Dose-Response Relationships of ACE Inhibitors and Angiotensin II Blockers

It is difficult to establish dose-response relationships for ACE inhibitors in patients with hyperternion or congestive heart failure. This has led to the widely held opinion that the effects of ACE inhibitors are hardly dose dependent. The purpose of this short discussion is to demonstrate that this class of compounds, as well as the more recent angiotemin II receptor antagonists, exhibit some very clear dose-response relationships when these are evaluated in normal volunteers based on the mechanisms for which they were designed. Characterization of these dose-response curves is important in order to use these drugs at their optimol dose and to obtain the maximal therapeutic benefi

Impact of body tilt on the central aortic pressure pulse.

The present work was undertaken to investigate, in young healthy volunteers, the relationships between the forward propagation times of arterial pressure waves and the timing of reflected waves observable on the aortic pulse, in the course of rapid changes in body position. 20 young healthy subjects, 10 men, and 10 women, were examined on a tilt table at two different tilt angles, -10° (Head-down) and + 45° (Head-up). In each position, carotid-femoral (Tcf) and carotid-tibial forward propagation times (Tct) were measured with the Complior device. In each position also, the central aortic pressure pulse was recorded with radial tonometry, using the SphygmoCor device and a generalized transfer function, so as to evaluate the timing of reflected waves reaching the aorta in systole (onset of systolic reflected wave, sT1r) and diastole (mean transit time of diastolic reflected wave, dMTT). The position shift from Head-up to Head-down caused a massive increase in both Tct (women from 130 ± 10 to 185 ± 18 msec P < 0.001, men from 136 ± 9 to 204 ± 18 msec P < 0.001) and dMTT (women from 364 ± 35 to 499 ± 33 msec P < 0.001, men from 406 ± 22 to 553 ± 21 msec P < 0.001). Mixed model regression showed that the changes in Tct and dMTT observed between Head-up and Head-down were tightly coupled (regression coefficient 2.1, 95% confidence interval 1.9-2.3, P < 0.001). These results strongly suggest that the diastolic waves observed on central aortic pulses reconstructed from radial tonometric correspond at least in part to reflections generated in the lower limbs

Plasma Angiotensin II and the Antihypertensive Action of Angiotensin-Converting Enzyme Inhibition

The measurement of immunoreactive "angiotensin II” in plasma cannot provide an accurate reflection of the efficacy of angiotensin-converting enzyme (ACE) inhibition because different angiotensin fragments interfere in all radioimmunoassays available so far. More complex methods are necessary in order to measure specifically angiotensin-(1-8)octapeptide. With such methodology it can be shown that no tolerance develops to the angiotensin II-reducing effect of ACE inhibitors after prolonged administration. Marked reduction of angiotensin II levels can be shown even in patients with primary aldosteronism. At peak blockade, the level of plasma angiotensin II is still related to circulating active renin and angiotensin I. Accordingly, because ACE inhibitors raise circulating angiotensin I in a dose-dependent fashion, this should be taken into account when dosing ACE inhibitors. The hypothesis that tissue renin-angiotensin systems play an important independent role in determining vasomotor tone is very interesting. However, any discussion on whether tissue or plasma renin determines the pharmacological effect of ACE inhibitors should be based on the simultaneous measurement of true angiotensin II in tissue and plasma under steady-state conditions. Am J Hypertens 1989;2:286-29

Prevalence of measured and reported multimorbidity in a representative sample of the Swiss population.

BACKGROUND: Little is known on the prevalence of multimorbidity (MM) in the general population. We aimed to assess the prevalence of MM using measured or self-reported data in the Swiss population. METHODS: Cross-sectional, population-based study conducted between 2003 and 2006 in the city of Lausanne, Switzerland, and including 3714 participants (1967 women) aged 35 to 75 years. Clinical evaluation was conducted by thoroughly trained nurses or medical assistants and the psychiatric evaluation by psychologists or psychiatrists. For psychiatric conditions, two definitions were used: either based on the participant's statements, or on psychiatric evaluation. MM was defined as presenting ≥2 morbidities out of a list of 27 (self-reported - definition A, or measured - definition B) or as the Functional Comorbidity Index (FCI) using measured data - definition C. RESULTS: The overall prevalence and (95% confidence interval) of MM was 34.8% (33.3%-36.4%), 56.3% (54.6%-57.9%) and 22.7% (21.4%-24.1%) for definitions A, B and C, respectively. Prevalence of MM was higher in women (40.2%, 61.7% and 27.1% for definitions A, B and C, respectively, vs. 28.7%, 50.1% and 17.9% in men, p < 0.001); Swiss nationals (37.1%, 58.8% and 24.8% for definitions A, B and C, respectively, vs. 31.4%, 52.3% and 19.7% in foreigners, all p < 0.001); elderly (>65 years: 67.0%, 70.0% and 36.7% for definitions A, B and C, respectively, vs. 23.6%, 50.2% and 13.8% for participants <45 years, p < 0.001); participants with lower educational level; former smokers and obese participants. Multivariate analysis confirmed most of these associations: odds ratio (95% Confidence interval) 0.55 (0.47-0.64), 0.61 (0.53-0.71) and 0.51 (0.42-0.61) for men relative to women for definitions A, B and C, respectively; 1.27 (1.09-1.49), 1.29 (1.11-1.49) and 1.41 (1.17-1.71) for Swiss nationals relative to foreigners, for definitions A, B and C, respectively. Conversely, no difference was found for educational level for definitions A and B and abdominally obese participants for all definitions. CONCLUSIONS: Prevalence of MM is high in the Lausanne population, and varies according to the definition or the data collection method

