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At least 109 records · Page 6Linked to original sources
PubMed2003

Benefit of using a triple-lumen catheter to monitor left atrial pressure.

BACKGROUND: Left atrial pressure (LAP) monitoring provides a useful option for management of hemodynamic status in pediatric open-heart surgical patients during the postoperative period. PATIENTS AND METHOD: We used a triple-lumen catheter placed into the left atrium transseptally to measure left atrial pressure. Twenty children that were operated on in our clinic are included in this study: 11 males and nine females. A 5-Fr. triple-lumen radio-opaque polyethylene catheter was used for the procedure. After the repair of the primary cardiac defect, the distal end of the catheter was repositioned transseptally and advanced into the left atrium. The proximal and middle line's distal orifices were left in the right atrium. Distal line was used as a left atrial pressure line, the middle line as a central venous pressure line, and the proximal line as a route for fluid infusion or drug administration. RESULTS: No mortality and no catheter-related complication were observed. No failure or complication occurred during withdrawal of the catheter. CONCLUSION: We conclude that this preliminary technique can be a useful and easy way of monitoring LAP, as well as providing central venous access.

Atrial Function, Left↗
PubMed2005

Development and positioning reliability of a TMS coil holder for headache research.

OBJECTIVE: Accurate and reproducible coil positioning is important for headache research using transcranial magnetic stimulation protocols. We aimed to design a transcranial magnetic stimulation coil holder and demonstrate reliability of test-retest coil positioning. METHODS: A coil holder was developed and manufactured according to three principles of stability, durability, and three-dimensional positional accuracy. Reliability of coil positioning was assessed by stimulating over the motor cortex of four neurologically normal subjects and recording finger muscle responses, both at a test phase and a retest phase several hours later. RESULTS: In all four subjects, repositioning of the transcranial magnetic stimulation coil solely on the basis of coil holder coordinates was accurate to within 2 mm. CONCLUSIONS: The coil holder demonstrated good test-retest reliability of coil positioning, and is thus a promising tool for transcranial magnetic stimulation-based headache research, particularly studies of prophylactic drug effect where several laboratory visits with identical coil positioning are necessary.

Equipment Design↗
PubMed1994

Sensitivity of wild-type human immunodeficiency virus type 1 reverse transcriptase to dideoxynucleotides depends on template length; the sensitivity of drug-resistant mutants does not.

Analysis of the three-dimensional structure of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) complexed with double-stranded DNA indicates that while many nucleoside-resistance mutations are not at the putative dNTP binding site, several are in positions to interact with the template-primer. Wild-type HIV-1 RT and two nucleoside-resistant variants, Leu74-->Val and Glu89-->Gly, have been analyzed to determine the basis of resistance. The ability of the wild-type enzyme to incorporate, or reject, a 2',3'-dideoxynucleoside triphosphate (ddNTP) is strongly affected by interactions that take place between the enzyme and the extended template strand 3-6 nt beyond the polymerase active site. Inspection of a model of the enzyme with an extended template suggests that this interaction involves the fingers subdomain of the p66 subunit in the vicinity of Leu74. These data provide direct evidence that the fingers subdomain of the p66 subunit of HIV-1 RT interacts with the template strand. The wild-type enzyme is resistant to ddITP if the template extension is 3 nt or less and becomes sensitive only when the template extends more than 3 or 4 nt beyond the end of the primer strand. However, the mutant enzymes are resistant with both short and long template extensions. Taken together with the three-dimensional structure of HIV-1 RT in complex with double-stranded DNA, these data suggest that resistance to the dideoxynucleotide inhibitors results from a repositioning or change in the conformation of the template-primer that alters the ability of the enzyme to select or reject an incoming dNTP.

Base Sequence↗
PubMed1988

["Ambulatory" monitoring of left ventricular function using a scintillation detection system. Evaluation of a new method].

To validate a new portable scintillation probe (VEST) for determination of LV function, 68 patients were studied after standard radionuclide angiography (RNA). Reproducibility of VEST LV-ejection fraction was good (rest r = 0.93; exercise r = 0.96) with unchanged probe position, somewhat less good after probe repositioning (r = 0.84) and correlated with RNA (rest r = 0.79; exercise r = 0.83). Long term measurements in 7 patients showed valid data for up to 12 hours. Combined with simultaneous two lead ECG recording VEST seems suitable for detection of transient changes of LV function such as occur during ischemia or due to drug treatment.

