The FIELDS Instrument Suite for Solar Probe Plus: Measuring the Coronal Plasma and Magnetic Field, Plasma Waves and Turbulence, and Radio Signatures of Solar Transients.

NASA's Solar Probe Plus (SPP) mission will make the first in situ measurements of the solar corona and the birthplace of the solar wind. The FIELDS instrument suite on SPP will make direct measurements of electric and magnetic fields, the properties of in situ plasma waves, electron density and temperature profiles, and interplanetary radio emissions, amongst other things. Here, we describe the scientific objectives targeted by the SPP/FIELDS instrument, the instrument design itself, and the instrument concept of operations and planned data products.

Dose-response effects of sotalol on cardiovascular function in conscious, freely moving cynomolgus monkeys.

BACKGROUND AND PURPOSE: The non-selective beta-adrenoceptor antagonist, D,L-sotalol (sotalol) is commonly employed as a positive control during preclinical cardiovascular safety pharmacology testing, mainly because of its ability to prolong QT interval duration. However, no information appears in the literature, except in abstract form, regarding the dose-response effects of sotalol in unanesthetized monkeys. The current study was conducted to determine the dose- and plasma-response effects of orally administered sotalol on cardiovascular function in conscious non-human primates. EXPERIMENTAL APPROACH: Male cynomolgus monkeys were implanted with telemetry devices and the effects of sotalol hydrochloride (5, 10 and 30 mg kg(-1) of body weight, p.o.) on arterial blood pressure, heart rate, body temperature and electrocardiogram waveform were continuously monitored for 6 h after dosing. Blood was sampled for the measurement of plasma concentrations of sotalol. KEY RESULTS: Sotalol dose dependently decreased heart rate and prolonged RR, PR, QT and corrected QT intervals, while having little or no effects on the QRS complex, arterial pressure or body temperature, over the dose range tested. When the data were related to plasma concentrations of sotalol, it was clear that the cardiovascular effects occurred in a similar pattern and to a comparable degree as those reported in human studies. CONCLUSIONS AND IMPLICATIONS: The current study helps demonstrate the validity of utilizing telemetry-instrumented non-human primates for the cardiovascular safety pharmacology assessment of drugs prior to first-in-human testing, and its findings may serve as a reference source for the dose- and plasma-response effects of orally administered sotalol in conscious monkeys.

Structure-based design of novel groups for use in the P1 position of thrombin inhibitor scaffolds. Part 2: N-acetamidoimidazoles.

Guided by X-ray crystallography of thrombin-inhibitor complexes and molecular modeling, alkylation of the N1 nitrogen of the imidazole P1 ligand of the pyridinoneacetamide thrombin inhibitor 1 with various acetamide moieties furnished inhibitors with significantly improved thrombin potency, trypsin selectivity, functional in vitro anticoagulant potency and in vivo antithrombotic efficacy. In the pyrazinoneacetamide series, oral bioavailability was also improved.

In vivo evaluation of the potency and bladder-vascular selectivity of the ATP-sensitive potassium channel openers (-)-cromakalim, ZD6169 and WAY-133537 in rats.

OBJECTIVE: To compare in vivo the potency and bladder-vascular selectivity of ATP-sensitive potassium channel openers (KCOs) (-)-cromakalim, WAY-133537 and ZD6169 and a muscarinic antagonist, tolterodine in rats. MATERIALS AND METHODS: Bladder and arterial pressures were monitored simultaneously, before and after increasing intravenous doses of compounds, in each of two urethane-anaesthetized rat bladder hyperactivity models: spontaneous non-voiding myogenic contractions secondary to partial outlet obstruction and volume-induced neurogenic contractions. RESULTS: (-)-Cromakalim, WAY-133537 and ZD6169 caused a dose-dependent suppression of spontaneous contractions in the obstructed model, with a 50% inhibition of the contraction area under the curve at doses of 0.06, 0.14 and 2.4 micro mol/kg (intravenous), respectively. Corresponding decreases in mean arterial pressure at these effective doses were 24%, 15% and 15%, respectively. The KCO potency rank order was the same and their relative potency highly comparable in the neurogenic model. There was complete inhibition of spontaneous contractions in obstructed rats at doses corresponding to approximately 50% inhibition of the neurogenic contractions. While tolterodine caused a dose-dependent inhibition of contractions in the neurogenic model, it was ineffective at inhibiting non-voiding contractions in obstructed rats. CONCLUSIONS: All KCOs tested caused significant decreases in arterial pressure at doses effective on the bladder in the model of obstructive instability, suggesting a lack of bladder-vascular selectivity. Similar KCO potency in both assays suggests no appreciable changes in KATP channel function as a result of partial outlet obstruction.

