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Background Blood pressure (BP) readings taken in clinics are often higher than BP readings taken in a research setting. Recent guidelines and clinical trials have highlighted the necessity of using automated office blood pressure (AOBP) devices and standardizing measurement procedures. The goal of the present study was to compare AOBP vs manual BP measurement in both research and clinical environments in which operators and devices were the same and measurement procedures were standardized and optimal. Methods Clinical manual BP and AOBP measurement estimates were gathered from a retrospective cohort of patients followed in a hypertension clinic. Research AOBP and manual BP measurement data were obtained from past research studies. Descriptive statistics and agreement analyses with Cohen kappa coefficients were developed. The AOBP/manual BP measurement gap between clinical and research follow-up was compared using an unpaired t test. Results Two hundred eighty-eight patients were included in the clinical cohort, and 195 patients contributed to research-grade BP data. All patients had hypertension. AOBP averages were lower than manual measurement averages in both clinical (−3.6 ± 14.9 mm Hg / −3.0 ± 8.8 mm Hg) and research (−2.7 ± 10.0 / −2.4 ± 6.3 mm Hg) environments. The gap between measurement methods did not differ between research and clinical data. Cohen kappa coefficient was lower in the clinical context because of greater variability and more time between BP measurements (5.5 ± 2.9 months). Conclusions Manual BP readings were slightly higher than AOBP estimates. The difference was not influenced by the real-world context of clinical practice. Office nonautomated BP measurements may still be valuable if measurement procedures are well standardized and performed by trained nurses.

Statin therapy is presented as a protection against ischemic heart disease (IHD) complications. As IHD is often a fatal disease, statins are thereby supposed to decrease cardiovascular mortality and increase life expectancy. However, these benefits are increasingly challenged in the medical community, the controversy being particularly intense when discussing the effects of statins in primary prevention and the consequences of statin discontinuation. Both primary prevention and treatment discontinuation have been recently used by investigators linked to the pharmaceutical industry to justify and boost prescription and consumption of statins and other cholesterol-lowering medications. We herein review some recent commercial data related to primary prevention with rosuvastatin and statin discontinuation and their respective effects on IHD and overall mortality rate. We conclude that (1) despite the recent hype raised by HOPE-3, the cholesterol-lowering rosuvastatin is likely not beneficial in intermediate-risk individuals without cardiovascular disease (primary prevention). This trial may even represent a typical example of how evidence-based medicine has been flawed in commercial studies. (2) Statin discontinuation does not lead to increased IHD and overall mortality, at least in the months following interruption of treatment. On the contrary, one might even conclude that statin discontinuation could save lives. One possible explanation of this apparently paradoxical finding is that statin discontinuers, in the same time they stop statin therapy, likely try to adopt a healthy lifestyle. Further studies are needed to confirm the real effects of statin discontinuation in various clinical conditions. In the meantime, it is not evidence based to claim that statin discontinuation increases mortality or saves lives.

Background Clinical guidelines are based on the results of several randomized controlled trials. However, due to the stringent exclusion criteria of these trials, their external validity may be low. We aimed to evaluate the external validity of the randomized controlled trials cited in the American College of Chest Physicians guidelines for the use of pharmacological thromboprophylaxis in hospitalized medical patients. Methods We conducted a cross-sectional, chart-review study of a random sample of patients admitted between July 1, 2013 and June 30, 2014 to the Internal Medicine ward of a large Canadian teaching university hospital. We identified the proportion of our population presenting exclusion criteria used in the randomized controlled trials cited in support of clinical care guidelines on thromboprophylaxis in the medical setting. Results Nine trials were identified for a total of 28,793 included patients following 23 distinct exclusion criteria. We included 429 patients. Median age was 65 years (interquartile ratio 51-77 years), and 236 (55%) were males. Of those not already anticoagulated at admission (n = 351), between 26% and 67% (weighted average, 51%) of our population presented at least one exclusion criterion, making them ineligible to be enrolled in randomized controlled trials. When restricting our population to patients with an indication for thromboprophylaxis based on a Padua risk score at admission ≥4, 21% to 76% (weighted average 55%) were ineligible to be enrolled in individual trials. Conclusions Our cross-sectional study illustrates that the external validity of randomized controlled trials cited in the guidelines was low in our population, and lower when applying the risk-stratification tool recommended by guidelines. This can bias the clinicians toward treating patients that were not represented in the supporting evidence.

