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Background The aim of this study was to examine the relationship between mortality and statin adherence using two different approaches to adherence measurement (summary versus repeated-measures). Methods A retrospective cohort study was conducted using administrative data from Saskatchewan, Canada between 1994 and 2008. Eligible individuals received a prescription for a statin following hospitalization for acute coronary syndrome (ACS). Adherence was measured using proportion of days covered (PDC) expressed either as: 1) a fixed summary measure, or 2) as a repeatedly measured covariate. Multivariable Cox-proportional hazards models were used to estimate the association between adherence and mortality. Results Among 9,051 individuals, optimal adherence (≥80%) modeled with a fixed summary measure was not associated with mortality benefits (adjusted HR 0.97, 95% CI 0.86 to 1.09, p = 0.60). In contrast, repeated-measures approach resulted in a significant 25% reduction in the risk of death (adjusted HR 0.75, 95% CI 0.67 to 0.85, p

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2013. This year's update includes 2 new recommendations. First, among nonhypertensive or stage 1 hypertensive individuals, the use of resistance or weight training exercise does not adversely influence blood pressure (BP) (Grade D). Thus, such patients need not avoid this type of exercise for fear of increasing BP. Second, and separately, for very elderly patients with isolated systolic hypertension (age 80 years or older), the target for systolic BP should be150 mm Hg (Grade C) rather than140 mm Hg as recommended for younger patients. We also discuss 2 additional topics at length (the pharmacological treatment of mild hypertension and the possibility of a diastolic J curve in hypertensive patients with coronary artery disease). In light of several methodological limitations, a recent systematic review of 4 trials in patients with stage 1 uncomplicated hypertension did not lead to changes in management recommendations. In addition, because of a lack of prospective randomized data assessing diastolic BP thresholds in patients with coronary artery disease and hypertension, no recommendation to set a selective diastolic cut point for such patients could be affirmed. However, both of these issues will be examined on an ongoing basis, in particular as new evidence emerges.

PURPOSE: We aimed to determine to what extent a telephone-based pharmacist intervention would (a) be utilized by individuals not attending a traditional cardiac rehabilitation (CR) program and (b) facilitate adherence to cardiovascular medications. METHODS: We conducted a randomized, controlled open-label trial among patients eligible for CR in Saskatoon, Canada. Patients were invited to participate in telephone-based CR, regardless of participation in the formal program. Subjects in the intervention group were assessed by the CR pharmacist and received education and counseling on medication adherence. The primary endpoint was adherence to cardiovascular medication assessed by electronic filling records over a minimum of 6 months. Mean adherence was expected to reach 70% during the followup period. RESULTS: Patient recruitment was halted early because of low enrollment. Of the 95 patients randomized, 90% had also registered in the traditional CR program. During the followup period, 129 telephone interactions were performed (median, 2 calls), with every subject taking part in at least 1 interaction. Over the study period, the mean adherence to all recently initiated cardiovascular medications combined was 88.8% in the intervention group and 89.9% in the usual care group (P = .73). CONCLUSIONS: Participation in traditional CR programs does not appear to be influenced by the availability of telephone-based education and support. Furthermore, the high rate of adherence among the control group may suggest that CR programs are attracting "healthy adherers" who volunteer for such programs, while missing those with the greatest need for health care system resources.

Hypertension Canada's Canadian Hypertension Education Program Guidelines Task Force provides annually updated, evidence-based recommendations to guide the diagnosis, assessment, prevention, and treatment of hypertension. This year, we present 4 new recommendations, as well as revisions to 2 previous recommendations. In the diagnosis and assessment of hypertension, automated office blood pressure, taken without patient-health provider interaction, is now recommended as the preferred method of measuring in-office blood pressure. Also, although a serum lipid panel remains part of the routine laboratory testing for patients with hypertension, fasting and nonfasting collections are now considered acceptable. For individuals with secondary hypertension arising from primary hyperaldosteronism, adrenal vein sampling is recommended for those who are candidates for potential adrenalectomy. With respect to the treatment of hypertension, a new recommendation that has been added is for increasing dietary potassium to reduce blood pressure in those who are not at high risk for hyperkalemia. Furthermore, in selected high-risk patients, intensive blood pressure reduction to a target systolic blood pressure ≤ 120 mm Hg should be considered to decrease the risk of cardiovascular events. Finally, in hypertensive individuals with uncomplicated, stable angina pectoris, either a β-blocker or calcium channel blocker may be considered for initial therapy. The specific evidence and rationale underlying each of these recommendations are discussed. Hypertension Canada's Canadian Hypertension Education Program Guidelines Task Force will continue to provide annual updates.

A rare case ofBacilluspanophthlamitis with extension to the prechiasmatic optic nerve secondary to hematogenous spreading after intravenous drug use is presented. A 27-year-old man with a recent history of trauma to the left eye presented with severe left eye pain following a binge of intravenous drug use. Visual acuity (VA) was LP. On examination he had chemosis, proptosis, elevated intraocular pressure, and a complete hyphema. CT-scan identified preseptal swelling, but no evidence of any posterior extension of the anterior process or orbital fractures. Topical and systemic therapy were initiated. On follow-up clinical examination less than 12 hours after presentation he had signs of a keratitis with worsening ophthalmoplegia and repeat imaging demonstrated posterior extension to the prechiasmatic optic nerve. Shortly after the cornea ruptured with cultures growingBacillus. The patient underwent enucleation and has had no further progression of infection. To the best of our knowledge, this is the first report ofBacilluspanophthalmitis presenting with signs of trauma with posterior extension to the prechiasmatic optic nerve.

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2012. The new recommendations are: (1) use of home blood pressure monitoring to confirm a diagnosis of white coat syndrome; (2) mineralocorticoid receptor antagonists may be used in selected patients with hypertension and systolic heart failure; (3) a history of atrial fibrillation in patients with hypertension should not be a factor in deciding to prescribe an angiotensin-receptor blocker for the treatment of hypertension; and (4) the blood pressure target for patients with nondiabetic chronic kidney disease has now been changed to < 140/90 mm Hg from < 130/80 mm Hg. We also reviewed the recent evidence on blood pressure targets for patients with hypertension and diabetes and continue to recommend a blood pressure target of less than 130/80 mm Hg.

