Hypertension and microvascular remodelling

In the present review, microvascular remodelling refers to alterations in the structure of resistance vessels contributing to elevated systemic vascular resistance in hypertension. We start with some historical aspects, underscoring the importance of Folkow's contribution made half a century ago. We then move to some basic concepts on the biomechanics of blood vessels, and explicit the definitions proposed by Mulvany for specific forms of remodelling, especially inward eutrophic and inward hypertrophic. The available evidence for the existence of remodelled resistance vessels in hypertension comes next, with relatively more weight given to human, in comparison with animal data. Mechanisms are discussed. The impact of antihypertensive drug treatment on remodelling is described, again with emphasis on human data. Some details are given on the three studies to date which point to remodelling of subcutaneous resistance arteries as an independent predictor of cardiovascular risk in hypertensive patients. We terminate by considering the potential role of remodelling in the pathogenesis of end-organ damage and in the perpetuation of hypertensio

The role of oxidative stress during inflammatory processes

The production of various reactive oxidant species in excess of endogenous antioxidant defense mechanisms promotes the development of a state of oxidative stress, with significant biological consequences. In recent years, evidence has emerged that oxidative stress plays a crucial role in the development and perpetuation of inflammation, and thus contributes to the pathophysiology of a number of debilitating illnesses, such as cardiovascular diseases, diabetes, cancer, or neurodegenerative processes. Oxidants affect all stages of the inflammatory response, including the release by damaged tissues of molecules acting as endogenous danger signals, their sensing by innate immune receptors from the Toll-like (TLRs) and the NOD-like (NLRs) families, and the activation of signaling pathways initiating the adaptive cellular response to such signals. In this article, after summarizing the basic aspects of redox biology and inflammation, we review in detail the current knowledge on the fundamental connections between oxidative stress and inflammatory processes, with a special emphasis on the danger molecule high-mobility group box-1, the TLRs, the NLRP-3 receptor, and the inflammasome, as well as the transcription factor nuclear factor-κ

Moderate hypercapnia exerts beneficial effects on splanchnic energy metabolism during endotoxemia

Purpose: Low tidal volume ventilation and permissive hypercapnia are required in patients with sepsis complicated by ARDS. The effects of hypercapnia on tissue oxidative metabolism in this setting are unknown. We therefore determined the effects of moderate hypercapnia on markers of systemic and splanchnic oxidative metabolism in an animal model of endotoxemia. Methods: Anesthetized rats maintained at a PaCO2 of 30, 40 or 60mmHg were challenged with endotoxin. A control group (PaCO2 40mmHg) received isotonic saline. Hemodynamic variables, arterial lactate, pyruvate, and ketone bodies were measured at baseline and after 4h. Tissue adenosine triphosphate (ATP) and lactate were measured in the small intestine and the liver after 4h. Results: Endotoxin resulted in low cardiac output, increased lactate/pyruvate ratio and decreased ketone body ratio. These changes were not influenced by hypercapnia, but were more severe with hypocapnia. In the liver, ATP decreased and lactate increased independently from PaCO2 after endotoxin. In contrast, the drop of ATP and the rise in lactate triggered by endotoxin in the intestine were prevented by hypercapnia. Conclusions: During endotoxemia in rats, moderate hypercapnia prevents the deterioration of tissue energetics in the intestin

0128 : Sca-1 positive cells, but not c-kit positive cells, differentiate into mature cardiomyocytes after brain natriuretic peptide treatment

