Anastasia S. Mihailidou

Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction

Myocardial ischemia-reperfusion leads to significant changes in redox state, decreased postischemic functional recovery, and cardiomyocyte apoptosis, with development and progression of heart failure. Ischemia-reperfusion in the isolated perfused rat heart has been used as a model of heart failure. Clinically, mineralocorticoid receptor blockade in heart failure decreases morbidity and mortality versus standard care alone. The effects of corticosteroids on infarct area and apoptosis were determined in rat hearts subjected to 30 minutes of ischemia and 2.5 hours of reperfusion. Both aldosterone and cortisol increased infarct area and apoptotic index, an effect half-maximal between 1 and 10 nM and reversed by spironolactone. Dexamethasone and mifepristone aggravated infarct area and apoptotic index, similarly reversed by spironolactone. Spironolactone alone reduced infarct area and apoptotic index below ischemia-reperfusion alone, in hearts from both intact and adrenalectomized rats. The present study shows that cardiac damage is aggravated by activation of mineralocorticoid receptors by aldosterone or cortisol or of glucocorticoid receptors by dexamethasone. Mifepristone unexpectedly acted as a glucocorticoid receptor agonist, for which there are several precedents. Spironolactone protected cardiomyocytes via inverse agonist activity at mineralocorticoid receptors, an effect near maximal at a relatively low dose (10 nM). Spironolactone acts not merely by excluding corticosteroids from mineralocorticoid receptors but as a protective inverse agonist at low concentration. Mineralocorticoid receptor antagonists may, thus, provide an additional therapeutic advantage in unstable angina and acute myocardial infarction.

Definition of ambulatory blood pressure targets for diagnosis and treatment of hypertension in relation to clinic blood pressure: prospective cohort study.

Background Twenty-four hour ambulatory blood pressure thresholds have been defined for the diagnosis of mild hypertension but not for its treatment or for other blood pressure thresholds used in the diagnosis of moderate to severe hypertension. We aimed to derive age and sex related ambulatory blood pressure equivalents to clinic blood pressure thresholds for diagnosis and treatment of hypertension. Methods We collated 24 hour ambulatory blood pressure data, recorded with validated devices, from 11 centres across six Australian states (n=8575). We used least product regression to assess the relation between these measurements and clinic blood pressure measured by trained staff and in a smaller cohort by doctors (n=1693). Results Mean age of participants was 56 years (SD 15) with mean body mass index 28.9 (5.5) and mean clinic systolic/diastolic blood pressure 142/82 mm Hg (19/12); 4626 (54%) were women. Average clinic measurements by trained staff were 6/3 mm Hg higher than daytime ambulatory blood pressure and 10/5 mm Hg higher than 24 hour blood pressure, but 9/7 mm Hg lower than clinic values measured by doctors. Daytime ambulatory equivalents derived from trained staff clinic measurements were 4/3 mm Hg less than the 140/90 mm Hg clinic threshold (lower limit of grade 1 hypertension), 2/2 mm Hg less than the 130/80 mm Hg threshold (target upper limit for patients with associated conditions), and 1/1 mm Hg less than the 125/75 mm Hg threshold. Equivalents were 1/2 mm Hg lower for women and 3/1 mm Hg lower in older people compared with the combined group. Conclusions Our study provides daytime ambulatory blood pressure thresholds that are slightly lower than equivalent clinic values. Clinic blood pressure measurements taken by doctors were considerably higher than those taken by trained staff and therefore gave inappropriate estimates of ambulatory thresholds. These results provide a framework for the diagnosis and management of hypertension using ambulatory blood pressure values.

Ambulatory blood pressure monitoring in Australia: 2011 consensus position statement

Objective: Although most national guidelines for the diagnosis and management of hypertension emphasize that the initiation and modification of blood pressure (BP)-lowering treatment should be related to absolute cardiovascular disease (CVD) risk, there is only limited information on how to incorporate ambulatory BP (ABP) monitoring into this framework. The objective of this initiative is to provide ABP equivalents for BP cut-points for treatment initiation and targets to be included into guidelines. Methods: A critical analysis of the best available evidence from clinical trials and observational studies was undertaken to develop a new consensus statement for ABP monitoring. Results: ABP monitoring has an important place in defining abnormal patterns of BP, particularly white-coat hypertension (including in pregnancy), episodic hypertension, masked hypertension, labile BP and nocturnal or morning hypertension. This consensus statement provides a framework for appropriate inclusion of ABP equivalents for low, moderate and high CVD risk patients. The wider use of ABP monitoring, although justified, is limited by its availability and cost due to the lack of medical subsidy in Australia. However, cost–benefit analysis does suggest a cost-saving in reduced numbers of inappropriate antihypertensive treatments. Conclusion: Although clinic measurement of BP will continue to be useful for screening and management of suspected and true hypertension, ABP monitoring provides considerable added value toward accurate diagnosis and the provision of optimal care in uncomplicated hypertension, as well as for patients with moderate or severe CVD risk.