INTRODUCTION Low socioeconomic status (SES) should be a robust predictor of medication nonadherence because it shares key features with the theoretical origins of this phenomenon. However, population-based studies have demonstrated weak associations overall, possibly because SES is inadequately represented. We compared the performance of multiple versus single-domain measures of SES as predictors of statin adherence. METHODS This retrospective cohort study used population-based administrative data mapped to area-level census information of individuals who received a statin medication following a hospitalization for coronary heart disease. One-year adherence was calculated by dividing the sum of all tablets dispensed by the total number of days in the observation period (365 d following the first statin dispensation). Logistic regression models were constructed and the relative impact of each SES measure was assessed by its adjusted odds ratio (OR) and improvement over the predictive accuracy of a reference model that included non-SES factors only. RESULTS More than two thirds (ie, 68.8%; 6517/9478) of eligible individuals exhibited optimal adherence (ie, ≥80%). The estimated impact of SES on optimal adherence differed depending on the SES measure tested. The highest performing single-domain measure, household income (OR=0.75; 95% confidence interval, 0.63-0.90; model c-statistic improvement 0.5%, P=0.04) generated a similar result to the multiple-domain measure (adjusted OR=0.74; 95% confidence interval, 0.62-0.88; model c-statistic improvement 0.7%, P=0.01). CONCLUSION Multidomain measurements of SES using administrative databases mapped to census data are not associated with better performance in predicting statin medication adherence compared with single-domain measures such as household income.

Objective The role of atenolol in the management of patients with hypertension is currently under scrutiny. Our aim was to evaluate the real-world consequences of recent clinical trial findings. Methods We conducted a retrospective, cohort study using linked administrative data from the province of Saskatchewan, Canada. Eligible subjects were first-ever users of antihypertensive medications between 1 January 1994 and 31 December 2003 and were grouped into four cohorts: atenolol, angiotensin-converting enzyme inhibitors (ACEI), thiazide diuretics, or calcium antagonists. Patients remained eligible during monotherapy only. Results We identified 19 249 eligible individuals (mean age 60.6 years) who were followed for a mean of 2.3 years (SD 2.0). The rate of myocardial infarction, unstable angina, stroke, or death occurred in similar frequencies among all cohorts: atenolol (2.3%), ACEI (3.6%), thiazide diuretics (2.9%), and calcium antagonists (3.9%). After adjustment for potential confounders, atenolol therapy was not associated with higher event rates than the other first-line agents, with hazard ratios ranging between 1.03 [95% confidence intervals (CI) 0.72–1.46] and 1.24 (95% CI 0.91–1.68) for all cohorts compared with atenolol. Similar results were observed upon stratifying the sample into subjects above and below 60 years of age. Conclusion The low event rates for all cohorts suggest that atenolol has not been associated with a significant burden of cardiovascular morbidity or mortality in its traditional role for uncomplicated hypertension. Further study is needed to identify the specific types of patients that should avoid atenolol as an antihypertensive agent.

Aldosterone antagonists are the mainstay of therapy in patients with hypertension due to primary aldosteronism. However, in our experience, these patients are sometimes placed on angiotensin-converting enzyme (ACE) inhibitors in accordance with guidelines applying to the general hypertensive population. We believe this practice is inappropriate because of the inability of ACE inhibitors to lower blood pressure in patients with low renin levels. Furthermore, pleiotropic effects of ACE inhibitors are unlikely to provide significant benefits in the absence of blood pressure reduction. Therefore, ACE inhibitors should be discouraged for the majority of patients with primary aldosteronism, even in the face of renal or cardiac disease.

The Canadian Hypertension Education Program reviews the hypertension literature annually and provides detailed recommendations regarding hypertension diagnosis, assessment, prevention, and treatment. This report provides the updated evidence-based recommendations for 2015. This year, 4 new recommendations were added and 2 existing recommendations were modified. A revised algorithm for the diagnosis of hypertension is presented. Two major changes are proposed: (1) measurement using validated electronic (oscillometric) upper arm devices is preferred over auscultation for accurate office blood pressure measurement; (2) if the visit 1 mean blood pressure is increased but < 180/110 mm Hg, out-of-office blood pressure measurements using ambulatory blood pressure monitoring (preferably) or home blood pressure monitoring should be performed before visit 2 to rule out white coat hypertension, for which pharmacologic treatment is not recommended. A standardized ambulatory blood pressure monitoring protocol and an update on automated office blood pressure are also presented. Several other recommendations on accurate measurement of blood pressure and criteria for diagnosis of hypertension have been reorganized. Two other new recommendations refer to smoking cessation: (1) tobacco use status should be updated regularly and advice to quit smoking should be provided; and (2) advice in combination with pharmacotherapy for smoking cessation should be offered to all smokers. The following recommendations were modified: (1) renal artery stenosis should be primarily managed medically; and (2) renal artery angioplasty and stenting could be considered for patients with renal artery stenosis and complicated, uncontrolled hypertension. The rationale for these recommendation changes is discussed.

Young Sprague-Dawley rats develop high blood pressure (BP) when exposed to a high salt intake, whereas adult ones generally do not. We investigated the role of renal cytochromes P450 4A (CYP 4A) and 2C (CYP 2C) in maintaining normal BP.Young (age 5 weeks) and adult (age 53 weeks) Sprague-Dawley rats were given either 20 mmol sodium carbonate (vehicle for clofibrate) or 0.9% saline to drink for 3 weeks. Some young animals received the peroxisome proliferator activated receptor (PPAR)alpha agonist clofibrate (80 mg daily). We measured tail-cuff and intra-arterial BP, weight change, sodium balance, 20-hydroxyeicosatetraenoic acid (20-HETE) excretion (by high-performance liquid chromatography), and renal expression of CYP 4A and CYP 2C (by real-time reverse transcriptase-polymerase chain reaction).Saline-treated adult animals remained normotensive: systolic BP (SBP) 117 +/- 2 mm Hg v 117 +/- 1 mm Hg in control animals. In contrast, young rats given saline developed increased SBP: 134 +/- 2 mm Hg v 115 +/- 2 mm Hg in control animals (P. 001). Interestingly, clofibrate lowered SBP to 102 +/- 2 mm Hg in saline-treated young rats but had no effect in control animals (114 +/- 2 mm Hg). Adult rats given saline increased renal expression of CYP 4A and 2C and excreted more 20-HETE. However, young rats given saline showed no induction, and even reduced CYP 4A and 2C, decreased urinary 20-HETE excretion, and retained sodium. Clofibrate increased renal CYP and 20-HETE excretion and prevented sodium retention.The products of renal CYP4A and 2C, including 20-HETE, aid in excreting salt. Animals that are unable to increase renal 20-HETE formation do not excrete sodium and are prone to hypertension.

