Arterial stiffness, pulse pressure, and the kidney.

Classical studies indicate that the contribution of kidneys to hypertension is almost exclusively related to the association between mean arterial pressure (MAP) and vascular resistance. Recent reports including estimates of glomerular filtration rate (GFR) have shown that pulse pressure (PP) and pulse wave velocity, 2 major indices of arterial stiffness, now emerge as significant predictors of cardiovascular risk and age-associated decline in GFR. Such findings are mainly observed in patients with hypertension and renal failure and in atherosclerotic subjects undergoing coronary angiography. In such patients, amplification of PP between ascending and terminal aorta at the renal site is constantly increased over 10mm Hg (P < 0.001), whereas MAP level remains continuously unmodified. This PP amplification is significantly associated with presence of proteinuria. Furthermore, increases in plasma creatinine and aortic stiffness are independently and positively correlated (P < 0.001) both in cross-sectional and longitudinal studies. All these relationships associating PP, arterial stiffness, and renal function are mainly observed in patients 60 years of age or older. Furthermore, in renal transplant patients and their donors, subjects have been recruited for evaluations of arterial stiffness and posttransplant decline in GFR. Determinants of GFR decline were evaluated 1 and 9 years after transplantation. The first year GFR decline was related to smoking and acute rejection, whereas the later was significantly and exclusively associated with donor age and aortic stiffness. Thus, in hypertensive humans, the observed association between PP and GFR suggests that the 2 parameters are substantially mediated by arterial stiffness, not exclusively by vascular resistance.

Impact of kinins in the treatment of cardiovascular diseases.

In recent years, ACE Inhibitors (ACEIs) and Angiotensin II receptor antagonists (also known as AT1 receptor antagonists (AT1-RAs), angiotensin receptor blockers (ARBs), or Sartans), have become the drugs of choice for the treatment of hypertension, heart and renal failure, coronary artery diseases, myocardial infarction and diabetes. By suppressing angiotensin and potentiating bradykinin effects, ACEIs and ARBs activate hemodynamic, metabolic and cellular mechanisms that not only reduce high blood pressure, but also protect the endothelium, the heart, the kidney and the brain, namely the target organs which are at risk in cardiovascular diseases. Major therapeutic benefits of these drugs are the reduction of cardiovascular events and the amelioration of the quality of life and of the patient survival. Results from large clinical trials have established that ACEIs and ARBs are efficient and safe drugs, suitable for the chronic treatments of cardiovascular diseases. Side effects are rare and easily manageable in most cases. The following is a brief review of the basic actions and mechanisms by which two opposing systems, the renin-angiotensin (RAS) and the kallikrein-kinin (KKS), interact in the regulation of cardiovascular and fluid homeostasis to keep the balance in healthy life and correct the imbalance in pathological conditions. Here we discuss how and why imbalances created by overactive RAS are best corrected by treatments with ACEI or AT1-RAs.

Characterization of hyaluronic acid interaction with calcium oxalate crystals: implication of crystals faces, pH and citrate.

Interaction between hyaluronic acid (HA) present at the surface of tubular epithelial cells and calcium oxalate monohydrate (COM) crystals is thought to play an important role in kidney stone formation. AFM-based force spectroscopy, where HA is covalently attached to AFM-probes, was used to quantify the interaction between HA and the surfaces of COM crystals. The work of adhesion of the HA-probe as well as the rupture force of single HA molecules were quantified in order to understand the molecular regulation of HA binding to COM crystals. Our results reveal that HA adsorbs to the crystal surface in physiological conditions. We also observed increased adhesion when the pH is lowered to a value that increases the risk of kidney stone formation. HA adhesion to the COM crystal surface can be suppressed by citrate, a physiological inhibitor of stone retention currently used in the treatment and prevention of kidney stone formation. Interestingly, we also observed preferential binding of HA onto the [100] face versus the [010] face, suggesting a major contribution of the [100] faces in the crystal retention process at the surface of tubular epithelial cells and the promotion of stone formation. Our results clearly establish a direct role for the glycosaminoglycan HA present at the surface of kidney tubular epithelium in the process of COM crystal retention.

