors. Internalization was defined by the loss in "surface receptors" detected at 4 degrees C on intact cells by the antagonists [3H]CGP-12177 or [125I]iodocyanopindolol, whereas down-regulation was defined as the loss in total cellular content of receptors [( 125I]iodocyanopindolol binding assayed at 37 degrees C). In wild-type cells, the beta-adrenergic agonist isoproterenol induced a rapid (t 1/2, approximately equal to 1 min) and reversible loss in surface receptors. The surface sites were lost at a rate similar to the rate of desensitization of beta-adrenergic receptor-mediated cyclic AMP generation of S49 cells. A series of S49 variants (cyc-, UNC, H21a) having lesions in NS (the guanine nucleotide binding protein that couples beta-receptors to adenylate cyclase) or with absent cAMP-dependent protein kinase activity (kin-), had a loss in surface sites that was equivalent to that of wild-type cells. By contrast, S49 variant cells having lesions in NS showed variable rates and extents of down-regulation of beta-adrenergic receptors. In wild-type and kin- S49 cells, beta-receptors down-regulated with a t 1/2 of approximately equal to 4 hr. Down-regulation was blunted in the cyc- and UNC variants that have altered coupling of receptors to NS, but it was faster in the H21a variant that retains receptor-NS interaction. Recovery of receptors after down-regulation occurred at a similar rate (t 1/2, approximately equal to 6 hr) in wild-type, UNC, and H21a cells. These results demonstrate that internalization of beta-adrenergic receptors may be necessary, but is not sufficient, to explain agonist-induced receptor down-regulation in S49 cells. The variable expression in the development of down-regulation in S49 variants implies that receptor-NS interaction regulates the fate of receptors linked to the stimulation of adenylate cyclase.

Animals↗
PubMed1985

Do agonists promote rapid internalization of beta-adrenergic receptors?

We used elution of radioligands at low pH to quantitate intracellular beta-adrenergic receptors on intact S49 lymphoma cells. We validated this method with respect to cell viability, beta-adrenergic receptor integrity, and transferrin receptors on these cells. On control cells, about 15% of the radiolabeled beta-adrenergic antagonists [3H]dihydroalprenolol and [125I]iodocyanopindolol specifically bound at 37 degrees C could not be eluted at low pH; these binding sites appear to be intracellular receptors that are inaccessible to the surface-restricted antagonist [3H]CGP-12177 [tritiated (+/-)-4-(3-t-butylamino-2-hydroxypropoxy)benzimidazole-2-one hydrochloride]. Incubation of cells with the agonist isoproterenol at 37 degrees C for 15 min did not change the number of [3H]dihydroalprenolol binding sites but reduced [3H]CGP-12177 binding sites by 50% or more. However, all specifically bound [3H]CGP-12177 and [3H]dihydroalprenolol were eluted by acid. In addition, the number of acid-elution-resistant [125I]iodocyanopindolol binding sites was not increased in cells coincubated with 1 microM isoproterenol and [125I]iodocyanopindolol for 15 min at 37 degrees C, even though those sites show a loss in apparent affinity for isoproterenol of about 2 orders of magnitude, a loss previously attributed to internalization. We conclude that the early phase of agonist-mediated desensitization of beta-adrenergic receptors in S49 cells does not coincide with the movement of receptors to intracellular sites; instead, agonist-modified receptors remain in association with the plasma membrane and are accessible to the extracellular environment. These "redistributed" receptors together with "cell-surface" and "intracellular" receptors represent three classes of beta-adrenergic receptors that can be selectively identified in intact target cells.

Adrenergic beta-Agonists↗
PubMed1985

Agonist-mediated regulation of alpha 1- and beta 2-adrenergic receptors in cloned MDCK cells.

Chronic exposure of cells to neurotransmitters and hormones can result in a decrease in receptor number (down-regulation). We asked whether two different types of receptors on the same cell that can both respond to a particular hormone are identically regulated. For this study we used MDCK-D-1, a cloned renal epithelial cell line that coexpresses alpha 1- and beta 2-adrenergic receptors, as a model system in which to examine the effects of an adrenergic agonist on the expression and function of these receptors. MDCK-D-1 cells retain differentiated features of renal tubular epithelium with respect to morphology and hormonal responsiveness. When MDCK-D-1 cells were incubated for 21 h with 100 microM epinephrine, alpha 1- and beta 2-receptor numbers decreased by 81 and 90%, respectively. The down-regulation of beta 2-receptors proceeded more rapidly than that of alpha 1-receptors. Down-regulated cells showed a greater than 80% loss of both alpha 1- and beta 2-adrenergic responses (alpha 1: stimulation of prostaglandin E2 release; beta 2: elevation of adenosine 3',5'-cyclic monophosphate levels). We conclude that in renal epithelial cells chronic exposure to a catecholamine agonist can result in a profound decrease in the number of alpha 1- and beta 2-receptors, this down-regulation is accompanied by a loss of adrenergic response, and the kinetics of receptor loss are different for alpha 1- and beta 2-receptors.