Ridogrel is a member of the class of drugs known as thromboxane receptor antagonists/thromboxane synthase inhibitors or TRASIs. In vitro and in vivo studies have confirmed it selectively reduces thromboxane A 2 (TXA 2 ) synthesis in platelets and elsewhere, while leaving the synthesis of other eicosanoids unchanged or even increased. Theoretically, it should produce a greater overall antithrombotic effect than aspirin. Some animal and human studies support this concept. A large phase III study confirmed the safety and efficacy of ridogrel in patients following myocardial infarction. It may also be useful in other clinical situations. In spontaneously hypertensive-stroke prone rats, ridogrel reduces blood pressure, but increases plasma renin activity. The antihypertensive effect is potentiated by losartan, an angiotensin-type I receptor antagonist. Ridogrel may also have efficacy in pregnancy induced hypertension, inflammatory bowel disease, and asthma.

Study Objective. To measure the extent of cardiovascular morbidity associated with nonadherence to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy. Design. Retrospective cohort study Data Source. Linked administrative health databases in Saskatchewan, Canada. Patients. A total of 1221 patients aged 30–70 years who received a new prescription for a statin drug between 1994 and 2001, within 1 year of their first cardiovascular event (i.e., myocardial infarction, unstable angina, ischemic stroke, percutaneous transluminal coronary angioplasty [PTCA], or coronary artery bypass graft [CABG]). Measurements and Main Results. Adherence was measured by the fill frequency (number of prescriptions filled during the observation period divided by months of observation). Patients with a fill frequency of 80% or greater were classified as adherent (661 patients); those with a fill frequency of 60% or less were classified as nonadherent (395 patients). The remaining 165 patients who had adherence rates of 61–79% were excluded analysis. The primary end point included a composite of myocardial infarction, unstable angina, PTCA, CABG, and death. Among 1056 patients, adherence was not associated with a reduction of the primary end point. However, patients in the adherent group were half as likely to experience a subsequent myocardial infarction as the patients in the nonadherent group (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.20–0.99, p=0.047). In patients younger than 65 years (both adherent and not), the associated reduction in myocardial infarction was even more profound (HR 0.14, 95% CI 0.04–0.46, p=0.001) and was accompanied by a trend for a lower frequency of unstable angina (HR 0.37, 95% CI 0.13–1.03, p=0.06). In patients 65 years or older (301 patients), adherence was not associated with significant changes in cardiovascular end points. Conclusion. A detectable excess of cardiovascular morbidity appears to be associated with nonadherence to statin therapy. Our analysis suggests that many occurrences of myocardial infarction could be prevented with improvements in adherence. Larger studies are necessary to determine the association between adherence and other cardiovascular end points.

Article-at-a-Glance Background Strategies to reduce health expenditures through the improvement of health and quality of care are in high demand. A group of experts formed a nonpartisan, independent work group, under the sponsorship of the National Managed Health Care Congress. Its goal was to establish a list of easy-to-understand, actionable, and usable recommendations to enable disease management program advocates to conduct basic-level evaluations. Recommendations The work group made recommendations concerning identification of reference and intervention population, population definitions, quantitative methods and data quality, confounding and bias, and stakeholder agreements/contracting. Case Study A case study was created to quantitatively illustrate some of the major issues raised by the work group. Five typical errors were simulated by applying different rules to the intervention population than to the reference population: differential inclusion (high versus low risk), differential exclusion (high versus low risk) and differential claims run-out. Compared with the true impact, four of the five errors resulted in a bias toward "intervention effect," while one (differential inclusion of high-risk patients) was biased against the "intervention effect." The direction and magnitude of the bias in natural settings will not necessarily follow this pattern.

Background: Staff in hospitals frequently travel between floors and choose between taking the stairs or elevator. We compared the time savings with these two options. Methods: Four people aged 26–67 years completed 14 trips ranging from one to six floors, both ascending and descending. We compared the amount of time per floor travelled by stairs and by two banks of elevators. Participants reported their fatigue levels using a modified Borg scale. We performed two-way analysis of variance to compare the log-transformed data, with participant and time of day as independent variables. Results: The mean time taken to travel between each floor was 13.1 (standard deviation [SD] 1.7) seconds by stairs and 37.5 (SD 19.0) and 35.6 (SD 23.1) seconds by the two elevators ( F = 8.61, p Interpretation: Taking the stairs rather than the elevator saved about 15 minutes each workday. This 3% savings per workday could translate into improved productivity as well as increased fitness.

We assessed whether cysteinyl leukotrienes mediate the vasoconstrictor responses to angiotensin II and endothelin-1 in the mesenteric vascular bed of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) perfused ex vivo at a constant flow rate of 5 ml/min with Krebs buffer. Maximal perfusion pressure response ( Emax) but not EC50values to angiotensin II ( P < 0.001) and endothelin-1 ( P < 0.01) were significantly higher in the SHR, whereas the responses to potassium chloride remained unchanged. Inclusion of the selective 5-lipoxygenase inhibitor AA-861 or the cysteinyl leukotriene receptor antagonist MK-571 significantly reduced the vasoconstrictor responses to angiotensin II but not to endothelin-1 and potassium chloride. The reduction in Emaxto angiotensin II was more pronounced in SHR ( P < 0.001) than in WKY ( P < 0.05) rats. Cysteinyl leukotrienes LTC4-, LTD4-, and LTE4(1 μM)-evoked vasoconstrictor responses were significantly higher in SHR ( P < 0.05), whereas LTB4failed to evoke any response in either strain. These data suggest that 5-lipoxygenase metabolites, particularly cysteinyl leukotrienes, contribute to the exaggerated vasoconstrictor responses to angiotensin II but not to endothelin-1.

Abstract —The vasodilatory capacity of insulin has been widely reported, yet some investigators have not noted this effect. Because insulin has been shown to enhance endothelin release, we speculated that endothelin could be attenuating insulin-evoked vasodilation. We examined the effect of ex vivo insulin perfusion on vascular resistance by using the Sprague-Dawley rat mesenteric vascular bed. In methoxamine-preconstricted preparations, insulin (3.0 pmol/L to 10 nmol/L) evoked a concentration-dependent decrease in perfusion pressure (PP) with a maximal response of 42.0±9.2%, whereas continuous exposure to 10 nmol/L insulin induced a 51.8±3.5% relaxation. Further exposure to 10 nmol/L insulin resulted in the generation of endothelin and a subsequent loss of the vasodilatory response. Indomethacin had no effect on vascular responses. The vasodilatory response was significantly inhibited by nitric oxide synthase inhibition (20.5±4.2%; P P P

Objectives Publically accessible blood pressure monitors are widely used, but little information is available on their accuracy. We compared blood pressure readings of 17 drug store monitors with those obtained using a validated home monitor (Omron BP742CAN) and both with those taken at home using the Canadian Hypertension Education Program protocol. Materials and methods Duplicate readings were taken using the drug store monitor (VitaStat, n=6, and PharmaSmart, n=11) on the left arm and the Omron on the right in three participants: two normal and one untreated hypertensive patient. We used Bland-Altman methods for comparison. We explored the correlation with average home blood pressure readings. Results Home average blood pressure for our three participants was 121±6/73±5, 106±6/62±4, and 142±8/81±7 mmHg. The mean systolic blood pressure difference (drug store-Omron) was -1.8±8.2 mmHg. Diastolic pressure difference was 1.7±5.6. Individual paired systolic differences varied from -19 to 14 mmHg. For the participant who required a large cuff, drug store systolic readings tended to be higher (4.1±6.7). In our three participants, drug store monitors as a group read higher than home systolic blood pressure: 7.5 [95% confidence interval (CI) 1.5-13.4], 1.2 (95% CI -4.0 to 6.4), and 1.0 (95% CI -2.5 to 4.4) mmHg. Diastolic blood pressure and heart rate differences were similar in magnitude. Conclusion On average, drug store monitors recorded lower systolic blood pressures and higher diastolic blood pressures than a validated monitor, but the difference was neither statistically nor clinically significant. Single reading comparisons showed a much broader range. In three participants, drug store monitors did reflect the average home blood pressure.