Exercise Test↗
PubMed1995

Sensitivity of striatal [11C]cocaine binding to decreases in synaptic dopamine.

We have previously shown that tracer concentrations of [11C]cocaine binding to the dopamine transporter (DAT) in human and baboon striatum can be visualized using positron emission tomography (PET). To determine whether the concentration of dopamine normally present in the synaptic cleft can compete with [11C]cocaine for transporter binding sites, we conducted baboon PET studies with drugs (sodium 4-hydroxybutyrate, four studies, 200 mg/kg; gamma-vinylGABA, three studies, 300 mg/kg; and citalopram, three studies, 2 mg/kg) expected to decrease synaptic dopamine. Each study involved two [11C]cocaine injections and PET scans separated by 2-4 h, with drug administration after the first injection, and without movement of the subject between scans. Time-activity data from striatum and from cerebellum were used with the arterial plasma input function to determine graphically by Logan plotting [11C]cocaine distribution volumes for the brain regions. Specific binding of [11C]cocaine to DAT in striatum was calculated as the distribution volume ratio (DVR) for striatum and cerebellum. In nine of the ten studies drug treatment produced a small increase in DVR (range, 1-11%), and in seven of these studies the increase was > or = 7%. The mean increase was 6.2 +/- 4.1%. The reproducibility of the DVR measure was assessed by comparing [11C]cocaine studies conducted without pharmacological treatments using individual baboons on separate days, and thus involving possible repositioning errors, as well as long-term changes in the state of the striatal dopamine system.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Sequence-selective intercalation of antitumour bis-naphthalimides into DNA. Evidence for an approach via the major groove.

LU 79553, a bis-naphthalimide drug highly active against human solid tumour xenografts, has been shown to bis-intercalate into DNA with a helix-unwinding angle of 37 degrees. Footprinting experiments with DNase I reveal that the drug is selective for mixed nucleotide sequences characterised by an alternating purine-pyrimidine motif, particularly those containing GpT (ApC) and TpG (CpA) steps. Derivatives bearing nitro or amino substituents on the naphthalimide chromophores bind at essentially identical sites. The footprinting profiles on tyrT DNA and on two fragments from pBS bear a remarkable resemblance to those determined for nogalamycin, an antibiotic which binds intercalatively leaving bulky carbohydrate substituents blocking both the major and minor grooves of the helix. Several lines of evidence indicate that the bis-naphthalimides recognise their preferred binding sites via the unusual expedient of intercalating from the major groove. Footprints on the complementary DNA strands sometimes appear staggered in the 5'direction. Repositioning the 2-amino group of G.C base pairs, which serves as a critical minor-groove marker, by substitution with inosine and/or 2,6-diaminopurine has little effect on the distribution of binding sites for LU 79553. The bis-naphthalimides affect the guanine-specific reaction with dimethyl sulfate (which reacts with the N7 position of the base located in the major groove) but not reactions with tetrachloropalladinate or methylene blue. Photoactivation of LU 79553-DNA complexes leads to a small amount of strand scission mainly at guanine residues. These observations make a strong case for binding via the major groove of the double helix, in contrast to nearly all common intercalating drugs, which could be important in explaining the unique biological selectivity of bis-naphthalimides.

Amides↗
PubMed1991

Limitations to the widespread usage of low-dose intra-arterial thrombolysis.

Despite encouraging results, intra-arterial thrombolysis (IAT) has not been readily accepted by British surgeons. In an attempt to clarify the reasons for this we sent a postal questionnaire to surgeons with a vascular interest, asking them to define their present attitude towards IAT. Subsequently, we re-analysed our own clinical data in the light of the answers received. In all 134 surgeons (58%) replied to the questionnaire; 48 (38%) never used IAT and 56 (45%) used it only occasionally. When stated, the main reasons for this limited use were the doubts about efficacy (45%) and lack of radiological support (47%). From November 1988 to August 1990 we used IAT for 82 occlusions (streptokinase 74, rt-PA8). Lysis was achieved in 82% of cases when treatment was started within 1 week of symptoms starting, and 62% with symptoms of longer duration. Following successful IAT no further treatment was required in 44% of cases, reconstruction was needed in 26% and angioplasty in 23%, one major amputation was performed. Unsuccessful lysis resulted in reconstruction in 40% of cases. Overall, the limb salvage rate was 89%. Major complications occurred in six cases. One patient sustained a fatal CVA and five bled from the catheter insertion site. Two of these patients required an emergency operation and one other, who had an angioplasty immediately following lysis, died. Minor complications included local haematoma formation (16), catheter problems (6), and allergic reactions (2). After insertion of the perfusing catheter, angiograms (median 4, maximum 10) were performed at intervals, with repositioning of the catheter if necessary, until lysis was complete.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon↗
PubMed2003