Hyperaldosteronemia in Rabbits Inhibits the Cardiac Sarcolemmal Na+-K+ Pump

Aldosterone upregulates the Na(+)-K(+) pump in kidney and colon, classical target organs for the hormone. An effect on pump function in the heart is not firmly established. Because the myocardium contains mineralocorticoid receptors, we examined whether aldosterone has an effect on Na(+)-K(+) pump function in cardiac myocytes. Myocytes were isolated from rabbits given aldosterone via osmotic minipumps and from controls. Electrogenic Na(+)-K(+) pump current, arising from the 3:2 Na(+):K(+) exchange ratio, was measured in single myocytes using the whole-cell patch clamp technique. Treatment with aldosterone induced a decrease in pump current measured when myocytes were dialyzed with patch pipette solution containing Na(+) in a concentration of 10 mmol/L, whereas there was no effect measured when the solution contained 80 mmol/L Na(+). Aldosterone had no effect on myocardial Na(+)-K(+) pump concentration evaluated by vanadate-facilitated [(3)H]ouabain binding or by K(+)-dependent paranitrophenylphosphatase activity in crude homogenates. Aldosterone induced an increase in intracellular Na(+) activity. The aldosterone-induced decrease in pump current and increased intracellular Na(+) were prevented by cotreatment with the mineralocorticoid receptor antagonist spironolactone. Our results indicate that hyperaldosteronemia decreases the apparent Na(+) affinity of the Na(+)-K(+) pump, whereas it has no effect on maximal pump capacity.

Na+ influx and Na+-K+pump activation during short-term exposure of cardiac myocytes to aldosterone

To examine the effect of aldosterone on sarcolemmal Na+ transport, we measured ouabain-sensitive electrogenic Na(+)-K+ pump current (Ip) in voltage-clamped ventricular myocytes and intracellular Na+ activity (alpha iNa) in right ventricular papillary muscles. Aldosterone (10 nM) induced an increase in both Ip and the rate of rise of alpha iNa during Na(+)-K+ pump blockade with the fast-acting cardiac steroid dihydroouabain. The aldosterone-induced increase in Ip and rate of rise of alpha iNa was eliminated by bumetanide, suggesting that aldosterone activates Na+ influx through the Na(+)-K(+)-2Cl- cotransporter. To obtain independent support for this, the Na+, K+, and Cl- concentrations in the superfusate and solution of pipettes used to voltage clamp myocytes were set at levels designed to abolish the inward electrochemical driving force for the Na(+)-K(+)-2Cl- cotransporter. This eliminated the aldosterone-induced increase in Ip. We conclude that in vitro exposure of cardiac myocytes to aldosterone activates the Na(+)-K(+)-2Cl- cotransporter to enhance Na+ influx and stimulate the Na(+)-K+ pump.

Methodology and technology for peripheral and central blood pressure and blood pressure variability measurement: Current status and future directions - Position statement of the European Society of Hypertension Working Group on blood pressure monitoring and cardiovascular variability

Office blood pressure measurement has been the basis for hypertension evaluation for almost a century. However, the evaluation of blood pressure out of the office using ambulatory or self-home monitoring is now strongly recommended for the accurate diagnosis in many, if not all, cases with suspected hypertension. Moreover, there is evidence that the variability of blood pressure might offer prognostic information that is independent of the average blood pressure level. Recently, advancement in technology has provided noninvasive evaluation of central (aortic) blood pressure, which might have attributes that are additive to the conventional brachial blood pressure measurement. This position statement, developed by international experts, deals with key research and practical issues in regard to peripheral blood pressure measurement (office, home, and ambulatory), blood pressure variability, and central blood pressure measurement. The objective is to present current achievements, identify gaps in knowledge and issues concerning clinical application, and present relevant research questions and directions to investigators and manufacturers for future research and development (primary goal).

Prospective study of early bereavement on psychological and behavioural cardiac risk factors.