Adrenergic alpha-Agonists↗
PubMed1985

Localization of beta 1- and beta 2-adrenergic receptors in rat kidney by autoradiography.

beta-Adrenergic receptor subtypes were localized and differentiated in rat kidney slices by in vitro autoradiography using the nonselective beta-antagonist [125I]iodocyanopindolol in the presence of the selective agents betaxolol (beta 1) and zinterol (beta 2). [125I]Iodocyanopindolol binding to kidney sections in the presence of these agents could be differentiated into high- and low-affinity components as predicted by the subtype selectivity of the compounds. Autoradiography revealed that: beta-adrenergic receptors were highly concentrated within the renal cortex, especially in glomeruli and juxtaglomerular granule cells, and to tubular sites in the cortex and medulla; [125I]iodocyanopindolol labeling of the juxtaglomeruluar granule cells was abolished at lower concentrations (10(-8) M) of betaxolol than was the labeling of glomeruli (10(-6)--10(-4) M); and zinterol had little effect on labeling of juxtaglomerular granule cells and glomeruli unless high concentrations were used, whereas the tubular labeling in medulla was much more sensitive to incubation with zinterol. These results indicate that beta 1- and beta 2-adrenergic receptor subtypes are differentially distributed within the kidney: beta 1, predominantly contained in juxtaglomerular granule cells and glomeruli, and beta 2, predominantly in medullary tubules. In vitro autoradiography provides a useful means to examine different receptor populations in discrete tissue areas.

Animals↗
PubMed1985

Subtype-selective down-regulation of rat renal cortical alpha- and beta-adrenergic receptors by catecholamines.

In the current studies, we have explored agonist-mediated down-regulation of adrenergic receptors in vivo. We infused catecholamines from sc implanted osmotic minipumps and examined the effects of the resultant increases in circulating levels of catecholamines on rat renal cortical alpha- and beta-adrenergic receptor subtypes, as assessed in radioligand binding studies. Infusion of epinephrine or norepinephrine (at 150 micrograms/kg X h) elevated plasma levels of each catecholamine 10- to 20-fold and decreased renal cortical alpha 1-receptor number about 50% without changing alpha 2-receptor number. Isoproterenol infusion (150 micrograms/kg X h) raised plasma levels of this catecholamine, but had no effect on the number of either alpha 1- or alpha 2-receptors. Renal cortical beta-adrenergic receptor number was decreased by infusion of all three catecholamines. However, the beta 1- and beta 2-adrenergic receptors were altered selectively by the different agonists. Infusion of norepinephrine decreased both beta 1- and beta 2-receptor number, but was more effective for the beta 1-receptors; this result was somewhat at variance with that we previously reported for rats bearing transplanted pheochromocytomas. The decrease in beta-receptor number due to epinephrine infusion was largely due to loss of the renal cortical beta 2-receptors. Infusion of isoproterenol decreased the number of both beta 1- and beta 2-receptors (69% and 75%, respectively). Infusion of norepinephrine maximally decreased the number of alpha 1-, beta 1-, and beta 2-receptors within 2 days, and the t 1/2 for receptor loss was about 12 h. beta-Receptors lost in response to isoproterenol infusion could not be recovered in a pellet prepared by high speed centrifugation of the supernatant derived from the preparation of renal cortical membranes. These results indicate that adrenergic receptor subtypes are differentially down-regulated by elevated levels of circulating catecholamines and that this differential loss of receptors depends on the nature of the receptor subtype, the agonist, and perhaps also whether catecholamines are infused rather than increased by pheochromocytoma.

Animals↗
PubMed1985

Agonist-induced redistribution of beta-adrenergic receptors on intact human mononuclear leukocytes: redistributed receptors are nonfunctional.