The hepatitis B virus polymerase mutation rtV173L is selected during lamivudine therapy and enhances viral replication in vitro.

Therapy of chronic hepatitis B virus (HBV) infection with the polymerase inhibitor lamivudine frequently is associated with the emergence of viral resistance. Genotypic changes in the YMDD motif (reverse transcriptase [rt] mutations rtM204V/I) conferred resistance to lamivudine as well as reducing the in vitro replication efficiency of HBV. A second mutation, rtL180M, was previously reported to partially restore replication fitness as well as to augment drug resistance in vitro. Here we report the functional characterization of a third polymerase mutation (rtV173L) associated with resistance to lamivudine and famciclovir. rtV173L was observed at baseline in 9 to 22% of patients who entered clinical trials of adefovir dipivoxil for the treatment of lamivudine-resistant HBV. In these patients, rtV173L was invariably found as a third mutation in conjunction with rtL180M and rtM204V. In vitro analyses indicated that rtV173L did not alter the sensitivity of wild-type or lamivudine-resistant HBV to lamivudine, penciclovir, or adefovir but instead enhanced viral replication efficiency. A molecular model of HBV polymerase indicated that residue rtV173 is located beneath the template strand of HBV nucleic acid near the active site of the reverse transcriptase. Substitution of leucine for valine at this residue may enhance polymerization either by repositioning the template strand of nucleic acid or by affecting other residues involved in the polymerization reaction. Together, these results suggest that rtV173L is a compensatory mutation that is selected in lamivudine-resistant patients due to an enhanced replication phenotype.

2-Aminopurine↗
PubMed2001

[Chronic non radicular cervicocephalic syndrome: CT-guided percutaneous RF-thermocoagulation of the zygapophysial joints].

PURPOSE: The objective of this study was to evaluate the clinical outcome of CT-guided radiofrequency- (RF-)thermocoagulation of cervical zygapophysial joints for chronic non radicular cervical pain syndrome using an improved posterior approach. METHODS: 169 patients were treated with CT-guided pericapsular drug instillation of steroids and local anaesthesia on the symptomatic and adjoining segments. 46 patients experienced an only short term pain relief after repeated CT-guided blocks and were therefore treated with CT-guided RF-neurolysis. For the microtherapeutic procedure the patients were placed on the CT-table in prone-position. A 23-gauge isolated aspiration canula (Leibinger) was placed vertically, under CT-guidance lateral to the zygapophysial joint to coagulate the capsular nerve endings. The probe was then repositioned to coagulate the medial and lateral branches of the corresponding segment-nerves' dorsal branches. The thermocoagulation was applied 3-4 times with 90 s. duration and a coagulation temperature of 70 degrees C. The coagulation-probe was drawn back 3-5 mm each time. No sedation or general anaesthesia was required. The treatments were carried out on out patient basis in local anaesthesia. Statistical data on pain sensation was acquired with the help of a standardized visual analogue pain scale (VAS) and by a questionnaire on treatment satisfaction and every day activities. Patients were examined and questioned on the 2nd, 7th, 30th and 90th day after the operation. RESULTS: After 90 days, 26 (56,5%) patients had experienced a definite pain reduction of >75% (VAS). 13 (28,3%) patients obtained alleviation of <50% (VAS), within the first three postoperative months. Seven (15,2%) patients reported <25% (VAS) pain relief. No intra- and postoperative complications were reported. CONCLUSIONS: CT-guided radiofrequency thermocoagulation is an effective, precise and secure, minimally invasive treatment for non radicular cervical pain that is caused by zygapophysial joint arthropathy, when CT-guided, lateral drug instillation does not cause a lasting improvement.

Electrocoagulation↗
PubMed1976

Orthostatic influences on cardiovascular responses to nitroglycerin in conscious dogs.

