Vanilloid receptor TRPV1, sensory C-fibers, and vascular autoregulation: a novel mechanism involved in myogenic constriction

Myogenic constriction describes the innate ability of resistance arteries to constrict in response to elevations in intraluminal pressure and is a fundamental determinant of peripheral resistance and, hence, organ perfusion and systemic blood pressure. However, the receptor/cell-type that senses changes in pressure on the blood vessel wall and the pathway that couples this to constriction of vascular smooth muscle remain unclear. In this study, we show that elevation of intraluminal transmural pressure of mesenteric small arteries in vitro results in a myogenic response that is profoundly suppressed following ablation of sensory C-fiber activity (using in vitro capsaicin desensitization resulted in 72.8+/-10.3% inhibition, n=8; P<0.05). Activation of C-fiber nerve endings by pressure was attributable to stimulation of neuronal vanilloid receptor, TRPV1, because blockers of this channel, capsazepine (71.9+/-11.1% inhibition, n=9; P<0.001) and ruthenium red (46.1+/-11.7% inhibition, n=4; P<0.05), suppressed the myogenic constriction. In addition, this C-fiber dependency is likely related to neuropeptide substance P release and activity because blockade of tachykinin NK1 receptors (66.3+/-13.7% inhibition, n=6; P<0.001), and not NK2 receptors (n=4, NS), almost abolished the myogenic response. Previous studies support a role for 20-hydroxyeicosatetraenoic acid (20-HETE) in myogenic constriction responses; herein, we show that 20-HETE-induced constriction of mesenteric resistance arteries is blocked by capsazepine. Together, these results suggest that elevation of intraluminal pressure is associated with generation of 20-HETE that, in turn, activates TRPV1 on C-fiber nerve endings resulting in depolarization of nerves and consequent vasoactive neuropeptide release. These findings identify a novel mechanism contributing to Bayliss' myogenic constriction and highlights an alternative pathway that may be targeted in the therapeutics of vascular disease, such as hypertension, where enhanced myogenic constriction plays a role in the pathogenesis.     

Acute blood pressure changes after the onset of atrioventricular nodal reentrant tachycardia: a time-course analysis

INTRODUCTION: We aimed to characterize blood pressure (BP) response at the beginning of atrioventricular nodal reentrant tachycardia (AVNRT) and its relationship to orthostatic challenge and variable atrioventricular interval. METHODS AND RESULTS: In this prospective study of 17 consecutive patients with documented AVNRT, mean BP was analyzed in the supine and upright positions during sinus rhythm, AVNRT, and pacing with atrioventricular delay of 150 msec (AV150) and 0 msec (AV0). Mean BPs were compared at 3-5 seconds, 8-10 seconds, and 28-30 seconds after the onset of AVNRT or pacing. BP decreased immediately after AVNRT initiation, with gradual recovery during the first 30 seconds from 71.9 +/- 16.5 mmHg to 86 +/- 13.8 mmHg, P < 0.01. A similar pattern was observed during AV0, but not during AV150, pacing. While supine, mean BP decrease was more pronounced during AVNRT and AV0 pacing (-26.1% and -32.1%, respectively) than during AV150 pacing (-8%, P = 0.02 and P = 0.07, respectively). This difference subsided 30 seconds after the onset of AVNRT or pacing. When upright, the mean BP time course was similar, but mean BP recovery during AVNRT was slower, and the difference between mean BP during AVNRT and AV150 persisted at 30 seconds. CONCLUSIONS: The initial mean BP decrease during AVNRT recovered gradually within 30 seconds. A short atrioventricular interval is associated with a greater mean BP decrease at the onset of tachycardia. These observations may explain clinical symptoms immediately after the onset of AVNRT.     

