The involvement of rTPJ in intention attribution during social decision making: A TMS study.

The mini-Ultimatum Game (mini-UG) is a bargaining game used to assess the reactions of a responder to unfair offers made by a proposer under different intentionality conditions. Previous studies employing this task showed the activation of responders' right temporoparietal junction (rTPJ), which could be related to its involvement in judgments of intentionality. To verify this hypothesis, in the present study we applied online transcranial magnetic stimulation (TMS) over the rTPJ in responders during the mini-UG, in which we manipulated intention attribution implicitly. A cover story was employed to induce participants to believe they were interacting with another agent. We expected that interfering with the rTPJ could affect the ability of responders to assume proposers' perspective, producing higher rates of rejections of unfair offers when offers are perceived as independent from responders' intentionality to inequality. Twenty-six healthy women voluntarily participated in the study. In the mini-UG, an unfair distribution of the proposer (8/2 offer) was pitted against one of three alternative offers: fair-alternative (5/5), no-alternative (8/2), hyperfair-alternative (2/8). During the task, a train of TMS pulses was delivered at proposers' offer presentation in blocks of active (rTPJ) or control (Vertex) stimulation according to an ABAB design. As expected, findings showed that rejection of the no-alternative offers was higher under TMS stimulation of the rTPJ compared with the control TMS. This effect was modulated by the degree of trustworthiness in the cover story. These data contribute defining the mechanisms and brain areas underpinning social decision making as assessed by bargaining tasks.

Prescribed performance control of a robotic manipulator with unknown control gain and assigned settling time.

This paper presents a control method for trajectory tracking of a robotic manipulator, subject to practical constraints and uncertainties. The proposed method is established upon an adaptive backstepping procedure incorporating a tangent-type barrier Lyapunov function and it preserves some important metrics of trajectory tracking such as fast and user-defined settling time response and robustness against actuation faults and unknown control gain. The proposed design maintains the system trajectory within a prescribed performance bound and relaxes the assumption of the bounded initial condition. These salient features preserve the system within a safety bound and, consequently, guarantee the system stability and safety. The performance of the proposed control method is validated on a 3-DOF PUMA 560 robotic manipulator benchmark model, with different operation scenarios. The simulation results confirm the effectiveness and robustness of the proposed control method.

Association Between Type 2 Diabetes and Changes in Myocardial Structure, Contractile Function, Energetics, and Blood Flow Before and After Aortic Valve Replacement in Patients With Severe Aortic Stenosis.

