Reduction In Systemic Blood Pressure Research Articles

Stage of chronic kidney disease is an outcome-predicting factor of angioplasty for atheromatous renal artery stenosis

Angioplasty with insertion of an endoprosthesis is an effective treatment for atheromatous renal artery stenosis (ARAS). However, this procedure may cause deterioration in renal function, and it is imperative to define the cases that could benefit from angioplasty. From 456 suspected renovascular hypertension cases, 33 were given a diagnosis of unilateral ARAS on renal arteriography. These unilateral ARAS cases were treated by angioplasty, and their baseline variables were evaluated with respect to the improvement achieved in post-angioplastic renal function of the treated side as measured by renal scintigram. The estimated glomerular filtration rate (eGFR) was the only variable that was significantly different between cases that showed improvement in renal function and those that did not. Cases that showed improvement in renal function had lower pre-angioplasty eGFR compared with cases that did not show improvement (59±24 ml min⁻¹ 1.73 m⁻² vs. 76±12 ml min⁻¹ 1.73 m⁻², P=0.04), and cases showing improvement were generally at later stages of chronic kidney disease (CKD). Most patients without improvement, who were generally at earlier stages of CKD, had a systemic blood pressure reduction after angioplasty. The present findings indicate that the baseline CKD stage could be used to predict the outcome of angioplasty for ARAS.

Myocardial Specific BNP Gene-Delivery Improves Diastolic Function and Ventricular Structure in Spontaneous Hypertensive Rodents

G-protein coupled receptors (GPCRs), in addition to signaling through heterotrimeric G proteins, also signal through b-arrestins. GPCR ‘‘biased ligands’’ preferentially engage a subset of receptor signals, for example activating either G-protein or b-arrestin mediated signals while limiting engagement of the other pathway, and thus elicit unique pharmacology compared to unbiased agonists or antagonists. TRV120027 is a potent, selective b-arrestin biased ligand of the angiotensin II type 1 receptor (AT1R). TRV120027 is a competitive antagonist of angiotensin II-stimulated G protein signaling, but stimulates b-arrestin recruitment and activates several kinase pathways, including p44/42 MAPK, Src, and eNOS phosphorylation via b-arrestin coupling. Consistent with this b-arrestin efficacy, and unlike unbiased antagonists, TRV120027 increases cardiomyocyte contractility in vitro. Moreover, in rat hemodynamic studies, including pressure-volume loop analysis, TRV120027 produced unique and differential cardiovascular pharmacology in vivo, when compared to classical unbiased AT1R antagonists. Like the unbiased AT1R antagonist telmisartan, TRV120027 administered via continuous intravenous infusion had minimal effects on heart rate and reduced mean arterial pressure to a similar degree. TRV120027, however, increased cardiac performance, as measured by the slope of the end-systolic pressure volume relationship (ESPVR), and preserved cardiac stroke volume. The effects of TRV120027 on the slope of the ESPVR and blood pressure were rapidly reversible. In stark contrast, treatment with telmisartan led to a protracted decline in the ESPVR slope and a reduction in stroke volume. In toxicology studies in the rat, supra-therapeutic doses of TRV120027 were generally well-tolerated and without adverse effects on renal function. TRV120027 was rapidly cleared, with a half-life of less than 2 minutes. This distinct in vivo pharmacokinetic and pharmacodynamic profile, including a reduction of systemic blood pressure and improved cardiac performance, coupled with a short half-life and rapid reversibility, suggest that TRV120027 represents a potentially ground-breaking new therapy for patients with heart failure, and validates the continued exploration GPCR biased ligands to selectively target specific receptor functions in drug discovery.

Baroreflex control of heart rate in the broad-nosed caiman Caiman latirostris is temperature dependent

It has been suggested that ectothermic vertebrates primarily control blood pressure to protect the pulmonary vasculature from oedema caused by high pressure, while endothermic vertebrates control blood pressure to maintain adequate oxygen delivery to the tissues. In the present study we have characterised how temperature affects the cardiac limb of the baroreflex in the intact unanaesthetized broad-nosed caiman (Caiman latirostris) by pharmacological manipulation of blood pressure in a “closed-loop” system. Sodium nitroprusside (SNP) and phenylephrine were used to manipulate arterial pressure and the resulting alterations in heart rate were used to calculate the gain of the baroreflex. Both drugs were infused as bolus injections in concentrations of 5, 10, 25, 50 and 100µgkg−1. The barostatic response was present at both 15 and 30°C, and, at both temperatures, C. latirostris responded to reductions in systemic blood pressure (Psys). At 30°C the baroreflex was more pronounced at a blood pressure lower than control value (52.3cmH2O) with a maximal baroreflex gain of 1.97beatsmin−1cmH2O−1 at a Psys of 41.9cmH2O, and therefore seems to counteract hypotension. In contrast, the maximal baroreflex at 15°C was found at a Psys almost equal to the control value. The highest baroreflex gain in response to change in blood pressure was measured at the highest temperature. Thus, C. latirostris exhibit a temperature dependent barostatic response.

