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PubMed2003

Roles of L-type Ca2+ and delayed-rectifier K+ currents in sinoatrial node pacemaking: insights from stability and bifurcation analyses of a mathematical model.

To elucidate the dynamical mechanisms of the sinoatrial (SA) node pacemaker activity, we investigated the roles of L-type Ca2+ (ICa,L) and delayed-rectifier K+ (IKr) currents in pacemaking by stability and bifurcation analyses of our rabbit SA node model (Kurata Y, Hisatome I, Imanishi S, and Shibamoto T. Am J Physiol Heart Circ Physiol 283: H2074-H2101, 2002). Equilibrium points (EPs), periodic orbits, stability of EPs, and Hopf bifurcation points were calculated as functions of conductance or gating time constants of the currents for constructing bifurcation diagrams. Structural stability (robustness) of the system was also evaluated by computing stability and dynamics during applications of constant bias currents (Ibias). Blocking ICa,L or IKr caused stabilization of an EP and cessation of pacemaking via a Hopf bifurcation. The unstable zero-current potential region determined with Ibias applications, where spontaneous oscillations appear, shrunk and finally disappeared as ICa,L diminished, but shrunk little when IKr was eliminated. The reduced system, including no time-dependent current except ICa,L, exhibited pacemaker activity. These results suggest that ICa,L is responsible for EP instability and pacemaker generation, whereas IKr is not necessarily required for constructing a pacemaker cell system. We further explored the effects of various K+ currents with different kinetics on stability and dynamics of the model cell. The original IKr of delayed activation and inward rectification appeared to be most favorable for generating large-amplitude oscillations with stable frequency, suggesting that IKr acts as an oscillation amplifier and frequency stabilizer. IKr may also play an important role in preventing bifurcation to quiescence of the system.

Animals↗
PubMed2005

Long-term retention of gait stability improvements.

Evidence of long-term modification of behavior-in particular, gait alterations in response to repeated exposure to slips-within the locomotor-balance control system is limited. The purpose of this study was to examine whether improvements in fall-resisting behavior as reflected by improvements in gait stability could be retained on a long-term basis. Eight healthy young subjects were exposed to a block of repeated slip trials during a single acquisition session consisting of five repeated slip exposures; the same subjects were then re-tested using the same protocol at a minimum of 12 mo later. Pre- and postslip gait stability for all slip trials was measured at touchdown (slipping limb) and liftoff (contralateral limb) based on the center of mass state (i.e., its instantaneous position and velocity) relative to the base of support (BOS) and the predicted thresholds for backward loss of balance. In the acquisition session, subjects were able to increase pre- and postslip stability, which significantly correlated with a decrease in the incidence of balance loss from 100% (1st slip) to 0% (5th slip). All subjects exhibited a similar balance loss on the first slip of the follow-up session. Nonetheless, subjects were able to retain the acquired preslip stability with feedforward control on the first slip but not the postslip stability related to the reactive response. Also, the subjects demonstrated a faster re-acquisition, with only one balance loss on the second slip of the follow-up session, as compared with seven balance losses on the acquisition session. Such rapid improvements were achieved by the significantly greater increase in post- compared with preslip stability; this increase was for the most part, a consequence of reductions in slip intensity (i.e., the peak BOS velocity). We concluded that a single acquisition session could only produce limited long-term retainable effects within the locomotor-balance control system. It appeared, however, that the CNS was still primed to more rapidly update its internal representation of gait stability during re-acquisition.

Accidental Falls↗
PubMed2000

Development and stability of alcohol consumption from adolescence into adulthood: the Amsterdam Growth and Health Longitudinal Study.

When studying long-term effects of alcohol consumption on health, the stability of alcohol consumption should be known. In this paper the development and stability of alcohol consumption were investigated. Seven measurements of alcohol consumption were carried out over a period of 20 years, starting at age 13 years, in a cohort of 65 men and 85 women. Effects of age, gender, and type of beverage on the stability of drinking as a dichotomous variable (drink or abstain) and on the stability of relative amounts of alcohol consumption were analyzed. The stability of the drink/abstain dichotomy was high (odds ratios>4) and increased with age. The stability of relative amounts of alcohol consumption was moderate (rS<0.6), and no effect of age was found. No sex effects were found, while the consumption of beer often showed higher stability than that of wine and spirits.

Adolescent↗
PubMed1988

Decreased membrane mechanical stability and in vivo loss of surface area reflect spectrin deficiencies in hereditary spherocytosis.

