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Biomedical subjects

S E Ross

Publications and source records attributed to S E Ross.

At least 19 recordsLinked to original sources
PubMed1999

Biochemical characterization of alpha-ketooxadiazole inhibitors of elastases.

A series of alpha-ketooxadiazole compounds was prepared and evaluated in vitro as potential inhibitors of human neutrophil elastase (HNE), proteinase-3 (PR-3), and porcine pancreatic elastase (PPE). Several compounds have been found to be very potent, fast, reversible, and selective inhibitors of HNE with Ki values below 100 pM. The highest kon value exceeded 10(7) M(-1) s(-1). Some alpha-ketooxadiazoles were also very effective against PR-3 and PPE with Ki values in the range of 5(-10) nM and 0.1(-2) nM, respectively. The two rings, 1,2,4- and 1,3,4-oxadiazole, are amenable to substitutions, extending the P' side of the inhibitor and allowing additional binding interactions at S' subsites of the enzyme. Nonpeptidic HNE inhibitors containing the oxadiazole heterocycle displayed promising oral bioavailability.

Cathepsin G↗
PubMed1999

Carboxyhemoglobin elevation in trauma victims.

BACKGROUND: Products of the hemeoxygenase enzyme include carboxyhemoglobin (COH) and bilirubin, which have protective effects in stressed states. Hemeoxygenase-1 enzyme up-regulates in states of oxidative stress. We hypothesized that COH is elevated in septic trauma patients compared with nonseptic patients. METHODS: A prospective study was carried out at a Level I trauma center involving all patients admitted to the trauma intensive care unit. During a 3.5-month period, 45 patients were enrolled, with 76 samples being drawn on admission and at later time points. The samples were classified as septic (Bone's criteria), stressed (based on expired gas analysis), or nonstressed nonseptic. Correlations with Acute Physiology and Chronic Health Evaluation III score, white blood cell count, temperature, partial pressure of oxygen, and percentage of inspired oxygen were evaluated. RESULTS: COH levels in samples drawn from patients presenting in shock (systolic blood pressure < or =90 mm Hg) were significantly higher than levels in samples from patients not in shock (systolic blood pressure >90 mm Hg) (3.27+/-1.09 vs. 2.75+/-0.64; p = 0.013). Samples from septic patients with infection were associated with significantly higher Injury Severity Scores (34.1+/-11.2 vs. 21.8+/-18.3; p< or =0.05) and a lower percentage of inspired oxygen (41.6+/-10.3 vs. 61.0+/-26.3; p< or =0.05). CONCLUSION: COH was significantly elevated in samples drawn during stress, sepsis, and shock states. There was overlap between sepsis and stress COH sample values, limiting the clinical usefulness of the assays in predicting sepsis. Further studies focusing on hemeoxygenase-1 expression and the role of its by-products in the outcomes of trauma patients are warranted.

APACHE↗
PubMed1999

Central nervous system metabolic and physiologic effects of laparoscopy.

We set out to determine whether the increases in intracranial pressure (ICP) associated with CO2 insufflation had any metabolic effect on the central nervous system in a head injury when compared with gasless laparoscopy (GL). To test this hypothesis, we looked at both the ICP and jugular bulb venous saturation (JVS), with and without a coexisting cerebral mass lesion. Twenty-five kilogram male pigs had tracheostomy, epidural balloon, pulmonary arterial catheter, arterial line, and jugular bulb catheter placed. Intravenous Pentobarbital was used for anesthesia. Either CO2 laparoscopy (CL; n=7) or GL (n=7) were performed both with and without an epidural balloon inflated to a baseline ICP of 25. Data were analyzed using the Student's t test with a P value <0.05 being significant. Cerebral perfusion pressure and most hemodynamic values did not differ. Both central venous pressure and peak inspiratory pressure were significantly elevated whenever CO2 insufflation took place, reflecting an increased intrathoracic pressure. When comparing both study groups, the partial pressure of CO2 did not differ. CL increases ICP significantly above the gasless group in our head injury model. This is most likely secondary to increased intrathoracic pressure. The question still remains whether these changes are clinically significant. We could not demonstrate significant metabolic effects secondary to laparoscopy. In patients suffering head injury, GL rather than CL might be safer to avoid ICP elevation. Additional studies looking at central nervous system metabolic and objective histopathologic effects should be undertaken with larger numbers of study animals.