Design and biological activity of (S)-4-(5-([1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino]methyl)imidazol-1-ylmethyl)benzonitrile, a 3-aminopyrrolidinone farnesyltransferase inhibitor with excellent cell potency.

The synthesis, structure-activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.

Functional role of alpha-calcitonin gene-related peptide in the regulation of the cardiovascular system.

It remains unknown whether the extent of vasoactive response to exogenous calcitonin gene-related peptide (CGRP) varies among different regional vascular beds. It is also unclear whether endogenous CGRP plays a functional role in regulating basal vascular activity. To address these two issues, experiments were conducted in 27 anesthetized rats instrumented with a carotid flow probe and catheters in a jugular vein, left ventricle (LV), and femoral artery, and in 6 conscious dogs, chronically instrumented with LV pressure gauge, aortic and atrial catheters, and ascending aortic, coronary, carotid, and renal flow probes. In both species, administration of human alpha-CGRP (0.1-0.5 microg/kg, i.v.) induced a dose-dependent peripheral vasodilation that was completely abolished by pretreatment with alpha-CGRP[8-37] (30 microg/kg/min, i.v.), a competitive antagonist of CGRP receptors. Regional blood flow measured by the radioactive microsphere technique in rats showed that the alpha-CGRP (0.3 microg/kg, i.v.)-induced increase in blood flow was greater (p < 0.05) in the heart (+53 +/- 16%) than in the brain (+14 +/- 6%). In the presence of beta-adrenergic receptor blockade with propranolol, however, the increases in blood flow in these two vascular beds were identical. In conscious dogs, alpha-CGRP (0.3 microg/kg, i.v.) produced similar increases in coronary (+24 +/- 6%), carotid (+26 +/- 3%), and renal (+26 +/- 6%) blood flow, which were different from the patterns induced by other vasodilators; at an equivalent level of reduction in mean arterial pressure and total peripheral resistance, alpha-CGRP increased coronary and carotid blood flow significantly less (p < 0.05) than adenosine or nitroprusside. Unlike alpha-CGRP, adenosine and nitroprusside, as expected, induced pronounced differential blood flow changes in these vascular beds. Neither systemic hemodynamics nor regional blood flow distribution was altered by the administration of a pharmacological blocking dose of alpha-CGRP[8-37] in the two species. Thus, we conclude that endogenous alpha-CGRP does not play an important role in cardiovascular regulation under normal, resting conditions, although exogenous alpha-CGRP induces a marked, comparable vasorelaxation in different regional vascular beds.

Management of malignant pineal germ cell tumors with residual mature teratoma.

OBJECTIVE: The treatment of intracranial mixed germ cell tumors presents a unique challenge, since eradication of malignant tumor by radiation and/or chemotherapy may spare the benign tumor component. We reviewed our surgical experience with residual malignant pineal germ cell tumors after neoadjuvant therapy. METHODS: Between 1987 and 1997, 16 patients with malignant intracranial germ cell tumors were treated at the Mayo Clinic with a protocol of neoadjuvant chemotherapy and radiation therapy. After the diagnosis was confirmed by histopathological examination, all patients were treated with four cycles of etoposide and cisplatin as well as external beam radiation therapy (range, 3030-5940 cGy). Six patients had an incomplete response to therapy, as demonstrated by observation of residual tumor on magnetic resonance imaging scans. Initial pathology in these six patients was germinoma in four and combinations of yolk sac tumor, embryonal carcinoma, malignant teratoma, and germinoma in two. Two patients had synchronous pineal and suprasellar tumors, with leptomeningeal dissemination. Tumor markers were elevated in four of the six patients at presentation. RESULTS: All patients with residual pineal tumors underwent surgical resection via an infratentorial, supracerebellar approach. Pathological examination revealed mature teratoma in five patients and amorphous debris in one patient. No patient had recurrent malignancy. Significant neurological morbidity occurred in one patient, with no mortality. At a mean follow-up of 23 months, no recurrence on magnetic resonance imaging has been documented. CONCLUSION: Residual pineal tumor occurring after treatment of malignant intracranial germ cell tumor with neoadjuvant therapy is likely to be mature teratoma. Operative resection of these benign recurrences is safe and effective.