Conflicting data exists on the influence of metformin on prostate cancer. We investigated the importance of metformin in patients treated with radiotherapy or brachytherapy.All patients from a large institutionalized database, treated for primary localized prostate cancer with either brachytherapy or external-beam radiotherapy ± androgen deprivation therapy were identified. Groups were compared by Kaplan-Meier analyses and Cox regression models. Multivariate analysis was adjusted for CAPRA-Score, type of treatment and age.A total of 2441 patients with complete data was identified. Among the 382 patients (16% of total) were diabetic. Two-hundred and eighty-one of the 382 diabetics (74%) were treated with metformin and 101 were treated with other anti-diabetic medication. Median follow up was 48 months (interquartile range [IQR] 24-84). Two-hundred eighteen patients (9%) died and 150 (6%) experienced biochemical recurrence (BCR). On unadjusted univariate analysis for BCR-free survival, metformin users showed a 50% reduction in BCR compared to non-metformin users. The results remained significant on multivariate analysis comparing diabetic metformin users to non-metformin users (diabetics and non-diabetics combined) (hazard ratio [HR] 0.5-0.6, p = 0.03-0.04) but lost its significance when adjusting for cancer aggressiveness. On multivariate analysis, diabetics had worse overall survival (OS) than non-diabetics (HR 1.5, 95% confidence interval [CI] 1.08-2.06, p = 0.01), but diabetics on metformin fared better than diabetics not taking metformin (HR 0.5, 95% CI 0.26-0.86, p = 0.01).Metformin use in this analysis appears to be associated with better BCR and OS. Larger datasets and prospective trials are warranted to validate these results.

Context Paper home blood pressure (HBP) charts are commonly brought to physicians at office visits. The precision and accuracy of mental calculations of blood pressure (BP) means are not known. Methods A total of 109 hypertensive patients were instructed to measure and record their HBP for 1 week and to bring their paper charts to their office visit. Study section 1: HBP means were calculated electronically and compared to corresponding in-office BP estimates made by physicians. Study section 2: 100 randomly ordered HBP charts were re-examined repetitively by 11 evaluators. Each evaluator estimated BP means four times in 5, 15, 30, and 60 s (random order) allocated for the task. BP means and diagnostic performance (determination of therapeutic systolic and diastolic BP goals attained or not) were compared between physician estimates and electronically calculated results. Results Overall, electronically and mentally calculated BP means were not different. Individual analysis showed that 83% of in-office physician estimates were within a 5-mmHg systolic BP range. There was diagnostic disagreement in 15% of cases. Performance improved consistently when the time allocated for BP estimation was increased from 5 to 15 s and from 15 to 30 s, but not when it exceeded 30 s. Conclusion Mentally calculating HBP means from paper charts can cause a number of diagnostic errors. Chart evaluation exceeding 30 s does not significantly improve accuracy. BP-measuring devices with modern analytical capacities could be useful to physicians.