Angiotensin II (Ang II) stimulates renal prostanoid and vascular endothelin-1 (ET-1) release. Most known Ang II effects are mediated by AT1 receptors. Our aim was to determine whether AT1 receptor activation mediates Ang II-evoked renal prostanoid and ET-1 release. Eleven healthy men were randomized in a crossover, double-blind fashion to receive 100 mg/day of losartan or matching placebo, for 8 days. Blood and urine were sampled before and after a 2-h infusion of Ang II at a rate previously determined to increase mean arterial pressure (MAP) by 25 to 30 mm Hg in each subject. After a 14-day washout, subjects received the alternate treatment. Pretreatment with losartan had little effect on baseline MAP, but increased plasma renin activity, and virtually eliminated the pressor response to Ang II infusion. Angiotensin II significantly increased prostanoid excretion after placebo; the prostanoid response to Ang II was even greater after losartan. Plasma ET-1 was not altered by Ang II infusion, with or without losartan. In contrast, urine ET-1 excretion rate decreased to 40% of baseline after Ang II but not after losartan pretreatment; losartan alone had no effect. We conclude that Ang II decreases renal ET-1 synthesis and release through the AT1 receptor. In contrast, Angiotensin II-mediated renal prostanoid synthesis does not require activation of AT1 receptors. These findings indicate that AT1 receptor antagonists could provide renal protection through indirect mechanisms.

Fenofibrate, a commonly used lipid lowering drug, induces the expression of the gene coding for cytochrome P450-4A, whose major product is 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a potassium channel antagonist, could increase or decrease blood pressure (BP). We studied the effects of four weeks of oral fenofibrate on BP, urine output (UVol), plasma renin activity (PRA), and urine protein excretion in young (4-5 weeks) stroke prone spontaneously hypertensive rats (SHRSP), older (25 weeks) SHRSP, Dahl salt sensitive rats (Dahl S) on a high salt diet, Dahl S rats on a normal salt diet, and normotensive Sprague-Dawley (SD) rats. Fenofibrate prevented the increase in BP in 4-5 week old SHRSP, reduced BP in 25 week old SHRSP, but had no effect on BP in normotensive SD rats. Similarly, fenofibrate prevented the increase in BP in Dahl S rats on a high salt diet, but had no effect in Dahl S rats on a low salt diet. Fenofibrate increased UVol (and reduced weight gain) in young SHRSP and tended to increase it in other groups. It also increased PRA 2 to 5-fold in all groups except older SHRSP. Young SHRSP receiving fenofibrate excreted significantly less urine protein than control rats. The drug reduced proteinuria in Dahl S rats on high salt diet, but had no significant effect on proteinuria in other groups. In summary, fenofibrate reduced blood pressure and weight gain, increased UVol and PRA, and reduced urine protein excretion in young SHRSP. Other groups of animals showed these changes to a variable, but directionally similar extent. These findings are consistent with a natriuretic effect of fenofibrate.Key words: hypertension, animal models, natriuresis, fenfibrate, lipid lowering agents.

Objective: Earlier, we reported that high insulin incubation in vitro leads to increased ETA receptor expression in cultured rat aortic smooth muscle cells (Diabetes 1998, 47: 934–944). Our later observation of enhanced endothelin-1 evoked vasoconstriction in aorta from the hyperinsulinemic obese Zucker rat indicated that this interaction might also be relevant in vivo. To further examine the relationship between insulinemia and endothelin, we characterized endothelin receptor expression and endothelin-1 peptide levels in vascular tissues and plasma from young and old obese Zucker rats. Methods: 12 and 40-week-old Zucker obese and lean rats were used. Plasma endothelin-1 levels and endothelin-1 peptide content in the mesenteric artery and in the thoracic aorta were examined by radioimmunoassay. Messenger RNA levels of endothelin-1 peptide and ETA and ETB receptors were examined in the aortic and mesenteric vessels using RT-PCR. Results : Obese rats from both age groups had significantly higher plasma levels of insulin (4–10 fold), total cholesterol (2–3 fold), triglycerides (10-fold), and glucose (∼1.5 fold) than their lean counterparts. There was a trend toward worsening lipoproteinemia and glycemia, but improved insulinemia with age in the obese rats. In association with these changes, obese rats exhibited attenuated endothelin-1 peptide and preproET-1 mRNA levels, but conversely elevated ETA and ETB receptor mRNA levels in both aortic and mesenteric vessels. Conclusion : These data suggest that vascular tissue from the metabolically dysregulated obese Zucker rat exhibits attenuated endothelin-1 peptide production and elevated endothelin receptor levels. Since elevated insulin levels have been linked to increased endothelin receptor expression, it is plausible that hyperinsulinemia upregulates endothelin receptors contributing to elevated vasoconstrictor responses to endothelin-1 in this model of obesity and hypertension.

Objectives. To test the delivery of prostaglandin E1 (PGE1) in novel transdermal liposomal formulations through foreskin and to determine whether there is a correlation between in vitro transdermal absorption and in vivo efficacy in patients with erectile dysfunction. Methods. The in vitro transdermal absorption of PGE1 through excised foreskin from liposomal formulations was tested in diffusion cells using radiolabeled drug. The in vivo studies were carried out on 5 patients (aged 54 to 70 years) in a double-blind, placebo-controlled fashion. The patients were treated topically on the penis with three different active formulations containing 0.05% PGE1 and a placebo at least 1 week apart. The change in systolic peak flow velocities in the cavernosal arteries after treatment was monitored by duplex color Doppler ultrasonography with spectral analysis every 15 minutes for 1 hour. Results. The permeability coefficient (Kp) of PGE1 from the three liposomal formulations tested was found to be 0.10, 1.66, and 3.82 3 10 24 cm/hr, respectively. Peak systolic flow velocities in the deep cavernosal arteries of patients increased significantly compared with preapplication values (0.05 , P # 0.1) after application of two of the transdermal liposomal PGE1 formulations tested (the two with the highest Kp). The highest mean peak systolic flow velocity was achieved at 45 minutes after application of the formulations. The most effective formulation in this study resulted in a sevenfold increase in mean flow velocity compared with baseline values. Conclusions. Topical application of PGE1 in a novel transdermal liposomal delivery system can enhance penetration of the drug into the deep cavernosal bodies and increase peak systolic flow velocities in patients with erectile dysfunction. The transdermal flux and permeability of PGE1 measured in vitro correlate well with the color Doppler ultrasound results in patients. The efficacy of a formulation in the development process may be predicted from in vitro absorption studies. UROLOGY 52: 838‐843, 1998. © 1998, Elsevier Science Inc. All rights reserved.