The influence of body position change on the arterial pressure and heart rate responses produced by acute short-acting and sustained-release dosage forms of nitroglycerin was evaluated in a series of chronically prepared, conscious beagle dogs. The upright repositioning of the dog to 60 degrees from horizontal markedly enhanced the hypotensive and bradycardic responses produced by both dosage forms. Since it has been suggested that the lowering of arterial pressure is an essential component resulting in the therapeutic usefulness of nitroglycerin in angina pectoris, the experimental orthostatic model could be a sensitive procedure for the laboratory assessment of drugs of this class.

Animals↗
PubMed1999

Crystal structure of human bleomycin hydrolase, a self-compartmentalizing cysteine protease.

BACKGROUND: Bleomycin hydrolase (BH) is a cysteine protease that is found in all tissues in mammals as well as in many other eukaryotes and prokaryotes. Although its conserved cellular function is as yet unknown, human bleomycin hydrolase (hBH) has clinical significance in that it is thought to be the major cause of tumor cell resistance to bleomycin chemotherapy. In addition, it has been reported that an allelic variant of hBH is genetically linked to Alzheimer's disease. RESULTS: We have determined the crystal structures of wild-type hBH and of a mutant form of the enzyme. The overall structure is very similar to that of the previously determined yeast homolog, however, there is a striking difference in the charge distribution. The central channel, which has a strong positive electrostatic potential in the yeast protein, is slightly negative in hBH. We have determined that hBH does not have the DNA-binding activity of the yeast protein and that the enzyme is localized to the cytoplasm. CONCLUSIONS: The difference in charge distribution between the yeast and human BH enzymes is most likely responsible for the difference in DNA-binding activity. Nevertheless, the C-terminal autoprocessing activity and the role of the C terminus as a determinant for peptidase activity are conserved between the yeast and human forms. The structure of hBH suggests that the putative Alzheimer's disease linked variation does not directly alter the intrinsic peptidase activity. Rather, the position of the mutation suggests that it could affect interactions with another protein, which may modulate peptidase activity through repositioning of the C terminus.

Alzheimer Disease↗
PubMed2004

Synergistic contributions of the functional groups of epinephrine to its affinity and efficacy at the beta2 adrenergic receptor.

The structural basis of ligand affinity can be approached by studying the interactions between a drug and receptor residues; the basis for efficacy is more complex and must involve activation-associated conformational changes. We have used wild-type (WT), a constitutively active mutant (CAM), and a "constitutively inactive" mutant beta2 adrenergic receptor (beta(2)AR) to investigate changes in the binding site that accompany binding and activation. The active state (R(*)) probably involves repositioning of at least some of the agonist-contact residues, thereby optimizing their interactions with agonist and resulting in a higher affinity for agonist. A comparison of the binding affinities of a series of phenethylamine derivatives for WT revealed a remarkable synergism between the various functional groups present in epinephrine. Binding affinity was essentially unchanged with addition of beta-OH, N-CH(3), or catechol OHs to phenethylamine. In contrast, when each of these same groups was added to the appropriate compound, already containing the other two groups, to make epinephrine, the increase in affinity was quite large (60- to 120-fold). An initial interaction between two or more contacts may stabilize an intermediate conformation of beta(2)AR, R', either by altering amino acid side chain rotamer conformations or by a more global conformational change involving the repositioning of transmembrane segments. The pattern of these effects was different in the CAM in that fewer interactions were required to observe the synergistic effect, consistent with the hypothesis that the CAM mutation enriches the proportion of receptors in R(*) or in R' from which R(*) is more readily assumed.

Adenylyl Cyclases↗
PubMed2005

Rapid decline in acute stimulation thresholds with steroid-eluting active-fixation pacing leads.