Background Home blood pressure (BP) measurement (HBPM) is recommended for the diagnosis and follow-up of high BP. It is unclear how this aspect of BP monitoring has evolved over the years and whether interventions could influence patient adherence to HBPM guidelines. Methods After a questionnaire-based cross-sectional study performed in 2010, a passive, multimodal intervention, focused on improving adherence to HBPM guidelines, was implemented. A second study was conducted in 2014 to measure its effect. Results In 2010 and 2014, 1010 and 1005 patients, respectively, completed the questionnaire. In 2010 and 2014, 82% and 84% of patients, respectively, self-measured their BP. Reporting of HBPM and adherence to recommended procedures was suboptimal. Only 34.0% of patients in 2010 and 31.7% in 2014 brought > 80% of their measurements to their doctor. Only 49.6% in 2010 and 52.9% in 2014 prepared > 80% of the time for HBPM. Only 48.1% in 2010 and 52.1% in 2014 rested for 5 minutes > 80% of the time before HBPM. Only 15% of patients in 2010 and 18% in 2014 were defined as sufficiently compliant with all HBPM procedures. Paired analysis of a subset of 535 patients who participated in the 2010 and 2014 studies showed no clinically significant differences in reliability between the 2 surveys. Conclusions Adherence to HBPM guidelines was suboptimal in 2010 and still is in 2014 despite a passive, multimodal intervention. Active training in HBPM procedures should be studied. Greater automation could improve HBPM reliability.

Automated office blood pressure (AOBP) measuring devices are increasingly recommended as preferred blood pressure (BP) diagnostic tools, but it is unclear how they compare and how clinical environments impact their performance.This prospective randomized factorial parallel 4-group study compared BP estimates by BpTRU (VSM MedTech, Vancouver, BC, Canada) and Omron HEM 907 (Omron Healthcare, Kyoto, Japan) devices in closed vs open areas. Patients diagnosed with hypertension were recruited during office visits. After baseline open-room AOBP measurement with the BpTRU, patients had a second BP measurement with either the BpTRU or HEM 907 in either open or closed areas. Absolute BP levels and differences between the first and second measurements were compared. Diagnostic performance was also assessed.Two hundred fifty-eight patients were studied. Their mean age was 66.2 ± 12.0 years, and 62% were men. The mean of first AOBP estimates was 127.4/73.3 mm Hg. Analyses of subsequent measurements revealed no influence of open or closed areas on BP means and diagnostic performance. Conversely, the Omron HEM 907 exceeded BpTRU systolic BP measurements by 4.6 mm Hg (0.01) in closed areas and by 3.9 mm Hg (0.01) in open areas. The discrepancy between devices was amplified at lower BP levels.Although different areas did not influence BP estimates, the Omron HEM 907 significantly exceeded BpTRU measurements on average and especially at lower BP levels. These differences should be considered when interchanging devices and could have clinical decision impacts in a population of patients treated for hypertension. Our results support the constant use of only 1 device type in a given clinic.

Background: Thromboprophylaxis for hospitalized patients with a high risk of venous thromboembolic events (VTEs) is strongly recommended but is not universally applied on medical units. Outside of randomized trials, there is minimal evidence that the usual medications reduce the incidence of clinically significant VTE. Methods: We conducted a retrospective cohort study including all patients admitted into a teaching medical unit during years 2001-2002, 2003-2004, 2005-2006, 2007-2008 and 2009-2010. Inclusion criteria for the analysis were having one or more risk factors for a VTE and no contraindication to thromboprophylaxis. Results: Of 2,369 patients reviewed, 1,302 satisfied the inclusion criteria. Between years 2001-2002 and 2009-2010, the proportion of patients receiving thromboprophylaxis increased from 29.2% to 76.4% (P < 0.0001) and the duration of thromboprophylaxis increased from 63% of hospital stay to 84% (P = 0.004). There was no statistically significant association between the number of risk factors and the rate of thromboprophylaxis. Overall, only 32 patients suffered from a VTE with no decrease in VTE incidence between years 2001-2002 and 2009-2010. A total of 107 patients had a bleeding event, and there was no statistically significant change in the incidence of bleeding during our study period. Conclusions: In our medical units, we found a statistically significant increase in the use of the thromboprophylaxis practice. However, this was not associated with any statistically significant impact on the VTE incidence. This suggests that patients given thromboprophylaxis could be better selected. J Clin Med Res. 2014;6(2):91-97 doi: http://dx.doi.org/10.14740/jocmr1712w