Although insulin has been shown to raise plasma concentrations of endothelin (ET) and up regulate vascular smooth muscle ETA receptor expression, the interaction of vanadate, an insulinomimetic agent, with the vascular ET system has not been investigated. We compared the effects of oral vanadate treatment (0.5 mg/ml; p. o.) and insulin infusion (12 mU · kg–1· min–1 s. c.) for two weeks on plasma ET concentrations and vascular responses to endothelin-1 (ET-1) and the α-1 adrenoceptor agonist, methoxamine, in aortic ring preparations from streptozotocin (STZ) diabetic and non-diabetic adult male Sprague-Dawley rats. Plasma ET concentrations were lower (p < 0.01) in STZ diabetic rats compared with normal control rats. Insulin and vanadate treatment restored plasma ET to normal (p < 0.01) in STZ rats and increased ET concentrations in the control (p < 0.05) group. Higher maximal tension responses to both ET-1 (p < 0.01) and methoxamine (p < 0.05) were present in STZ rats in both endothelium intact and denuded aortic preparations compared with the control group. Both insulin and vanadate treatment returned these responses to normal. It is concluded that low plasma concentrations of insulin and high plasma glucose in STZ diabetic rats are accompanied by lower concentrations of plasma ET. Insulin and vanadate treatment restores diminished plasma ET to control concentrations and attenuates exaggerated agonist(s)-evoked vascular smooth muscle responses in STZ-induced diabetic rats. In addition to well known beneficial metabolic effects, insulin and vanadate may beneficially affect cardiovascular regulation in the STZ diabetic rat by correcting abnormal ET activity. [Diabetologia (1998) 41: 1233–1240]

The aim of this study was to assess the rate and extent of transcutaneous delivery of prostaglandin E 1 (PGE 1 ) from various formulations [liposomal, novel biphasic, and nonliposomal (oil/water cream) delivery systems] in vitro using diffusion cells and in vivo using laser doppler flowmetry, to aid in the development of a topically active preparation for the treatment of male sexual dysfunction. Percutaneous absorption through adult human foreskin was tested in flowthrough diffusion cells using [ 3 H]PGE 1 . Nine healthy volunteers participated in the crossover, randomized, double-blind, placebocontrolled study, where 0.1 g of each preparation was applied to a 4 cm 2 area on the forearm. Laserflo BPM 2 blood perfusion monitor with Model P-430 skin probe was used for evaluating skin blood perfusion. Encapsulation of PGE 1 into novel biphasic delivery systems resulted in significantly increased skin blood perfusion relative to traditional liposomal, nonliposomal, and placebo formulations (6.25 ± 1.58 vs 2.72 ± 0.79, 0.53 ± 0.64, and 0.58 ± 0.06 mL LD /min/100 g, respectively, n = 9). The in vitro absorption of PGE 1 through foreskin correlated well with the in vivo data (respective permeability coefficients 3.33, 1.57, and 1.40 x 10– 4 cm/h). Formulation parameters greatly influence the absorption of PGE 1 through skin as measured by laser doppler flowmetry, but by the application of a novel topical delivery technology, a significant enhancement of PGE 1 delivery can be achieved.

While insulin is known to promote vascular smooth muscle (VSM) relaxation, it also enhances endothelin-1 (ET-1) secretion and action in conditions such as NIDDM and hypertension. We examined the effect of insulin pretreatment on intracellular free calcium ([Ca2+]i) responses to ET-1 in cultured aortic smooth muscle cells (ASMCs) isolated from Sprague-Dawley (SD) rats and measured ET(A) receptor characteristics and ET-1-evoked tension responses in aorta obtained from insulin-resistant, hyperinsulinemic Zucker-obese (ZO) and control Zucker-lean (ZL) rats. Pretreatment of rat ASMCs with insulin (10 nmol/l for 24 h) failed to affect basal [Ca2+]i levels but led to a significant increase in peak [Ca2+]i response (1.7-fold; P < 0.01) to ET-1. The responses to IRL-1620 (an ET(B) selective agonist), ANG II, and vasopressin remained unaffected. ET-1-evoked peak [Ca2+]i responses were significantly attenuated by the inclusion of the ET(A) antagonist, BQ123, in both groups. The ET(B) antagonist, BQ788, abolished [Ca2+]i responses to IRL-1620 but failed to affect the exaggerated [Ca2+]i responses to ET-1. Saturation binding studies revealed a twofold increase (P < 0.01) in maximal number of binding sites labeled by 125I-labeled ET-1 in insulin-pretreated cells and no significant differences in sites labeled by 125I-labeled IRL-1620 between control and treatment groups. Northern blot analysis revealed an increase in ET(A) mRNA levels after insulin pretreatment for 20 h, an effect that was blocked by genistein, actinomycin D, and cycloheximide. Maximal tension development to ET-1 was significantly greater (P < 0.01), and microsomal binding studies using [3H]BQ-123 revealed a twofold higher number of ET(A) specific binding sites (P < 0.01) in aorta from ZO rats compared with that of ZL rats. These data suggest that insulin exaggerates ET-1-evoked peak [Ca2+]i responses via increased vascular ET(A) receptor expression, which may contribute to enhanced vasoconstriction observed in hyperinsulinemic states.

Two multicenter, double-blind, placebo-controlled, parallel group studies were conducted to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of the angiotensin II receptor (AT1 subtype) antagonist irbesartan. The effect of irbesartan withdrawal and the effect of adding hydrochlorothiazide (HCTZ) to irbesartan were also assessed. After a placebo lead-in phase, all patients were randomized to 8 weeks of double-blind therapy with either placebo (n = 158) or irbesartan at doses of 1, 5, 10, 25, 50, 100, 200, or 300 mg (n = 731 total) orally once daily. Irbesartan reduced blood pressure in a dose-related manner. Reductions from baseline in trough seated diastolic blood pressure ranged from 7.5 mm Hg for 50 mg irbesartan to 11.6 mm Hg for 300 mg irbesartan. At week 8, statistically significant reductions over placebo were observed in trough seated blood pressure with all irbesartan doses > or = 50 mg. These reductions reached statistical significance versus placebo within 2 weeks with 100, 200, and 300 mg irbesartan. Plasma irbesartan concentrations correlated with dose. Angiotensin II and aldosterone levels generally showed dose-related changes, consistent with AT1 receptor blockade. In patients not controlled at 8 weeks, the addition of 12.5 mg HCTZ resulted in further dose-related reductions in blood pressure. Irbesartan demonstrated a placebo-like safety profile and no dose-related toxicity. Irbesartan, administered alone or in combination with HCTZ, was well tolerated. Withdrawal of irbesartan did not result in rebound hypertension or adverse events. Thus, once-daily irbesartan is both an effective and safe antihypertensive agent for the treatment of mild-to-moderate hypertension.

Vascular smooth-muscle cells (VSMCs) isolated from genetically hypertensive animals show increased intracellular free calcium levels ([Ca 2+ ] i ) in response to endothelin-l (ET-1). The differences in time course and distribution of Ca 2+ increase after addition of ET-I within the VSMCs are unknown. Therefore, ET-1-evoked changes in fluo-3 fluorescence were determined using a confocal laser scanning microscope in primary cultures of aortic smooth-muscle cells (ASMCs) from 12-week-old male Sprague-Dawley (SD) rats, Wistar-Kyoto (WKY) rats, and spontaneously hypertensive rats (SHR). Syto-11 staining enabled the assessment of intracellular free [Ca 2+ ] i changes in the cytosolic ([Ca 2+ ] c ), perinuclear ([Ca 2+ ] p ), and nuclear ([Ca 2+ ] n ) regions. In the basal state, [Ca 2+ ] was evenly distributed throughout the rat ASMCs. There were no significant differences in basal fluorescence values among the three strains. ET-I evoked a concentration-dependent increase in fluo-3 intensity. The peak [Ca 2+ ]; rise to ET-1 was much more rapid in ASMCs from SHR and WKY strains. The changes in [Ca 2+ ] n were greater than in [Ca 2+ ] c . Pretreatment of rat ASMCs with BQ-123 (an ET A antagonist) and BQ-788 (an ET B antagonist) abolished the rapid peak rise and the slow sustained elevation in [Ca 2+ ] i , respectively. The nonselective antagonist bosentan attenuated both phases of the ET-1 response in all three strains. The ET B -selective agonist IRL 1620 evoked a significant elevation in [Ca 2+ ] n values at 2 min in the ASMCs of SHR. These data suggest that ET A activation is linked to initial rapid increases in [Ca 2+ ] c and [Ca 2+ ] n , whereas ET B activation promotes slow [Ca 2+ ] n signaling, particularly in ASMCs of SHR.

Renal transplantation studies indicate that some form of renal dysfunction underlies the development of hypertension in Dahl salt-sensitive (S) rats; however, the factors responsible for altering kidney function remain to be determined. Previous studies have indicated that Dahl S rats require a higher renal perfusion pressure to excrete the same amount of sodium and water as normotensive rats and that this is due largely to an elevation in Cl− transport in the thick ascending limb of the loop of Henle. There are now five lines of evidence that suggest an abnormality in the renal metabolism of arachidonic acid by enzymes of the P4504A family may contribute to the increase in loop Cl− transport and the development of hypertension in Dahl S rats. In this regard, the formation of 20-HETE and the levels of P4504A protein are reduced in the outer medulla of Dahl S rats. Perfusion of the loop of Henle of Dahl S rats with exogenous 20-HETE normalizes the elevated loop Cl− transport. In addition, a genetic marker in the P4504A2 gene, which encodes for the enzyme that makes 20-HETE, cosegregates with the development of hypertension in an F2 cross of Dahl S and Lewis rats. Finally, induction of renal production of 20-HETE with clofibrate prevents the development of hypertension in Dahl S rats and inhibition of renal 20-HETE formation produces hypertension in Lewis rats fed a high salt diet. These results implicate the CYP4A2 locus as a candidate gene that contributes to the alterations in renal function and the development of hypertension in Dahl S rats.

BackgroundAlthough conventional wisdom suggests that low socioeconomic status (SES) is a robust predictor of medication nonadherence, the strength of this association remains unclear.Objectives1) To estimate the proportion of studies that identified SES as a potential risk indicator of nonadherence, 2) to describe the type of SES measurements, and 3) to quantify the association between SES and nonadherence to antihypertensive pharmacotherapy.MethodsA systematic review and meta-analysis research design was used. We searched multiple electronic databases for studies in English or French examining nonadherence to antihypertensive medications measured by electronic prescription databases where explanatory factors were considered. Two authors independently assessed quality, described the SES measure(s), and recorded its association with nonadherence to antihypertensives. A random-effects model meta-analysis was performed, and heterogeneity was examined by using the I2 statistic.ResultsFifty-six studies with 4,780,293 subjects met the inclusion criteria. Twenty-four of these studies (43%) did not report any SES measures. When it was reported (n = 32), only seven (13%) examined more than one component but none performed a multidimensional assessment. Most of the studies relied on income or income-related measures (such as prescription-drug benefits or co-payments) (27 of 32 [84%]). Meta-analysis could be quantified in 40 cohorts reported in 30 studies. Overall, the pooled adjusted risk estimate for nonadherence according to SES (high vs. low) was 0.89 (95% confidence interval 0.87–0.92; I2 = 95%; P < 0.001). Similar patterns were observed in all subgroups examined.ConclusionsPublished studies have not found a strong association between low SES and nonadherence to antihypertensive medications. However, important limitations in the assessment of SES can be identified in virtually all studies. Future studies are required to ascertain whether a stronger association is observed when SES is determined by comprehensive measures.

We determined changes in blood pressure, cardiac output, and total peripheral conductance evoked by intravenous infusions of angiotensin II (Ang II) in conscious, unrestrained normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) before and after pretreatment with bosentan, a nonselective endothelin antagonist. Blood pressure was recorded by radiotelemetry and cardiac output by ultrasonic transit-time flow probes. Bosentan per se failed to affect basal blood pressure and evoked only small changes in cardiac output and total peripheral conductance in both strains. The pressor effects of Ang II were exaggerated in SHR compared with WKY. Strikingly, bosentan pretreatment blunted the increases in blood pressure, the fall in cardiac output, and the decreases in conductance evoked by lower doses of Ang II but not higher doses of the peptide. This effect was observed in both rat strains but was more pronounced in SHR. These data suggest that endothelin contributes to the hemodynamic effects of Ang II in both SHR and WKY and that endothelin may contribute to the exaggerated pressor responsiveness of SHR to Ang II.

Abstract We compared the role of endothelium and of endothelin in mediating the vasoconstrictor responses to angiotensin II (Ang II) in three vascular smooth muscle preparations—aorta, mesenteric artery, and tail artery—isolated from adult male Sprague-Dawley rats. The vasoconstrictor potency for Ang II in blood vessels with endothelium varied in the following rank order: aorta>mesenteric artery>tail artery. Although the maximal tension responses to Ang II were similar for mesenteric and tail arteries, it was significantly lower in aorta. Endothelium removal led to a leftward shift in the concentration-response curves to Ang II in the aorta but a rightward shift in the mesenteric artery. Strikingly, Ang II failed to evoke tension responses in tail artery in the absence of endothelium. The endothelin-A (ET A )–selective antagonist BQ-123 blocked the responses to Ang II in a noncompetitive manner, with partial and complete attenuation of responses in the endothelium-intact mesenteric and tail artery preparations, respectively. In contrast, BQ-123 did not affect the responses to Ang II in the aorta. BQ-123 also failed to affect the responses to Ang II in endothelium-denuded mesenteric artery rings. The Ang II type 1 (AT 1 ) receptor–selective antagonist losartan competitively blocked the responses to Ang II in the three tissues (pA 2 , 8.3 to 8.7) when endothelium was present. These data suggest that there are endothelium-dependent regional variations in vascular tissue sensitivity to Ang II. The vasoconstrictor response to Ang II in rat aorta involves activation of AT 1 receptors located on vascular smooth muscle cells, whereas the response in mesenteric artery involves activation of both vascular and endothelial AT 1 receptors. In contrast, the responses to Ang II in the tail artery may be mediated by the indirect stimulation of vascular smooth muscle ET A receptors subsequent to the activation of endothelial AT 1 receptors likely linked to the release of endothelins.

Purpose: During residency, many physicians find it difficult to maintain a healthy lifestyle; however, there is little objective data available. In this study, residents’ health behaviours and cardiovascular risk status were compared with those of medical students. Methods: Medical residents (n=55, postgraduate years 1 to 4) were compared with medical students (n=62, years 1-4). The main dependent variable was the average number of steps per day (assessed using a pedometer) at work and leisure over three days, during which subjects were not on call or post-call. In addition, all subjects completed a three day food log. Frequency of vigorous exercise was assessed by a single question. Body mass index (BMI), waist circumference, blood pressure, total and high-density lipoprotein cholesterol, smoking habits and random blood glucose were measured, and Framingham Risk Score coronary artery disease 10 year probabilities (FRS) were calculated. Results: Residents recorded 8344±3520 steps per day while students recorded 10703±3986 (p < 0.002). 35% of residents and 52% of students averaged more than 10,000 steps per day and senior residents took fewer steps than junior residents. Both groups frequently failed to achieve the recommended daily servings of fruits and vegetables; on average, 3.5±2.0 servings for residents and 5.4±2.2 for students (p < 0.0001). BMI and FRS were higher among the residents in comparison with the students. Conclusion: Medical residents at our institution appear less active and consume fewer servings of fruits and vegetables than undergraduate medical students. These differences are associated with higher BMI, waist circumference and cardiovascular risk.

Purpose: The lazaroids are a new class of potent free-radical scavengers. We tested whether U-74389G, a lazaroid, could attenuate some of the adverse cardiopulmonary effects of sepsis. Methods: Dogs were randomized to receive either 10 mg/kg U-74389G (n = 10), or a saline control (n = 11). After baseline measurements of hemodynamics and gas exchange, they were then randomized to receive either 0.2 mg/kg endotoxin or a saline infusion. Measurements of hemodynamics and gas exchange were repeated. The study was concluded 70 minutes after endotoxin infusion and the lungs were then removed for histologic evaluation. Results: In endotoxin-treated control animals, P02 decreased (278 ± 123 mm Hg to 67 ± 13 mm Hg, P < .05) and intrapulmonary shunt increased (12.9% ± 1.1% to 28.2% ± 11.4%, P < .05) after endotoxin. Pretreatment with U-74389G attenuated the decrease in PO2 (476 ± 61 mm Hg to 226 ± 143) and the increase in intrapulmonary shunt (12.6% ± 6.1% to 14.3% ± 6.8%) observed after endotoxin. The extent of lung injury and systemic hemodynamics were similar between control or U-74389G-treated dogs. Conclusions: A free-radical-scavenger can attenuate the gas exchange defect commonly associated with endotoxin but it does not improve the derangement of systemic hemodynamics.

A pulmonary injury of varying severity occurs routinely after cardiopulmonary bypass. We studied the pulmonary complications of partial cardiopulmonary bypass in four groups of dogs to better define the injury and to evaluate the efficacy of two interventions (addition of a leukocyte filter or cyclooxygenase inhibition) on preservation of systemic oxygenation. All animals received a standard anesthetic (pentobarbital, morphine, and vecuronium) and, after sternotomy, three groups of animals received 3 hours of partial cardiopulmonary bypass. The animals were randomized to receive partial bypass alone ( n = 6), indomethacin and bypass ( n = 5), or a leukocyte filter and bypass ( n = 5). A fourth group ( n = 5) did not receive bypass and served as a time control. We measured blood gases and also obtained histologic samples to assess the degree of lung injury. We found that bypass alone caused a significant reduction ( p

Methylglyoxal (MG) is a highly reactive metabolite physiologically presented in all biological systems. The effects of MG on diabetes and hypertension have been long recognized. In the present study, we investigated the potential role of MG in obesity, one of the most important factors to cause metabolic syndrome. An increased MG accumulation was observed in the adipose tissue of obese Zucker rats. Cell proliferation assay showed that 5-20 µM of MG stimulated the proliferation of 3T3-L1 cells. Further study suggested that accumulated-MG stimulated the phosphorylation of Akt1 and its targets including p21 and p27. The activated Akt1 then increased the activity of CDK2 and accelerated the cell cycle progression of 3T3-L1 cells. The effects of MG were efficiently reversed by advanced glycation end product (AGE) breaker alagebrium and Akt inhibitor SH-6. In summary, our study revealed a previously unrecognized effect of MG in stimulating adipogenesis by up-regulation of Akt signaling pathway and this mechanism might offer a new approach to explain the development of obesity.

Validity of Heart Failure (HF) diagnoses from administrative records has not been extensively evaluated, especially with respect to small / unselected hospitals.To determine the positive predictive value of a primary / most responsible diagnosis of HF among a general population of subjects discharged from Saskatchewan hospitals.Using administrative health records from the Province of Saskatchewan, Canada, we identified subjects experiencing their first HF hospitalization between 1994 and 2003. From this cohort, we randomly selected 500 subjects for individual validation using Framingham and Carlson criteria.The 466 charts available for analysis, 74% (345/466) and 63.9% (298/466) of subjects met criteria for a clinical diagnosis of HF based on Framingham or Carlson criteria, respectively; 57.5% (268/466) met both criterion. Provincial hospitals (located in the largest urban centres) were associated with the highest proportion of confirmed HF diagnoses (87.8% by Framingham criteria) compared to progressively smaller hospitals (regional 77.9%; district 64.2%; and community 60.0%). Accuracy also differed when stratified by physician category. Cardiologists and internists were associated with the highest rates of confirmed diagnoses [(97.5% (39 / 40) and 85.0% (34 / 40)]) compared to general practitioners [(73.1% (95 / 130)]) and other physicians [(69.1% (177 / 256)]), by Framingham criteria.Hospital discharge abstracts indicating HF are frequently inaccurate. These findings have important implications for the epidemiologic study of HF as well as the clinical management of patients.

Purpose: Vitamin D Deficiency is common, particularly in northern latitudes. We examined the association between vitamin D status and hypertension in late pregnancy. Methods: A case-control study was conducted during two time periods: September-October, 2008, and January-March, 2009, in women near term. A case was defined as having two or more documented blood pressure readings above 140/90 (either/or) at any time during pregnancy (n=78). Controls had at least two blood pressure readings, with none above 140/90 during pregnancy (n=109). Serum 25-hydroxyvitamin D (25(OH)D) was measured in all participants. Results: In the summer, 13% of controls and 29% of the cases had 25(OH) D levels < 50 nmol/L. During the winter, these numbers rose to 44% and 49% respectively. Both cases and controls were more likely to be vitamin D deficient in the winter (p=0.002). There was a negative correlation between BMI and 25(OH)D (r=-0.202, p=0.002). In univariate analysis, cases had lower 25(OH)D (p=0.046), but also higher body mass index, so that in multivariate analysis 25(OH)D status was no longer significant. There was no difference in mean oral daily vitamin D intake (dietary intake and supplements, 746 and 785 IU respectively). Controls gained less weight in pregnancy. There was a negative correlation between the highest blood pressure measured in pregnancy and 25(OH)D levels (r= -0.118; p=0.012). Conclusion: There is a high prevalence of vitamin D deficiency in pregnant women recruited in Saskatoon, Saskatchewan. Women with low circulating vitamin D concentrations are more likely to have hypertension.

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2011. The major guideline changes this year are: (1) a recommendation was made for using comparative risk analogies when communicating a patient's cardiovascular risk; (2) diagnostic testing issues for renal artery stenosis were discussed; (3) recommendations were added for the management of hypertension during the acute phase of stroke; (4) people with hypertension and diabetes are now considered high risk for cardiovascular events if they have elevated urinary albumin excretion, overt kidney disease, cardiovascular disease, or the presence of other cardiovascular risk factors; (5) the combination of an angiotensin-converting enzyme (ACE) inhibitor and a dihydropyridine calcium channel blocker (CCB) is preferred over the combination of an ACE inhibitor and a thiazide diuretic in persons with diabetes and hypertension; and (6) a recommendation was made to coordinate with pharmacists to improve antihypertensive medication adherence. We also discussed the recent analyses that examined the association between angiotensin II receptor blockers (ARBs) and cancer.

Tumor necrosis factor-alpha (TNF-alpha) causes systemic hypotension, pulmonary vasodilation, and loss of hypoxic pulmonary vasoconstriction. NG-monomethyl-L-arginine (L-NMMA) inhibits nitric oxide (NO) production and prevents some systemic manifestations of TNF-alpha. We tested using an isolated perfused canine lobe whether NO also mediates the pulmonary vascular effects of TNF-alpha. Total resistance (RT) was measured during control and hypoxic ventilation over a 90-min period in six control lobes, five lobes treated with TNF-alpha (250 micrograms), six lobes treated with L-NMMA (200 mg), and five lobes treated with L-NMMA (200 mg) + TNF-alpha (250 micrograms). In the control lobes RT increased (P < 0.02) from 0.0474 +/- 0.0105 to 0.0677 +/- 0.0133 cmH2O.ml-1 x min during normoxic and hypoxic ventilation, respectively. RT decreased (P < 0.05) from a baseline of 0.0593 +/- 0.0133 to 0.0449 +/- 0.0176 cmH2O.ml-1 x min 30 min after TNF-alpha administration and did not further change during hypoxic ventilation (0.0475 +/- 0.0107 cmH2O.ml-1 x min). L-NMMA pretreatment did not prevent the TNF-alpha-induced loss of hypoxic pulmonary vasoconstriction, with values of RT unchanged from normoxic (0.0541 +/- 0.0067 cmH2O.ml-1 x min) to hypoxic (0.0545 +/- 0.0078 cmH2O.ml-1.min) ventilation (P > 0.10) in the L-NMMA + TNF-alpha group after TNF-alpha administration. We conclude that NO is not the mediator responsible for the acute pulmonary vascular effects of TNF-alpha.

Objective: To compare blood pressure readings obtained with two commonly used oscillometric monitors: Omron HEM 711 AC (OM) and Welch-Allyn 52000 series NIBP/oximeter (WA) with mercury sphygmomanometers (Merc) in subjects with atrial fibrillation. Methods: We recruited 51 hemodynamically stable subjects with atrial fibrillation. Fifty four subjects in normal sinus rhythm served as controls. Supine blood pressure readings in each arm were recorded simultaneously using one monitor and Merc. The second monitor then replaced the first and readings were repeated. Merc was then switched to the opposite arm, and both monitors retested. Apical heart rates were ascertained with a stethoscope. We used the averaged, same arm Merc readings as “gold standard”. Results: Automated blood pressure readings were obtained in all control subjects and in all but three of those with atrial fibrillation. Both monitors, and operators, noted a difference between apical and radial/brachial pulse rates: apical-recorded: Merc 6.1±15.0; OM 5.5±13.7; WA 10.0±21.2 beats per minute. Both monitors were accurate in controls: over 90% of readings were within 10 mmHg of averaged Merc, and both achieved European Hypertension Society standards. In subjects with atrial fibrillation, about one quarter of all oscillometric readings differed from Merc by more than 10 mmHg. Both falsely high and falsely low readings occurred, some up to 30 mmHg. There was no relation between accuracy and heart rate. Conclusions: Single blood pressure readings, taken with oscillometric monitors in subjects with atrial fibrillation differ, often markedly, from those taken manually. Health care professionals should record multiple readings manually, using validated instruments when making therapeutic decisions.