BACKGROUND AND AIM: There is an increasing use of active-fixation leads for cardiac pacing, yet concerns remain regarding initial high stimulation thresholds. The aim was to perform a detailed analysis of pacing parameters at the time of implantation to determine when lead repositioning should be considered. METHODS: We performed a prospective observational study of consecutive new pacemaker implants. Detailed analysis of pacing parameters was collected at 2-minute intervals for 10 minutes, and at day 1 and week 8 following implant. RESULTS: Ninety-four patients underwent implantation of 79 dual-chamber and 15 single-chamber pacemakers using active-fixation leads in both chambers. An initial threshold of >1 V was demonstrated in 45/94 (48%) ventricular leads (mean threshold 1.5 +/- 0.3 V). This declined rapidly to 0.9 +/- 0.3 V at 4 minutes (P < 0.01), 0.7 +/- 0.3 V at 10 minutes (P < 0.01), and 0.6 +/- 0.3 V at day 1 (P < 0.01). At day 1, 43/45 leads were <1 V. There were 79 atrial leads. An initial threshold of >1 V (mean 1.7 +/- 0.6 V) was demonstrated in 41/79 (52%) leads falling significantly to 1.1 +/- 0.5 V at 4 minutes (P < 0.01), 0.9 +/- 0.4 V at 10 minutes (P < 0.01), and 0.6 +/- 0.2 V at day 1 (P < 0.01). At 10 minutes, 32 of 41 leads demonstrated a threshold of <1 V with all leads <1 V at day 1. Thresholds were maintained medium term. CONCLUSIONS: Active-fixation leads are commonly associated with initially high thresholds that fall rapidly. An initial threshold of 2 V should be provisionally accepted and retested at 4 minutes. The majority will have a threshold of <1 V the following day. A failure of a high threshold to decline at 4 minutes requires lead repositioning.

Adult↗
PubMed1991

[Cellular transplants for Parkinson's disease].

In rats with a lesion of the dopaminergic nigrostriatal pathway induced by 6-hydroxydopamine (6-OHDA), the histologic and functional viability of the striatal implant of fetal mesencephalic substantia nigra has been demonstrated. In the same model, the implant of adrenal medulla is also effective but less lasting. In monkeys with parkinsonism induced by MPTP there are suggestions of effectiveness of the fetal mesencephalic implant and also of other tissues such as placenta and sympathetic ganglion or sural nerve. Now the possibility of a better functional recovery by acting on the neuronal growth factors is being evaluated. In patients with Parkinson's disease, the accumulated experience indicates that 32% are improved with adrenal medulla implant, but the best candidates are those who also benefit from the available drug therapy without the risks of surgery. The implant of fetal tissue has been carried out in about 90 patients, with very variable results. In the most thoroughly investigated patients the improvement has been moderate. The future research points to the identification of the factors that control and regulate striatal reinnervation and the use of genetically determined cells. That would permit a more precise reposition of the biochemical deficiency in Parkinson's disease, without the ethical and practical problems derived from the use of fetal tissue.

Adrenal Medulla↗
PubMed2006

Management of end-stage central venous access in children referred for possible small bowel transplantation.

UNLABELLED: The 3-year survival after small bowel transplantation (SBTx) has improved to between 73% and 88%. Impaired venous access for parenteral nutrition can be an indication for SBTx in children with chronic intestinal failure. AIM: To report our experience in management of children with extreme end-stage venous access. SUBJECTS: The study consisted of 6 children (all boys), median age of assessment 27 months (range, 13-52 months), diagnosed with total intestinal aganglionosis (1), protracted diarrhea (1), and short bowel syndrome (4), of which gastroschisis (2) and malrotation with midgut volvulus (2) were the causes. All had a documented history of more than 10 central venous catheter insertions previously. All had venograms, and 1 child additionally had a magnetic resonance angiogram to evaluate venous access. Five of 6 presented with thrombosis of the superior vena cava (SVC) and/or inferior vena cava. METHODS: Venous access was reestablished as follows: transhepatic venous catheters (5), direct intra-atrial catheter via midline sternotomy (4), azygous venous catheters (2), dilatation of left subclavian vein after passage of a guide wire and then placing a catheter to reach the right atrium (1), radiological recanalization of the SVC and placement of a central venous catheter in situ (1), and direct puncture of SVC stump(1). Complications included serous pleural effusion after direct intra-atrial line insertion, which resolved after chest drain insertion (1), displacement of transhepatic catheter needing repositioning (2), and SVC stent narrowing requiring repeated balloon dilatation. OUTCOME: Four children with permanent intestinal failure on assessment were offered SBTx, 3 of which were transplanted and were established on full enteral nutrition; the family of 1 child declined the procedure. In the remaining 2 children in whom bowel adaptation was still a possibility, attempts were made to provide adequate central venous access as feeds and drug manipulations were undertaken. One of them received liver and SBTx nearly 3 years after presenting with end-stage central venous access, because attempts to achieve independence from parenteral nutrition had failed. The other child died immediately after a transhepatic venous catheter placement, possibly from a nutritional depletion syndrome as no physical cause of death was found. Direct intra-atrial catheters in transplanted children proved to be adequate for the management of uncomplicated transplantation, although the usual infusion protocol had to be modified considerably, and the lack of access would have been critical if massive blood transfusion had been required during the transplant procedure. CONCLUSION: It was possible to reestablish central venous access in all cases. However, this was time consuming and difficult to assemble a skilled team consisting of one of more: surgeon, cardiologist, interventional radiologist, and transplant anesthetist. Small bowel transplantation is easier and safer with adequate central venous access, and we advocate liaison with an SBTx center at an early stage.