Animals↗
PubMed1998

A role for the p38 mitogen-activated protein kinase/Hsp 27 pathway in cholecystokinin-induced changes in the actin cytoskeleton in rat pancreatic acini.

Cholecystokinin (CCK) and other pancreatic secretagogues have recently been shown to activate signaling kinase cascades in pancreatic acinar cells, leading to the activation of extracellular signal-regulated kinases and Jun N-terminal kinases. We now show the presence of a third kinase cascade activating p38 mitogen-activated protein (MAP) kinase in isolated rat pancreatic acini. CCK and osmotic stress induced by sorbitol activated p38 MAP kinase within minutes; their effects were dose-dependent, with maximal activation of 2.8- and 4.4-fold, respectively. The effects of carbachol and bombesin on p38 MAP kinase activity were similar to those of CCK, whereas phorbol ester, epidermal growth factor, and vasoactive intestinal polypeptide stimulated p38 MAP kinase by 2-fold or less. Both CCK and sorbitol also increased the tyrosyl phosphorylation of p38 MAP kinase. Using the specific inhibitor of p38 MAP kinase, SB 203580, we found that p38 MAP kinase activity was required for MAP kinase-activated protein kinase-2 activation in pancreatic acini. SB 203580 reduced the level of basal phosphorylation and blocked the increased phosphorylation of Hsp 27 after stimulation with either CCK or sorbitol. CCK treatment induced an initial rapid decrease in total F-actin content of acini, followed by an increase after 40 min. Preincubation with SB 203580 significantly inhibited these changes in F-actin content. Staining of the actin cytoskeleton with rhodamine-conjugated phalloidin and analysis by confocal fluorescence microscopy showed disruption of the actin cytoskeleton after 10 and 40 min of CCK stimulation. Pretreatment with SB 203580 reduced these changes. These findings demonstrate that the activation of p38 MAP kinase is involved not only in response to stress, but also in physiological signaling by gastrointestinal hormones such as CCK, where activation of Gq-coupled receptors stimulates a cascade in which p38 MAP kinase activates MAP kinase-activated protein kinase-2, resulting in Hsp 27 phosphorylation. Activation of p38 MAP kinase, most likely through phosphorylation of Hsp 27, plays a role in the organization of the actin cytoskeleton in pancreatic acini.

Actins↗
PubMed1998

Regulation of CCAAT/enhancer binding protein alpha (C/EBP alpha) gene expression by thiazolidinediones in 3T3-L1 adipocytes.

Thiazolidinediones are a class of antidiabetic drugs that induce preadipocyte differentiation by binding and activating peroxisome proliferator-activated receptor gamma 2. Although thiazolidinediones are commonly thought of as insulin-sensitizing agents, these drugs have opposing and antagonistic effects to that of insulin on CCAAT/enhancer binding protein alpha (C/EBP alpha) gene expression in fully differentiated 3T3-L1 adipocytes. Thiazolidinediones induce expression of C/EBP alpha mRNA and protein, while insulin stimulates a rapid decline in C/EBP alpha mRNA and protein. When added in combination, thiazolidinediones block the suppression of C/EBP alpha mRNA by insulin; however, thiazolidinediones do not block the insulin-induced decline in GLUT4 mRNA, indicating that repression of C/EBP alpha mRNA is not required for insulin to suppress expression of a C/EBP alpha-responsive gene such as GLUT4. Instead, insulin may regulate GLUT4 mRNA by inactivating C/EBP alpha through dephosphorylation as well as by inducing the expression of the dominant-negative form of C/EBP beta (liver inhibitory protein), since both of these processes occur in the presence of thiazolidinediones.

3T3 Cells↗
PubMed1998

Therapeutic actions of cyclosporine and anti-tumor necrosis factor alpha in collagen-induced arthritis and the effect of combination therapy.