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of left ventricular dysfunction after aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Persistent impairments in myocardial energetics and myocardial blood flow (MBF) may underpin this observation. Using phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance, this study tested the hypothesis that patients with severe AS and T2D (AS-T2D) would have impaired myocardial energetics as reflected by the phosphocreatine to ATP ratio (PCr/ATP) and vasodilator stress MBF compared with patients with AS without T2D (AS-noT2D), and that these differences would persist after AVR. METHODS: Ninety-five patients with severe AS without coronary artery disease awaiting AVR (30 AS-T2D and 65 AS-noT2D) were recruited (mean, 71 years of age [95% CI, 69, 73]; 34 [37%] women). Thirty demographically matched healthy volunteers (HVs) and 30 patients with T2D without AS (T2D controls) were controls. One month before and 6 months after AVR, cardiac PCr/ATP, adenosine stress MBF, global longitudinal strain, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and 6-minute walk distance were assessed in patients with AS. T2D controls underwent identical assessments at baseline and 6-month follow-up. HVs were assessed once and did not undergo 6-minute walk testing. RESULTS: Compared with HVs, patients with AS (AS-T2D and AS-noT2D combined) showed impairment in PCr/ATP (mean [95% CI]; HVs, 2.15 [1.89, 2.34]; AS, 1.66 [1.56, 1.75]; P<0.0001) and vasodilator stress MBF (HVs, 2.11 mL min g [1.89, 2.34]; AS, 1.54 mL min g [1.41, 1.66]; P<0.0001) before AVR. Before AVR, within the AS group, patients with AS-T2D had worse PCr/ATP (AS-noT2D, 1.74 [1.62, 1.86]; AS-T2D, 1.44 [1.32, 1.56]; P=0.002) and vasodilator stress MBF (AS-noT2D, 1.67 mL min g [1.5, 1.84]; AS-T2D, 1.25 mL min g [1.22, 1.38]; P=0.001) compared with patients with AS-noT2D. Before AVR, patients with AS-T2D also had worse PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.66 [1.56, 1.75]; P=0.04) and vasodilator stress MBF (AS-T2D, 1.25 mL min g [1.10, 1.41]; T2D controls, 1.54 mL min g [1.41, 1.66]; P=0.001) compared with T2D controls at baseline. After AVR, PCr/ATP normalized in patients with AS-noT2D, whereas patients with AS-T2D showed no improvements (AS-noT2D, 2.11 [1.79, 2.43]; AS-T2D, 1.30 [1.07, 1.53]; P=0.0006). Vasodilator stress MBF improved in both AS groups after AVR, but this remained lower in patients with AS-T2D (AS-noT2D, 1.80 mL min g [1.59, 2.0]; AS-T2D, 1.48 mL min g [1.29, 1.66]; P=0.03). There were no longer differences in PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.51 [1.34, 1.53]; P=0.12) or vasodilator stress MBF (AS-T2D, 1.48 mL min g [1.29, 1.66]; T2D controls, 1.60 mL min g [1.34, 1.86]; P=0.82) between patients with AS-T2D after AVR and T2D controls at follow-up. Whereas global longitudinal strain, 6-minute walk distance, and NT-proBNP all improved after AVR in patients with AS-noT2D, no improvement in these assessments was observed in patients with AS-T2D. CONCLUSIONS: Among patients with severe AS, those with T2D demonstrate persistent abnormalities in myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function after AVR; AVR effectively normalizes myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function in patients without T2D.

Social Context and Tool Use Can Modulate Interpersonal Comfort Space.

Recent research has investigated whether the representation of space around the body, in terms of reach-action (imagining of reaching another person) and comfort-social (tolerance of the other's proximity) spaces, may reflect a shared sensorimotor basis. Some studies exploiting motor plasticity induced by tool use have not observed sensorimotor identity (i.e., the same mechanisms that underlie, based on sensory information, the representation of proximal space in terms of action possibilities, goal-directed motor actions, and anticipation of the sensorimotor consequences), whereas evidence to the contrary has also emerged. Since the data are not fully convergent, here we wondered whether or not the combination of motor plasticity induced by tool use and the processing of the role of social context might reflect a similar modulation in both spaces. To this end, we conducted a randomized control trial with three groups of participants (N = 62) in which reaching and comfort distances were measured in Pre- and Post-tool-use sessions. The tool-use sessions were conducted under different conditions: (i) in the presence of a social stimulus (determining the social context) (Tool plus Mannequin group); (ii) without any stimulus (Only Tool group); (iii) in the presence of a box (Tool plus Object group) as a control condition. Results showed an extension of comfort distance in the Post-tool session of the Tool plus Mannequin group compared with the other conditions. Conversely, the reaching distance was larger after tool use than at the Pre-tool-use session, independently of the experimental conditions. Our findings suggest that motor plasticity impacts reaching and comfort spaces to different degrees; while reaching space is markedly sensitive to motor plasticity, comfort space needs qualification of social context information.

The response of regional well-being to place-based policy interventions.

Enhancing the well-being of its citizens is the central remit of the EU's regional policy, but as yet, there is no analysis of the effects of EU regional policy on local well-being. The aim of this paper is to examine this relationship. To do this, we define a novel regionalised well-being measure and we exploit a dataset on regional expenditure in a continuous treatment framework. Based on both parametric and semi-parametric approaches, our analysis demonstrates that the EU regional development policy does influence regional well-being differently from GDP. We find evidence of a linear monotonic response of well-being growth to total transfers, although this effect varies according to the time lag considered and the level of development of the region.