A-315456: a selective alpha(1D)-adrenoceptor antagonist with minimal dopamine D(2) and 5-HT(1A) receptor affinity.

In functional assays, A-315456, N-[3-(cyclohexylidene-(1H-imidazol-4-ylmethyl))phenyl]ethanesulfonamide, behaved as an alpha(1D)-adrenoceptor subtype selective antagonist (pA(2)=8.34) in the rat aorta. It was 83-fold less potent at the alpha(1B)-adrenoceptor subtype expressed in the rat spleen, and was inactive at the alpha(1A)-adrenoceptor subtype expressed in the rat vas deferens. Radioligand binding assays also revealed high affinity (pK(i)=8.71) for the alpha(1D)-adrenoceptor subtype and weaker affinities at the alpha(1A)-adrenoceptor (pK(i)=6.23) and alpha(1B)-adrenoceptor (pK(i)=7.86). In comparison to its potent affinity at the alpha(1D)-adrenoceptor subtype, A-315456 was 3020-, 794- and 38-fold weaker at the dopamine D(2)-, 5-HT(1A)-, and alpha(2a)-adrenoceptors, respectively. These studies indicate that A-315456 is a potent and selective alpha(1D)-antagonist that may serve as a useful pharmacological ligand to probe the physiological role of the alpha(1D)-adrenoceptor subtype in normal and disease states.

Screening mammography and breast cancer treatment patterns in older women.

OBJECTIVE: To examine the impact of mammography screening on treatment options received by a cohort of older breast cancer patients. SETTING AND POPULATION: We studied 718 newly diagnosed breast cancer patients, 67 years and over, diagnosed with TNM Stage I and II disease between 1995 and 1997 at 29 hospitals in five regions. METHODS: Data were collected from patients, surgeons, and medical records. A breast cancer diagnosis was considered to have been by screening mammography if so reported by both patient and medical records. Bivariate and logistic regression were used to identify predictors of a women having her cancer detected by screening mammography and the relationships between mode of detection, stage of disease at diagnosis, and local treatment. RESULTS: Women with high school or greater education were 1.75 times (95%, CI 1.11-2.75) more likely to have their cancers diagnosed by screening mammography than women who had not completed high school, controlling for other factors. Screening found earlier stage disease: 96% of women with mammographically diagnosed cancer had T1 lesions, compared to 81% of women diagnosed by other means (p = 0.001). Women with mammography detected lesions were more likely to have ductal cancer, and to be referred to radiation oncologists more than women diagnosed by other means. Controlling for stage and histology, screening remained associated with a higher likelihood of receiving breast conserving surgery (BCS) with radiation (RT) (OR 1.56, 95%, CI 1.10-2.22) than other local therapies. CONCLUSIONS: Beyond the impact on stage, ductal cancers were more likely to be diagnosed by screening. Mammographically detected lesions were associated with referrals to radiation oncologists and higher rates of BCS and RT. Research is needed to explain the residual independent effects of mammography screening on breast cancer treatment.

ABT-702 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin- 3-yl)pyrido[2,3-d]pyrimidine), a novel orally effective adenosine kinase inhibitor with analgesic and anti-inflammatory properties. II. In vivo characterization in the rat.

Adenosine kinase (AK; EC 2.7.1.20) is a key intracellular enzyme regulating intra-and extracellular concentrations of adenosine (ADO), an endogenous neuromodulator, antinociceptive, and anti-inflammatory autocoid. AK inhibition provides a means of potentiating local tissue concentrations of endogenous ADO, and AK inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. The effects of ABT-702, a novel, potent (IC(50) = 1.7 nM), and selective non-nucleoside AK inhibitor were examined in rat models of nociception and acute inflammation. ABT-702 was orally effective and fully efficacious to suppress nociception in a spectrum of pain models in the rat, including carrageenan-induced thermal hyperalgesia, the formalin test of persistent pain, and models of nerve injury-induced and diabetic neuropathic pain (tactile allodynia after L5/L6 spinal nerve ligation or streptozotocin injection, respectively.) ABT-702 was especially potent at relieving inflammatory thermal hyperalgesia (ED(50) = 5 micromol/kg p.o.). ABT-702 was also effective in the carrageenan-induced paw edema model of acute inflammation (ED(50) = 70 micromol/kg p.o.). The antinociceptive and anti-inflammatory effects of ABT-702 were blocked by selective ADO receptor antagonists, consistent with endogenous ADO accumulation and ADO receptor activation as a mechanism of action. The antinociceptive effects of ABT-702 were not blocked by the opioid antagonist naloxone. In addition, ABT-702 showed less potential to develop tolerance to its antinociceptive effects compared with morphine. ABT-702 had no significant effect on rotorod performance or heart rate (at 30-300 micromol/kg p.o.), mean arterial pressure (at 30-100 micromol/kg p.o.), or exploratory locomotor activity (at

