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Biomedical subjects

L G Allen

Publications and source records attributed to L G Allen.

11 recordsLinked to original sources
PubMed1992

A new class of bradykinin antagonists: synthesis and in vitro activity of bissuccinimidoalkane peptide dimers.

A systematic study on the dimerization of the bradykinin (BK) antagonist D-Arg0-Arg1-Pro2-Hyp3-Gly4-Phe5-Ser6-D-Phe 7-Leu8-Arg9 has been performed. The first part of this study involved compounds wherein dimerization was carried out by sequentially replacing each amino acid with cysteine and cross-linking with bismaleimidohexane. The second part of this study utilized a series of bissuccinimidoalkane dimers wherein the intervening methylene chain was varied systematically from n = 2 to n = 12 while the point of dimerization was held constant at position 6. The biological activities of these dimers were then evaluated on BK-induced smooth muscle contraction in two different isolated tissue preparations: guinea pig ileum (GPI) and rat uterus (RU). Several of the dimeric BK antagonists displayed remarkable activities and long durations of action. In addition, dimerization at position 4, 7, 8, or 9 produced dimeric analogues with markedly reduced potency. Rank order of antagonist potency as a function of dimerization position is as follows: rat uterus, 6 greater than 5 greater than 0 greater than 2 greater than 1 greater than 3 much greater than 4, 7, 8, 9; guinea pig ileum, 6 greater than 5 greater than 3 greater than 2 greater than 1 greater than 0 much greater than 4, 7, 8, 9. Evaluation of the linker length as represented by the number of methylene units indicated an optimal distance between the two monomeric peptides of six to eight methylene moieties. These studies also revealed that the carbon-chain length significantly affected the duration of action in vitro and resulted in partial agonism effects when n greater than 8. The optimum activity in vitro was achieved with dimerization at position 6 and n = 6 (designated herein as compound 25; alternatively, CP-0127). Similar effects in potency were also seen when the monomeric antagonist D-Arg0-Arg1-Pro2-Hyp3-Gly4-Phe5-Ser6-D-Phe 7-Phe8-Arg9 (NPC-567) was dimerized using similar chemistry. These results suggest that the development of BK antagonists of significant therapeutic potential may be possible using a dimerization strategy that can overcome the heretofore limiting problems of potency and in vivo duration of action found with many of the BK antagonists in the literature.

Amino Acid Sequence↗
PubMed1991

Association of psychiatric manifestations with antibodies to ribosomal P proteins in systemic lupus erythematosus.

PURPOSE: The goal of this study was to determine whether elevated serum levels of antibodies to ribosomal P proteins (anti-P antibodies) are associated with neuropsychiatric manifestations in patients with systemic lupus erythematosus (SLE). Additional experiments examined characteristics of these antibodies that might be associated with pathogenicity. PATIENTS AND METHODS: A large number of serum samples were collected from patients with SLE, control subjects with other rheumatic diseases, and normal individuals. At the time serum samples were obtained, patients with SLE were categorized according to the presence of psychosis, depression, and other manifestations of central nervous system (CNS) involvement. Serum anti-P antibody activity was quantitated by an enzyme-linked immunosorbent assay utilizing a synthetic peptide corresponding to the major P protein epitope. RESULTS: In a group of 79 normal individuals, mean (+/- SE) IgG anti-P activity was 0.01 +/- 0.003 and no individuals had values greater than 3 SD above the mean. Similar results were obtained measuring IgM anti-P activity. Normal levels were found in all sera from 21 patients with rheumatoid arthritis. Of 119 patients demonstrating various patterns of antinuclear and anticytoplasmic antibody activity, elevated anti-P levels were found only in patients with SLE. Overall, 19% of 269 patients with SLE demonstrated elevated levels of IgG or IgM anti-P antibodies, including 14% of 187 patients without and 29% of 82 patients with neuropsychiatric manifestations. The frequency of positive test results varied greatly depending on the nature of the CNS involvement. The frequency in patients with severe depression (n = 8) and psychosis (n = 29) was 88% and 45%, respectively, compared with only 9% in patients with nonpsychiatric neurologic disease (n = 45). For the entire SLE group, the odds ratio for the association of anti-P antibodies and severe psychiatric manifestations was 7.63 with a 95% confidence interval of 3.61 to 16.14. In a review of 187 patients with SLE originally classified as not having severe psychiatric disease, seven of 10 patients being treated with antidepressant medications had elevated levels of anti-P antibodies. In serial studies, the serum level of anti-P antibodies appeared to correlate with the activity of psychiatric disease and did not correlate with the activity of other manifestations of SLE. Anti-P antibodies in nearly all patients were IgG and directed primarily to the C-terminal 11 amino acids of the P protein. No difference in these characteristics was observed when patients with and without psychiatric manifestations were compared. Paired serum and cerebrospinal fluid (CSF) samples were also obtained from eight patients with active neuropsychiatric disease. Even when expressed as a fraction of the total IgG present, anti-P activity was markedly lower in CSF than in serum. CONCLUSIONS: Elevated levels of autoantibodies to the C-terminal region of ribosomal P proteins appear to be a specific marker for SLE, and are associated with both severe depression and psychosis in this disease. This assay is easily reproducible and may help distinguish SLE-induced psychiatric disease from that caused by other processes.