Epidemiological model based periodic intervention policies for COVID-19 mitigation in the United Kingdom.

As the UK, together with numerous countries in the world, moves towards a new phase of the COVID-19 pandemic, there is a need to be able to predict trends in sufficient time to limit the pressure faced by the National Health Service (NHS) and maintain low hospitalisation levels. In this study, we explore the use of an epidemiological compartmental model to devise a periodic adaptive suppression/intervention policy to alleviate the pressure on the NHS. The proposed model facilitates the understanding of the progression of the specific stages of COVID-19 in communities in the UK including: the susceptible population, the infected population, the hospitalised population, the recovered population, the deceased population, and the vaccinated population. We identify the parameters of the model by relying on past data within the period from 1 October 2020 to 1 June 2021. We use the total number of hospitalised patients and the fraction of those infected who are being admitted to hospital to develop adaptive policies: these modulate the recommended level of social restriction measures and realisable vaccination target adjustments. The analysis over the period 1 October 2020 to 1 June 2021 demonstrates our periodic adaptive policies have the potential to reduce the hospitalisation by 58% on average per month. In a further prospective analysis over the period August 2021 to May 2022, we analyse several future scenarios, characterised by the relaxation of restrictions, the vaccination ineffectiveness and the gradual decay of the vaccination-induced immunity within the population. In addition, we simulate the surge of plausible variants characterised by an higher transmission rate. In such scenarios, we show that our periodic intervention is effective and able to maintain the hospitalisation rate to a manageable level.

Surgical Techniques and Outcomes in Patients With Intra-Cardiac Abscesses Complicating Infective Endocarditis.

Background: An intra-cardiac abscess is a serious complication of both native (NV-IE) and prosthetic valve infective endocarditis (PV-IE). Despite being an accepted indication for surgery, controversies remain regarding the optimal timing and type of operation. We aimed to report the outcomes of patients managed for intra-cardiac abscesses over more than a decade. Methods: Patients aged ≥18 years managed for intra-cardiac abscess between 1 January 2005 and 31 December 2017 were identified from a prospectively collected IE database. The primary outcome was 30-day mortality in operated patients and secondary outcomes were freedom from re-infection, re-operation and long-term mortality comparing those patients with aortic root abscess who underwent aortic valve replacement (AVR) and those who received aortic root replacement (ARR). Results: Fifty-nine patients developed an intra-cardiac abscess, and their median age was 55 (43-71) years; among them, 44 (75%) were men, and 10 (17%) were persons who injected drugs. Infection with beta-haemolytic streptococci was associated with NV-IE (p = 0.009) and coagulase-negative staphylococci with PV-IE (p = 0.005). Forty-four (75%) underwent an operation, and among those with aortic root abscess, 27 underwent AVR and 12 ARR. Thirty-day mortality was associated with infection with S. aureus (p = 0.006) but not the type or timing of the operation. Survival in operated patients was 66% at 1 year and 59% at 5 years. In operated patients, none had a relapse, although six developed late recurrence. Freedom from infection, re-operation and long-term mortality were similar in patients undergoing AVR compared to ARR. Conclusion: Patients diagnosed with intra-cardiac abscess who were not operated on had very poor survival. In those who underwent an operation, either by AVR or ARR based upon patient factors, imaging and intra-operative findings outcomes were similar.

An enormous right atrial myxoma highlights the role of echocardiography in heart failure pathways: a case report.