Incubation of human mononuclear leukocytes (MLN) with isoproterenol rapidly desensitizes beta-adrenergic receptors, i.e. isoproterenol-stimulated cAMP accumulation decreases. This desensitization is accompanied by a redistribution of the receptor into a cellular environment to which hydrophilic compounds have limited access. We found that the total number of beta-receptors [defined as binding of [3H]dihydroalprenolol (DHA) inhibited by 1 microM propranolol] was unchanged in the desensitized MNL. In control MNL, virtually all DHA binding was inhibited by 1 microM CGP-12177, suggesting that all of these receptors are on the cell surface, whereas in desensitized cells, only 33 +/- 2% (mean +/- SEM) of the DHA binding was inhibited by CGP-12177. We quantitated the sequestered receptors by subtracting the number of surface receptors from the total number of receptors. The sequestered receptors were homogeneous, with an affinity for DHA identical to that of surface receptors (Kd, 0.66 +/- 0.12 vs. 0.62 +/- 0.08 nM). The time courses of desensitization and sequestration were identical. The functional status of the sequestered receptors was assessed using the agonist zinterol, which (unlike catecholamines) is quite hydrophobic. Zinterol competed for DHA binding to both sequestered and surface receptors, whereas isoproterenol only competed for binding to the surface receptors. However, cAMP accumulation in desensitized MNL was reduced to the same extent regardless of whether isoproterenol or zinterol was used as the agonist. These results demonstrate that desensitization of intact cells to beta-agonists cannot be attributed to limited accessibility of the sequestered receptors to catecholamines, but, rather, that the sequestered receptors are not functionally coupled to adenylate cyclase.

Adrenergic beta-Antagonists↗
PubMed1985

Episodic catatonia, hypertension, and tachycardia: elevated plasma catecholamines.

We studied autonomic function in a 34-year-old woman who had episodes of catatonia, hypertension, and tachycardia. In one of these episodes, epinephrine and norepinephrine levels were extremely high. Catecholamine clearance was normal. Platelet alpha 2-adrenergic receptors were normal in number and affinity. Results of the phenylephrine infusion test suggested that these episodes were due to central activation of the sympathetic nervous system.

Adult↗
PubMed1985

Regulation of cyclic AMP accumulation in lymphoid cells.

We have examined several features of the regulation of cyclic AMP accumulation in lymphoid cells isolated from peripheral blood of human subjects and in the murine T-lymphoma cell line, S49, S49 cells are unique because of the availability of variant clones with lesions in the pathway of cyclic AMP generation and response. We found that human lymphoid cells prepared at 4 degrees C showed substantially greater cyclic AMP accumulation in response to histamine and the beta-adrenergic agonist isoproterenol than did cells prepared at ambient temperature. The muscarinic cholinergic agonist carbamylcholine and peptide hormone somatostatin failed to inhibit cyclic AMP accumulation in human lymphoid cells and treatment with pertussis toxin (which blocks function of Gi, the guanine nucleotide binding protein that mediates inhibition of adenylate cyclase) only minimally increased cyclic AMP levels in these cells. Thus the Gi component of adenylate cyclase appears to play only a small role in modulating cyclic AMP levels in this mixed population of lymphoid cells. Incubation of whole blood with isoproterenol desensitized human lymphocytes to subsequent stimulation with beta agonist. This desensitization was associated with a redistribution of beta-adrenergic receptors such that a substantial portion of the receptors in intact cells could no longer bind a hydrophilic antagonist. Wild-type S49 lymphoma cells showed a similar redistribution of beta-adrenergic receptors after a few minutes' incubation with agonist. Based on studies in S49 variants, this redistribution is independent of components distal to receptors in the adenylate cyclase/cyclic AMP pathway. By contrast, a more slowly developing, agonist-mediated down-regulation of beta-adrenergic receptors was blunted in variants with defective interaction between receptors and Gs, the guanine nucleotide binding protein that mediates stimulation of adenylate cyclase. Unlike results in human lymphoid cells, S49 cells show a prominent inhibition of cyclic AMP accumulation mediated by Gi; this inhibition is promoted by somatostatin and blocked by pertussis toxin. Inhibition by Gi is unable to account for the marked decrease in ability of the diterpene forskolin to maximally stimulate adenylate cyclase in S49 variants having defective Gs. These results emphasize that both Gs and Gi component are important in modulating cyclic AMP accumulation and receptors linked to adenylate cyclase in S49 lymphoma cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗
PubMed1985

Radioligand binding and functional assays demonstrate postsynaptic alpha 2-receptors on proximal tubules of rat and rabbit kidney.

We have explored the localization of renal alpha 2-adrenoceptors by radioligand binding techniques and studies of 22Na+ influx into isolated renal tubular cells. Initially, we validated the use of the alpha 2-adrenergic antagonist [3H]rauwolscine as a high-affinity (Kd = 2.5 +/- 0.65 nM) probe that binds to a single class (Hill slope = 0.94 +/- 0.06) of alpha 2-adrenoceptors in rat renal cortical membranes (Bmax = 340 +/- 50 fmol/mg). [3H]Rauwolscine and [3H]yohimbine identified an identical number of sites, but [3H]rauwolscine bound with a several-fold higher affinity. Treatment of rats with 6-hydroxydopamine depleted renal norepinephrine greater than 80% but failed to alter the number or affinity of renal cortical alpha 2-receptors, thus suggesting that these alpha 2-receptors are not located on presynaptic sites. Further evidence for the postsynaptic localization of these receptors was obtained by in vitro autoradiographic studies, which showed that [3H]rauwolscine sites were preferentially located on proximal tubular cells, and by functional assays with isolated rabbit proximal tubular cells. In the latter studies, Na+-H+ antiport activity was stimulated up to 2-fold by the selective alpha 2-adrenergic agonist guanabenz, and this stimulation was blocked by yohimbine but not by the alpha 1-blocker prazosin. Although amiloride was able to block this response to guanabenz, radioligand binding studies demonstrated that amiloride can compete for [3H]rauwolscine sites at the concentrations used to block Na+-H+ antiport activity. These data suggest that alpha 2-adrenoceptors are present on proximal tubular cells in rats and rabbits and that these receptors appear to stimulate Na+-H+ antiport activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗
PubMed1985

