The alkylating agent isothiocyanatobenzyl imidazoline (IBI) was synthesized to investigate the unique receptor interacting properties of imidazolines. On the isolated rabbit iris sphincter, IBI produced concentration-dependent responses with an EC50 of 18 mumol/1, and at the highest concentration tested the maximum contraction of the tissue was 50% of the carbachol maximum. At equiactive concentrations with the similar washing procedure, the total duration of responses to IBI and carbachol was 24 and 3 min, respectively. After repeated washing, the sphineter relaxes to the control baseline of tone but, after reexposure to IBI for 6 h, failed to contract, indicating that desensitization or irreversible block has developed. Unlike with carbachol, the sphincter contraction to IBI was not affected by atropine 1 mumol/1, indomethacin 1 mumol/1, verapamil 10 mumol/1, or nifedipine 10 mumol/1. At a higher concentration of nifedipine and papaverine 100 mumol/1, the response to IBI was blocked. Furthermore, the contractile response to IBI was abolished by Ca++ removal from the medium. Under similar conditions, 26 +/- 8% of the maximum response to carbachol was preserved. Thus influx of extracellular as well as rise in intracellular Ca++ appears vital for the contractile response to IBI. IBI did not contract the iris dilator, but shifted the concentration-response curve to the alpha-adrenoceptor activator, phenylephrine, to the right with a reduction in the maximum response. The tissue failed to regain the sensitivity to phenylephrine after 6 h of repeated washing. Phentolamine and nifedipine provided a small but significant protection of the response to phenylephrine against the irreversible block by IBI. Based on chemical and pharmacological properties of IBI, it is concluded that the molecule acts in the rabbit as an irreversible agonist on unidentified receptors of the iris sphineter and an irreversible antagonist of multiple receptors on the iris dilator. These molecular properties of IBI are clearly different from that of the parent imidazoline molecule tolazoline.

Adrenergic alpha-Agonists↗

PubMedDate not supplied

In vivo phosphorus-31 NMR spectroscopy of abnormal myocardial high-energy phosphate metabolism during cardiac stress in hypertensive-hypertrophied non-human primates.

To study the functional and metabolic correlates of left ventricular hypertrophy [LVH] in non-human primates, 7 hypertensive baboons [papio anubis] with 4.6 +/- 0.1 years of hypertension produced by a two-kidney one-clip model, and echocardiographically documented concentric LVH underwent serial phosphorus-31 [P-31] NMR Spectroscopy studies at rest and during inotropic cardiac stress produced by dobutamine infusion [5 micrograms/kg/minute]. Responses in LVH baboons were compared to those in 5 normotensive, sex and weight-matched control animals. The ratio of P-31 NMR-S derived inorganic phosphates [Pi] to phosphocreatine [PCr] was significantly greater at rest in LVH baboons [0.53 +/- 0.06 versus controls = 0.41 +/- 0.17; P less than 0.05]. With dobutamine drug stress, the Pi/PCr ratio rose significantly in LVH baboons [0.77 +/- 0.15 versus 0.56 +/- 0.16; P less than 0.05 at 15 minutes]. Despite hemodynamic recovery, the 5 minute post-dobutamine Pi/PCr ratio remained elevated compared to baseline in LVH baboons only [0.78 +/- 0.16 versus 0.53 +/- 0.06; P less than 0.05]. In pre-instrumented baboons [n = 5], the 'transfer function' of cardiac work [heart rate x LV end-systolic pressure x + dp/dt max] versus Pi/PCr ratio was abnormally shifted rightward and downward [r = 0.80] with LVH as compared to the linearly increasing response in controls. We conclude that in vivo P-31 NMR Spectroscopy studies during dobutamine stress demonstrate reduced PCr stores, delayed metabolic recovery following cessation of inotropic stress, and an abnormal rightward shift in the 'transfer function' in LVH baboons.

Adenosine Triphosphate↗

PubMedDate not supplied

Is solubility in vitro a reliable predictor of iron bioavailability?

In this paper we have described physiological factors that are likely to influence iron bioavailability, reviewed chemical properties of iron important to its absorption, and addressed the question posed in the title. Intestinal transit times, luminal pH, and diffusion barriers resulting from gastrointestinal mucus may affect absorption. The tendency of iron to form large-molecular-weight species and to bind to macromolecules may limit its absorption. Iron solubility following in vitro gastrointestinal digestion is a reliable predictor of ascorbic acid effects on bioavailability but not of protein effects. Solubility of low-molecular-weight iron is better than simple solubility for predicting iron bioavailability.

Animals↗

PubMedDate not supplied

Dipyridamole technetium 99m sestamibi myocardial tomography as an independent predictor of cardiac event-free survival after acute ischemic events.