Is Obstructive Sleep Apnea a Risk Factor for Hypertension?—Differences between the Wisconsin Sleep Cohort and the Sleep Heart Health Study

Is Obstructive Sleep Apnea a Risk Factor for Hypertension?—Differences between the Wisconsin Sleep Cohort and the Sleep Heart Health Study

The unequal influences of the left and right vagi on the control of the heart and pulmonary artery in the rattlesnake,Crotalus durissus

Autonomic control of the cardiovascular system in reptiles includes sympathetic components but heart rate (f(H)), pulmonary blood flow (Q(pul)) and cardiac shunt patterns are primarily controlled by the parasympathetic nervous system. The vagus innervates both the heart and a sphincter on the pulmonary artery. The present study reveals that whereas both the left and right vagi influence f(H), it is only the left vagus that influences pulmonary vascular resistance. This is associated with the fact that rattlesnakes, in common with some other species of snakes, have a single functional lung, as the other lung regresses during development. Stimulation of the left cervical vagus in anaesthetised snakes slowed the heart and markedly reduced blood flow in the pulmonary artery whereas stimulation of the right cervical vagus slowed the heart and caused a small increase in stroke volume (V(S)) in both the systemic and pulmonary circulations. Central stimulation of either vagus caused small (5-10%) reductions in systemic blood pressure but did not affect blood flows or f(H). A bilateral differentiation between the vagi was confirmed by progressive vagotomy in recovered snakes. Transection of the left vagus caused a slight increase in f(H) (10%) but a 70% increase in Q(pul), largely due to an increase in pulmonary stroke volume (V(S,pul)). Subsequent complete vagotomy caused a 60% increase in f(H) accompanied by a slight rise in Q(pul), with no further change in V(S,pul). By contrast, transection of the right vagus elicited a slight tachycardia but no change in V(S,pul). Subsequent complete vagotomy was accompanied by marked increases in f(H), Q(pul) and V(S,pul). These data show that although the heart receives bilateral vagal innervation, the sphincter on the pulmonary artery is innervated solely by the left vagus. This paves the way for an investigation of the role of the cardiac shunt in regulating metabolic rate, as chronic left vagotomy will cause a pronounced left-right shunt in recovered animals, whilst leaving intact control of the heart, via the right vagus.

Selective cyclooxygenase-2 (COX-2) inhibition reduces proteinuria in renal patients

Renoprotection is predicted by the antiproteinuric efficacy of a pharmacological agent. Non-steroidal anti-inflammatory drugs (NSAIDs) interfering non-selectively in the prostaglandin system have strong antiproteinuric potency without reduction of systemic blood pressure. The effect of the selective COX-2 inhibitor rofecoxib in proteinuric patients is unknown, granted recently reported detrimental effects in non-renal patients. Short-term effects of rofecoxib on proteinuria and blood pressure as compared to NSAID and RAAS blockade were studied. Sixteen stable patients [mean proteinuria 4.4 g/ day; MAP 103 mmHg)] were included after a wash-out period. Hydrochlorothiazide 12.5 mg QD was given throughout. Additional blood pressure control was ensured by non-RAAS blocking antihypertensive agents. Patients received rofecoxib 25 mg QD, 50 mg QD and indomethacin 75 mg BID in randomized order for 4 weeks. Thereafter, a subset of the included patients (n = 11) received lisinopril 40 mg QD for 6 weeks preceded by a wash-out period. Rofecoxib exerted a dose-dependent antiproteinuric effect. As compared to rofecoxib 25 and 50 mg, indomethacin was more effective [-18, -28 versus -49% (n = 16; P < 0.05)]. As compared to rofecoxib 50 mg, lisinopril was more effective [-21 versus -51% (n = 11; P < 0.05)]. No significant blood pressure changes were observed after rofecoxib and indomethacin, whereas lisinopril had a significant antihypertensive effect. Selective COX-2 inhibition reduces proteinuria without reduction of systemic blood pressure, pointing towards a specific renal effect, and may serve as a novel non-hypotensive adjunct antiproteinuric treatment.