Whereas marked variations in the clinical manifestations of hereditary spherocytosis have long been recognized, we have only recently begun to define the molecular basis for this heterogeneity. An important unanswered question is whether decreased spectrin results in reduced membrane mechanical stability, and if this reduction in membrane mechanical stability can be related to in vivo surface area loss. Using the ektacytometer, we quantitated membrane surface area and stability in erythrocytes from 18 individuals with hereditary spherocytosis and deficiencies of spectrin (30-80% of normal spectrin level). Membrane mechanical stability was reduced and the magnitude of the reductions correlated with the spectrin content. Moreover, the reductions in mechanical stability correlated with in vivo loss of membrane surface area. These data indicate that decreased spectrin content results in reduced membrane mechanical stability and surface area loss in vivo. We conclude that partial deficiencies of spectrin, reductions in membrane mechanical stability, and loss of membrane surface area are directly related and are major features determining the heterogeneous clinical manifestations of hereditary spherocytosis.

Biomechanical Phenomena↗
PubMed1994

The long-term stability of depressive subtypes.

OBJECTIVE: This study used the concept of diagnostic stability to examine the validity of three subtypes of major depression. METHOD: Patients with major depressive disorder (N = 424) were assigned baseline diagnoses according to structured interviews and the Research Diagnostic Criteria. Follow-up evaluations took place at 6-month intervals over the next 5 years and annually for an additional 3 years. During this period 424, 246, 163, and 96 of the patients who had recovered from the index episode had one, two, three, and four recurrences, respectively, of major depressive disorder. The kappa statistic was used to quantify the likelihood that patients with the psychotic, agitated/retarded, or endogenous subtype of depression in a given episode would again manifest that subtype in subsequent episodes. RESULTS: The psychotic subtype showed the most enduring diagnostic stability across multiple subsequent episodes. Even after three intervening episodes, patients with baseline psychotic major depression were five times more likely to develop a psychotic depression than were other depressed patients. For all three subtypes, diagnostic stability was greater for contiguous episodes than for noncontiguous episodes. Psychotic, agitated/retarded, and endogenous subtypes showed significant stability after control for the bipolar/unipolar and primary/secondary distinctions. The endogenous subtype was stable among patients with primary depression but not among those with secondary depression. CONCLUSIONS: The psychotic subtype was the most valid of the subtypes tested from the perspective of diagnostic stability. The fact that stability across adjacent episodes exceeded stability across more distantly spaced episodes may reflect state-dependent determinants, and these are likely to vary by subtype.

Bipolar Disorder↗
PubMed2006

Tropomyosin modulates erythrocyte membrane stability.

The ternary complex of spectrin, actin, and 4.1R (human erythrocyte protein 4.1) defines the nodes of the erythrocyte membrane skeletal network and is inseparable from membrane stability under mechanical stress. These junctions also contain tropomyosin (TM) and the other actin-binding proteins, adducin, protein 4.9, tropomodulin, and a small proportion of capZ, the functions of which are poorly defined. Here, we have examined the consequences of selective elimination of TM from the membrane. We have shown that the mechanical stability of the membranes of resealed ghosts devoid of TM is grossly, but reversibly, impaired. That the decreased membrane stability of TM-depleted membranes is the result of destabilization of the ternary complex of the network junctions is demonstrated by the strongly facilitated entry into the junctions in situ of a beta-spectrin peptide, containing the actin- and 4.1R-binding sites, after extraction of the TM. The stabilizing effect of TM is highly specific, in that it is only the endogenous isotype, and not the slightly longer muscle TM that can bind to the depleted membranes and restore their mechanical stability. These findings have enabled us identify a function for TM in elevating the mechanical stability of erythrocyte membranes by stabilizing the spectrin-actin-4.1R junctional complex.

Actins↗
PubMed1996

Stabilization of the B-type natriuretic peptide mRNA in cardiac myocytes by alpha-adrenergic receptor activation: potential roles for protein kinase C and mitogen-activated protein kinase.