A new approach to determine rates of receptor appearance and disappearance in vivo. Application to agonist-mediated down-regulation of rat renal cortical beta 1- and beta 2-adrenergic receptors.

We have developed a method for the assessment of agonist-induced down-regulation of receptors in vivo in terms of rates of receptor appearance and disappearance. This method involves computer-assisted analysis of the kinetics of receptor loss during agonist infusion and of the recovery of receptor number upon the removal of the agonist. These kinetics are analyzed in terms of a steady state model that allows estimation of the rate constants for receptor appearance, kappa ap, and receptor disappearance, kappa dp. Several tests establish that the model can fit experimentally derived data very well. In testing this model, we examined the in vivo down-regulation and recovery of rat renal cortical membrane beta 1- and beta 2-adrenergic receptors in response to infusion of the agonist isoproterenol from subcutaneously implanted osmotic minipumps. During recovery from down-regulation, the beta 1-receptors have a t 1/2 of 45 hr and a kappa ap of 1.6%/hr, and the beta 2-adrenergic receptors a t 1/2 of 18 hr and a kappa ap of 3.9%/hr. During down-regulation, the t 1/2 for both receptors is 12 hr, while kappa ap for beta 1-receptors and beta 2-receptors are 3 and 2.3%/hr, respectively. To the extent that the kinetics of recovery from down-regulation reflect "basal" receptor metabolism, the data indicate that enhanced receptor clearance of both receptor subtypes from the plasma membrane contribute to down-regulation, but changes in rates of receptor appearance may occur as well. The use of this computer modeling technique for defining kinetics of changes in receptor number from one steady state level to another should provide a generally useful means to assess hormone and neurotransmitter receptor metabolism in vivo.

Animals↗
PubMed1984

Serum-stimulated cyclic-AMP production in S49 lymphoma cells grown in serum-free medium.

Growth of S49 lymphoma cells with horse serum leads to an increase in cellular cAMP phosphodiesterase activity and a resultant loss of hormone- and cholera-toxin-stimulated cAMP accumulation. We now show that the serum requires protein synthesis to produce these effects. Further, we show that acute addition of serum to wild-type S49 cells, grown in serum-free medium, rapidly (under 2 min) and transiently (under 30 min) stimulates cellular cAMP, 10-fold over basal levels. This 'acute' effect of serum was not observed in UNC S49 cells, suggesting that a functional Ns, the guanine nucleotide regulatory component that mediates stimulation of adenylate cyclase, is required for the serum-mediated stimulation of cellular cAMP. Serum added acutely to wild-type S49 cells also augmented cAMP accumulation in response to isoproterenol and forskolin. The half-maximally effective concentrations of horse serum that acutely stimulated or more slowly decreased the cAMP accumulation were approx. 0.2% and 2.0%, respectively. Preliminary attempts to characterize further the serum factor indicate that it has a high (250 000-300 000) molecular weight and is insensitive to boiling; chromatography on Sepharose CL-6B yields a 100-fold purification. Thus, the serum contains one or more components that activate adenylate cyclase, increase cellular cAMP levels and ultimately induce cAMP phosphodiesterase in S49 lymphoma cells.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1984

A hypothesis linking intracellular sodium, membrane receptors, and hypertension.

Studies in clinical and experimental hypertension have identified alterations both in intracellular [Na+] and in response to hormones and neurotransmitters. We propose a hypothesis that links these two alterations. Based on recent data showing that changes in intracellular [Na+] can alter the affinity and function of platelet alpha2-adrenergic receptors, we hypothesize that elevated intracellular [Na+] in hypertension leads to enhanced response at membrane receptors. This enhancement in response to hormones and/or neurotransmitters could then contribute to the development and maintenance of the hypertensive state. Because a variety of membrane receptors are Na+-sensitive (e.g., adrenergic, muscarinic cholinergic, opiate, angiotensin, dopamine, histamine H1), this mechanism may be operative at one or more receptor types located in tissues critical to the pathophysiology of hypertension.

Animals↗