Platelet glycoprotein IIb/IIIa receptor inhibitor preserves coronary flow reserve during progressive coronary arteriostenosis in swine.

Thrombosis resulting from blood platelet aggregation via glycoprotein (GP) IIb/IIIa receptor activation triggers the local release of vasoactive substances. Therefore, inhibition of these receptors could affect coronary vasoactive function during thrombotic coronary arteriostenosis. Twenty pigs were instrumented with an aortic catheter and with hydraulic occluders and flow probes on both the left anterior descending (LAD) and the left circumflex (LCx) coronary arteries. One of these 2 coronary arteries was repeatedly injured by external clamping for 15-second periods at 30-minute intervals while the pigs were given either a GP IIb/IIIa receptor inhibitor (L-739,758) (n=5), heparin (n=5), aspirin (n=3), or saline (n=7). There were no baseline differences between the 4 groups in mean arterial pressure, resting coronary blood flow (CBF), or reactive hyperemic response (RHR), which was induced by brief coronary artery occlusion and expressed as flow debt repayment. After multiple injuries, resting CBF had decreased by 95+/-2% (ie, nearly complete coronary artery occlusion) at 15+/-4 minutes in the control group, whereas in the heparin-, aspirin-, and GP IIb/IIIa inhibitor-treated groups, resting CBF had decreased by only 21+/-7% at 18+/-3 minutes, 15+/-3% at 18+/-5 minutes, and 15+/-7% at 21+/-4 minutes, respectively, suggesting that heparin, aspirin, and the GP IIb/IIIa inhibitor each prevented injury-induced coronary artery occlusion. After the initial injury, the RHR was progressively reduced in the control and heparin- and aspirin-treated groups but not in the GP IIb/IIIa inhibitor-treated group. At a comparable level of resting CBF ( approximately 15% below baseline), the RHR was reduced more in the control (-56+/-9%), heparin-treated (-49+/-9%), and aspirin-treated (-61+/-12) groups (P:<0.05) than in the GP IIb/IIIa inhibitor-treated group (-26+/-6%). When the resting CBF had decreased by approximately 35%, the RHR still was reduced significantly more (P<0.01) in the heparin-treated group (-64+/-9%) than in the GP IIb/IIIa inhibitor-treated group (-21+/-6%). In a separate group of control pigs (n=4) subjected to 2 injuries, coronary perfusion pressure distal to the injury site was reduced by 14+/-1 mm Hg from the arterial pressure, and the RHR was 20+/-6%. When the distal coronary perfusion pressure was reduced similarly (-14+/-1 mm Hg) in a separate group of GP IIb/IIIa inhibitor-treated pigs (n=4) by 2 injuries and the use of a hydraulic occluder, the RHR was 130+/-16% (P<0.01 versus control). Our data demonstrate for the first time that a platelet GP IIb/IIIa receptor inhibitor can preserve the distal coronary vasodilatory response during progressive coronary arteriostenosis.

Chronic therapy with an ET(A/B) receptor antagonist in conscious dogs during progression of congestive heart failure. Intracellular Ca(2+) regulation and nitric oxide mediated coronary relaxation.