OBJECTIVE: To define the mechanisms of action of 2 novel drugs, cyclosporine and anti-tumor necrosis factor alpha (TNFalpha), in collagen-induced arthritis and to determine the effect of combination therapy. METHODS: Type II collagen-immunized DBA/1 mice with established arthritis were treated with cyclosporine alone, anti-TNFalpha alone, cyclosporine plus anti-TNFalpha, or saline. RESULTS: Cyclosporine was found to ameliorate arthritis, suppress interferon-gamma (IFNgamma) production by CD4+ T cells, and reduce TNFalpha expression in arthritic joints. However, cyclosporine did not directly inhibit TNFalpha production by macrophages, indicating that the decrease in TNFalpha expression observed in vivo was probably an indirect consequence of the reduction in type 1 T helper cell activity. Anti-TNFalpha also reduced IFNgamma production by T cells, indicating that TNFalpha is involved in the cellular immune response to collagen. Combined treatment with cyclosporine plus anti-TNFalpha had an additive therapeutic effect. CONCLUSION: Although cyclosporine and anti-TNFalpha target different points in the inflammatory pathway, there is an overlap in the consequences of their actions in vivo.

Animals↗
PubMed1998

Rapid sequence induction for intubation by an aeromedical transport team: a critical analysis.

Airway control is the initial priority in the management of the injured patient. The purpose of this investigation was to evaluate the experience of an aeromedical transport team in the utilization of rapid sequence induction (RSI) for endotracheal intubation in the prehospital setting. Records of a consecutive series of injured patients undergoing RSI between June 1988 and July 1992 by a university-based aeromedical transport team were reviewed for demographics, intubation mishaps, and pulmonary complications. The relationship between intubation mishaps and pulmonary complications was analyzed. Eighty-four patients were studied with a mean age of 30.8 +/- 15.3 years. The mean Revised Trauma Score was 11.3 +/- 2.4, and the mean Injury Severity Score (ISS) was 19.6 +/- 11.5. Intubation mishaps occurred in 15 patients (18%), and pulmonary complications developed in 22 (29%) of the 75 patients surviving longer than 24 hours. There was no relationship between intubation mishaps and pulmonary complications. Abbreviated Injury Scale (AIS) face score was significantly higher in patients with intubation mishaps, compared with patients without mishaps (1.1 +/- 1.2 and 0.5 +/- 0.9, respectively, P < .05, Wilcoxon rank-sum). ISS and AIS chest were higher in patients with pulmonary complications, compared with those without (25.7 +/- 12.6 and 17.4 +/- 10.3 and 2.2 +/- 1.8 and 1.0 +/- 1.5, ISS and AIS respectively; P < .05, Wilcoxon rank-sum). Eighty-one patients (96%) underwent successful RSI, 73 (87%) on the first attempt. Failure to intubate occurred in three patients (4%). Performed under strict protocol by appropriately trained aeromedical transport personnel, RSI is an effective means to facilitate endotracheal intubation in the injured patient requiring definitive airway control. Pulmonary complications were related to injury severity and not to intubation mishaps.

Adolescent↗
PubMed1998

Ureteral trauma: preoperative studies neither predict injury nor prevent missed injuries.

BACKGROUND: Ureteral injuries are uncommon, and the necessity, accuracy, and optimal use of perioperative testing remains unknown. Delays in diagnosis have also been associated with significant morbidity, including loss of renal function. STUDY DESIGN: The records of all patients (n = 20) admitted with ureteral injuries to two Level I trauma centers during a 5-year period were reviewed. Data collected included patient demographics, mechanism of injury, degree of associated injuries, and presence of gross or microscopic hematuria. The use of any pre- or intraoperative testing was specifically noted. The location of the ureteral injury was obtained from the operative notes. The morbidity and mortality associated with ureteral injuries in the primarily diagnosed and the delayed groups were assessed. Presenting signs and symptoms, diagnostic testing, and the urologic management of the patients in the delayed group were reviewed. RESULTS: All patients were men whose ages ranged from 15 to 72 years, with a mean age of 29. The mechanisms of injury were gunshot wounds in 15, stab wounds in 4, and blunt vehicular trauma in 1. Excluding other urologic injuries, the incidence of hematuria related to the ureteral injury alone was 53%. A total of 10 pre- and intraoperative studies were performed, only 2 demonstrated the ureteral injury. Seventeen patients had their injuries diagnosed primarily. In this group, the ureter was repaired by suturing and stenting in 12, suturing without a stent in 1 and ureterocystostomy in 4. Delayed diagnosis of their ureteral injuries occurred in three patients. All three missed injuries occurred in the upper portion of the left ureter. All ureters were successfully repaired. There were no mortalities in this group, nor did any patient require a nephrectomy. CONCLUSIONS: Direct visualization of the injury is the best and most accurate diagnostic modality in ureteral trauma. These results reinforce that a thorough exploration of all retroperitoneal hematomas after penetrating trauma remain an integral part of the total abdominal exploration for trauma.