Opioids for cancer pain: the challenge of optimizing treatment.

During 2007, 11.7 million US men and women of all ages suffered from some form of invasive cancer. During their illness, at least 70% (8.2 million) will experience pain sufficiently severe to require chronic opioid treatment. Cancer-induced pain is usually described under 3 headings: acute pain, chronic pain, and breakthrough pain. Among patients with chronic, persistent cancer pain controlled by around-the-clock analgesics, there is a high prevalence of breakthrough pain-often precipitated by some form of physical activity. Breakthrough pain seems best treated by a powerful, fast-acting opioid such as intravenous morphine or transmucosal fentanyl. At present, opioids are virtually the only analgesics capable of controlling moderate and severe cancer pain. In recent years, a veritable arsenal of opioids with a wide range of pharmacologic properties has become available for use in different pain situations. The World Health Organization has developed a 3-step "analgesic ladder" to guide management of cancer pain, based on the pain's severity, estimated by means of a 1 to 10 numeric rating scale. As the severity of the pain escalates, more potent (World Health Organization Step III) opioids are used. When faced with a difficult case of cancer pain, the physician must choose-from an array of options-the safest and most effective opioid analgesic and the most appropriate delivery system. Such decisions require an adequate understanding of the available opioids and experience with their use. The pharmacodynamic response to a given opioid depends on the nature of the receptor to which the opioid binds and its affinity for the receptor. Morphine activates the µ-opioid receptors, resulting in not only analgesia and sedation, but also euphoria, respiratory depression, constipation, and pruritus. The existence of a number of opioid receptor subtypes, each with its own repertoire of responses, has given rise to the hope (as yet unrealized) that an opioid can be found (or engineered) that will selectively produce adequate analgesia and sedation without, at the same time, causing unwanted adverse effects. Furthermore, suitable neurostimulatory or neuroinhibitive methods involving the central nervous system are being sought that can amplify the analgesic action of opioids. In the search for antinociceptive agents as efficacious as currently available opioids, but without their troublesome adverse effects, the endogenous opioids, such as the endomorphins, are being examined as offering possible solutions to the adverse effect problem.

Adventitia: the vital wall of conduit arteries.

Adventitia surrounds, nourish, and protect large conductance vessels. This important outer layer has long been forgotten by researchers because interest in vascular diseases has focused mainly on resistance arteries, as shown by the numerous publications on the subject. However, involvement of large vessels in the pathogenesis of vascular diseases is beginning to be recognized. Indeed, the stiffness of conductance arteries could be a precursor event of high blood pressure. Pathological changes that occur in adventitia, increased vasa vasorum permeability for example, may lead or precipitate vascular diseases. Adventitia can also be affected by luminal events like shear stress and possibly atherosclerosis that may trigger adverse responses in the adventitial tissue. These adventitial changes and interrelationships, as well as the structure, including the afferent and efferent autonomic nervous system, and functions of adventitia are the subject of the present review. There is no doubt that the medical and scientific community would greatly benefit from awareness and a better consideration of adventitia and that more studies focusing on this part of blood vessels will lead to an improved comprehension of the different diseases affecting them.

Pre-exercise hyperhydration delays dehydration and improves endurance capacity during 2 h of cycling in a temperate climate.