Elastic behaviour of the carotid artery in intact spontaneously hypertensive rats

Intact spontaneously hypertensive rats (SHR) were studied to assess the effect of prolonged antihypertensive treatment on the elastic behaviour of the external carotid artery. Thirty-week-old SHR received the ACE inhibitor captopril, the ateriolar dilator hydralazine or their vehicle for 6 weeks. These rats were compared to normotensive, vehicle treated WKY rats. The internal diameter of the carotid artery was measured continuously in halothane-anaesthetized rats using an echo-tracking device, and intra-arterial pressure was also monitored continuously, on the controlateral side. Captopril- and hydralazinetreated SHR as well as normotensive controls had similar blood pressure values. No significant shift in the distensibility-pressure curves was observed among vehicle-treated SHR and WKY rats or the SHR which had received captopril or hydralazine. Histological examination of the carotid artery fixed ex vivo with paraformaldehyde showed a significant increase in cross-sectional area in vehicle-treated SHR as compared to their normotensive counterparts. These results therefore suggest that the elastic behaviour of elastic arteries is not necessarily altered by the structural changes developing in response to hypertensio

The renin—angiotensin system in refractory heart failure: clinical, hemodynamic and hormonal effects of captopril and enalapril

Studies using a competitive inhibitor of angiotensin II (saralasin) or converting enzyme inhibitors (teprotide, captopril, enalapril) have established that the renin-angiotensin system participates in the control of vascular tone in congestive heart failure both in experimental settings and in patients. In man, the marked decrease in left ventricular filling pressure and the variable increase in stroke volume induced by renin-angiotensin blockade suggests that angiotensin II actively constricts venous as well as arteriolar vascular beds. Captopril, in doses of 25 to 150 mg p.o. TID, maintains its efficacy during chronic administration with persistent clinical and hemodynamic improvement as well as increased exercise tolerance. In our experience, enalapril, 10 mg p.o., improves cardiac function within 4 to 6 h as reflected by a 30% decrease in left ventricular filling pressure, a 28% increase in stroke volume in the face of unchanged heart rate. Clinical improvement, enhanced exercise tolerance and characteristic hormonal responses suggest that enalapril also maintains its efficacy during long-term treatment. Chronic angiotensin II converting enzyme inhibition appears to be a major advance in the treatment of patients with severe congestive heart failure, refractory to digitalis and diuretic

P619Role of Toll-like receptor 5 in the development of post-myocardial infarction inflammation

Background: Inflammatory processes play a key role in the pathophysiology of myocardial infarction (MI). Genetic deletion of toll-like recpetors (TLRs), especially TLR2 and TLR4 have shown protective role in murine models of MI. The role of other TLRs remains unknown. We have previously shown that cardiomyocytes express TLR5 and that the ligand of TLR5, flagellin, activates the NF-kappaB and MAPK pathways in cardiomyocytes. We also have shown that injection of flagellin induces acute systolic dysfunction in vivo in mice. Aim: Determine the role of TLR5 in the development of post-MI inflammation. Methods: A murine model of myocardial infarction was done by a 30 minutes ligation of the left anterior descending coronary artery followed by 2 hours of reperfusion. Infarct size was measured by standard Evans blue/TTC staining. Plasma creatine kinase (CK) was quantified as a read out of myocardial necrosis. Tissue and plasma cytokines (MIP-2, MCP-1, IL-6) were quantified by ELISA. To determine the extent of tissue lipid peroxidation we used malondialdehyde and 4-hydroxynonenal-HIS adduct assays. Tissue protein oxidation was tested by protein carbonyl ELISA kit. Phosphorylation of MAPK was analyzed by western blot. Results: Genetic suppression of TLR5 induced a significant increase of myocardial infarct size and plasma CK, of biochemical markers of myocardial oxidative stress, and cytokine levels in the heart and the plasma after MI. These effects were associated with a marked enhancement of p38 phosphorylation in the heart from TLR5 KO mice. Conclusion: TLR5 protects from acute myocardial injury and reduces local and systemic inflammation during myocardial infarction. The mechanisms may involve reduced p38 signaling, decreased oxidative stress and attenuated cytokine expression. Research supported by the Swiss National Science Foundation, Grant n° 310030_135394/

Natriuretic Peptide Receptor B modulates the proliferation of the cardiac cells expressing the Stem Cell Antigen-1.

Brain Natriuretic Peptide (BNP) injections in adult "healthy" or infarcted mice led to increased number of non-myocyte cells (NMCs) expressing the nuclear transcription factor Nkx2.5. The aim of this study was to identify the nature of the cells able to respond to BNP as well as the signaling pathway involved. BNP treatment of neonatal mouse NMCs stimulated Sca-1 <sup>+</sup> cell proliferation. The Sca-1 <sup>+</sup> cells were characterized as being a mixed cell population involving fibroblasts and multipotent precursor cells. Thus, BNP treatment led also to increased number of Sca-1 <sup>+</sup> cells expressing Nkx2.5, in Sca-1 <sup>+</sup> cell cultures in vitro and in vivo, in the hearts of neonatal and adult infarcted mice. Whereas BNP induced Sca-1 <sup>+</sup> cell proliferation via NPR-B receptor and protein kinase G activation, CNP stimulated Sca-1 <sup>+</sup> cell proliferation via NPR-B and a PKG-independent mechanism. We highlighted here a new role for the natriuretic peptide receptor B which was identified as a target able to modulate the proliferation of the Sca-1 <sup>+</sup> cells. The involvement of NPR-B signaling in heart regeneration has, however, to be further investigated