Observations suggest that traditional anticoagulant therapy, maintaining an international normalized ratio (INR) of approximately 2.0 to 3.0, could be more intensive than is necessary for the long-term prevention of recurrent venous thromboembolism. The value of less-intensive warfarin anticoagulation, with a target INR of 1.5 to 1.9, was therefore examined in a randomized, double-blind study enrolling 738 consecutive patients having one or more episodes of venous thromboembolism. All had completed at least 3 months of conventional oral anticoagulant therapy. Participants were assigned to continue on warfarin with a target INR of either 2.0-3.0 or 1.5-1.9 and were followed up for 2.4 years on average. To be eligible, patients must have had confirmed, symptomatic, proximal deep venous thrombosis or pulmonary embolism with no apparent major risk factor. The mean INR was 1.8 for patients assigned to low-intensity treatment and 2.4 in the usual-intensity group. Nine major bleeding episodes occurred in patients on low-intensity treatment, for a rate of 1.1 per 100 person-years. The 8 such episodes in the traditional treatment group represented a rate of 0.9 per 100 person-years. Including minor bleeding episodes, rates were 4.9 and 3.7 per 100 person-years, respectively. There were no fatal or intracranial bleeds in either treatment group. Older patients were more likely to have major bleeding. Venous thromboembolism recurred at rates of 1.9 events per 100 person-years in the low-intensity group and 0.7 per 100 person-years with traditional treatment, a statistically significant difference. Five episodes in the low-intensity group and 3 in the usual-intensity group occurred after warfarin was discontinued. There was 1 death in the low-intensity group caused by pulmonary embolism and 2 such deaths in the conventional treatment group. These findings show that conventional warfarin anticoagulation is more effective than a low-intensity regimen for preventing recurrent venous thromboembolism; the risk is lowered by approximately two thirds. At the same time, low-intensity treatment does not appear to make bleeding less likely.

To evaluate the long-term clinical and hemodynamic effectiveness of aortic stent placement in cases of failure of intended infrarenal percutaneous transluminal aortic angioplasty (PTAA).Fifty-three patients who underwent technically successful PTAA were compared with 24 patients who underwent aortic stent placement because of PTAA failure (19 patients) or ulcerated lesions (five patients) that otherwise would have been treated surgically because of the embolization hazard associated with PTAA alone. Clinical patency was defined as the absence or improvement of symptoms after the intervention. Hemodynamic patency was defined as a normal Doppler waveform in the common femoral arteries, an ankle-brachial index greater than 0.95, or the absence of a thigh-brachial pressure gradient.Three-year clinical and hemodynamic patency rates, respectively, were 85% and 79% for PTAA and 69% and 43% for aortic stent placement. No morbidity was encountered. With use of the Cox proportional hazards model, two significant risk factors were retained for restenosis: unchanged smoking habit (P =.04) and small dilatation diameter (P =.001). Aortic stent placement, performed in patients with a smaller aortic diameter (10.3 vs. 12.7 mm for PTAA), appeared to be a predictive factor for restenosis by using univariate analysis. By using the Cox proportional hazards model, however, the restenosis rates after PTAA and aortic stent placement were not significantly different.When aortic diameter is taken into consideration, there is no evidence that clinical outcome after secondary aortic stent placement would be poorer than technically successful PTAA.

Background Patients who have a first episode of venous thromboembolism in the absence of known risk factors for thrombosis (idiopathic thrombosis) are often treated with anticoagulant therapy for three months. Such patients may benefit from longer treatment, however, because they appear to have an increased risk of recurrence after anticoagulant therapy is stopped. Methods In this double-blind study, we randomly assigned patients who had completed 3 months of anticoagulant therapy for a first episode of idiopathic venous thromboembolism to continue receiving warfarin, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0, or to receive placebo for a further 24 months. Our goal was to determine the effects of extended anticoagulant therapy on rates of recurrent symptomatic venous thromboembolism and bleeding. Results A prespecified interim analysis of efficacy led to the early termination of the trial after 162 patients had been enrolled and followed for an average of 10 months....