Adult↗
PubMed1989

Neuropeptide Y-containing nerves in rat gonads: sex difference and development.

The objectives of the present study were 1) to evaluate for a sex difference in innervation of adult rat gonads by neuropeptide Y-immunoreactive (NPY-I) nerves and 2) to examine the development of innervation of rat gonads by NPY-I nerves during the fetal and neonatal periods. With fluorescence immunocytochemistry, NPY-I nerves were profuse in adult ovarian tissues. Ovarian blood vessels were particularly well innervated by NPY-I nerves, and nerves were also detected in interstitial gland tissues. No nerves were found within the testis, and NPY-I nerves were only rarely located within the tunica albuginea. During fetal life, ovaries were devoid of NPY-I nerves; however, nerves were visualized within the connective tissue immediately peripheral to the ovary on fetal Day 22. As early as postnatal Day 2, NPY-I nerves were observed in connective tissue septa of the developing ovary. By postnatal Day 12, NPY-I nerves surrounded developing follicles and blood vessels of the ovarian cortex. In the developing testis after postnatal Day 5, NPY-I nerves were limited to the tunica albuginea and surrounding large subcapsular blood vessels. Structures within the testis lacked innervation by NPY-I nerves. These anatomical studies suggest that NPY-I nerves are absent in the gonads during fetal life and grow into the ovary and not the testis during the perinatal period and that NPY-I nerves may play a role in the functioning of the rat ovary, but may not be important in control of testicular function.

Animals↗
PubMed1988

Gonadal steroids and neuropeptide Y-opioid-LHRH axis: interactions and diversities.

We report that the two classes of regulatory neuropeptides, neuropeptide Y (NPY) and endogenous opioid peptides (EOP), modulate luteinizing hormone (LH) release in diverse fashion in gonad-intact rats. Each neuropeptide acts at two loci, the hypothalamus and pituitary, to excite (NPY) or inhibit (EOP) LH release. At the hypothalamic level, NPY stimulates luteinizing hormone releasing hormone (LHRH) release, a response mediated by alpha 2-adrenoreceptors and amplified in the presence of adrenergic agonists. At the pituitary level, NPY acts in concert with LHRH to amplify the LH response. In contrast, EOP inhibit LHRH release by decreasing the supply of excitatory adrenergic signals in the vicinity of LHRH neurons in the preoptic-tuberal pathway, and at the pituitary level, they decrease LH release in response to LHRH. Further, the gonadal steroidal milieu facilitates NPY neurosecretion and postsynaptic expression of NPY in concert with adrenergic system; a similar clear-cut facilitatory effect of gonadal steroids on EOP secretion is not yet obvious. Our additional studies imply that the EOP system has the potential to increase sensitivity towards gonadal steroids and that to induce the preovulatory LH surge the neural clock may decrease the inhibitory EOP tone prior to the critical period on proestrus. This antecedent neural event allows the excitatory adrenergic and NPY signals to evoke LHRH secretion at a higher frequency approximating that seen in ovariectomized rats. Further studies are under way to delineate the steroid-induced subcellular events that integrate the action of these regulatory peptides in the control of the episodic LHRH secretion pattern which sustains basal and cyclic gonadotropin release in the rat.

Androgens↗
PubMed1988

Evidence that a decrease in opioid tone on proestrus changes the episodic pattern of luteinizing hormone (LH) secretion: implications in the preovulatory LH hypersecretion.