Abdominal Injuries↗
PubMed1998

Efficacy of the motor component of the Glasgow Coma Scale in trauma triage.

BACKGROUND: National guidelines recommend that patients with Glasgow Coma Scale (GCS) scores of less than 14 be triaged to trauma centers. We hypothesized that the motor component of the GCS (GCSM) would be equally sensitive as the total GCS in head injury triage. METHODS: A 2-year retrospective review of 3,235 injured adults transported directly to a Level I trauma center. RESULTS: One thousand four hundred ten patients (44%) had prehospital GCS scores recorded. GCSM was found to have a sensitivity of 0.90 for Abbreviated Injury Scale (AIS) score = 5 head injury and 0.61 for AIS score > 3 injury, whereas the GCS had sensitivities of 0.92 and 0.62, respectively (p = not significant). Specificities were equal at 0.85 for AIS score = 5 and 0.89 for AIS score > 3. CONCLUSION: GCSM is equivalent to GCS for prehospital triage, and in view of its simplicity it should replace the GCS in triage schemes.

Adolescent↗
PubMed1997

Suppression of TNF-alpha expression, inhibition of Th1 activity, and amelioration of collagen-induced arthritis by rolipram.

Rolipram is a type IV phosphodiesterase inhibitor that suppresses inflammation and TNF-alpha production. As anti-TNF-alpha therapy is effective in rheumatoid arthritis, we investigated the effect of rolipram on collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. Rolipram was administered after the onset of clinical arthritis at doses of 0.5, 3, 5, or 10 mg/kg twice daily, with a dose-dependent therapeutic effect on clinical severity and joint erosion. Immunohistochemical analysis of joints of rolipram-treated mice revealed 67% reduction in TNF-alpha-expressing cells compared with control arthritic mice. In vitro studies using bone marrow-derived macrophages confirmed that rolipram directly suppressed TNF-alpha and IL-12 production following stimulation with IFN-gamma and LPS. The effect of rolipram on T cell activity was studied by measuring Th1/Th2 cytokine production by collagen-stimulated draining lymph node cells from arthritic mice treated in vivo with rolipram. Rolipram reduced IFN-gamma production and increased IL-10, indicating that rolipram down-regulated the ongoing Th1 response to type II collagen. Finally, the effect on CIA of combination therapy was studied using rolipram plus either anti-TNF-alpha or anti-CD4 mAbs. Rolipram plus anti-TNF-alpha was not therapeutically additive, whereas rolipram plus anti-CD4 mAb was clearly additive. This result indicates that the therapeutic effects of rolipram overlap with TNF-alpha blockade, but are complementary to anti-CD4 treatment. It is therefore proposed that a major mechanism of action of rolipram in CIA is suppression of TNF-alpha activity. These findings suggest that type IV phosphodiesterase inhibitors may be effective in pathologic conditions, such as RA, with overexpression of TNF-alpha.

Animals↗
PubMed1997

Signaling pathways through which insulin regulates CCAAT/enhancer binding protein alpha (C/EBPalpha) phosphorylation and gene expression in 3T3-L1 adipocytes. Correlation with GLUT4 gene expression.