Transepithelial transport across Caco‐2 cell monolayers of antihypertensive egg‐derived peptides. PepT1‐mediated flux of Tyr‐Pro‐Ile

This paper examines the in vitro transepithelial transport of antihypertensive peptides derived from egg proteins using Caco-2 cell monolayers. Ovokinin (FRADHPFL) was absorbed intact through the Caco-2 cell epithelium, although it was also susceptible to the action of brush-border aminopeptidases that yielded shorter fragments prior to their transport. The tripeptide YPI was resistant to cellular peptidases and transported through the monolayer, what suggests that the reduction in systemic blood pressure caused by this peptide may be mediated by effects at tissue level. Its pathway for transepithelial absorption was examined using inhibitors of the different mechanisms for oligopeptide transport in the intestinal tract. The main route involved in the transepithelial flux of YPI is probably the peptide H(+)-coupled transporter PepT1. These results highlight the potential of antihypertensive peptides to be used in the formulation of functional foods.

Hypotension in anaesthetized patients during aneurysm clipping: not as bad as expected?

Patients with aneurysmal subarachnoid haemorrhage (SAH) often have disturbed autoregulation of cerebral blood flow. A reduction in systemic blood pressure during surgery may therefore lead to delayed cerebral ischaemia (DCI). To assess the incidence and severity of intra-operative hypotension, we performed a retrospective cohort study in 164 patients with recent SAH and surgical clipping of the aneurysm. Intra-operative hypotension was defined in three levels of severity, as a decrease in mean arterial pressure (DeltaMAP) of more than 30%, 40% or 50% compared with the pre-operative pressure. For each patient the total amount of time with intra-operative hypotension was retrieved. Logistic regression analysis was performed to study the relation between intra-operative hypotension and the occurrence of DCI and poor outcome. A period with DeltaMAP>30% occurred in 128 patients (78%) with a median duration of this period of 105 min (25-75 per thousand 50-171 min). DeltaMAP>40% occurred in 88 patients (54%) and DeltaMAP>50% occurred in 22 patients (13%). In univariate analysis, DeltaMAP>50% was associated with poor outcome. After adjusting for age and World Federation of Neurological Surgeons grade, the association with poor outcome was no longer statistically significant [odds ratio (OR) 1.018; 95% CI 0.996-1.041]. Hypotension during surgical clipping of intracranial aneurysms occurred frequently. In our study population of patients mostly in good clinical condition, hypotension was not confirmed as an independent risk factor for DCI or poor outcome. Anaesthesia may have had a cerebral protective effect.

Renal Effects of β2-Adrenoceptor Agonist and the Clinical Analysis in Children

The objectives of the present study were to define the contribution of beta2-adrenoceptors (beta2-ARs) agonists to renal physiology and to investigate whether over-expression of renal beta2-ARs might be implicated in the pathogenesis of renal dysfunction in children as an adverse effect of beta2-AR activation. The renal functional responses to the systemic injection of the beta2-AR agonist terbutaline in Wistar rats over-expressing renal beta2-AR were compared with those of nontreated rats. Furthermore, we evaluated intrarenal beta2-AR expression in 34 children (age 2-15 y) and the changes in serum creatinine levels of 99 children (age 1-15 y) who received beta2-AR agonists. The animal study showed that the suppression of glomerular function by terbutaline was associated with a reduction in systemic blood pressure and over-expression of renal beta2-ARs. Moreover, in rats over-expressing renal beta2-ARs, administration of terbutaline resulted in a high mortality rate after a lipopolysaccharide challenge. The clinical study showed that renal beta2-AR expression gradually increased with age and was up-regulated by steroid therapy. These findings indicate that the renal dysfunction caused by beta2-AR agonists can be explained, at least partly, by enhanced beta2-AR expression in the kidney. This may have important implications for the use of beta2-AR agonists in the treatment of sick children with, for example, steroid therapy or endotoxemia.