Whether the use of pre-exercise hyperhydration could improve the performance of athletes who do not hydrate sufficiently during prolonged exercise is still unknown. We therefore compared the effects of pre-exercise hyperhydration and pre-exercise euhydration on endurance capacity, peak power output and selected components of the cardiovascular and thermoregulatory systems during prolonged cycling. Using a randomized, crossover experimental design, 6 endurance-trained subjects underwent a pre-exercise hyperhydration (26 ml of water x kg body mass(-1) with 1.2 g glycerol x kg body mass(-1)) or pre-exercise euhydration period of 80 min, followed by 2 h of cycling at 65% maximal oxygen consumption (VO(.)2max) (26-27 degrees C) that were interspersed by 5, 2-min intervals performed at 80% V(.)O2max. Following the 2 h cycling exercise, subjects underwent an incremental cycling test to exhaustion. Pre-exercise hyperhydration increased body water by 16.1+/-2.2 ml.kg body mass(-1). During exercise, subjects received 12.5 ml of sports drink x kg body mass(-1). With pre-exercise hyperhydration and pre-exercise euhydration, respectively, fluid ingestion during exercise replaced 31.0+/-2.9% and 37.1+/-6.8% of sweat losses (p>0.05). Body mass loss at the end of exercise reached 1.7+/-0.3% with pre-exercise hyperhydration and 3.3+/-0.4% with pre-exercise euhydration (p<0.05). During the 2 h of cycling, pre-exercise hyperhydration significantly decreased heart rate and perceived thirst, but rectal temperature, sweat rate, perceived exertion and perceived heat-stress did not differ between conditions. Pre-exercise hyperhydration significantly increased time to exhaustion and peak power output, compared with pre-exercise euhydration. We conclude that pre-exercise hyperhydration improves endurance capacity and peak power output and decreases heart rate and thirst sensation, but does not reduce rectal temperature during 2 h of moderate to intense cycling in a moderate environment when fluid consumption is 33% of sweat losses.

Modulation of aquaporin-2/vasopressin2 receptor kidney expression and tubular injury after endotoxin (lipopolysaccharide) challenge.

OBJECTIVE: Sepsis-induced organ dysfunctions remain prevalent and account for >50% of intensive care unit admissions for acute renal failure with a mortality rate nearing 75%. In addition to the fact that the mechanisms underlying the pathophysiology of sepsis-related acute renal failure are unclear, the impact on septic-induced acute renal failure of either norepinephrine, a gold-standard vasopressor, and arginine vasopressin, a candidate alternative, are not well understood. DESIGN: Randomized and controlled in vivo study. SETTING: Research laboratory and animal facilities. SUBJECTS: Adult rats treated with endotoxin (lipopolysaccharide) and/or vasopressors. INTERVENTIONS: Rats were intraperitoneally injected with lipopolysaccharide (12 mg/kg) or saline and then infused with either saline, 0.375 microg/microL arginine vasopressin, or 32.5 microg/microL norepinephrine for 18 hrs. These vasopressor rates yielded respective targeted blood levels observed in human septic shock. MEASUREMENTS AND MAIN RESULTS: Renal function, including glomerular filtration rate and fraction, renal blood flow, aquaporin-2, and arginine vasopressin-2 (V2 receptor) networking, water and salt handling, and urinary protein excretion, were evaluated. After lipopolysaccharide challenge arginine vasopressin infusion: 1) impaired creatinine clearance without affecting renal blood flow, glomerular filtration rate, and fraction but reduced free-water clearance, both of which being partially restored by the V2 receptor antagonist SR-121463B; 2) decreased the recognized ability of arginine vasopressin alone to recruit aquaporin-2 to the apical membrane increase its mRNA expression and urinary release; 3) increased urinary protein content but decreased specific kidney injury molecule-1, and Clara cell protein-16 release (p < 0.05 vs. lipopolysaccharide alone). Conversely, norepinephrine infusion did not add to lipopolysaccharide-induced alteration of urine biochemistry, except for improved creatinine clearance and increased microalbuminuria. CONCLUSION: In this endotoxic model, dose-targeted arginine vasopressin infusion increased lipopolysaccharide-induced renal dysfunction without affecting renal blood flow and glomerular function, but with particular disruption of aquaporin-2/V2 receptor networking, consecutive decreased salt and water handling ability. This is in clear contrast with norepinephrine infusion and suggests specific arginine vasopressin-induced "tubular epithelial dysfunction."

Predisease biological markers: early diagnosis and prevention of arterial hypertension.