We read with interest the paper by Rosenson et al. [(1)][1], who performed a retrospective analysis showing that only a “disappointing” 27% in a 5% random sample of Medicare patients 65 to 74 years of age hospitalized for acute myocardial infarction or revascularization from 2007 to 2009 had

We report a case of a 52-year-old Caucasian woman diagnosed with a synchronic arterial and venous thrombosis as an initial presentation of an acute promyelocytic leukemia (APL). After the diagnosis, the patient was treated with all trans-retinoic acid and arsenic chemotherapy concomitant to systemic anticoagulation. This treatment regimen led to a complete remission and absence of relapse of the thrombosis or APL during the follow-up. To our knowledge, this presentation is the second case in the literature. We use this opportunity to emphasize the importance of performing a complete medical evaluation in cases of unusual thromboembolic events. J Clin Med Res. 2014;6(5):388-391 doi: http://dx.doi.org/10.14740/jocmr1864w

BACKGROUND: Some patients develop fatigue while taking warfarin, but causality is uncertain. OBJECTIVE: To assess whether warfarin use is associated with fatigue. METHODS: This investigation was a substudy of a randomized double-blind trial in 13 outpatient thromboembolism clinics. Subjects who had received one month of open-label warfarin therapy for venous thromboembolism due to a transient risk factor were randomly assigned to receive warfarin or placebo for 2 months and followed for another 9 months after stopping the study drug. Fatigue was measured using a Likert scale, and change of fatigue was measured by the patient's global rating. RESULTS: In 87 subjects, the overall ratings of fatigue were 0.1 unit lower (95% CI 0.6 units lower to 0.4 units higher) while taking warfarin. Global rating for change in fatigue intensity showed no increase of fatigue with warfarin use. CONCLUSIONS: The short-term use of warfarin was not associated with symptoms of fatigue.

The contractile responses and generation of intracellular second messengers in response to endothelin-1 (ET-1), a potent vasoconstrictor peptide released locally by endothelial cells and involved in the regulation of vascular tone, were investigated in different segments of the vascular tree of adult 18-week-old spontaneously hypertensive rats (SHR) as compared with age-matched Wistar–Kyoto (WKY) rats. Aorta rings of SHR showed lower maximum response to ET-1 in comparison with WKY rats. Rings of the main superior mesenteric artery of SHR and WKY showed similar responses to ET-1. Small mesenteric resistance arteries of SHR, mounted on a wire myograph, developed similar tension to those of WKY rats in response to ET-1. The dose–response of inositol phosphates to ET-1 was significantly blunted in thoracic aorta of SHR compared with WKY rats, whereas it was similar in the mesenteric arterial bed. Baseline 1,2-diacylglycerol content was higher in thoracic aorta of SHR than WKY, while it was similar in the mesenteric arterial bed of the two strains. The response of 1,2-diacylglycerol to ET-1 was blunted in aorta of SHR, whereas no significant differences in diacylglycerol accumulation could be found in mesenteric vessels between SHR and WKY. In small mesenteric arteries, the dose–response to ET-1 of cytosolic free calcium, measured with the fluorescent dye Fura 2-AM, was similar in the two groups of rats. We conclude that in the aorta of 18-week-old SHR there is reduced generation of second messengers (inositol phosphates and diacylglycerol), which underlies its decreased response to ET-1 In mesenteric vessels (both proximal and distal) signal transduction is similar in SHR and WKY, and as a result contractile responses in both species are comparable. The responses to ET-1 of the arterial tree in terms of contractility and second messenger generation may reflect the adaptive processes taking place as a consequence of elevated blood pressure within the arterial wall of different segments of the vasculature of SHR.Key words: inositol phosphate, phospholipids, diacylglycerol, cytosolic calcium, second messengers, conduit and resistance arteries, Wistar–Kyoto rats.