In cardiac myocytes, B-type natriuretic peptide (BNP) expression is induced with the rapid kinetics of a primary response gene. Like many other primary response gene transcripts, the BNP mRNA possesses destabilizing elements and is believed to be short-lived. The rapid induction of a short-lived transcript could be achieved partty by agonist-mediated increases in mRNA t1/2. Accordingly, the present study was undertaken to evaluate whether the alpha 1-adrenergic receptor agonist, phenylephrine (PE), a known inducer of BNP expression, could stabilize the BNP mRNA and, if so, what signaling pathways might be involved. In primary myocardial cells treated with a transcription inhibitor, the t1/2 of the BNP mRNA was found to be about 1 h in the absence of PE; however, in the presence of PE, the t1/2 increased to 5 h. It was shown that neither the calmodulin kinase inhibitor, KN-62, nor the protein tyrosine kinase inhibitor, tyrphostin, blocked PE-mediated stabilization of the BNP mRNA. However, either the protein kinase C (PKC) inhibitor, GF 109203X, or the mitogen-activated protein kinase kinase (MAPKK) inhibitor, PD 098059, effected some blockade of the stabilizing effects of PE. While maximal doses of PD 098059 nearly completely blocked PE-activated MAPK, stabilization was only partially inhibited. Moreover, maximal doses of GF 109203X, which only partially blocked PE-activated MAPK, nearly completely inhibited stabilization. Thus, while MAPK appears to be required for maximal agonist-mediated stabilization, PKC seems to play a dominant role, participating through both MAPK-dependent and -independent pathways. These results establish roles for both the PKC and MAPK families in alpha 1-adrenergic receptor-mediated stabilization of the BNP mRNA, suggesting that the rapid induction of BNP expression might be due, in part, to this agonist-mediated increase in mRNA t1/2.

Adrenergic alpha-Agonists↗
PubMed1995

Lactate dehydrogenase A subunit messenger RNA stability is synergistically regulated via the protein kinase A and C signal transduction pathways.

We have identified and studied a posttranscriptional mechanism of lactate dehydrogenase A (LDH) subunit gene expression at the level of mRNA stability. Using the well differentiated rat C6 glioma cell line as a model system, the effects of activators of the protein kinase A and C pathways on the half-life of LDH A mRNA were measured by two independent methods: 1) by the RNA synthesis inhibitor-chase method using actinomycin D, and 2) by analysis of decay of LDH A [3H]mRNA in [3H]uridine-labeled cells. By each method, the half-life of relatively short-lived LDH A mRNA was increased 5- to 7-fold in 8- (4-chloro-phenylthio) cAMP or forskolin-treated and about 3-fold in 12-0-tetradecanoylphorbol-13- acetate (TPA) or dioctanoylglycerol-treated cells. Forskolin acted synergistically with TPA to prolong LDH A mRNA half-life from 55 min to more than 20 h. The relatively rapid basal decay rate of LDH A mRNA was also considerably slowed in the presence of the protein phosphatase inhibitor okadaic acid, suggesting a functional role for protein phosphorylation in the stabilization process. In glioma cells stably transformed with a protein kinase A catalytic subunit expression vector, overexpression of the catalytic subunit stabilized LDH mRNA to the degree seen in forskolin-treated cells. In cells transfected with a protein kinase A inhibitor-expression vector, cAMP-mediated stabilization of LDH A mRNA half-life was prevented. Furthermore, both staurosporin and 3- [1-(3-dimethylaminopropyl)-indol-3-yl]-3-(indol- 3-yl)- maleimide, inhibitors of protein kinase C, prevented the TPA-induced stabilization of LDH A mRNA. We conclude from the experimental data that the protein kinase A and C signal pathways play an active functional role in regulating LDH A mRNA stability and act cooperatively to achieve LDH A mRNA stability regulation.

Animals↗
PubMed1988

Posterior stabilization of cervical spine fractures and subluxations using plates and screws.

Posterior stabilization of cervical spine fractures and subluxations with metal plates and screws is commonly used in Europe, but has rarely been employed by neurosurgeons in North America, where stabilization has usually been achieved with wires supplemented by bone grafts or acrylic. The limitations of the more commonly used stabilization techniques include the failure to achieve rotational stability, the necessity for intact laminae, and the requirement for bone grafting. We therefore examined the efficacy of posterior cervical plating in 19 patients who had posttraumatic instability of the cervical spine between C3 and C7 without residual spinal cord compression and 1 patient who had a subluxation as a result of osteomyelitis. Two patients had no neurological deficit, 4 had partial deficits, and 14 had no neurological function below the level of injury. Operation was performed after patients were medically stable and maximal reduction of fractures was achieved (usually within 48 hours). The plates are made of vitallium and contain two or three holes 13 mm apart through which 16-mm screws are placed bilaterally into the center of the articular masses of two or three adjacent vertebrae to stabilize one or two motion segments. Bone grafting is not performed. Patients are mobilized on the day after operation in a Philadelphia collar, which is worn for 3 months. Fourteen patients had stabilization of one motion segment and 6 had stabilization over two motion segments. The mean follow-up is 9.2 months. In a single patient with ankylosing spondylitis, plate fixation failed when screws pulled out. No patient experienced neurological deterioration as a result of the operative procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1984

Role of local adaptation in the fading of stabilized images.