Novel Rho Kinase Inhibitors with Anti-inflammatory and Vasodilatory Activities

Increased Rho kinase (ROCK) activity contributes to smooth muscle contraction and regulates blood pressure homeostasis. We hypothesized that potent and selective ROCK inhibitors with novel structural motifs would help elucidate the functional role of ROCK and further explore the therapeutic potential of ROCK inhibition for hypertension. In this article, we characterized two aminofurazan-based inhibitors, GSK269962A [N-(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4, 5-c]pyridin-6-yl]oxy}phenyl)-4-{[2-(4-morpholinyl)ethyl]-oxy}benzamide] and SB-7720770-B [4-(7-{[(3S)-3-amino-1-pyrrolidinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine], as members of a novel class of compounds that potently inhibit ROCK enzymatic activity. GSK269962A and SB-772077-B have IC50 values of 1.6 and 5.6 nM toward recombinant human ROCK1, respectively. GSK269962A also exhibited more than 30-fold selectivity against a panel of serine/threonine kinases. In lipopolysaccharide-stimulated monocytes, these inhibitors blocked the generation of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha. Furthermore, both SB-772077-B and GSK269962A induced vasorelaxation in preconstricted rat aorta with an IC50 of 39 and 35 nM, respectively. Oral administration of either GSK269962A or SB-772077-B produced a profound dose-dependent reduction of systemic blood pressure in spontaneously hypertensive rats. At doses of 1, 3, and 30 mg/kg, both compounds induced a reduction in blood pressure of approximately 10, 20, and 50 mm Hg. In addition, administration of SB-772077-B also dramatically lowered blood pressure in DOCA salt-induced hypertensive rats. SB-772077-B and GSK269962A represent a novel class of ROCK inhibitors that have profound effects in the vasculature and may enable us to further evaluate the potential beneficial effects of ROCK inhibition in animal models of cardiovascular as well as other chronic diseases.

Rapid pacing to facilitate transcatheter prosthetic heart valve implantation

We describe the technique of, and our experience with, rapid ventricular burst pacing to facilitate transcatheter heart valve implantation. Endovascular therapeutic procedures frequently require the precise placement of implantable devices. The precision of transcatheter device deployment may be hampered by cardiac motion or the effects of intravascular flow. Burst pacing is associated with a reduction in stroke volume, cardiac output, transvalvular flow, and cardiac motion. Rapid pacing was used in 40 consecutive patients with severe aortic stenosis undergoing implantation of catheter-delivered prosthetic valves. Clinical, procedural, and hemodynamic records were reviewed. A mean of 5 +/- 2 burst pacing sequences at rates of 150-220 min(-) (1) were used during balloon valvuloplasty and valve deployment. The duration of pacing required during valve deployment was 12 +/- 3 sec. Pacing was relatively well tolerated when cautiously used with judicious recovery intervals and pressor support. Rapid pacing was associated with a rapid and effective reduction in systemic blood pressure, pulse pressure, transvalvular flow as well as cardiac and catheter motion. Rapid pacing is a relatively reliable technique to facilitate precise transcatheter deployment of prosthetic heart valves and other endovascular therapeutic devices.

Reproducible loss of CA1 neurons following carotid artery occlusion combined with halothane-induced hypotension

The 2-vessel occlusion approach to produce global ischemia in rats requires concomitant reduction of systemic blood pressure. We have utilized the hypotensive effect of halothane administrated by artificial respiration to prevent respiratory arrest and to ensure stable physiological conditions. Systemic blood pressure was reduced to 40–45 mm Hg by instant adjustments of the halothane concentration. Bilateral occlusion of the carotid arteries caused a profound and reproducible ischemia, as analyzed by laser-Doppler flowmetry. In the rats exposed to 11, 12, or 13 min of ischemia, 5% died and 5% developed seizures. The extent of neuronal death in CA1 was highly correlated to the duration of ischemia. Following 11 min of ischemia, CA1 neuronal cell death, as analyzed by Fluoro-Jade, was absent 1 day after injury, variable at day 4, and consistent at day 7. The numbers of cresyl violet- and NeuN-positive neurons at day 7 were 8% and 20% of control, respectively. OX42 immunoreactivity was low and variable at day 4, but pronounced at day 7. In conclusion, this rat global ischemia model is relatively simple to perform, has a low mortality, and produces a profound and highly reproducible delayed cell death of hippocampal CA1 neurons.