This review examines 2 potentially important morbid changes that may precede the onset of hypertension-capillary rarefaction (CR) and large artery rigidity (LAR). The mechanisms responsible for CR, currently measured in the skin microcirculation, as well those responsible for LAR, have yet to be fully delineated. Nor has the duration been determined of the latent period between the occurrence of these lesions and the onset of blood pressure elevation. It has been known for 2 decades that, because of the kidney's relatively rigid capsule, alterations in the abundant postglomerular microcirculation network (which can accommodate circa 80% of total renal blood flow) can lead to endothelial plasma leakage. Even a small amount of plasma leakage can increase interstitial pressure and lead to capillary collapse and CR. Simultaneously, or at a later time, these alterations could have an impact on the reflection wave profile in the thoracic aorta and, via abnormal endothelial proliferation and other vascular effects, give rise to LAR. Nonpharmacologic and/or pharmacologic interventions have been shown to exert positive effects on CR and/or LAR. Recent studies have demonstrated the beneficial actions of a bradykinin B2-receptor antagonist (HOE140) in the spontaneously hypertensive rat, the classic rat model for essential hypertension. The fact that CR and LAR both precede blood pressure elevation could serve as a basis for designing strategies to prevent hypertension from occurring. Because modern tools capable of measuring CR and LAR noninvasively have been developed, it should soon be feasible to identify these 2 prehypertension markers in individual patients.

A meta-analysis of the effects of glycerol-induced hyperhydration on fluid retention and endurance performance.

The authors determined, through a meta-analytic approach, whether glycerol-induced hyperhydration (GIH) enhances fluid retention and increases endurance performance (EP) significantly more than water-induced hyperhydration (WIH). Collectively, studies administered 23.9 +/- 2.7 mL of fluid/kg body weight (BW) with 1.1 +/- 0.2 g glycerol/kg BW, and hyperhydration was measured 136 +/- 15 min after its onset. Compared with WIH, GIH increased fluid retention by 7.7 +/- 2.8 mL/kg BW (P < 0.01; pooled effect size [PES]: 1.64 +/- 0.80, P < 0.01, N = 14). The use of GIH was associated with an improvement in EP of 2.62% +/- 1.60% (P = 0.047; PES: 0.35 +/- 0.13, P = 0.014, N = 4). Unarguably, GIH significantly enhances fluid retention better than WIH. Because of the dearth of data, the effect of GIH on EP must be further investigated before more definitive conclusions can be drawn as to its ergogenic property.

Large arteries and the kidney.

In subjects with chronic renal disease, high systolic blood pressure (SBP) is the most modifiable cardiovascular (CV) risk factor that enables prevention of the progression of chronic kidney disease renal failure and the occurrence of CV events. Although large-artery stiffness and wave reflections are the principal hemodynamic determinants of SBP, their precise role in the progression of chronic renal disease has been poorly investigated. However, in subjects with mild to severe renal insufficiency, increased arterial stiffness and reduced creatinine clearance are closely related, independently of age; mean arterial pressure level; and presence of other traditional risk factors, including atherosclerotic plaques. Through inflammatory mechanisms, as well as through the development of arterial calcifications (including microscopic) and sodium-related alterations in extracellular matrix composition, arterial stiffness is associated with significant SBP and increased pulse pressure (PP). In the presence of renal dysfunction, frequently observed in elderly hypertensive or diabetic subjects, or even in some living donors, the resulting increase in PP may be transmitted toward and across glomeruli, even when peripheral blood pressure values are maintained. This alteration alone may initiate glomerulosclerosis and/or tubulointerstitial damage, eventually leading to CV events. In subjects with end-stage renal disease and high CV risk, pharmacological modulation of the renin-angiotensin system has been shown to prevent independently such complications.

Structure of large arteries: orientation of elastin in rabbit aortic internal elastic lamina and in the elastic lamellae of aortic media.