We provide evidence that the fading of stabilized images and the formation of negative afterimages result from the same local adaptive process. We measure thresholds for stabilized, static, sine-wave gratings and for stabilized flickering sine-wave gratings. We then measure the contrasts of the negative afterimages formed by the threshold-contrast stabilized, static stimuli. (The threshold-contrast flickering gratings produce no visible afterimages.) We find that the difference between the thresholds for stabilized, static gratings and the thresholds for slowly flickering gratings is equal to the contrasts of the afterimages produced by the stabilized, static gratings. We conclude that the fading of these stabilized gratings can be accounted for completely by local adaptation (the process underlying the formation of negative afterimages.

Adaptation, Ocular↗
PubMed2005

Trehalose and 6-aminohexanoic acid stabilize and renature glucose-6-phosphate dehydrogenase inactivated by glycation and by guanidinium hydrochloride.

A number of naturally occurring small organic molecules, primarily involved in maintaining osmotic pressure in the cell, display chaperone-like activity, stabilizing the native conformation of proteins and protecting them from various kinds of stress. Most of them are sugars, polyols, amino acids or methylamines. In addition to their intrinsic protein-stabilizing activity, these small organic stress molecules regulate the activity of some molecular chaperones, and may stabilize the folded state of proteins involved in unfolding or in misfolding diseases, such as Alzheimer's and Parkinson's diseases, or alpha1-antitrypsin deficiency and cystic fibrosis, respectively. Similar to molecular chaperones, most of these compounds have no substrate specificity, but some specifically stabilize certain proteins, e.g., 6-aminohexanoic acid (AHA) stabilizes apolipoprotein A. In the present work, the capacity of 6-aminohexanoic acid to stabilize non-specifically other proteins is demonstrated. Both trehalose and AHA significantly protect glucose-6-phosphate dehydrogenase (G6PD) against glycation-induced inactivation, and renatured enzyme already inactivated by glycation and by guanidinium hydrochloride (GuHCl). To the best of our knowledge, there are no data on the effect of these compounds on protein glycation. The correlation between the recovery of enzyme activity and structural changes indicated by fluorescence spectroscopy and Western blotting contribute to better understanding of the protein stabilization mechanism.

Aminocaproic Acid↗
PubMed1998

Temporal stability of diagnostic criteria for antisocial personality disorder in male alcohol dependent patients.

We evaluated the temporal stability of diagnostic criteria for antisocial personality disorder in 432 male alcohol dependent patients. Indicators for temporal stability were criterion continuation (i.e., the proportion of current or recent diagnoses among those with a lifetime diagnosis) and criterion duration (i.e., the length of time between the first occurrence and the last occurrence). In addition, the effect of diagnostic status (ASPD- versus ASPD+) on stability was examined. Among the criteria, "no regard for the truth" showed consistently high stability; "recklessness" showed moderate to high stability; "inconsistent work behavior," "failure to meet financial obligations," "failure to plan ahead" and "parental irresponsibility" showed consistently low stability. The continuation and duration parameters diverged with respect to "nonconformism" and "irritability/aggressiveness." Temporal stability for "nonconformism" was consistently greater among those with ASPD than among those without. It was concluded that both continuation and duration rates clearly differentiated among criteria. This new criterion-based approach seems to be useful as a strategy for improving the ASPD criteria set.

Adult↗
PubMed2005

Intrinsic musculoskeletal properties stabilize wiping movements in the spinalized frog.

The mechanical stability properties of hindlimb-hindlimb wiping movements of the spinalized frog were examined. One hindlimb, the wiping limb, was implanted with 12 electromyographic (EMG) electrodes and attached to a robot that both recorded its trajectory and applied brief force perturbations. Cutaneous electrical stimulation was applied to the other hindlimb, the target limb, to evoke the hindlimb-hindlimb wiping reflex. Kinematic and EMG data from both unperturbed trials and trials in which a phasic perturbation was applied were collected from each spinalized frog. In the perturbed behaviors, we found that the initially large displacement attributable to the perturbation was compensated such that the final position was statistically indistinguishable from the unperturbed final position in all of the frogs, thus indicating the dynamic stability of these movements. This stability was robust to the range of perturbation amplitudes and nominal kinematic variation observed in this study. In addition, we investigated the extent to which intrinsic viscoelastic properties of the limb and proprioceptive feedback play a role in stabilizing the movements. No significant changes were seen in the EMGs after the perturbation. Furthermore, deafferentation of the wiping limb did not significantly affect the stability of the wiping reflex. Thus, we found that the intrinsic viscoelastic properties of the hindlimb conferred robust stability properties to the hindlimb-hindlimb wiping behavior. This stability mechanism may simplify the control required by the frog spinal motor systems to produce successful movements in an unpredictable and varying environment.