We have studied the LH secretion pattern evoked by diminution in the opioid tone produced by iv naloxone (NAL) infusion between 1100-1400 h on proestrus, the LH secretion pattern occurring spontaneously between 1430-1730 h on proestrus and the LH secretion pattern produced by exogenous LHRH administered either as a 10 ng/pulse at 20-, 30-, or 60-min intervals or infused continuously at a rate of 30 ng/h between 1200-1700 h in rats given pentobarbital at 1100 h on proestrus. Infusion of 0.5 ng NAL/h raised plasma NAL levels to 200-300 ng/ml and augmented LH secretion, as evident by increments in pulse amplitude and frequency discharge to one every 37.5 min from an average of one every 75 min in saline-infused control rats. A 4-fold increase in circulating NAL levels, produced by 2 mg/h NAL infusion, further augmented the frequency of LH episodes to 30-33 min and induced a surge-like LH secretion pattern which resembled that seen on the afternoon of proestrus. Further analysis of the secretory pattern of the preovulatory LH surge (n = 7) showed LH pulses of increased amplitude during the basal phase (n = 4), ascending phase (n = 2), and plateau and descending phases (n = 3); in two rats the LH rise was steep, and no LH pulses were identified. A LHRH pulse (10 ng/pulse) delivered at 20- or 30-min intervals or continuous infusion of LHRH at a rate of 30 ng/h produced LH surges, with peak levels reaching the range seen on the afternoon of proestrus. Further, despite the fact that 10 ng LHRH/pulse at 20-min intervals reproduced a proestrous-type LH surge, only 40% of the LHRH pulses were followed by identifiable LH pulses. Surprisingly, despite the observations that NAL evoked robust LH episodes, the basal pattern of FSH secretion in these rats was not altered. These findings show that a decrease in opioid tone on proestrus accelerates episodic LH discharge to the range that occurs after gonadectomy. A quantitative relationship between the degree of restraint on the opioid tone imposed by NAL and the magnitude of the LH response can be demonstrated. The evidence suggests that the preovulatory LH surge may occur in an episodic fashion and that it can be reproduced by LHRH delivered at a frequency rate of LH pulses seen in ovariectomized rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Interactions between neuropeptide Y and adrenergic systems in the stimulation of luteinizing hormone release in steroid-primed ovariectomized rats.

Intraventricular injection of neuropeptide Y (NPY) stimulates LH release in estradiol benzoate- and progesterone-primed (EBP) ovariectomized rats. Because adrenergic neurotransmitters, norepinephrine (NE) and epinephrine (E), show intraneuronal coexistence with NPY in certain brain regions of the rat and there are similarities in the effects of NPY and NE/E on LH release, we investigated the possible interaction of NPY and adrenergic receptor systems in the stimulation of LH release in EBP-treated ovariectomized rats. The experiments were designed to determine whether NPY exerted its effects via adrenergic receptors and whether combined administrations of NPY and NE can act synergistically or in an additive manner to enhance the LH release response. Permanent stainless steel cannulae were placed in the third ventricle of the brain, and the rats were ovariectomized. Two weeks after surgery, rats were injected with EB (30 micrograms/rat) and P (15 mg/rat). Two days later, the effects of either vehicle alone (control) or various adrenergic and dopaminergic receptor antagonists and an opiate receptor agonist on stimulation of LH release by NPY were assessed. Intraventricular injection of 0.47 nmol NPY increased plasma LH levels at 10, 20, and 30 min in control rats. The NPY-induced LH response was not blocked by pretreatment with any of the following drugs: the alpha-adrenoreceptor antagonist phenoxybenzamine, the alpha 1-adrenoreceptor antagonist prazosin, beta-adrenoreceptor antagonist propranolol, the dopamine receptor antagonist pimozide, or the opiate receptor agonist morphine. All of these drugs affect LH release in other circumstances. On the other hand, the alpha 2-adrenoreceptor antagonist yohimbine significantly attenuated the NPY-induced LH increments. In the second study dealing with the possible synergistic or additive interactions between NPY and NE, we observed that when doses of NPY and NE that separately were only minimally effective in stimulating LH release were administered together, the amounts of LH secreted were greater than the sum of the individual responses. However, when NE and NPY were given together in doses that alone had either no stimulatory or maximal stimulatory effects, there were no additive or synergistic effects on LH release.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Evidence that a decrease in opioid tone may evoke preovulatory luteinizing hormone release in the rat.