We sought to determine whether thrombophilic defects increase recurrent venous thromboembolism (VTE) during warfarin therapy. Six hundred sixty-one patients with unprovoked VTE who were randomized to extended low-intensity (international normalized ratio [INR], 1.5-1.9) or conventional-intensity (INR, 2.0-3.0) anticoagulant therapy were tested for thrombophilia and followed for a mean of 2.3 years. One or more thrombophilic defects were present in 42% of patients. The overall rate of recurrent VTE was 0.9% per patient-year. Recurrent VTE was not increased in the presence of factor V Leiden (hazard ratio [HR], 0.7; 95% CI, 0.2-2.6); the 20210G>A prothrombin gene mutation (HR, 0); antithrombin deficiency (HR, 0); elevated factor VIII (HR, 0.7; 95% CI, 0.1-5.4); elevated factor XI (HR, 0.7; 95% CI, 0.1-5.0), or elevated homocysteine (HR, 0.7; 95% CI, 0.1-5.3), but showed a trend to an increase with an antiphospholipid antibody (HR, 2.9; 95% CI, 0.8-10.5). Compared with patients with no thrombophilic defects, the rate of recurrence was not increased in the presence of one (HR, 0.7; 95% CI, 0.2-2.3) or more than one (HR, 0.7; 95% CI, 0.2-3.4) defect. We conclude that single or multiple thrombophilic defects are not associated with a higher risk of recurrent VTE during warfarin therapy.

To evaluate the safety and long-term clinical and hemodynamic results of percutaneous transluminal angioplasty (PTA) of the infrarenal aorta.During nearly 10 years, 102 patients with symptomatic infrarenal atherosclerotic aortic stenosis underwent PTA. Follow-up information was available in 92 patients (17 men, 75 women; mean age, 51.9 years). Stenosis involved the aortic bifurcation in 18 patients and only the infrarenal abdominal aorta in 74 patients. Technical success was defined as residual stenosis less than 50% or a pressure gradient less than 10 mm Hg after PTA. Clinical patency was defined as the absence or improvement of symptoms after PTA. Hemodynamic patency was defined as a normal Doppler waveform in the common femoral arteries, an ankle-brachial ratio greater than 0.95, or the absence of a thigh-brachial pressure gradient.Technical success was achieved in 78 patients after PTA. After 10 years, primary clinical and hemodynamic patency rates were 72% and 46%, respectively. After a mean follow-up of 51 months, 15 of the 22 symptomatic recurrences were due to aortic restenosis; 11 of these were treated with repeated PTA with or without stent placement, and three eventually required aortic surgery. No morbidity was encountered.Infrarenal aortic PTA proved to be safe and provided durable, long-term clinical improvement. In this group of relatively young patients, the clinical patency rate of PTA was equivalent to that of aortic surgery but with less morbidity.

Purpose To compare the efficacy and safety of streptokinase (SK) and urokinase (UK) in the treatment of local thrombolysis. Patients and Methods Over a 24-month period, 40 patients with 45 lower limb arterial occlusions of less than 45 days duration underwent intraarterial fibrinolysis. Twenty occlusions were treated with recombinant UK and tissue culture-derived UK, and 25 occlusions were treated with SK. The study was retrospective, but the two groups were very homogeneous in terms of vascular surgical history, medical risk factors, and occlusion characteristics. Results Complete lysis (95% or more) was achieved in 84% of SK infusions and 89% of UK infusions. Endoluminal and surgical interventions as well as clinical outcomes of SK and UK treatment were comparable. However, infusion time was significantly longer for SK treatment: 28.5 hours versus 19.1 hours for UK treatment ( P =.035). Complication rates were not statistically significantly different. Average length of stay in the intensive care unit was identical (2.2 days) for both groups, and the difference in hospital stay was not statistically significant (7.7 days for SK vs 8.7 days for UK). Conclusion At the concentrations and doses used, the efficacy and safety of SK and UK were comparable, despite longer SK infusion time.