Background: Increasing evidence supports the role of emotional stress in the onset of cardiovascular disease. Although bereavement is a major emotional stress with both acute and more long‐term features, the mechanism of its association with cardiovascular risk is not well understood, in particular because of limited studies of acute bereavement. The aim of the study was to identify psychological and behavioural changes in acute bereavement and potential modifiers of these changes.

Placebo-Controlled Biofeedback Blood Pressure Effect in Hypertensive Humans

The role of biofeedback in blood pressure control remains ill-defined because of nonspecific (placebo) effects, small study numbers, and the technical limitations of continuous pressure feedback. Clarification of its potential is awaited by those seeking a nonpharmacological approach to blood pressure control. This study examines the capability for systolic pressure lowering of 5 mm Hg or more using continuous pressure feedback in a statistical sample of untreated, well-characterized, mildly hypertensive individuals. Subjects were randomized in a double-blind study to active or placebo biofeedback. Placebo consisted of a modified contingency approach, using a partial disguise based on a digital high pass filter with 15 elements. Blood pressure-lowering capability was assessed during two laboratory sessions. Continuous visual feedback resulted in 11 of 28 subjects on active treatment and 12 of 28 on placebo treatment lowering their systolic pressure by 5 mm Hg or more (11 +/- 5.6 and 12 +/- 8.4 mm Hg, respectively; P = NS). Prestudy pressure was well-matched (153 +/- 9/97 +/- 4 and 154 +/- 8/98 +/- 4 mm Hg, respectively). An initial small difference in diurnal profile did not change. These findings indicate that among mildly hypertensive individuals, almost half can lower systolic pressure at will for short periods. This capability is independent of the real or placebo nature of the feedback signal. We conclude that there is no specific short-term biofeedback pressure-lowering capability in hypertensive individuals. Further exploration is needed to determine whether specific components of the placebo effect can be delineated, whether personality characteristics influence the response, and whether further biofeedback training can alter the outcome.

HMG CoA reductase inhibition reduces sarcolemmal Na(+)-K(+) pump density.

OBJECTIVES HMG CoA reductase inhibitors reduce cellular availability of mevalonate, a precursor in cholesterol synthesis. Since the cholesterol content of cell membranes is an important determinant of Na(+)-K(+) pump function we speculated that treatment with HMG CoA reductase inhibitors affects Na(+)-K(+) pump activity. METHODS We treated rabbits and rats for 2 weeks with the HMG CoA reductase inhibitor lovastatin and measured Na(+)-K(+) pump current (I(p)) in isolated rabbit cardiac myocytes using the whole cell patch-clamp technique, K-dependent p-nitrophenyl phosphatase (p-NPPase) activity in crude myocardial and skeletal muscle homogenates, and vanadate-facilitated 3H-ouabain binding in intact skeletal muscle samples from rats. RESULTS Treatment with lovastatin caused statistically significant reductions in I(p), myocardial and skeletal muscle K-dependent p-NPPase activity and 3H-ouabain binding in the myocardium and skeletal muscle. The lovastatin-induced decrease in I(p) was eliminated by parenteral co-administration of mevalonate. However, this was not related to cardiac cholesterol content. CONCLUSIONS Treatment with lovastatin reduces Na(+)-K(+) pump activity and abundance in rabbit and rat sarcolemma.

Angiotensin regulates the selectivity of the Na+-K+ pump for intracellular Na+

Treatment of rabbits with angiotensin-converting enzyme (ACE) inhibitors increases the apparent affinity of the Na+-K+pump for Na+. To explore the mechanism, we voltage clamped myocytes from control rabbits and rabbits treated with captopril with patch pipettes containing 10 mM Na+. When pipette solutions were K+ free, pump current ( I p) for myocytes from captopril-treated rabbits was nearly identical to that for myocytes from controls. However, treatment caused a significant increase in I pmeasured with pipettes containing K+. A similar difference was observed when myocytes from rabbits treated with the ANG II receptor antagonist losartan and myocytes from controls were compared. Treatment-induced differences in I p were eliminated by in vitro exposure to ANG II or phorbol 12-myristate 13-acetate or inclusion of the protein kinase C fragment composed of amino acids 530-558 in pipette solutions. Treatment with captopril had no effect on the voltage dependence of I p. We conclude that ANG II regulates the pumps selectivity for intracellular Na+ at sites near the cytoplasmic surface. Protein kinase C is implicated in the messenger cascade.