BACKGROUND: A total of 137 consecutive patients with recent uncomplicated myocardial infarction (n = 31) or unstable angina (n = 106) were studied to determine the relative prognostic value of predischarge clinical risk stratification and intravenous dipyridamole stress sestamibi (MIBI) myocardial tomography in patients unable to exercise maximally after an acute ischemic coronary event. METHODS AND RESULTS: Patients were followed up after the index study for 10 +/- 5 months (range 1 to 23 months) to ascertain cardiac events that occurred in 20 patients (15%): nonfatal myocardial infarction (n = 5) or cardiac death (n = 15). Cardiac event rates were 35% in patients with a recent myocardial infarction and 8% in the group with unstable angina (p < 0.001). Patients with these cardiac events had more frequent abnormal MIBI study results, fixed defects, and reversible plus fixed (combined) defects (all p < 0.05). The univariate relative risk of death or myocardial infarction associated with an abnormal MIBI study was 6.0 (95% confidence limits 0.8 to 44.7). Multivariate stepwise logistic regression models identified an abnormal MIBI study and either fixed or reversible MIBI defects as being predictive of death or myocardial infarction (all p < 0.05). The Mantel-Haentzel 1-year cardiac event-free survival rate was excellent in 27 patients with a normal MIBI single-photon computed emission tomographic scan (100%) but significantly reduced in the 110 patients with an abnormal MIBI study (80%; p < 0.05 vs normal subjects). The presence of combined MIBI defects was associated with the poorest event-free survival rate (66%; difference not significant vs fixed or reversible defects only). CONCLUSION: We conclude that predischarge dipyridamole MIBI tomography provided independent prognostic information in this population of patients who were unable to exercise after a recent acute ischemic coronary event.

Aged↗

PubMedDate not supplied

Alterations in myocardial free fatty acid clearance precede mechanical abnormalities in canine tachycardia-induced heart failure.

BACKGROUND: The purpose of this study was to evaluate whether abnormalities of free fatty acid metabolism are present before the onset of overt mechanical dysfunction in dogs with tachycardia-induced heart failure. We studied six dogs chronically instrumented to allow assessment of left ventricular function in the pressure-volume plane. METHODS AND RESULTS: Free fatty acid clearance was assessed according to the washout rate of a free fatty acid analog, iodophenylpentadecanoic acid ([123I]PPA or IPPA). IPPA clearance was measured within 1 hour of the hemodynamic assessment. The animals were studied under baseline conditions and 11.7 +/- 3.6 days after ventricular pacing at a rate of 240 beats/min. Hemodynamic studies after pacing showed a nonsignificant increase in left ventricular end-diastolic pressure (11.7 +/- 4.7 to 17.4 +/- 6.5 mm Hg) and a nonsignificant decrease in the maximum derivative of pressure with respect to time (1836 +/- 164 vs 1688 +/- 422 mm Hg/sec). There was also no change in the time constant of left ventricular relaxation, which was 34.8 +/- 7.67 msec before and 35.3 +/- 7.3 msec after pacing. However, a significant prolongation in the clearance half-time of [123I]PPA, from 86.1 +/- 23.9 to 146.5 +/- 22.6 minutes (p < 0.01) was found. Thus abnormal lipid clearance appears before the onset of significant mechanical dysfunction in tachycardia-induced heart failure. CONCLUSION: This suggests that abnormal substrate metabolism may play an important role in the pathogenesis of this condition.

Animals↗

PubMedDate not supplied

Alogia, attentional impairment, and inappropriate affect: their status in the dimensions of schizophrenia.

Previous factor analyses have shown that at least three factors are needed to encompass the positive and negative symptoms of schizophrenia. Despite marked similarities across studies, it remains unclear whether certain symptoms such as alogia, attentional impairment, and inappropriate affect are more closely related to negative or positive symptoms. An exploratory analysis was undertaken of the separate items on the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) that constitute the global rating of alogia, as well as the global ratings of attentional impairment and inappropriate affect in 90 schizophrenic patients. Findings indicate that inappropriate affect loads significantly with bizarre behavior and positive formal thought disorder on a disorganization factor, whereas attentional impairment loads significantly on psychotic, disorganization, and negative symptom factors. The global rating of alogia appears to comprise both positive and negative symptoms, with the item poverty of content of speech loading on the disorganization factor, and other items such as poverty of speech, blocking, and increased latency loading on the negative symptom factor. It is concluded that three dimensions are needed to characterize the symptoms of schizophrenia as measured by the SAPS/SANS. The use of three dimensions may be a robust way to further explore the relationship between signs and symptoms and their underlying mechanisms in schizophrenia.

Adolescent↗

PubMedDate not supplied

Clozapine's effect on negative symptoms in treatment-refractory schizophrenics.

Clozapine has proven to be more effective than typical antipsychotics in treatment-refractory schizophrenic patients, and some evidence suggests that it may be particularly useful in treating the negative symptoms of schizophrenia. However, it is unclear whether this observation reflects improvement in "primary" or "secondary" negative symptoms. We hypothesized that a portion of clozapine's effect on negative symptoms would be related to an improvement in positive (psychotic and disorganization) symptoms, a decrease in extrapyramidal side effects (EPSE), and/or a decrease in depressive symptoms. The remainder of its effect would be related to a direct effect on the neural circuits or pathologic processes responsible for the negative symptoms. Twenty-nine treatment-refractory schizophrenics treated with clozapine for 6 weeks were studied. The core negative symptoms measured by the Scale for the Assessment of Negative Symptoms ([SANS] affective flattening, anhedonia/asociality, avolition/apathy, and alogia) all improved with clozapine treatment. Overall, there was a 31% improvement in negative symptoms, a 32% improvement in psychotic symptoms, and a 35% improvement in disorganization. The improvement in negative symptoms was correlated with improvement in disorganization, but not with improvement in psychotic symptoms, depression, or drug-induced EPSE. Although there was a correlation between improvement in negative symptoms and improvement in disorganization, there was a suggestion that the two are changing in parallel, but are independent of each other. It appears that at least a portion of clozapine's effect on core negative symptoms is mediated through a direct effect on the underlying pathophysiology of schizophrenia associated with negative symptoms.

Adult↗