Search PubMed⌕ Search

Biomedical subjects

T M Reilly

Publications and source records attributed to T M Reilly.

At least 73 records · Page 4Linked to original sources
PubMed1989

Antihypertensive mechanism of captopril in renal hypertensive rats: studies with a nonpeptide angiotensin II receptor antagonist and an angiotensin II monoclonal antibody.

The validity of using EXP6803, a nonpeptide angiotensin II (AII) receptor antagonist, and KAA8, an AII monoclonal antibody, as specific tools for studying the physiology of AII has been established previously. In this study, we used these specific probes to examine the role of blocking AII formation in the antihypertensive effect of captopril in conscious renal artery-ligated rats (RALRs), a high renin, renal hypertensive model. Mean arterial pressure and plasma renin activity in a typical group of RALRs averaged 175 +/- 5 mm Hg and 28.2 +/- 6.2 ng of angiotensin 1 per ml/hr (n = 6), respectively. The antihypertensive effect of captopril (3 mg/kg i.v.) was determined in RALRs given either EXP6803 (30 mg/kg + 2 mg/kg/min i.v.) or KAA8 (10 mg + 1 mg/min i.v. per rat) with the corresponding vehicle-treated RALRs. These doses of EXP6803 and KAA8 were very effective in blocking the pressor response to AII but not to norepinephrine or vasopressin in RALRs. Captopril decreased mean arterial pressure by 44 +/- 2 and 53 +/- 8 mm Hg in the groups treated with the vehicles of EXP6803 (n = 5) and KAA8 (n = 5), respectively. In the presence of EXP6803 (n = 5) or KAA8 (n = 5), the antihypertensive effect of captopril was almost or totally abolished. Indomethacin did not alter the antihypertensive effect of captopril. These results suggest that the antihypertensive effect of captopril in conscious RALRs is due mainly to the blockade of AII formation. Furthermore, circulating AII rather than locally formed AII appears to play a major role in maintaining hypertension in hypertension in RALRs.

Angiotensin II↗
PubMed1988

Characterization of a panel of monoclonal antibodies against human tissue-type plasminogen activator.

Five murine monoclonal antibodies have been produced against the 1-chain form of human tissue plasminogen activator (t-PA). Affinity constants, calculated from data generated in a solid phase radioimmunoassay, ranged from 4.9 x 10(8)M-1 to 2.3 x 10(9) M-1 for these antibodies. This panel was classified into three groups based on the antibodies' effects on both the plasminogen activation and amidolytic activities of t-PA: complete inhibitors (CD2), partial inhibitors (DB10), and those with limited effects (AE5, BA10 and EG2). This same pattern for the five antibodies was observed in an assay measuring the binding of 125I-t-PA to its fast-acting inhibitor, PAI-1. It is concluded that this panel of antibodies defines at least three domains on the t-PA molecule, including its catalytic site.

Antibodies, Monoclonal↗
PubMed1988

Characterization of the functional antagonism and antihypertensive activity displayed by a monoclonal antibody to angiotensin II.

In the present study, we have characterized the specificity and potency of KAA8, a monoclonal antibody displaying a high affinity for angiotensin II (AII), as a functional antagonist of AII in vitro and in vivo. In addition, we have studied its antihypertensive effect in the awake renal artery-ligated rat, whose elevated levels of plasma renin activity and sensitivity to captopril and saralasin define it as a renin-angiotensin system-dependent hypertensive model. Our results utilizing isolated rabbit aorta strips and pithed rats suggest that KAA8 is a specific AII functional antagonist because it selectively inhibited the AII response in these models without altering the effects of norepinephrine and vasopressin. In renal artery-ligated rats, KAA8, at 15 mg/kg i.v., decreased mean blood pressure from 148 +/- 3 to 119 +/- 4 mm Hg at 10 min postinjection (n = 9) and greatly inhibited the pressor response to AII but not to vasopressin. In contrast, a control immunoglobulin G1 molecule did not change mean blood pressure or influence the pressor effect of AII in this model. Pretreatment with captopril or saralasin, but not prazosin or hydralazine, blocked the antihypertensive effect of KAA8 in these renal hypertensive rats. These results suggest that the antibody KAA8 displays specific functional AII antagonism and, as such, may represent a specific probe for studying the physiologic roles of AII.

Angiotensin II↗
PubMed1987

Functional antagonism by monoclonal antibody to digoxin in the guinea-pig atria.

A monoclonal antibody with a high affinity for digoxin (Ka = 1.14 X 10(9) M) was produced by somatic cell fusion. This antibody, designated 35/6.1, displayed little or no cross reactivity with other steroids. In the guinea-pig atria, 35/6.1 antagonized functionally the positive inotropic effect of digoxin but did not alter that of isoproterenol. Our results suggest that this monoclonal antibody may represent a useful probe for studying the physiological role of the putative endogenous digoxin-like factor in various pathophysiological conditions.