Improved Interpretation of Flow Maps Obtained by Scanning Laser Doppler Flowmetry Using a Rat Model of Retinal Artery Occlusion

To improve the interpretation of Heidelberg Retina Flowmeter (HRF; Heidelberg Engineering GmBH, Dosselheim, Germany) flow maps by examining the influence of specific vascular structures and focus depth in the presence and absence of retinal blood flow. HRF flow maps were recorded from the inferior retina of anesthetized Brown Norway rats over a wide range of focus levels, before and after laser occlusion of the retinal circulation. Analysis of the resultant flow maps showed that the sample window was positioned on a retinal artery, arteriole, or vein, or in a retinal capillary area, with or without a visible underlying choroidal vessel. The relationship between HRF-measured flow (arbitrary units) and focus depth was determined for each location. At the conclusion of each experiment, the effect of reduction of systemic blood pressure on the choroidal circulation and the level of background signal in the HRF flow map with no ocular blood flow were assessed. The strongest flow signals came from the retinal arteries, veins, and arterioles and were reduced to choroidal background level after occlusion of the central retinal artery. Larger choroidal vessels also contributed strong flow signals. In contrast, the flow signal from the retinal capillary area was weak and unaffected by retinal artery occlusion. Changing the depth of focus significantly altered the contribution from the major retinal arteries, arterioles, and veins, but no significant depth effect was seen for retinal capillaries or choroidal vessels. The HRF flow signal remaining when systemic blood pressure was reduced to zero was not significantly different from the capillary sampling location when the eye was normally perfused. In the pigmented rat eye, the HRF signal from retinal capillaries is not significantly different from the background noise unrelated to blood flow. Strong flow signals can be obtained from the retinal arteries, retinal arterioles, retinal veins, and choroidal vessels. Current HRF flow maps in the rat therefore reflect blood flow in the larger elements of the microvasculature rather than the capillary network.

Low-dose dual blockade of the renin–angiotensin system improves tubular status in non-diabetic proteinuric patients

Treatment with agents that inhibit the renin-angiotensin system is commonly regarded as a gold standard renoprotective strategy in patients with chronic kidney diseases. For maximum antiproteinuric effect, the dose titration of these agents is recommended. This therapeutic strategy is not used for proteinuric patients who are not able to receive high doses of angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonists. In patients with primary glomerulonephritis (n=24), a randomized, triple-treatment, triple-period, cross-over study was performed to compare the effects of combined therapy with benazepril 5 mg and losartan 25 mg and monotherapy with either agent alone at a two-fold higher dose on the extent of tubular injury as assessed by alpha1-microglobulin (alpha1-m) excretion and the plasma level of transforming growth factor-beta1 (TGF-beta1). Combination therapy significantly reduced alpha1-m excretion compared to either agent used alone: 178.29+/-27.36 to 99.63+/-13.03 mg/g creatinine for losartan + benazepril vs 178.29+/-27.36 to 161.59+/-23.22 mg/g creatinine for benazepril alone (p<0.05; ANOVA) and 178.29+/-27.36 to 99.63+/-13.03 mg/g creatinine for losartan + benazepril vs 178.29+/-27.36 to 173.45+/-27.69 mg/g creatinine for losartan alone (p<0.05; ANOVA). There was a significant correlation between change in alpha1-m excretion and reduction in proteinuria (r=0.704; p=0.023). There were no differences in TGF-beta1 level between the studied treatments. Systemic blood pressure reduction did not differ among the therapies. Combination therapy with angiotensin-converting enzyme inhibitor and angiotensin II subtype 1 receptor antagonists at very small doses may be superior to monotherapy with these agents at higher doses as far as tubular injury is concerned. We speculate that such a therapeutic strategy may be a useful approach for patients who are known not to be capable of receiving optimal renoprotective doses of these regimens.

The effect of valsartan on regression of left ventricular hypertrophy in type 2 diabetic patients.

The aim of the present study was to examine the effects of an angiotensin II receptor antagonist, valsartan, on echocardiographically proven left ventricular hypertrophy (LVH) in patients with type 2 diabetes. Outpatients with type 2 diabetes mellitus were recruited at Niigata University Hospital. The left ventricular mass index (LVMI) was calculated by echocardiography. LVH was considered to be present if the LVMI was > 131 g/m(2) in males and > 100 g/m(2) in females. Patients with LVH received a low dose (40 mg/day) of valsartan for 12 months. This low dose had no clinical effect on blood pressure. Of the 38 patients who entered the study, 14 (36.8%) had LVH. After only 6 months of valsartan therapy, the mean LVMI decreased significantly, from 126.5 +/- 27.8 to 119.0 +/- 23.5 g/m(2) (p < 0.01 vs. baseline). Also, a significant decrease was observed after 12 months (116.5 +/- 30.9 g/m(2), p < 0.05 vs. baseline). