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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 benefit

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 hypertension

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 diuretics

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_135394/1

Background: Inflammation comes out to be a critical biological process in the pathophysiology of myocardial infarction (MI). We hypothesize that this inflammation is triggered by necrotic cardiomyocytes (Cmc) that release a set of endogenous molecules (DAMPs: danger-associated molecular patterns) activating inflammatory responses in cardiac fibroblasts. Aim: Analyze in vitro the immune activation of cardiac fibroblasts exposed to necrotic Cmc conditioned media. Methods: Primary neonatal murine cardiac fibroblasts and Cmc were obtained by digestion of neonatal hearts and differential plating technique allowing a selection for cardiomyocytes and cardiac fibroblasts. Cmc were killed by necrotic stimuli including oxidants (hydrogen peroxide) and mechanic stresses (freeze-thaw). Necrosis was assessed using Hoechst/PI stainings. Fibroblasts were exposed to necrotic Cmc conditioned media and mRNA expression of inflammatory genes was measured by real-time PCR and ELISA. Activation of signaling pathways was analyzed by western blot. We used cardiac cells from Myd88-/-, Trif-/- and Nlrp3-/- animals to evaluate the contribution of TLRs/IL1-R and NLRP3 inflammasome in the sensing of necrotic DAMPs. Results: mRNA expression of chemokines such as MCP-1, MIP-2 and IP-10 were induced in fibroblasts exposed to necrotic Cmc conditioned media. Alternatively, fibroblasts exposed to necrotic fibroblasts conditioned media showed a lower increase in mRNA expression of these chemokines. In addition, in fibroblasts from Myd88-/- mice, response to Cmc conditioned media was fully abrogated whereas no difference was observed in Trif-/- and Nlrp3-/- fibroblasts. Conclusion: Cardiac fibroblasts are able to produce a rapid and specific inflammatory response to necrotic Cmc conditioned media involving the expression of neutrophil and monocyte chemoattractants. The dependence on MyD88 adaptor protein strongly suggests that this response relies on TLR/IL-1R signaling. These results engage cardiac fi

We assessed the inhibitory effect of DuP 753, an orally active angiotensin II receptor antagonist, on the pressor action of exogenous angiotensin I and II in healthy volunteers. In a single dose study, doses of 2.5, 5, 10, 20, and 40 mg of DuP 753 or placebo were tested serially at one week intervals. In the multiple dose study, the administration of placebo or DuP 753 (5, 10, 20, or 40 mg, per os once daily) for eight consecutive days was evaluated. The blood pressure response to angiotensin I and II was inhibited in a dose-dependent fashion with a blocking effect still present 24 h post drug. DuP 753 also induced a dose-dependent compensatory rise in plasma renin. This new compound was well tolerated by these normal volunteers. Thus, DuP 753 appears to be a well tolerated, orally active, potent and long-lasting antagonist of angiotensin II in humans. Am J Hypertens 1991;4:350S-354S