Animals↗
PubMed1987

Monoclonal antibodies to angiotensin II.

Three hybridomas producing monoclonal antibodies to angiotensin II were generated using somatic cell fusion techniques. Dissociation constants, determined by Scatchard analysis of radioimmunoassay data, were 9.3 X 10(-10) M, 1.5 X 10(-9) M and 1.8 X 10(-8) M for antibodies KAA8, ICH2 and ICA10, respectively. The antibodies exhibited various degrees of cross-reactivity towards peptide metabolites of angiotensin II, but minimal cross-reactivity towards antagonists created by substituting the hormone at both the amino and carboxy terminus. In contrast to a rabbit polyclonal angiotensin II antibody preparation, the three monoclonal antibodies competed effectively with angiotensin receptors on rat adrenal cortical microsomes for hormone binding. These antibodies may have broad utility for a number of applications in angiotensin II research.

Adrenal Cortex↗
PubMed1987

A monoclonal anti-idiotypic antibody which mimics angiotensin II in inducing a population of anti-hormone antibodies.

IG12, a syngeneic monoclonal anti-idiotypic antibody, was raised against an idiotype on a monoclonal antibody, ICH2, with specificity for the octapeptide hormone angiotensin II (AII). Competitive radioimmunoassays, and ELISAs utilizing AII antiserum raised in different species (rats and rabbits), indicate that IG12 detects a private idiotypic determinant at or near the paratopic region of the ICH2 combining site. Immunization of syngeneic mice with either IG12 or IG12 coupled to keyhole limpet hemocyanin induced a population of anti-anti-idiotypic antibodies that shared two properties with ICH2: the binding of AII and the binding to IG12. Antibodies from these anti-anti-idiotypic populations were also partially active in inhibiting the interaction between AII and ICH2. To our knowledge, this is the first demonstration of a monoclonal anti-idiotypic antibody mimicking a physiological hormone in inducing a population of anti-hormone antibodies.

Angiotensin II↗
PubMed1986

Production of idiotypic and anti-idiotypic antibodies by BALB/c mice in response to immunizations with glucagon, vasopressin, or insulin: supporting evidence for the network concept.

After immunizations with glucagon or vasopressin, either conjugated to keyhole limpet hemocyanin or adsorbed to polyvinylpyrrolidone, both anti-hormone and anti-receptor activities were detectable in the serum of injected mice. Anti-hormone activity was identified by ELISA techniques; anti-receptor activity, by determining the ability of serum samples to compete with labeled hormone for glucagon or vasopressin receptors on rat liver plasma membranes. Anti-receptor activity appeared only after the peak anti-hormone response to each immunogen had been established, and required intensive immunizations (six to nine monthly injections). The presence of anti-idiotypic antibodies in serum samples containing glucagon or vasopressin anti-receptor activity was confirmed by demonstrating selective binding of such samples to corresponding rabbit idiotypic antibodies. Serum from mice immunized with insulin also contained anti-hormone activity, as determined by ELISA, and anti-receptor activity, as determined by noting insulin-mimicking properties in stimulating glucose transport in rat adipocytes. The anti-insulin receptor activity developed after only one boost with the hormone. These results are consistent with Jerne's network hypothesis in that the glucagon, vasopressin, and insulin anti-receptor activity may be attributed to antibodies produced in mice as part of an idiotypic-anti-idiotypic network.

Animals↗
PubMed1986

The presentation and treatment of delusional parasitosis: a dermatological perspective.

A postal survey of dermatologists identified 365 patients with a presumptive diagnosis of delusional parasitosis. One hundred and forty-four dermatologists had seen at least 1 such patient in the previous 5 years and 78 were current. The data provided on 53 patients who met the study criteria were examined in more detail. Racial origin, marital status and age at presentation varied widely. Females predominated in the older age-groups, but there was an equal sex distribution under the age of 50. Abnormal personality traits were commonly identified, especially of the obsessional type. Physical disorders associated with pruritus co-existed in a substantial minority. Previous dermatological and psychiatric disorders were uncommon and non-specific. The disorder was often, though not invariably, of long duration. Relatively few patients were successfully referred to psychiatrists. Dermatologists often treated the disorder effectively, especially when neuroleptic agents were employed. Pimozide appeared to be particularly helpful in many patients.

Adult↗
PubMed1982

On the mechanism of isoproterenol-induced desensitization of adenylate cyclase in cultured differentiated hepatocytes.