Catheterization, Central Venous↗
PubMed2001

Extraction as a treatment alternative follows repeated trauma in a severely handicapped patient.

Handicapped patients with protruding maxillary incisors are prone to repeated dental trauma. A 13-year-old girl with cerebral palsy, severe mental retardation and seizure disorder was referred to our department for restoring the traumatized anterior teeth. Despite drug combination, the frequency of seizure attack was around 10 times a month. The oral examination showed multiple caries, gingival hyperplasia, class II malocclusion with 14 mm overjet and deep overbite. During the first 3 years of a 7-year follow-up period, six episodes of anterior tooth trauma due to seizure attack occurred. The trauma-related treatment performed included endodontic therapy, multiple composite restorations, apical repositional flap, and finally extraction of all four upper incisors with fabrication of a semi-fixed band-retained denture. The denture restored normal overbite and overjet with improved esthetics. For 4 years following the fabrication of denture, no trauma occurred to the anterior teeth in later seizure attacks. Considering inadequate control of seizure disorder, little ability of the patient to receive comprehensive orthodontic treatment, poor prognosis of restorations, and possible future injuries, the removal of non-functional, nonesthetic, trauma-susceptible incisor teeth can be justified as an alternative to tooth preservation.

Adolescent↗
PubMed1989

The antihypertensive properties of a synthetic prostanoid: RS-93427.

The antihypertensive activity of RS-93427, a synthetic prostanoid, was evaluated in conscious restrained spontaneously hypertensive rats. RS-93427 possesses potent antihypertensive activity when administered orally, intraduodenally, intravenously, or subcutaneously but not topically. The blood pressure reducing activity of RS-93427 in normotensive rats was comparable to that in hypertensive animals. No signs of tolerance to the antihypertensive effects were observed following fourteen days of oral administration of RS-93427. The synthetic prostanoid minimally enhanced the orthostatic hypotensive responsiveness to vertical, head up, repositioning of the restrained rats. The relative usefulness of the platelet antiaggregatory and antihypertensive properties of RS-93427 will have to be determined by clinical studies.

Administration, Cutaneous↗
PubMed2000

Bidirectional allosteric effects of agonists and GTP at alpha(2A/D)-adrenoceptors.

Agonists and GTP exert reciprocal effects on the stability of the G protein-coupled receptor/G protein complex, implying bidirectional control over the receptor/G protein interface. To investigate this relationship, we compared the ability of a series of hydroxyl-substituted phenethylamine and imidazoline agonists to stimulate [(35)S]guanosine 5'-O-(3-thio)triphosphate ([(35)S]GTPgammaS) binding in membranes from alpha(2A/D)-adrenergic receptor-transfected PC12 cells with the magnitude of the GTP-induced reduction in agonist affinity in [(3)H]rauwolscine-binding studies. Agents previously described as full and partial agonists in functional studies showed similar relative efficacies in promoting GTP binding (r = 0.97) as well as similar relative potencies (r = 0.94). Efficacy among agonists for promotion of [(35)S]GTPgammaS binding was closely correlated with the relative influence of GTPgammaS on agonist binding (r = 0.97), consistent with a bidirectional allosteric influence by agonists and GTP on receptor/G protein complexation. In an additional series of tolazoline derivatives, a range in efficacy from full agonism to strong inverse agonism was observed, depending on the presence or absence of hydroxyl substituents. Together these results suggest that agonist-induced repositioning of transmembrane helices via their hydroxyl interactions is a critical determinant of the stability of the receptor/G protein complex and therefore of agonist efficacy.

Adrenergic Agonists↗