We have assessed the effects on LH release of prolonged naloxone (NAL) treatment before the critical period on proestrus. When LH secretion was monitored at 5-min intervals immediately after the start of continuous NAL infusion (2 mg/0.6 ml saline X h iv) at 1000 h, two types of responses were observed. In three of six rats, a small increase (1-2 ng rat LHRH-2/ml) during the first hour was followed by a sharp rise to 4-5 ng/ml in the second hour and a gradual return to baseline levels (0.5-1.00 ng/ml) in the third hour of infusion. In the remaining rats, LH responses were small with peak levels reaching 2 ng/ml range. When the effects were monitored 1 h after starting NAL infusion at 1000 h, the LH response was improved. Peak LH levels observed shortly before or after 1200 h varied between 4-14 ng/ml and in some rats the levels were comparable to those seen normally in the afternoon of proestrus (9-24 ng/ml). However, delaying the start of NAL infusion to 1200 h produced LH surges before 1400 h, with peak levels (27.5 +/- 5.5 ng/ml) in the range of normal preovulatory LH surges (peak levels 16.6 +/- 2.5 ng/ml), followed by a steady decrease in LH secretion. Additionally, sc NAL pellets implanted at 0930 h provoked premature LH hypersecretion with a temporal pattern (0930-1430 h) and magnitude (peak levels, 26.3 +/- 4.3 ng/ml between 1100-1200 h) comparable to the normal preovulatory LH surge observed after 1330 h. Since NAL is believed to antagonize the inhibitory effects of endogenous opioids on LH secretion, the results of this study imply that a sustained restraint on this inhibitory opioid tone can elicit the LH surge before the critical period on proestrus. These findings are in accord with our thesis that the neural clock that normally triggers the preovulatory LH surge may transiently decrease the inhibitory opioid tone to allow expression of crucial neural events which culminate in preovulatory LH secretion.

Animals↗
PubMed1985

Comparison of the effects of neuropeptide Y and adrenergic transmitters on LH release and food intake in male rats.

In view of the recent demonstrations that Neuropeptide Y (NPY) and adrenergic transmitters coexist in neurons of the rat brain, we have compared the effects of intraventricular (Ivt) injections of NPY and catecholamines on LH release and food intake in intact male rats. Of the three catecholamines, dopamine (DA), norepinephrine (NE) and epinephrine (E), only E (5.3 micrograms or 15.9 micrograms/rat) significantly stimulated LH release, although NE and E (5.3 micrograms/rat) were equally effective in eliciting food intake in satiated rats. Ivt administration of 10 micrograms NPY significantly stimulated LH release, whereas either lower (0.5 or 2 micrograms/rat) or higher (25 micrograms/rat) doses were ineffective. In contrast, NPY at doses of 0.5 - 10 micrograms/rat increased cumulative food intake in a dose-related fashion. These findings present preliminary evidence of the physiological correlates of the neuronal coexistence of adrenergic transmitters and NPY in the brain and raise the possibility that NPY may normally act either independently, in concert with or via adrenergic systems to evoke LH release and feeding responses in the rat.

Animals↗
PubMed1985

Effects of abdominal vagotomy on serum LH concentrations in female rats.

Vagotomy on the morning of pro-oestrus did not prevent the pro-oestrous LH surge and rats became oestrous on the following day. However, vagotomized rats then exhibited a period of acyclicity which lasted for 20.4 +/- 1.3 (s.e.m.) days. Food intake and body weight also declined after vagotomy. During the first week after vagotomy, afternoon LH surges generally did not occur, a pattern which was similar in animals pair fed with vagotomized rats. However, pair-fed rats showed oestrous cycles while vagotomized rats were acyclic. At 7 days after vagotomy, LH surges were induced by oestradiol benzoate and progesterone treatment of ovariectomized rats. Vagotomy suppressed the post-ovariectomy increase in serum LH at 7 and 21 days after surgery. These results, combined with those of other studies, suggest impairment of LH release in vagotomized rats.

Animals↗
PubMed1979

Infant heart rate response to trigeminal airstream stimulation: determination of normal and deviant values.

In this study, trigeminal airstream stimulation is used on a group of normal, sleeping infants to screen for reflex bradycardia. Infants were tested at 1--3 days and at 4, 8, 12, and 16 weeks of age. The usual heart rate response was acceleration above the prestimulus level. The amount of heart rate change was seen to depend on prestimulus rate and, to a lesser extent, postconceptional age. Multiple regression analysis of the data provided estimates of expected responses, given postconceptional age and prestimulus heart rate. From these, ranges were established for classification of normal or abnormal responses. Six deviant data points over 2 SDs from expected values were identified. Two of these represented heart rate increases and four were heart rate decreases. One deviant heart rate decrease was over 3 SDs from the mean. Although the deviant increases were thought to represent exaggerated startles, the more severe heart rate decreases were believed to be a reflex resembling the diving reflex.

Heart Rate↗