To examine potential intracellular signalling abnormalities of endothelin-1 (ET-1) and vasopressin (AVP) which may contribute to blood pressure elevation, contractility and inositol phosphate levels in intact arteries and calcium transients in vascular smooth muscle cells were investigated after stimulation with these peptides in pre-hypertensive 5 week-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) rats. Contractility of aorta in response to ET-1, AVP and norepinephrine (NE) was blunted in SHR relative to WKY. Contraction of mesenteric resistance arteries induced by ET-1 was similar in both groups, whereas sensitivity in response to NE and AVP was greater in SHR. Basal inositol phosphate in aorta and mesenteric arteries was elevated in SHR, but ET-1 and AVP-stimulated inositol phosphate responses were similar in both groups. Calcium transients induced by ET-1 and AVP in vascular smooth muscle cells were similar in young SHR and WKY. In contrast, in adult rats inositol phosphate responses to ET-1 were blunted in aorta of SHR, but were normal in mesenteric arteries. Inositol phosphate responses to AVP were similar in both rat strains of rats both in aorta and mesenteric arteries except for accumulation of inositol trisphosphate, which was enhanced in mesenteric arteries of SHR. Calcium mobilization in vascular smooth muscle cells from adult SHR also exhibited enhanced responses to AVP. In conclusion, in young SHR, blunted ET-1 and AVP-induced contraction in aorta and enhanced AVP-induced mesenteric artery contraction are associated with normal inositol phosphate production and calcium mobilization. Signal transduction in response to ET-1 and AVP is depressed in aorta of pre-hypertensive SHR after the step of inositol phosphate generation and calcium mobilization. Resistance vessel reactivity to AVP is enhanced in young SHR at steps following inositol phosphate generation and calcium mobilization. These results argue against a role of ET-1, but suggest the possible involvement of AVP in the development of this model of genetic hypertension.

To assess the effects of age on responsiveness of atrial natriuretic factor (ANF) release, and the possible contribution of cardiac sympathetic activity, in young (n = 8) and older normotensives (n = 7), the effects of cardiac volume load on plasma ANF, central venous pressure, and general hemodynamics were evaluated. Studies were performed after pretreatment with placebo or 80 mg propranolol. Cardiac volume loading increased central venous pressure by 3–5 mmHg (1 mmHg = 133.3 Pa); β-blockade did not affect this response. Cardiac volume load caused significant increases in heart rate (10–15 beats/min) and cardiac index (by 0.7–0.8 L∙min−1∙m−2) and decreases in plasma catecholamines. Propranolol attenuated the increases in heart rate and cardiac index. These hemodynamic responses did not differ significantly between the two groups of subjects. Cardiac volume load significantly increased plasma ANF, by 87 ± 21 pg/mL in the young normotensives and by 212 ± 33 pg/mL in the older normotensives (p

Vascular tissues such as rat aorta and mesenteric arteries are extensively used experimentally for the study of cardiovascular diseases. To further our understanding of the signal transduction mechanisms involved in responses to several potent vasoconstrictors, such as [Arg8]vasopressin (AVP), endothelin 1 (ET-1), and prostaglandin F2α (PGF2α), we have investigated the time course for production of inositol monophosphate (InsP1), bisphosphate (InsP2), and trisphosphate (InsP3) in response to these agonists as well as their relative potency for phosphatidylinositol hydrolysis. Time-course studies of production of the different inositol phosphates in response to AVP and PGF2α showed an early increase after 15–30 s of stimulation. Thereafter InsP3 declined towards baseline, with a secondary increase towards steady state after 5–10 min. Rapid turnover of InsP3 was reflected by accumulation of InsP1 and InsP2 in the presence of LiCl (20 mM) to inhibit monophosphatases. After 15–30 min of stimulation, there was accumulation of the Ins(1,3,4)P3 isomer. All three agonists induced greater accumulation of InsP2 in mesenteric arteries than in thoracic aorta, suggesting that turnover of Ins(1,4,5)P3 may be faster in the former than in the latter. The accumulation of total inositol phosphates induced by maximum concentrations of ET-1 was greater than in response to AVP or PGF2α. Dose–response curves showed that the rank order of potency for stimulation of production of inositol phosphates was AVP > ET-1 > PGF2α, similar to the sensitivity of blood vessels to these agents. Comparison of responses to ET-1 and ET-3 showed that the receptors stimulated by endothelins were of the isopeptide selective ETA subtype. In conclusion, all three agonists (AVP, ET-1, PGF2α) stimulate phospholipase C activity in rat aorta and in mesenteric arteries, although with different potencies. This study demonstrates that intact blood vessels allow a detailed investigation of inositol phosphate responses to different agonists of interest in cardiovascular research.Key words: phosphoinositide metabolism, phospholipase C, inositol trisphosphate, vasoconstrictors, blood vessels.