This study was designed to further our understanding of the elastic ultrastructure of vessels. Scanning electron microscopy and transmission electron microscopy were used to study the histomorphologic properties of the elastic fibers of rabbit aorta after purification of the elastin by means of hot alkaline treatments. The elastic fibers of whole rabbit aorta samples were also studied using confocal microscopy. Morphological assessment revealed that the elastin fibers contained in the elastic lamellae of media are perpendicular to the blood flow, and that the elastic fibers of the internal elastic lamina are parallel to the luminal flow. In conclusion, the structure of the elastin making up the elastic lamellae of the media is oriented in such a way as to sustain the circumferential mechanical stress of pulsation. By contrast, the structure of the elastin fibers that make up the internal elastic lamina provides little mechanical support for the circumferential tension, but can support longitudinal loading and act as a fenestrated membrane.

Review article: organ perfusion/permeability-related effects of norepinephrine and vasopressin in sepsis.

PURPOSE: One invariable hallmark of severe sepsis is generalized tissue "malperfusion" and hyperpermeability secondary to microcirculatory/capillary leakage. This review focuses on direct and/or indirect influences of norepinephrine, as a standard of care, and vasopressin, as an alternative vasoactive drug, on organ and tissue perfusion/permeability in severe sepsis. SOURCE: English and French language articles and books published between 1966 and 2005 were identified through a computerized Medline search using the terms "sepsis, permeability, norepinephrine and vasopressin". Relevant publications were retrieved and scanned for additional sources. PRINCIPAL FINDINGS: There are few randomized clinical trials comparing different vasopressors in sepsis; most available literature consists of clinical reports, animal experiments and occasional reviews. Based on the best current evidence from these sources, we describe the status of major organ perfusion/permeability in sepsis (i.e., the lung, the kidney, the heart, the intestine/gut) in the context of sepsis-induced organ dysfunction/failure. Potential and differential therapeutic effects of the vasopressors norepinephrine and arginine-vasopressin, in the setting of sepsis, are identified. CONCLUSIONS: In the treatment of sepsis, arginine-vasopressin exhibits organ-specific heterogeneity in vascular responsiveness, compared to norepinephrine. While norepinephrine is a current standard of care in sepsis, arginine-vasopressin shows promise for the treatment of septic shock.

Sleep and vascular disorders.

It is not surprising that cardiovascular diseases such as congestive heart failure and coronary insufficiency can give rise to varying degrees of sleep impairment; it is less readily appreciated that certain physiologic events occurring during sleep-as well as long-term unsatisfactory sleep-may cause or increase the risk of cardiovascular conditions such as hypertension, atherosclerosis, stroke, and cardiac arrythmias. Heart rate abnormalities during sleep in normotensive subjects predict later cardiovascular disease, and their early identification alerts the physician to undertake preventive measures. Maneuvers, such as induction of hypoxia, can elicit abnormal blood pressure responses during sleep, and such responses have been used to identify impending cardiovascular problems that could become therapeutic targets. The spontaneously hypertensive rat has been used to examine the effect of sympathetic nervous system (SNS) activity on the heart under a variety of experimental conditions, including quiet and paradoxical sleep. The results have disclosed significant differences between the responses of spontaneously hypertensive rats and normal rats to SNS stimulation. Exploration of other pathophysiologic pathways affected by exposure to light and dark, including those responsive to the cyclic production of melatonin, will improve our understanding of the effect of disruptions of the circadian cycle on cardiovascular function. There is growing evidence that melatonin can influence important processes such as fluid, nitrogen, and acid-base balance. Human subjects whose nocturnal arterial blood pressure fails to show the "normal" decrement during sleep ("nondippers") are also prone to sleep poorly, exhibit increased SNS activity during sleep, and have an increased risk of total and cardiovascular disease mortality. Chronic sleep deficit is now known to be a risk factor for obesity and may contribute to the visceral form of obesity that underlies the metabolic syndrome. The rising prevalence of obstructive sleep apnea and central sleep apnea is linked to the modern-day epidemic of obesity. Obstructive sleep apnea is associated with an enhanced risk of having a new stroke or a transient ischemic attack.

Bradykinin B2 type receptor activation regulates fluid and electrolyte transport in the rabbit kidney.