BACKGROUND: Although it is known that endothelin (ET-1) is elevated in heart failure (HF), it remains unclear if chronic ET(A/B) receptor antagonism affects the progression of HF, particularly by affecting coronary vasoactivity and left ventricular (LV) diastolic function. METHODS: We examined the effects of an ET(A/B) receptor antagonist, L-753,037 (oral bid for 6 weeks, n=7), and vehicle (n=8) in conscious dogs with previously implanted aortic, coronary sinus and left atrial catheters, LV pressure gauge, aortic flow probe, LV dimension crystals and pacers. RESULTS: Baseline hemodynamics were similar in the two groups. During the development of rapid pacing-induced HF, treatment with the ET(A/B) antagonist significantly reduced total peripheral resistance and increased cardiac output compared to vehicle. After 2 weeks of pacing, LV diastolic function (tau) was improved (P<0.05) in the ET(A/B) antagonist group (+6+/-2 ms) compared to the vehicle group (+12+/-2 ms). In addition, ET(A/B) antagonist treatment attenuated the increase in mean left atrial pressure and LV end-diastolic pressure that occurred during heart failure in vehicle-treated animals. However, LV systolic function (LV dP/dt, fractional shortening and Vcfc) neither at rest nor in response to dobutamine was altered by ET(A/B) antagonist treatment. Also, ET(A/B) antagonist treatment did not affect the progressive increases in LV dimension. After 6 weeks of pacing, maximal Ca(2+) transport in isolated cardiac sarcoplasmic reticulum (SR) was reduced (P<0.02) in the vehicle-treated compared to the ET(A/B) antagonist-treated dogs (1.34+/-0.09 vs. 1.60+/-0.06 micromol/mg/min, respectively). The improvement in SR function in the ET(A/B) antagonist-treated dogs was associated with a significant attenuation of the reduction in protein expression of SERCA2a and calsequestrin observed in the vehicle-treated dogs. Coronary arteries isolated from the dogs treated with the ET(A/B) antagonist exhibited enhanced (P<0.01) coronary endothelium-dependent relaxation compared to the vehicle group, while coronary responses to an NO donor were identical in the two groups. Plasma NO levels in the coronary sinus during the late stage of HF were higher (P<0.05) in the ET(A/B) antagonist group (40+/-2 microM) compared to the vehicle group (18+/-2 microM). CONCLUSIONS: We conclude that in conscious dogs during the development of HF induced by rapid pacing, chronic inhibition of ET(A/B) receptors does not affect resting myocardial contractile function nor reserve, but reduces vascular resistance and improves LV diastolic function. After 6 weeks of pacing, the reduction in intracellular Ca(2+) regulation by the SR is also attenuated, and endothelium-dependent coronary relaxation is improved, which appears to be related to the preservation of coronary NO levels.

Patterns of breast carcinoma treatment in older women: patient preference and clinical and physical influences.

BACKGROUND: Older women have high rates of breast carcinoma, and there are substantial variations in the patterns of care for this population group. METHODS: The authors studied 718 breast carcinoma patients age 67 years and older who were diagnosed with localized disease between 1995 and 1997 from 29 hospitals in 5 regions. Data were collected from patients, charts, and surgeons. Logistic regression analysis was used to evaluate determinants of treatment. RESULTS: Women who were concerned about body image were 1.8 times more likely (95% confidence interval [95% CI], 1.1-2.8) to receive breast conservation surgery and radiotherapy than women without this preference, controlling for other factors. In contrast, women who preferred receiving no therapy beyond surgery were 3.9 times more likely (95% CI, 2.9-6.1) to undergo mastectomy than other women, after considering other factors. Radiotherapy was omitted after breast conservation 3.4 times more often (95% CI, 2.0-5.6) among women age 80 years and older than among women ages 67-79 years, controlling for covariates. Black women tended to have radiotherapy omitted after breast conservation surgery 2.0 times more often (95% CI, 0.9-4.4) than white women (P = 0.09). Women age 80 years and older also were 70% less likely (odds ratio = 0.3; 95% CI, 0.1-0.8) to receive chemotherapy than women ages 67-79 years, controlling for health, functional status, and other covariates. CONCLUSIONS: After considering other factors, patient preferences and age were found to be associated with breast carcinoma treatment patterns in older women. Further research and training are needed to provide care for the growing population of older women that is both clinically appropriate and consonant with a woman's preferences.

Arrhythmogenic potential of positive inotropic agents.