Preserved left ventricular ejection fraction following atrioventricular junction ablation and pacing for atrial fibrillation

Introduction: Right ventricular apical (RVA) pacing creates ventricular dyssynchrony and may compromise left ventricular ejection fraction (LVEF). The impact of RVA pacing in patients who have undergone atrioventricular junction (AVJ) ablation for atrial fibrillation (AF) is unclear. We sought to determine whether RVA pacing after AVJ ablation for patients with AF compromises LVEF in the short- or long-term.
Methods/Results: We studied 286 patients with AF who underwent AVJ ablation and RVA pacing at our institution between 1990 and 2002. Patients were stratified into a short-term follow-up group (LVEF reassessed by echocardiography within a year after AVJ ablation, n = 134) and a long-term group (LVEF reassessed after a year, n = 152). Among all 286 patients (mean follow-up 20 months), we observed no change in mean LVEF after AVJ ablation and RVA pacing (48% before vs. 48% after, P = 0.42). Short-term follow-up patients had a statistically significant improvement in mean LVEF (46% before vs. 49% after, P = 0.03), whereas there was no statistically significant change in mean LVEF in long-term follow-up patients (49% before vs. 48% after, P = 0.37). Only 9% of short-term patients, 15% of long-term patients, and 1% of patients with baseline LVEF ≤ 40% experienced ≥10% absolute decrease in LVEF. Baseline LVEF > 40% was a multivariate predictor of LVEF decline.
Conclusions: RVA pacing after AVJ ablation does not compromise LVEF in the short- or long-term for the vast majority of patients. Better predictors are needed to help us select patients for biventricular pacing after AVJ ablation.     

Ascites: Aetiology,mortality and the prevalence of spontaneous bacterial peritonitis

Objective. To assess the aetiology, prognosis and prevalence of spontaneous bacterial peritonitis (SBP) in patients hospitalized for ascites. The validity of an elevated (>11 g/l) serum-ascites albumin gradient (SAAG) in the diagnostic work-up was evaluated. Mortality trends were observed over two periods of time. Material and methods. A total of 231 consecutive patients who underwent diagnostic paracentesis between February 1994 and December 1998 and January 2005 and March 2007 were included in the study. The definition of SBP comprised polymorphonuclear cell count >250/mm³ without evidence of other intra-abdominal source of infection. SAAG was obtained and the Child-Pugh classification applied. Survival rates were obtained from medical records. Results. The most common causes of ascites were alcohol liver cirrhosis (n=143; 62%), malignancy (n=30; 13%), non-alcoholic cirrhosis (n=11; 5%) and malignancy with cirrhosis (n=11; 5%). The prevalence of SBP in cirrhosis was 6.7% (95% CI 2.8–10.5%). Overall mortality rates at 1 month, 6 months and 1 year were 22%, 40% and 48%, respectively, and remained unchanged between the intervals. Patients with grade C liver disease had higher 1-month (26% versus 6%), and 6-month (44% versus 27%) mortality rates than grade B patients, but commensurate 1-year mortality (49% versus 47%). SAAG was ≥11 g/l in 85% of patients with obvious portal hypertension and in 30% with malignancy, ascites albumin level ≤9 g/l in 69% and 20%, respectively. Conclusions. Mortality in patients with ascites was high. The occurrence of SBP was relatively low in our series, with a high proportion of alcoholic cirrhosis. SAAG was inaccurate in differentiating ascites caused by portal hypertension or malignancy.     

Recurrent Zoonotic Transmission of Nipah Virus into Humans, Bangladesh, 2001�C2007

Human Nipah outbreaks recur in a specific region and time of year in Bangladesh. Fruit bats are the reservoir host for Nipah virus. We identified 23 introductions of Nipah virus into human populations in central and northwestern Bangladesh from 2001 through 2007. Ten introductions affected multiple persons (median 10). Illness onset occurred from December through May but not every year. We identified 122 cases of human Nipah infection. The mean age of case-patients was 27 years; 87 (71%) died. In 62 (51%) Nipah virus–infected patients, illness developed 5–15 days after close contact with another Nipah case-patient. Nine (7%) Nipah case-patients transmitted virus to others. Nipah case-patients who had difficulty breathing were more likely than those without respiratory difficulty to transmit Nipah (12% vs. 0%, p = 0.03). Although a small minority of infected patients transmit Nipah virus, more than half of identified cases result from person-to-person transmission. Interventions to prevent virus transmission from bats to humans and from person to person are needed.     

Perceived job security and sickness absence: a study on moral hazard

A moral hazard problem was investigated by analysing the individual behaviour of female and male employees with regard to utilisation of sickness insurance in connection with perceived job security. It was hypothesised that employees with a higher perceived job security take more frequent sickness absence. Perceived higher job security is indicated by three variables, namely a permanent job contract, no unemployment history, and native ethnicity. The effect of perceived job security is expected to be stronger on short-term than on long-term sickness absence, since a medical certificate is required for the latter. Public health survey data from Stockholm County, Sweden, covering the year 2002 was used. Using logistic regression analyses separately for short- and long-term sickness absence and for females and males, we found that short-term sickness absence is more strongly influenced by perceived job security than long-term sickness absence. We observe indications of moral hazard in both female and male employees. However, the three indicators of perceived job security have a different influence on females and males.