Bradykinin is an important autacoid produced in the kidney, regulating both renal function and blood pressure. In vivo studies in anesthetized rabbits, revealed that BK induced diuresis (UV), natriuresis (U(Na)V) and was not associated with renal hemodynamic changes. These diuretic and natriuretic effects were blocked by the BK-B2 antagonist HOE-140. BK also inhibits vasopressin (AVP)-stimulated water flow (L(p)) in microperfused rabbit cortical collecting ducts (rCCD), in a concentration-dependent fashion, consistent with its in vivo diuretic effects. BK-B1 antagonist Leu8-des-Arg9-BK did not alter the effect of BK on Lp, but HOE-140 completely blocked the inhibitory effects of BK on Lp. While BK did not increase [Ca2+]i in fura-2 loaded freshly microdissected rCCD, BK increased [Ca2+]i in immortalized cultured rCCD cells demonstrating different signaling mechanisms are activated by BK in microdissected versus cultured rCCD. In microperfused rCCD, neither the protein kinase C inhibitor staurosporine nor the phospholipase C (PLC) inhibitor U-73,122 attenuated the BK response arguing against activation of PLC/PKC by BK in rCCD. We conclude: (1) BK induces UV and U(Na)V by a BK-B(2) receptor; (2) BK inhibits AVP-stimulated Lp by a BK-B2 receptor suggesting that its effects on Lp are not via a PLC/PKC; (3) finally, BK raises [Ca2+]i in rCCD cells by a BK-B2 receptor mechanism.

Depression and cardiovascular disease: a reciprocal relationship.

Until relatively recently, depression has been considered a purely "mental" disorder and therefore in the natural domain of psychologists and psychiatrists. However, recent epidemiological studies have revealed that aging, physical and psychological stress, chronic pain, several metabolic disorders such as insulin resistance and established diabetes, alcoholism, inflammatory conditions, and vascular disorders such as arterial hypertension all may be associated with depression. The present review examines some of these depression-associated factors and the mechanisms by which they might give rise to vascular disorders such as atherosclerosis, microcirculation endothelial dysfunction, and interstitial disturbances leading to organ damage. A number of disorders involving the circulation can lead progressively and insidiously to large artery rigidity, remodeling of peripheral arteries, and alterations of the microcirculation of large blood vessels. Perturbations in vasa vasorum blood flow may contribute to atherogenesis, in addition to the influence of numerous cellular events involved in inflammation (tumor necrosis factor alpha, interleukin 1 beta, etc). Since Hans Selye first described the neuroendocrine cascade generated by experimentally induced stress half a century ago, phenomena such as the axonal release of neurotransmitters (including serotonin), accumulation of metabolites such as homocysteine, platelet-activating factor, and nitric oxide also have been implicated in the pathogenesis of depression. Moreover, vascular consequences of depression such as heart rate and pulse pressure variations may lead to endothelial dysfunction in critical microcirculation networks (cerebral, myocardial, and renal) and initiate physicochemical alterations in interstitial compartments adjacent to vital organs. The appropriate use of ambulatory monitoring of vascular parameters, such as heart rate and pulse pressure, and eventually, early identification of genetic and metabolic markers may prove helpful in the early detection of events preceding and predicting the clinical manifestations of depression.

Long-term protection of obese Zucker rat kidneys from fibrosis and renal failure with an angiotensin-converting enzyme inhibitor/diuretic combination.

Some combinations of antihypertensive agents were shown to reduce proteinuria in patients with renal failure. However, preventive effects of such combinations on renal structure and function are presently unknown when treatment is administered before the onset of renal abnormalities. We thus investigated the long-term effects of an angiotensin-converting enzyme (ACE) inhibitor (perindopril)/diuretic (indapamide) combination (per/ind) in the Zucker rat, a classical model of chronic renal failure associated with obesity, hyperlipidemia, and insulin resistance. Two-month-old lean and obese Zucker rats, presenting normal renal structure and function at this young age, received per/ind (0.76 + 0.24 mg/kg of body weight/day) or the vehicle of this combination by daily gavage. After 8.5 consecutive months of treatment, those 10.5-month-old rats were used for determination of renal structural and functional parameters which were examined using standard renal clearance experiments and kidney tissue analysis. Per/ind prevented focal and segmental glomerular hyalinosis and tubulo-interstitial damage in obese rats. Treatment was also associated with a significant reduction in several staining markers of glomerular and interstitial fibrosis. The hypertrophy of superficial glomeruli and the mesangial expansion of deep glomeruli observed in control rats were reduced in per/ind-treated obese rats. The severe proteinuria observed in 10.5-month-old control obese rats was prevented by per/ind, while glomerular filtration and renal hemodynamic parameters reached similar values to those obtained in lean animals. These results show that long-term treatment with this ACE inhibitor/diuretic combination protects renal structure and function in the obese Zucker rat, emphasizing the potential efficiency of such therapy in renal failure prevention.