The clinical use of positive inotropic agents has been associated with increased mortality, with proarrhythmia speculated to be a contributing factor. This study compares the arrhythmogenic potentials of six positive inotropic agents representing different mechanistic classes: the beta-adrenergic agonist dobutamine, the adenylyl cyclase activator forskolin, the phosphodiesterase-III inhibitor milrinone, the cardiac glycoside ouabain, and the sodium channel agonists DPI 201-106 and BDF 9148. These agents were studied in dogs with anterior myocardial infarction using lower and higher dose i.v. regimens targeted to elicit 20-40% and 70-90% increases in LV+dP/dt, respectively. Precipitation of new ventricular arrhythmia by programmed ventricular stimulation was observed in all treatment groups. Incidences of new arrhythmia were comparable in the lower dose regimens, ranging from 16.7% (3/18 animals with BDF 9148) to 31.6% (6/19 animals with DPI 201-106), and in the higher dose regimens, ranging from 10.0% (1/10 animals with milrinone) to 27.7% (5/18 animals with DPI 201-106). The overall incidence of new ventricular arrhythmia ranged from 27.3% (3/11 animals with ouabain) to 47.4% (9/19 animals with DPI 201-106). No differences were observed in underlying infarct size or time from infarction to electrophysiologic study between subgroups of animals in which new arrhythmias were precipitated vs. those remaining non-responsive in any treatment group. The positive inotropic agents tested displayed diverse total group effects on heart rate, electrocardiographic intervals including QTc and ventricular refractoriness. Within individual treatment comparisons revealed a general but not universal pattern of greater ventricular refractory period values in newly inducible vs. non-inducible subgroups in the DPI 201-106, BDF 9148 and ouabain (low and high dose); milrinone and dobutamine (high dose) treatment groups. These findings indicate that regardless of underlying cellular mechanism of action, the six positive inotropic agents tested all displayed comparable proarrhythmic potentials unrelated to underlying infarct size and time from infarction. This observation suggests the general shared property of increased myocardial contractility, potentially adversely affecting myocardial oxygen balance, myocardial perfusion and electrical stability in the setting of previous myocardial infarction, to be a common underlying cause for arrhythmogenesis. Additionally, alterations in ventricular refractoriness and repolarization may contribute significantly to proarrhythmia with some positive inotropic interventions.

ABT-627, an endothelin ET(A) receptor-selective antagonist, attenuates tactile allodynia in a diabetic rat model of neuropathic pain.

Tactile allodynia, the enhanced perception of pain in response to normally non-painful stimulation, represents a common complication of diabetic neuropathy. The activation of endothelin ET(A) receptors has been implicated in diabetes-induced reductions in peripheral neurovascularization and concomitant endoneurial hypoxia. Endothelin receptor activation has also been shown to alter the peripheral and central processing of nociceptive information. The present study was conducted to evaluate the antinociceptive effects of the novel endothelin ET(A) receptor-selective antagonist, 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N, N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627), in the streptozotocin-induced diabetic rat model of neuropathic pain. Rats were injected with 75 mg/kg streptozotocin (i. p.), and drug effects were assessed 8-12 weeks following streptozotocin treatment to allow for stabilization of blood glucose levels (>/=240 mg/dl) and tactile allodynia thresholds (

The perception of available social support is related to reduced cardiovascular reactivity in Phase II cardiac rehabilitation patients.

OBJECTIVE: Numerous studies have observed a relationship between social support (SS) and post coronary event survival. Laboratory research suggests one mechanism regulating this relationship may be exaggerated cardiovascular reactivity (CVR). What has not been as well explored is (1) whether the SS-CVR relationship holds up for a heart diseased sample, and (2) whether this relationship is evidenced only in supportive environments or can be found as a function of generalized perception of being socially supported. Thus, the purpose of this study was to examine the relationship of perceived SS and a locally supportive presence to CVR to a speech-induced stressor in post coronary event patients. METHOD: Forty-one Phase II cardiac rehabilitation patients participated in a research protocol that consisted of BP and HR measurement during two identical affective stress interviews where local support was systematically varied by presence or absence of a friendly small pet dog. Perception of SS was assessed by completion of psychosocial questionnaire packet that included measures of SS, anger expression and pet attachment. RESULTS: Repeated measures ANCOVAs revealed that patients who believed they had greater SS available to them during difficult times exhibited significantly less CVR for MAP (p<.007) and DBP (p<.024). No significant main effects for local support (pet presence) and no interactions between local and perceived support were found. CONCLUSIONS: These findings are of interest as they: (a) demonstrate an association between reduced CVR and higher (amounts of) SS in a clinical sample; (b) demonstrate this effect in a sample medicated to dampen CV levels and surges; (c) suggest that perceived amount of SS provides an ameliorative influence on CVR independent of situational support; (d) suggest that for certain conditions pet-models of support may be ineffective at establishing an local support presence.