BACKGROUND: Myxomata are rare, benign, primary tumours of the heart which can present with a variety of symptoms depending on size, location, and mobility. Here, we report a case of enormous right atrial myxoma, obliterating the right atrial and right ventricular cavities presenting with symptoms of heart failure. CASE SUMMARY: A 66-year-old Caucasian female presented to primary care with symptoms of right heart failure and was found to have elevated N-terminal pro B-type natriuretic peptide of 2829 ng/L (normal value <125 ng/L). The patient was referred for urgent evaluation to the integrated heart failure service at our institution. Echocardiography revealed an enormous mobile mass attached to the right atrial septum, extending into the right ventricle and inferior vena cava measuring 90 × 42 mm. The patient underwent urgent surgical resection. Perioperative transoesophageal echocardiography demonstrated severe tricuspid regurgitation, which was treated with tricuspid annuloplasty ring. The patient made an uneventful recovery and was discharged. Subsequent imaging showed a reduction in right ventricular dimensions and improved systolic function. DISCUSSION: This case serves to remind us of the critical role of echocardiography in the diagnosis and management of people with breathlessness and raised natriuretic peptides. Therapies for heart failure are guided by ejection fraction, therefore timely and accurate diagnosis is critical. Moreover, as in this case, echocardiography can also identify other features of critical relevance to patient care.

Space at home and psychological distress during the Covid-19 lockdown in Italy.

Prolonged periods of restrictions on people's freedom of movement during the first massive wave of the COVID-19 pandemic meant that most people engaged in all their daily activities at home. This suggested the need for the spatial features of the home and its occupants' perception of them to be investigated in terms of people's wellbeing. The present study was conducted on a large sample (N = 1354) drawn from different Italian regions. It examined the relationship between the "objective" and "subjective" dimensions of the home, measured in terms of objective home crowding and satisfaction with the space at home, in relation to perceived stress and the perceived risk of COVID-19 infection during the lockdown. The results showed that perceived stress is influenced by objective home crowding through the mediation of satisfaction with the space at home. These associations were more pronounced in younger generations. The negative association between satisfaction with the space at home and perceived stress was higher, the lower the perceived COVID-19 risk.

Social Distance during the COVID-19 Pandemic Reflects Perceived Rather Than Actual Risk.

Interpersonal space (IPS) is the area surrounding our own bodies in which we interact comfortably with other individuals. During the COVID-19 pandemic, keeping larger IPS than usual, along with wearing a face mask, is one of the most effective measures to slow down the COVID-19 outbreak. Here, we explore the contribution of actual and perceived risk of contagion and anxiety levels in regulating our preferred social distance from other people during the first wave of the COVID-19 pandemic in Italy. In this study, 1293 individuals from six Italian regions with different levels of actual risk of infection participated in an online survey assessing their perceived risk to be infected, level of anxiety and IPS. Two tasks were adopted as measures of interpersonal distance: the Interpersonal Visual Analogue Scale and a questionnaire evaluating interpersonal distance with and without face mask. The results showed that the IPS regulation was affected by how people subjectively perceived COVID-19 risk and the related level of anxiety, not by actual objective risk. This clarifies that the role of threat in prompting avoidant behaviors expressed in increased IPS does not merely reflect environmental events but rather how they are subjectively experienced and represented.

ICD lead extraction: Not a benign procedure. External chest compression: Not a benign manoeuvre.

This is the case of a 45-year-old man who was electively admitted to our hospital for revision and extraction of his faulty implantable cardioverter-defibrillator lead and box. The procedure was complicated by cardiac tamponade requiring pericardiocentisis (unsuccessful) and cardiopulmonary resuscitation. The patient was then rushed to theatre for emergency sternotomy and institution of cardiopulmonary bypass. A tear in the superior vena cava was identified and repaired. Unfortunately, the patient suffered of a liver laceration, due to chest compression, which required emergency laparotomy. The aim of this report is to highlight the combination and management of two rare life-threatening complications that occurred in a single case.

Iatrogenic Supravalvular Aortic Stenosis.