Effects of perindopril on elastic and structural properties of large arteries in essential hypertension.

BACKGROUND: Perindopril, an angiotensin-converting enzyme (ACE) inhibitor, is a well-recognized antihypertensive drug. Its ability to protect against cardiovascular events in hypertension has also been demonstrated. It decreases the stiffness of the larger arteries; questions remain as to the mechanisms involved and whether it is blood pressure (BP) control-dependent. OBJECTIVES: To correlate the BP response to ACE inhibition therapy with changes in arterial stiffness as evaluated by pulse wave velocity (PWV), and to correlate these changes in arterial stiffness with alterations in indicators of vascular collagen metabolism serum levels of metalloproteinase (MMP)-1 and tissue inhibitor of MMP-1 (TIMP-1). METHODS: A total of 162 patients aged 18 to 70 years with stage 1 and 2 essential hypertension (diastolic BP 95 mmHg to 114 mmHg) were enrolled to receive six months (M6) of therapy with the ACE inhibitor, perindopril. Patients were either treatment-naïve or had not received any antihypertensive treatment for at least six months before the study. RESULTS: Mean BP was significantly reduced after two months (M2) of therapy (P=0.00001) and remained stable thereafter. In addition to the significant mean changes in PWV observed at M2 (P=0.00001), further reductions in PWV were noted at M6 (P=0.007). The change in PWV between baseline (M0) and M2 was significantly correlated to all BP parameters at M0 (correlation coefficient at M2 was 0.189 or greater). However, no correlation was seen regarding BP parameters at M2 and further M2 to M6 changes in PWV, suggesting a decrease of arterial stiffness independent of BP reduction. The expression of TIMP-1 and MMP-1 was highly variable and demonstrated no correlation with BP or PWV. CONCLUSIONS: Reductions in BP and PWV appear to be correlated during the first two months of perindopril therapy. After six months, PWV continues to decrease independently of any further reduction in BP, suggesting the occurrence of a pressure-independent pharmacological remodelling of the arterial wall. A long-term, double-blind, randomized trial could be required to confirm that the observed increase in vascular distensibility induced by perindopril is related to a mechanism of action other than a reduction in BP.

Comparative effects of vasopressin, norepinephrine, and L-canavanine, a selective inhibitor of inducible nitric oxide synthase, in endotoxic shock.