Animals↗
PubMed2005

pH dependence thermal stability of a chymotrypsin inhibitor from Schizolobium parahyba seeds.

The thermal stability of a Schizolobium parahyba chymotrypsin inhibitor (SPCI) as a function of pH has been investigated using fluorescence, circular dichroism, and differential scanning calorimetry (DSC). The thermodynamic parameters derived from all methods are remarkably similar and strongly suggest the high stability of SPCI under a wide range of pH. The transition temperature (T(m)) values ranging from 57 to 85.3 degrees C at acidic, neutral, and alkaline pH are in good agreement with proteins from mesophilic and thermophilic organisms and corroborate previous data regarding the thermal stability of SPCI. All methods gave transitions curves adequately fitted to a two-state model of the unfolding process as judged by the cooperative ratio between the van't Hoff and the calorimetric enthalpy energies close to unity in all of the pH conditions analyzed, except at pH 3.0. Thermodynamic analysis using all these methods reveals that SPCI is thermally a highly stable protein, over the wide range of pH from 3.0 to 8.8, exhibiting high stability in the pH region of 5.0-7.0. The corresponding maximum stabilities, DeltaG(25), were obtained at pH 7.0 with values of 15.4 kcal mol(-1) (combined fluorescence and circular dichroism data), and 15.1 kcal mol(-1) (DSC), considering a DeltaC(p) of 1.72 +/- 0.24 kcal mol(-1) K(-1). The low histidine content ( approximately 1.7%) and the high acidic residue content ( approximately 22.5%) suggests a flat pH dependence of thermal stability in the region 2.0-8.8 and that the decrease in thermal stability at low pH can be due to the differences in pK values of the acidic groups.

Calorimetry, Differential Scanning↗
PubMed1975

The relative roles of iodination and iodothyronine content on thyroglobulin stability.

We have independently varied the degree of iodination and of iodothyronine formation over a wide range by acutely administering various doses of perchlorate and/or methimazole to severely iodine-deficient rats 30 min before giving 131-I- with graded quantities (1-100 mug of 127-I-). Thyroids were removed 4 h later and the soluble protein analyzed for labelled iodoamino acid composition and with sucrose density gradient ultracentrifugation. Since the total thyroid iodine content before administering 127I- was less than 1 mug, calculation of the degree of iodination and iodothyronine content of the labelled Tgb could be made from the known specificity of the injected labelled iodide. Newly organified iodine ranged from smaller than 0.1 to 1.4 mug/thyroid and labelled iodothyronines from smaller than 5 to 962 pmoles/thyroid. Both the degree of iodination and iodothyronine content varied directly with Tgb stability in the absence of inhibitors. But when Tgb iodination was kept constant, Tgb stability at pH 10.1 varied directly with iodothyronine content. When iodothyronine content was kept constant, Tgb stability was independent of the degree of iodination. Correlation of stability with iodothyronine content was highly significant (r=0.79, Psmaller than 0.001) but not of stability with iodine content (r=0.49, P larger than 0.05). We conclude that the primary determinant of Tgb stability in mild alkali is the iodothyronine content and not the degree of iodination of the protein. The increased Tgb stability may be induced by coupling between iodotyrosil residues of different 12 S subunits rather than between residues of the same 12 S subunit.

Animals↗
PubMed2000

The ankylos endosseous dental implant: assessment of stability up to 18 months with the Periotest.