Antiarrhythmic efficacy of selective blockade of the cardiac slowly activating delayed rectifier current, I(Ks), in canine models of malignant ischemic ventricular arrhythmia.

BACKGROUND: To date, the lack of potent and selective inhibitors has hampered the physiological assessment of modulation of the cardiac slowly activating delayed rectifier current, I(Ks). The present study, using the I(Ks) blocker L-768,673, represents the first in vivo assessment of the cardiac electrophysiological and antiarrhythmic effects of selective I(Ks) blockade. METHODS AND RESULTS: In an anesthetized canine model of recent (8.5+/-0.4 days) anterior myocardial infarction, 0.003 to 0.03 mg/kg L-768,673 IV significantly suppressed electrically induced ventricular tachyarrhythmias and reduced the incidence of lethal arrhythmias precipitated by acute, thrombotically induced posterolateral myocardial ischemia. Antiarrhythmic protection afforded by L-768,673 was accompanied by modest 7% to 10% increases in noninfarct zone ventricular effective refractory period, 3% to 5% increases in infarct zone ventricular effective refractory period, and 4% to 6% increases in QTc interval. In a conscious canine model of healed (3 to 4 weeks) anterior myocardial infarction, ventricular fibrillation was provoked by transient occlusion of the left circumflex coronary artery during submaximal exercise. Pretreatment with 0.03 mg/kg L-768,673 IV elicited a modest 7% increase in QTc, prevented ventricular fibrillation in 5 of 6 animals, and suppressed arrhythmias in 2 additional animals. CONCLUSIONS: The present findings suggest that selective blockade of I(Ks) may be a potentially useful intervention for the prevention of malignant ischemic ventricular arrhythmias.

EXP3174, the AII antagonist human metabolite of losartan, but not losartan nor the angiotensin-converting enzyme inhibitor captopril, prevents the development of lethal ischemic ventricular arrhythmias in a canine model of recent myocardial infarction.

OBJECTIVES: The antiarrhythmic efficacies of the competitive angiotensin II (AII) antagonist losartan, losartan's more potent noncompetitive AII antagonist human metabolite EXP3174 and the angiotensin-converting enzyme inhibitor captopril were assessed in a canine model of recent myocardial infarction. BACKGROUND: Multiple hemodynamic and electrophysiologic effects of AII may contribute to cardiac electrical instability. In the recent Losartan Heart Failure Study, Evaluation of Losartan in the Elderly (ELITE), a 722-patient trial primarily designed to assess effects on renal function, an unexpected survival benefit was observed with losartan compared with captopril, with the lower mortality using losartan primarily confined to a reduction in sudden cardiac death. METHODS: Intravenous losartan (1 mg/kg + 0.03 mg/kg/min), EXP3174 (0.1 mg/kg + 0.01 mg/kg/min), captopril (1 mg/kg + 0.5 mg/kg/h) or vehicle were infused in anesthetized dogs with recent (8.1 +/- 0.4 days) anterior myocardial infarction. Electrolytic injury of the left circumflex coronary artery to induce thrombotic occlusion and posterolateral ischemia was initiated 1 h after the start of treatment. RESULTS: Losartan, EXP3174 and captopril elevated plasma renin activities and comparably and significantly reduced mean arterial pressure. No significant electrocardiographic or cardiac electrophysiologic effects were noted with any treatment. Incidences of acute posterolateral ischemia-induced lethal arrhythmias were: vehicle, 7/9 (77%); losartan, 6/8 (75%); EXP3174, 2/8 (25%; p < 0.05 vs. vehicle control); captopril, 7/10 (70%). There were no among-group differences in time to onset of acute posterolateral ischemia or underlying anterior infarct size. CONCLUSIONS: EXP3174, but not losartan nor captopril, reduced the incidence of lethal ischemic ventricular arrhythmia in this preparation. The antiarrhythmic efficacy of EXP3174 may be due to an attenuation of deleterious effects of local cardiac AII formed during acute myocardial ischemia or, alternatively, a non-AII-related activity specific to EXP3174. These findings suggest that in humans, metabolic conversion of losartan to EXP3174 may afford antiarrhythmic protection.