Norepinephrine (NE), a standard of care, AVP, an alternative candidate, and L-canavanine (LC), a selective inhibitor of inducible nitric oxide synthase, were compared for efficacy and innocuousness on global and regional hemodynamics, plasmatic and tissue lactate-to-pyruvate ratio (L/P), tissue high-energy phosphates, renal function, and tissue capillary permeability in a rat model of endotoxic normokinetic shock. Mean arterial pressure (MAP) decreased ( approximately 35%) but aortic blood flow increased during endotoxin infusion (P < 0.05 vs. control). Additionally, there was a decrease in mesenteric (MBF) and renal (RBF) blood flows along with regional-to-systemic ratio (P < 0.05 vs. control). All tested drugs restored MAP to basal levels but slightly decreased abdominal aortic flow; however, RBF and MBF remained unchanged. Endotoxin significantly decreased diuresis and inulin clearance ( approximately 3- to 4-fold), whereas AVP or LC attenuated this drop (P < 0.05 vs. control). In contrast, NE did not improve endotoxin-induced renal dysfunction. Endotoxin induced gut and lung hyperpermeability (P < 0.05 vs. control). Endotoxin-induced gut hyperpermeability was inhibited by AVP, LC, and NE. Endotoxin-induced lung hyperpermeability was further worsened by NE ( approximately 2-fold increase) but not AVP infusion (P < 0.05 vs. endotoxin). LC significantly improved endotoxin-induced pulmonary hyperpermeability. Endotoxin increased renal lactate and decreased renal ATP. NE did not change renal lactate or renal ATP. AVP and LC decreased renal lactate and normalized renal ATP. Finally, endotoxin was associated with increased lactate levels and L/P ( approximately 2- and 1.5-fold increases vs. control, respectively), whereas AVP and LC, but not NE, normalized both parameters after endotoxin challenge. These results suggest that, in a short-term endotoxic shock model, AVP improves systemic hemodynamics without side effects and has particular beneficial effects on renal function.

Arterial stiffness and kidney function.

The vascular hallmark of subjects with end-stage renal disease undergoing hemodialysis is increased aortic stiffness, a phenomenon independent of mean arterial blood pressure, wall stress, and standard cardiovascular risk factors such as plasma glucose, cholesterol, obesity, and smoking. These observations suggest that subtle links might associate arterial stiffness and kidney function in normotensive and hypertensive populations. Recently, aortic pulse wave velocity and creatinine clearance have been shown to be statistically associated in subjects with plasma creatinine < or =130 micromol/L, again independently of mean arterial blood pressure and classical cardiovascular risk factors. This association was even shown to predominate in subjects younger than age 55 years. In addition, acceleration of aortic pulse wave velocity with age was more important in these subjects than in untreated normotensive control individuals, and the phenomenon was consistently predicted by baseline plasma creatinine values. Among all antihypertensive drugs, angiotensin-converting enzyme inhibitors only were shown to exhibit a significant and independent effect on aortic stiffness. The use of these drugs was significantly associated with improvement of large aortic stiffness in subjects treated for hypertension. In conclusion, increased stiffness of central arteries is independently associated with reduced creatinine clearance in subjects with mild to severe renal insufficiency, indicating that kidney diseases may interact not only with small but also with large conduit arteries, independently of age, blood pressure level, and classical cardiovascular risk factors. Whether sodium, divalent ionic species (calcium, phosphates), and the renin-angiotensin-aldosterone system play a role in such alterations remains to be elucidated.

Impact of aging on the body's vascular system.

In this review, the effect of aging on the body's vascular system is considered in terms of potential mechanisms involved in target organ damage. First, the effects of aging on body fluid compartments, including changes that occur in subdivisions of the interstitial space (quite heterogeneous among organs), are described, with particular reference to the macromolecular composition of the fluid compartments. Second, the structure and function of different segments of the vascular system during aging are examined, with emphasis on: (1) large arterial conduits responsible for isolated systolic hypertension; (2) arteries most responsible for peripheral resistance (the "resistance arteries"); (3) microcirculation networks, including the vasa vasorum; and (4) large collecting veins that can have such an important effect on the cardiac output. Third, a detailed discussion is provided of the heterogeneous macromolecular composition of interstitial fluid compartments that are involved in the critical traffic of vital substrates, including pharmacologic agents, in transit from the systemic circulation to the various organs. The strategic position of interstitial fluid compartments, situated as they are between microcirculation networks and vital organs, is considered to be critically involved in the morbidity and mortality caused by the vascular diseases afflicting elderly persons. Finally, with respect to "physiological" and/or "morbid" aging, a re-examination is undertaken of the target organ damage observed in elderly individuals who suffer from isolated systolic hypertension, type II diabetes mellitus, peripheral vascular disease, chronic heart failure, and renal failure. Potentially new and noninvasive approaches available to clinicians for early detection of large artery rigidity are considered, along with the possible benefits of nonpharmacologic and/or pharmacologic interventions.