Dose Response of MTLn3 Cells to Serial Dilutions of Arsenic Trioxide and Ionizing Radiation

MTLn3 cells derived from mouse mammary epithelium are known to be highly malignant and are resistant to both radio- and chemo-therapy. We exposed MTLn3 cells to various doses of inorganic Arsenic trioxide (As₂O₃) in combination with ionizing radiation. Cells were treated with a series of As₂O₃ concentrations ranging from 20 μM to 1.22 nM for 8 hour, 24 hour and 48 hour periods. Post-treated cell proliferation was quantified by measuring mitochondrial activity and DNA analysis. Cells exposed to radiation and As₂O₃ at concentration greater than 1.25 μM showed apoptosis and radiations alone treated cells were statistically not different from the control. Hormesis was observed for As₂O₃ concentrations in the range of 0.078 μM to 0.625 μM while the combined chemo and radiation treatments of the cells did not affect the hormetic effect. We have demonstrated that As₂O₃ (in the presence and absence of ionizing radiation) in specific low concentrations induced apoptosis in the otherwise chemoresistant cancer cells. This low concentration-mediated cell death is immediately followed by a surge in cell survival. Low dosing dosimetry is highly desirable in metronomic therapy however, it has a narrow window since necrosis, hormesis, apoptosis and other dose-dependent biological processes take place in this region. Further quantifiable dosimetry is highly desired for routine clinical practice.     

Metastatic ewing sarcoma to the heart simulating adriamycin cardiotoxicity

A 20-year-old man with metastatic Ewing Sarcoma developed severe congestive heart failure. Because he had been treated with a large amount of Adriamycin, the diagnosis was initially thought to be Adriamycin cardiotoxicity. However, ante- and post-mortem studies revealed the presence of massive cardiac metastases. At post-mortem, there was no evidence of Adriamycin cardiotoxicity. This case emphasizes that cardiac metastases must be consideredin the differential diagnosis of heart failure in patients treated with Adriamycin.     

RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists

Prostacyclin (PGI2) possesses various physiological functions, including modulation of nociception, inflammation and cardiovascular activity. Elucidation of these functions has been hampered by the absence of selective IP receptor antagonists. Two structurally distinct series of IP receptor antagonists have been developed: 4,5-dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxy-benzyl)-phenyl]-amine (RO1138452) and R-3-(4-fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO3244794).RO1138452 and RO3244794 display high affinity for IP receptors. In human platelets, the receptor affinities (pKi) were 9.3 +/- 0.1 and 7.7 +/- 0.03, respectively; in a recombinant IP receptor system, pKi values were 8.7 +/- 0.06 and 6.9 +/- 0.1, respectively. Functional antagonism of RO1138452 and RO3244794 was studied by measuring inhibition of carbaprostacyclin-induced cAMP accumulation in CHO-K1 cells stably expressing the human IP receptor. The antagonist affinities (pKi) of RO1138452 and RO3244794 were 9.0 +/- 0.06 and 8.5 +/- 0.11, respectively. Selectivity profiles for RO1138452 and RO3244794 were determined via a panel of receptor binding and enzyme assays. RO1138452 displayed affinity at I2 (8.3) and PAF (7.9) receptors, while RO3244794 was highly selective for the IP receptor: pKi values for EP1 (< 5), EP3 (5.38), EP4 (5.74) and TP (5.09). RO1138452 (1-10 mg kg(-1), i.v.) and RO3244794 (1-30 mg kg(-1), i.v.) significantly reduced acetic acid-induced abdominal constrictions. RO1138452 (3-100 mg kg(-1), p.o.) and RO3244794 (0.3-30 mg kg(-1), p.o.) significantly reduced carrageenan-induced mechanical hyperalgesia and edema formation. RO3244794 (1 and 10 mg kg(-1), p.o.) also significantly reduced chronic joint discomfort induced by monoiodoacetate. These data suggest that RO1138452 and RO3244794 are potent and selective antagonists for both human and rat IP receptors and that they possess analgesic and anti-inflammatory potential.