Osseointegration is an ongoing histometric process that may vary during clinical function. The implant must be stable at uncovering, which reflects the status of bone-implant interface. The physiology of bone healing associated with endosseous implants suggests that this process occurs between 8 and 12 months, and Periotest values (PTVs) tend to reflect changes in the stability of the bone-implant interface. Stability generally increases gradually from the time of uncovering to an optimal PTV that occurs at a point close to 12 months. This stable interface must remain intact for long-term clinical survival. Rapid development of this optimal PTV is highly desirable in order to prevent premature overloading of the bone-implant interface. The Ankylos implant is a new screw-type implant design in which the thread pitch and length vary to maximize trabecular bone contact. The purpose of this report is to evaluate to 18 months the stability (PTVs) of this implant design. More than 457 implants were placed and followed for a period of 18 months by the multicentered, multidisciplinary Ankylos Implant Clinical Research Group (AICRG). Implant stability (PTVs) was assessed using the Periotest at abutment connection and at 3, 6, 9, 12, and 18 months after uncovering. The Periotest values for all implants rapidly reached an optimal status between uncovering (-3.1 PTVs) and 3 months (-3.4 PTVs). This rapid increase in stability has not previously been reported for other implant designs. The mandibular arch was more negative (-3.8 PTVs) at uncovering as compared with the PTVs for the maxillary arch (-1.7 PTVs). Negative PTVs were recorded (1) as length and diameter increased, (2) as bone density increased, (3) in certain jaw regions, (4) as the number of implants/case increased, and (5) for implants stabile at placement. The Ankylos screw implant design produced rapid stabilization 3 months after uncovering.

Analysis of Variance↗
PubMed2003

Bone density: its influence on implant stability after uncovering.

Primary implant stability and bone density are variables that have long been considered to be essential to achieving predictable osseointegration and long-term clinical survival. Although the dentist can control most factors associated with implant survival, bone density is the one factor that cannot be controlled. Measuring implant stability would assist in determining if an implant has integrated and is ready for the fabrication of the final prosthesis. Changes in implant stability in each type of Bone Quality (BQ-1, -2, -3, and -4), which may occur with time, have not been studied. Such information could help identify well-integrated implants and identify changes associated with impending implant failure. Several studies have used the Periotest instrument to study implant stability. Use of the Periotest implant stability will be studied during each phase of implant treatment for each bone density, and a range for clinically satisfactory integration will be suggested. Implant stability changes over time, and the changes are different for each bone density as the bone surrounding the nonhydroxyapatite implant becomes denser. This is clearly demonstrated in a postmortem histological specimen. The changes in implant stability (Periotest Values [PTVs]) are more apparent in BQ-1 and BQ-2 bone and less apparent in BQ-3 and BQ-4 bone. The Periotest is capable of providing valuable information concerning favorable or unfavorable changes in the bone-implant interface after uncovering. In addition, it can help identify when an implant is ready to be loaded. A new range of PTVs (-5 to -2) is suggested for monitoring the status of implants. Implants with PTVs more positive than -2 would indicate a bone-implant complex that may be marginal.

Bone Density↗
PubMed1977

Differences between in-vitro and in-vivo potencies of corticotrophins: an interpretation in terms of metabolic stability.

Relative activities of a series of corticotrophin analogues have been measured by means of five different bioassays using the rat. Similarities in the relative potencies of various ACTH analogues determined using lipolysis or steroidogenesis in vivo and for the lipolytic and steroidogenic responses of fat pads and adrenal slices in vitro emerged and support the concept of a close structural relationship between the ACTH receptors in adipose and adrenal tissues in the rat. Potencies based on the steroidogenic response of isolated adrenal cells, adrenal slices or in-vivo experiments differed markedly from each other. Inactivation of peptides did not occur in the isolated cell assay, so it is likely that this assay estimates potency at the receptor level. A number of arguments suggest that the difference between the isolated cell assay and the other steroidogenic assays lies solely in the effects of peptide inactivation in the latter, and this allows the relative metabolic stabilities for the peptide analogues in these assays to be calculated. In this way it can be shown that: (1) Replacement of L-Ser by D-Ser in amino acid position 1 markedly increases the metabolic stability of the peptide and has only a slight effect on receptor properties. (2) Shortening at the NH2-terminus reduces the activity of peptides at the receptor level by several orders of magnitude, but increases their relative metabolic stability. (3) Introduction of amide groups at the CO2H-terminus markedly increases receptor potency of (1-16), (1-17) and (1-18) ACTH without affecting their metabolic stability in vivo. However, amidation of the CO2H-terminus does have a large effect on metabolic stability in the adrenal slice assay. (4) Replacement of Arg by Lys in positions 17 and 18 of (1-18) ACTH increases potency at the receptor level (adrenal cells) but has little effect on metabolic stability. The comparison of potencies obtained in the various assays, therefore, throws light on the significance of each assay. In addition, the effects of structural modification of analogues can be separately evaluated with respect to the metabolic stability of a peptide and its potency at the receptor level.

Adrenal Cortex Hormones↗