The Brain Natriuretic Peptide (BNP) is a cardiac hormone, which promotes the recovery of cardiac function and the preservation of cardiac tissue in animal models of heart diseases. Its cardiac protective role in animals was attributed to fibrosis inhibition, as well as to reduction of cardiomyocyte apoptosis and hypertrophy. Recently, we demonstrated that BNP induces heart regeneration via the stimulation of cardiac precursor cell (CPC) proliferation and differentiation into mature cardiomyocytes.The aim of our study was to identify which CPC’s subset is able to respond to BNP stimulation.Cardiac precursor cells identified as being Sca-1+ Nkx2.5+ or c-kit+ Nkx2.5+ cells, expressed in neonatal and adult hearts BNP’s receptors (NPR-A and NPR-B), showing their ability to be activated by BNP treatment. Cell sorting experiments based on the expression of Sca-1 or c-kit were performed on nonmyocyte cells isolated from neonatal wild-type hearts. Sca-1+ and c-kit+ cells were cultured up to 3 weeks with or without BNP in differentiating medium. Sca-1 positive cells, which contained few c-kit+ cells, responded clearly to BNP stimulation by upregulating mRNA levels of genes coding for Nkx2.5, Mlc-2v, c-kit, Sca-1, beta and alpha MHC. Furthermore, higher number of Troponin I+ cells was detected in BNP treated cells compared to untreated cells, suggesting that Sca-1+ cells differentiated after BNP stimulation into mature cardiomyocytes. BNP treatment of c-kit+ cells didn’t induce the upregulation of mRNA coding for cardiomyocyte specific genes. However, we determined that c-kit positive cells spontaneously differentiated into mature cardiomyocytes during the 3 weeks of cell culture without BNP stimulation.To determine which receptor is involved, Sca-1+ cells, isolated from neonatal hearts of NPR-A or NPR-B deficient mice, were treated with BNP. The effects of BNP on wild type and NPR-A KO cells did not differ substantially. However, Sca-1+ cells isolated from NPR-B deficient hearts couldn’t respond anymore to BNP stimulation.Thus, BNP specifically stimulates via NPR-B Sca-1+ cell differentiation into cardiomyocytes. c-kit+ cells display clearly a cardiogenic potential which is BNP independent

Pathophysiological mechanisms of catecholamine and cocaine-mediated cardiotoxicity

Overactivation of the sympatho-adrenergic system is an essential mechanism providing short-term adaptation to the stressful conditions of critical illnesses. In the same way, the administration of exogenous catecholamines is mandatory to support the failing circulation in acutely ill patients. In contrast to these short-term benefits, prolonged adrenergic stress is detrimental to the cardiovascular system by initiating a series of adverse effects triggering significant cardiotoxicity, whose pathophysiological mechanisms are complex and only partially elucidated. In addition to the development of myocardial oxygen supply/demand imbalance induced by the sustained activation of adrenergic receptors, catecholamines can damage cardiomyocytes by fostering mitochondrial dysfunction, via two main mechanisms. The first one is calcium overload, consecutive to β-adrenergic receptor-mediated activation of protein kinase A and subsequent phosphorylation of multiple Ca2+-cycling proteins. The second one is oxidative stress, primarily related to the transformation of catecholamines into "aminochromes,” which undergo redox cycling in mitochondria to generate copious amounts of oxygen-derived free radicals. In turn, calcium overload and oxidative stress promote mitochondrial permeability transition and cardiomyocyte cell death, both via the apoptotic and necrotic pathways. Comparable mechanisms of myocardial toxicity, including marked oxidative stress and mitochondrial dysfunction, have been reported with the use of cocaine, a common recreational drug with potent sympathomimetic activity. The aim of the current review is to present in detail the pathophysiological processes underlying the development of catecholamine and cocaine-induced cardiomyopathy, as such conditions may be frequently encountered in the clinical practice of cardiologists and ICU specialists

Nonselective versus Selective Inhibition of Inducible Nitric Oxide Synthase in Experimental Endotoxic Shock

The effects of two nitric oxide synthase (NOS) inhibitors with different isoform selectivity were compared in a murine model of endotoxemia. Mice challenged with 70 mg/kg intraperitoneal (ip) lipopolysaccharide (LPS) were treated 6 h after LPS with either NG-γ-L-arginine methyl ester (LNAME, nonselective NOS inhibitor, 10-60 mg/kg), L-canavanine (selective inhibitor of inducible NOS, 50-300 mg/kg), or saline (0.2 mL) given ip. In a subset of mice, plasma concentrations of nitrate (NO breakdown product), lipase (pancreas injury), lactate dehydrogenase, and transaminases (liver injury) were measured 16 h after LPS. Although both inhibitors reduced plasma nitrate, they produced contrasting effects on survival and organ injury. L-NAME enhanced liver damage and tended to accelerate the time of death, while L-canavanine significantly reduced mortality and had no deleterious effects in terms of organ damage. These results indicate that nonselective NOS inhibitors are detrimental in endotoxic shock and support the potential usefulness of selective inducible NOS inhibitors in this settin