Treatment of 3T3-L1 adipocytes with insulin (IC50 approximately 200 pM insulin) or insulin-like growth factor-1 (IC50 approximately 200 pM IGF-1) stimulates dephosphorylation of CCAAT/enhancer binding protein alpha (C/EBPalpha), a transcription factor involved in preadipocyte differentiation. As assessed by immunoblot analysis of one- and two-dimensional PAGE, insulin appears to dephosphorylate one site within p30C/EBPalpha and an additional site within p42C/EBPalpha. Consistent with insulin causing dephosphorylation of C/EBPalpha through activation of phosphatidylinositol 3-kinase, addition of phosphatidylinositol 3-kinase inhibitors (e.g. wortmannin) blocks insulin-stimulated dephosphorylation of C/EBPalpha. In the absence of insulin, wortmannin or LY294002 enhance C/EBPalpha phosphorylation. Similarly, blocking the activity of FKBP-rapamycin-associated protein with rapamycin increases phosphorylation of C/EBPalpha in the absence of insulin. Dephosphorylation of C/EBPalpha by insulin is partially blocked by rapamycin, consistent with a model in which activation of FKBP-rapamycin-associated protein by phosphatidylinositol 3-kinase results in dephosphorylation of C/EBPalpha. The dephosphorylation of C/EBPalpha by insulin, in conjunction with the insulin-dependent decline in C/EBPalpha mRNA and protein, has been hypothesized to play a role in repression of GLUT4 transcription by insulin. Consistent with this hypothesis, the decline of GLUT4 mRNA following exposure of adipocytes to insulin correlates with dephosphorylation of C/EBPalpha. However, the repression of C/EBPalpha mRNA and protein levels by insulin is blocked with an inhibitor of the mitogen-activated protein kinase pathway without blocking the repression of GLUT4 mRNA, thus dissociating the regulation of C/EBPalpha and GLUT4 mRNAs by insulin. A decline in C/EBPalpha mRNA and protein may not be required to suppress GLUT4 transcription because insulin also induces expression of the dominant-negative form of C/EBPbeta (liver inhibitory protein), which blocks transactivation by C/EBP transcription factors.

3T3 Cells↗
PubMed1997

T cell receptor-induced phosphorylation of Sos requires activity of CD45, Lck, and protein kinase C, but not ERK.

Stimulation of the T cell antigen receptor (TCR) activates signaling pathways involving protein kinases, phospholipase Cgamma1, and Ras. How these second messengers interact to initiate distal activation events is an area of intense scrutiny. In this report, we confirm that TCR ligation results in phosphorylation of Sos, a guanine nucleotide exchange factor for Ras. This requires expression of both the CD45 tyrosine phosphatase and the Lck protein tyrosine kinase and depends upon signaling via protein kinase C. In contrast to previous studies examining requirements for Sos phosphorylation following insulin and epidermal growth factor receptor engagement, we show that TCR-induced phosphorylation of Sos does not require activation of the mitogen-activated protein kinase/extracellular-signal regulated kinase (MEK/ERK) pathway. However, the basal phosphorylation of Sos in T cells is affected by either MEK or MEK-dependent kinases. Although Sos phosphorylation results in its dissociation from Grb2 following insulin stimulation in Chinese hamster ovary cells, TCR engagement on the Jurkat T cell line fails to elicit a similar effect. These data demonstrate that the kinases responsible for Sos phosphorylation differ following ligation of various cell surface receptors and that the consequences of Sos phosphorylation relies, at least in part, on sites of its phosphorylation.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Three domains of SLP-76 are required for its optimal function in a T cell line.

We and others have shown that overexpression of SLP-76 augments TCR-stimulated IL-2 promoter activity in the Jurkat T cell line. In this report we investigate the signaling mechanisms through which SLP-76 mediates its effect on T cell activation. We show that overexpressed SLP-76 acts downstream of TCR-stimulated protein tyrosine kinases, but does not affect calcium signaling. Overexpression of SLP-76 does, however, augment TCR stimulation of both ERK (extracellular signal-regulated kinase) activity and a reporter construct driven by activating protein-1 binding sites. Structure/function analysis reveals that three distinct regions of SLP-76, each important for protein associations, are required for augmentation of TCR-induced nuclear factor-AT activity. These data suggest that SLP-76 functions as an adapter molecule that requires three unique domains to link proximal TCR signals in T cells.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Bradykinin antagonists in human systems: correlation between receptor binding, calcium signalling in isolated cells, and functional activity in isolated ileum.

The determination of the relationship between ligand affinity and bioactivity is important for the understanding of receptor function in biological systems and for drug development. Several physiological and pathophysiological functions of bradykinin (BK) are mediated via the B2 receptor. In this study, we have examined the relationship between B2 receptor (soluble and membrane-bound) binding of BK peptidic antagonists, inhibition of calcium signalling at a cellular level, and in vitro inhibition of ileum contraction. Only human systems were employed in the experiments. Good correlations between the studied activities of BK antagonists were observed for a variety of different peptidic structures. The correlation coefficients (r) were in the range of 0.905 to 0.955. In addition, we analyzed the effect of the C-terminal Arg9 removal from BK and its analogs on B2 receptor binding. The ratios of binding constants (Ki(+Arg)/Ki(-Arg)) for the Arg9 containing compounds and the corresponding des-Arg9 analogs varied from about 10 to 250,000. These ratios strongly depend on the chemical structures of the compounds. The highest ratios were observed for two natural agonist pairs, BK/des-Arg9-BK and Lys0-BK/des-Arg9-Lys0-BK.