In previous studies a decreased responsiveness to endothelin-1 (ET-1) of conduit arteries and resistance vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats was found in comparison with uninephrectomized controls. Decreased isometric force, number of receptors, and inositol phosphate accumulation were reported in the DOCA-salt animals. In the present study effects of ET-1 on cytosolic free calcium, inositol phosphates, and 1,2-diacylglycerol were investigated in blood vessels of DOCA-salt hypertensive rats. Basal cytosolic free calcium, measured with the fluorescent dye fura-2, was 201 +/- 41 nmol/l in mesenteric arteries of DOCA-salt rats and 45 +/- 9 nmol/l in uninephrectomized controls (p less than 0.01). The maximal response of cytosolic free calcium (to 30 nmol/l ET-1) was 176 +/- 22% of the basal value for DOCA-salt and 242 +/- 6% for uninephrectomized rats (p less than 0.05). The concentration giving 50% of the maximum response was 9.0 and 6.5 nmol/l for DOCA-salt rats and controls, respectively. Inositol phosphate production after stimulation with 100 nmol/l ET-1 in the presence of LiCl was lower by at least 30% (p less than 0.01) in both aorta and mesenteric arteries of DOCA-salt hypertensive versus control rats. Basal levels of diacylglycerol in aorta were similar in DOCA-salt rats and in controls and did not respond to a 100 nmol/l ET-1 stimulation in the DOCA-salt rats, in contrast to the increase found in the control uninephrectomized rats (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The vasoconstrictor effect, the binding, and the response of inositol phosphates to endothelin-1 (ET-1) were investigated in blood vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats within 2 weeks of development of hypertension and in uninephrectomized control rats. In DOCA-salt and uninephrectomized rats, plasma levels of endothelin were similar (1.2 +/- 0.1 fmol/ml). Thoracic aorta and mesenteric artery rings devoid of endothelium presented significantly decreased responses to increasing concentrations of ET-1. Binding of ET-1 to mesenteric artery membranes was significantly lower in DOCA-salt rats (106 +/- 22 fmol/mg protein) than in uninephrectomized rats (172 +/- 19 fmol/mg protein, p less than 0.05), whereas affinity was similar. Phosphoinositide metabolism was examined in aorta and mesenteric arteries after incubation with [3H]myoinositol. Inositol phosphates were separated by high-performance liquid chromatography. In response to 100 nmol/l ET-1, accumulation of inositol 1,4,5-trisphosphate after 20 seconds and of inositol monophosphate, inositol bisphosphate, and inositol 1,3,4-triphosphate after 30 minutes (in the presence of 25 mmol/l LiCl) were significantly lower in DOCA-salt hypertensive than in uninephrectomized control rats, in both aorta and mesenteric arteries. In conclusion, decreased density of ET-1 receptors in DOCA-salt hypertensive rats results in decreased activation of phospholipase C and, consequently, reduced vasoconstriction induced by ET-1. Because the decrease in vasoconstrictor effects of ET-1 is found in the absence of endothelium, it is likely that receptor downregulation rather than prior receptor occupancy underlies these findings.