We describe a case of hemolytic anemia and proximal anastomotic site stenosis following emergency repair of a Type A aortic dissection. This rare complication led to a reoperation to correct the iatrogenic aortic stenosis and cure the consequent hemolysis. A "sandwich" technique (with two Teflon strips on the outside and inside of the aortic wall) was used in the initial repair to reinforce the suture line and prevent bleeding from the aortic anastomoses. At the time of reoperation, the inner Teflon strip at the proximal aortic anastomosis was found to have inverted into the aortic lumen, as suggested by the preoperative magnetic resonance imaging. Surgical treatment consisted of resecting the portion of inner Teflon that had turned in and tacking the remaining part back onto the aortic wall. The observed hemolysis was likely due to the turbulent flow associated with the supra-aortic stenosis and the collision of red cells with the internal Teflon strip. The patient made an uncomplicated recovery with no further hemolysis and was discharged on postoperative day 8.

Effects of freeze-dried red wine on cardiac function and ECG of the Langendorff-perfused rat heart.

The effect of freeze-dried red wine (FDRW) on cardiac function and electrocardiogram (ECG) in Langendorff-isolated rat hearts was investigated. FDRW significantly decreased left ventricular pressure and coronary perfusion pressure, the latter being dependent on the activation of both phosphatidylinositol 3-kinase and eNOS. FDRW did not affect the QRS and QT interval in the ECG, although at 56 µg of gallic acid equivalents/mL, it prolonged PQ interval and induced a second-degree atrioventricular block in 3 out of 6 hearts. This is the first study demonstrating that at concentrations resembling a moderate consumption of red wine, FDRW exhibited negative inotropic and coronary vasodilating activity leaving unaltered ECG, whereas at very high concentrations, it induced arrhythmogenic effects.

AAV2/8 vectors purified from culture medium with a simple and rapid protocol transduce murine liver, muscle, and retina efficiently.

During the production of some adeno-associated virus (AAV) serotypes, a large amount of vectors is found in the medium of producing cells. For their purification, previous protocols used tangential flow filtration (TFF) of the medium followed by iodixanol gradient centrifugation. Taking advantage of the higher purity of the medium than the cell-derived material as the source of AAV, we tested a simple method that combines production of large culture medium volumes containing AAV from cell stacks with medium clarification+TFF without further time-consuming and nonscalable centrifugation. To test this, we selected AAV2/8, which is emerging as a favored serotype for transduction of liver, muscle, and retina and abundantly found in the extracellular medium. We show that yields and in vitro infectivity of AAV2/8 vectors produced from the culture medium using this method are higher than those of vectors purified from the same cell lysate using a conventional CsCl2 gradient ultracentrifugation-based method, although purity appears inferior. In addition, we found that the transduction efficiency of AAV2/8 purified from medium was similar to that of AAV2/8 purified from the same cell lysate in the murine liver, muscle, and retina. Considering that the purification protocol from the medium we describe requires 3 hr as opposed to the 63 hr of a conventional two-round CsCl2-gradient ultracentrifugation+desalting, we conclude that TFF of the medium containing AAV2/8 represents a quick and scalable method to purify research-grade vectors for use in animal models.

Primary bi-atrial Burkitt lymphoma with severe inflow impairment in an immunocompetent patient.

We report herein a case of sporadic primary cardiac bi-atrial Burkitt lymphoma (BL) occurred in a 67-year-old white immunocompetent patient and presenting with signs and symptoms of severe bilateral atrioventricular inflow impairment. Extranodal BL involving the heart is rare and seldom recognized clinically. Delayed discovery contributes to significant mortality. In the case presented extended surgical excision and intensive combination chemotherapy regiments resulted in complete remission at 1 year.

Variation in the bitter-taste receptor gene TAS2R38, and adiposity in a genetically isolated population in Southern Italy.

OBJECTIVE: Variation in the bitter-taste receptor gene, TAS2R38 confers the ability to taste 6-n-propylthiouracil (PROP). The objective of this study was to relate TAS2R38 haplotypes and PROP-tasting phenotypes to adiposity in a genetically isolated population. We hypothesized that the nontaster phenotype would be associated with higher BMI and waist circumference (WC) in females, and that dietary restraint would mediate this relationship. METHODS AND PROCEDURES: Participants were 540 healthy inhabitants of the genetically isolated village of Carlantino in southern Italy who were 15-89 years of age at the time of the study. Haplotype analyses were performed and PROP tasting was assessed using a filter paper method. Height, weight, and WC were measured and restrained eating was assessed using a brief questionnaire. RESULTS: Nontaster females had higher BMI and WC than females who were phenotypic tasters, and this relationship was specific to females with low dietary restraint. Regression analysis showed that BMI declined by 1.7 units across taster groups in females when the model included the PROP by restraint interaction. PROP phenotype was not significantly associated with WC in the regression models. Polymorphisms in TAS2R38 were not associated with BMI or WC in females. Neither TAS2R38 haplotype nor PROP phenotype was strongly related to BMI or WC in males. DISCUSSION: These data support previous findings of a relation between the nontaster phenotype and higher BMI in females that is modified by dietary restraint. Assessment of PROP phenotypes might provide unique information about adiposity that is not captured by haplotype analysis alone.

Vascular myorelaxing activity of isolates from South African Hyacinthaceae partly mediated by activation of soluble guanylyl cyclase in rat aortic ring preparations.

The vasorelaxing effect of isolates (compounds 1, 2, 3, and 4 (homoisoflavanones), compound 5 (sesquiterpenoid), compounds 6 and 7 (bufadienolides)) from the South African Hyacinthaceae has been assessed using rat aortic ring preparations. Compounds 2, 3, and 4 inhibited the tonic contraction induced by both 60 mM K(+) (K60) and phenylephrine, compound 3 being the most potent. Compounds 5, 6, and 7 caused a modest concentration-dependent relaxation, whereas compound 1 was ineffective. Under K25- or K60-induced depolarization, compound 3 displayed antispasmodic effects not reversed by tetraethylammonium. Under precontraction induced with phenylephrine, compound 3 shifted to the left the concentration-relaxation curves of either isoprenaline or sodium nitroprusside. 1 H-[1,2,4] oxidazolol [4,3-a] quinoxalin-1-one shifted to the right the concentration-relaxation curve of compound 3, while 3'-isobutyl-1-methylxanthine had no effect. In the absence of extracellular Ca(2+), compound 3 (estimated pIC50 = 4.66) and ryanodine reduced the response to phenylephrine. Phenylephrine-stimulated influx of extracellular Ca(2+) was markedly reduced when tissues were pretreated with compound 3 (pIC50 = 5.14) or nifedipine, but stimulated by ryanodine. Compound 3 partially antagonized the contraction induced by phorbol 12-myristate-13-acetate. To our knowledge, this has been the first account describing the vasodilating activity of homoisoflavonoids: compound 3 proved an effective vasorelaxing agent, partly acting via the activation of soluble guanylyl cyclase.

Vascular activity of two silicon compounds, ALIS 409 and ALIS 421, novel multidrug-resistance reverting agents in cancer cells.

PURPOSE: The aim of this study was to investigate the effects of two novel multidrug-resistance reverting agents, ALIS 409 [1,3-dimethyl-1,3-p-fluorophenyl-1,3(3-morfolinopropyl)-1,3-disiloxan dihydrochloride] and ALIS 421 [1,3-dimethyl-1,3-(4-fluorophenyl)-1,3[3(4-buthyl)-(1-piperazinyl)-propyl]-1,3-disiloxan tetrahydrochloride], on vascular functions in vitro. EXPERIMENTAL DESIGN: A comparison of their mechanical and electrophysiological actions in rat aorta rings and single rat tail artery myocytes, respectively, was performed. RESULTS: In endothelium-denuded rat aorta rings, ALIS 409 and ALIS 421 antagonized 60 mM K(+)-induced contraction in a concentration-dependent manner with IC(50) values of 52.2 and 15.5 microM, respectively. ALIS 409 and ALIS 421 inhibited L-type Ca(2+) current recorded in artery myocytes in a concentration-dependent manner with IC(50) values of 6.4 and 5.6 microM, respectively. In rat aorta, ALIS 409 and ALIS 421 antagonized the sustained tonic contraction induced by phenylephrine with IC(50) values of 58.0 and 13.7 microM (endothelium-denuded rings) and of 73.9 and 31.9 microM (endothelium-intact rings), respectively. In endothelium-denuded rings, ryanodine reduced significantly the response to phenylephrine in the absence of extracellular Ca(2+) whereas nifedipine, ALIS 409 or ALIS 421 did not affect it. Phenylephrine-stimulated influx of extracellular Ca(2+) was markedly reduced when tissues were pretreated with ALIS 409, ALIS 421 or nifedipine, and stimulated when they were pretreated with ryanodine. Application of ALIS 409 (up to 100 microM) to intact rat aorta rings failed to induce mechanical responses. CONCLUSIONS: Our results provide functional evidence that the myorelaxing effect elicited either by ALIS 409 or by ALIS 421 involved mainly the direct blockade of extracellular Ca(2+) influx. This effect, however, took place at concentrations much higher than those effective as modifiers of multidrug resistance in cancer cells.

3,5-dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7): a new multidrug resistance inhibitor devoid of effects on Langendorff-perfused rat heart.

Cardiac effects of 3,5-dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7), a novel multidrug resistance (MDR) inhibitor, in Langendorff-perfused rat heart have been investigated and compared to that of nifedipine. Nifedipine decreased concentration-dependently (IC50=8.89+/-1.09x10(-8) M) left ventricular pressure leaving unaltered coronary perfusion pressure, whereas DP7 did not affect both parameters. Nifedipine did not modify both QRS and QT intervals of electrocardiogram (ECG). Second-degree atrioventricular block or ventricular rhythm occurred in presence of nifedipine, however, in 4 out of 6 hearts. DP7, up to 30 microM, failed to alter ECG parameters. In conclusion, DP7, may represent a lead compound for the development of potent dihydropyridine MDR chemosensitizers devoid of cardiac effects.

Mechanisms of the antispasmodic activity of 3,5-di-t-butyl catechol (DTCAT) on rat vascular smooth muscles.

In skeletal muscle sarcoplasmic reticulum vesicles, 3,5-di-t-butyl catechol (DTCAT) promotes the release of Ca(2+) through the activation of ryanodine receptor Ca(2+) channels. DTCAT mechanical and electrophysiological effects have now been investigated in rat aorta rings and single tail artery myocytes. Rat aorta rings incubated with either 30 microM ryanodine or 100 microM DTCAT developed tension, which averaged 36% and 7%, respectively, of that induced by phenylephrine. DTCAT reduced concentration-dependently both aorta ring contractions to high K(+) (IC(50)=13.5 microM) and L-type Ba(2+) current (IC(50)=22.0 microM) in isolated myocytes. Tetraethylammonium did not reverse the antispasmodic effect of DTCAT in rings stimulated with either 25 or 60 mM K(+). DTCAT relaxed concentration-dependently phenylephrine-pre-contracted rings with intact endothelium (IC(50)=10.9 microM). This effect was markedly reduced by pre-incubation of rings with 100 microM Nomega-nitro-l-arginine methyl ester. DTCAT antagonised phenylephrine-induced contractions in endothelium-deprived rings, either in the presence or in the absence of ryanodine (IC(50)=18.7 microM and 39.8 microM, respectively). Furthermore, both DTCAT (IC(50)=53.3 microM) and ryanodine reduced significantly the response to phenylephrine in the absence of extracellular Ca(2+). Phenylephrine-stimulated influx of extracellular Ca(2+) was markedly inhibited when tissues were pre-treated with DTCAT (IC(50)=19.0 microM) as well as nifedipine. DTCAT (>100 microM) was also able to antagonise the contractions induced by phorbol 12-myristate, 13-acetate. In conclusion, this is the first demonstration that DTCAT inhibits vascular smooth muscle voltage-operated Ca(2+) channels and promotes the release of endothelial nitric oxide. Ryanodine receptor Ca(2+) channels activation or the impairment of the contractile apparatus by DTCAT seem to play a secondary role in its vascular activity.