Bradykinin↗
PubMed1997

Surface expression of hemopoietic cell phosphatase fails to complement CD45 deficiency and inhibits TCR-mediated signal transduction in a Jurkat T cell clone.

Previous studies have shown that the protein tyrosine phosphatase CD45 is required for initiation of signal transduction through several lymphoid receptors. In contrast, there is increasing evidence that another protein tyrosine phosphatase, hemopoietic cell phosphatase (known as HCP, SHP, PTP1C, SHPTP-1, or PTPN6), is a negative regulator of signaling in hemopoietic cells. To determine the effect of HCP on signal transduction through the TCR, HCP was expressed as a chimeric molecule with extracellular and transmembrane domains of the HLA-A2 molecule (A2/HCP) on wild-type Jurkat T cells and the CD45-deficient variant, J45.01. In this report, we show that expression of A2/HCP, unlike A2 chimeras containing the enzymatic regions of CD45, fails to rescue TCR-mediated signal transduction in J45.01. Furthermore, expression of A2/HCP on wild-type Jurkat T cells results in diminished inositol phosphate production following TCR ligation as well as markedly diminished nuclear factor of activated T cells promoter activity. Surprisingly, however, TCR-mediated tyrosine phosphorylation of phospholipase C gamma 1 remains intact in the Jurkat cells expressing the A2/HCP chimera. These experiments provide further evidence that HCP can serve a negative regulatory role in receptor-mediated signaling in immune cells. Additionally, our studies suggest that surface expression of HCP in T cells may provide a means to identify phosphotyrosine-containing proteins that are required for coupling signaling pathways initiated by ligation of the T cell Ag receptor.

Calcium↗
PubMed1997

Secondary emergency department triage (supertriage) and trauma team activation: effects on resource utilization and patient care.

BACKGROUND: Not all field triage patients need full trauma team activation. Secondary emergency department (ED) triage (supertriage), a clinical and anatomic screen, determines trauma team versus ED management. The purpose was to study the effects of supertriage on injury severity and disposition by patients managed with and without team activation. METHODS: Observational study of consecutive patients transported for alert consideration undergoing supertriage by a trauma nurse. Chart review was performed for disposition and Injury Severity Score. Contingency table or t test with p < or = 0.05 was used for data analysis. RESULTS: One hundred ninety patients were screened; 74% of the 54 with positive supertriage and team activation needed the operating room in 24 hours or the intensive care unit versus 46% of cases with negative supertriage managed in the ED and admitted (p = 0.015). Of the 35 admitted ED patients, 10 required the operating room and 6 required the intensive care unit. CONCLUSIONS: Supertriage identified a majority requiring team activation; however, resources must be available for the seriously injured not meeting field or hospital triage criteria.

Adolescent↗
PubMed1997

In vitro studies of a bradykinin B1/B2 antagonist linked to a human neutrophil elastase inhibitor; a heterodimer for the treatment of inflammatory disorders.

Inflammatory disorders typically have a complex etiology and involve a multitude of inflammatory mediators, and hence, a polytherapeutic approach to these diseases would seem appropriate. In certain chronic inflammatory conditions, we believe that bradykinin (BK) and human neutrophil elastase (HNE) are cooperatively involved. We have previously synthesized compounds with inhibitory activity toward both the BK B2 receptor and HNE. The present study describes single compounds designed to incorporate HNE inhibitory activity and BK B1 and B2 antagonist activity. A proprietary HNE inhibitor (HNEI, CP-955) was directly linked via amide bond formation to a peptide-based combined BK B1/B2 antagonist (B-9430). Three compounds were made using different linking positions in the antagonist peptide. For all compounds, B1 and B2 receptor binding in human cloned receptors was at least 10-fold less than that of B-9430, whereas in the in vitro guinea pig ileum B2 receptor functional assay, the compounds had potencies equivalent to B-9430. Compound I was found to have a fourfold increase in HNEI activity compared with CP-955, whereas compounds II and III were inactive. These data clearly demonstrate that it is possible to retain BK B1/B2 receptor antagonist and HNE activity in a heterodimer.

Amino Acid Sequence↗