The adenylate cyclase of cultured differentiated RL-PR-C hepatocytes is desensitized to 1-isoproterenol by exposure to this beta-agonist. Virtually complete desensitization occurred by 60 min (intact cells) or 30 min (isolated plasma membranes). Isoproterenol was maximally effective at 10 micrometers, although substantial desensitization occurred at isoproterenol concentrations as low as 10 nM. Protein synthesis was not required for desensitization. Recovery from desensitization under tissue culture conditions was only 25% complete by 24 h. Maximum desensitization was accompanied by only a modest 35% decrease in binding sites (as determined by binding assays with [3H]dihydroalprenolol), with no change in binding affinity. Adenylate cyclase desensitized to 1-isoproterenol responded normally to guanine nucleotides and to fluoride, suggesting that the regulatory and catalytic proteins were not the sites of the desensitization "defect'. Using N-ethylmaleiimide to inactive the regulatory and catalytic proteins, and dicyclohexylcarbodiimide to inactivate the beta-adrenergic receptor, of intact hepatocytes, various heterologous cell fusion hybrids were produced, and their adenylate cyclases tested for responsiveness to 1-isoproterenol; only hybrids containing "desensitized' receptor failed to respond to isoproterenol. These results suggest that the mechanism of desensitization to isoproterenol involves only the receptor component of the receptor-regulatory protein(s)-adenylate cyclase complex, and that the receptors are reduced in number and/or ability to interact with the regulatory protein as a result of the desensitization process.

Adenylyl Cyclases↗
PubMed1981

Interaction of guanine nucleotides with adenylate cyclase in normal and spontaneously transformed RL-RP-C cloned rat hepatocytes.

Spontaneous transformation of RL-PR-C hepatocytes leads to alterations in the adenylate cyclase complex which include a lower than normal basal level of activity, a loss of sensitivity to exogenous GTP, and a decreased sensitivity to isoproterenol. Both normal and transformed membranes possess substantial GTPase activity. Treatment of transformed hepatocyte membranes with either isoproterenol plus GMP or with cholera toxin, under conditions that displace tightly bound GDP, restored the GTP effect on adenylate cyclase, and eliminated the lag in the activation by guanyl-5'-yl-imidodiphosphate. Such pretreatment also enhanced guanine nucleotide effects on the adenylate cyclase of normal hepatocytes. These results are explainable on the basis that transformation increases adenylate cyclase-associated GTPase activity, and increases occupancy of nucleotide regulatory sites by inactive or inhibitory guanine nucleotides, e.g., GDP. Seemingly, both catecholamines and cholera toxin promote an exchange reaction at the regulatory sites, resulting in clearance of these sites of inhibitory nucleotides.

Adenylyl Cyclases↗
PubMed1981

Restoration of glucagon responsiveness in spontaneously transformed rat hepatocytes (RL-PR-C) by fusion with normal progenitor cells and rat liver plasma membranes.

Spontaneously transformed RL-PR-C rat hepatocytes, unlike their normal differentiated progenitor cells, are insensitive to glucagon, although seemingly possessing large numbers of glucagon receptors and although retaining guanyl nucleotide regulatory protein-adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] system that responds to catecholamines, cholera toxin, and fluoride ions. Biochemical fusions between normal RL-PR-C hepatocytes or purified rat liver plasma membranes (whose adenylate cyclases were previously irreversibly inactivated with N-ethylmaleimide) with spontaneously transformed hepatocytes produced hybrids whose basal and fluoride-stimulated adenylate cyclase activities reflected those of the parental transformed cells but that now responded to glucagon. Using cholera toxin-catalyzed ADP-riboxylation of transformed hepatocytes to mark their guanyl nucleotide regulatory protein, fusiong such cells with N-ethylmaleimide-treated normal hepatocytes, and examining glucagon stimulation of adenylate cyclase activity in fusion hybrids produced results suggesting that the regulatory protein of the transformed cells is functionally normal. In fusion experiments between N-ethylmaleimide-treated hepatocytes and igeon erythrocytes, we found that normal, but not transformed, hepatocytes were effective in conferring glucagon sensitivity upon erythrocytes. Glucagon binding data revealed that, whereas normal RL-PR-C hepatocytes have two independent classes of binding sites, one of higher and the other of lower affinity, transformed cells possess only the low-affinity receptors. From these and previous observations, it is possible to conclude that the insensitivity of spontaneously transformed RL-PR-C hepatocytes to glucagon is due to the loss, during the transformation process, of the high-affinity glucagon receptor.

Adenylyl Cyclase Inhibitors↗
PubMed1978

Successful treatment with pimozide of delusional parasitosis.

An introduction to the concept of delusional parasitosis is presented. The persistent and refractory nature of the condition is emphasized. A case history is described in which a 67-year-old spinster, with classical symptoms of this condition, responded extremely favourably to simply administered pharmacotherapy. The authors allude to five similar patients also treated successfully by the same method. It is suggested that dermatologists might profitably treat this condition without recourse to psychiatric referral, which can often be counter-productive.

Aged↗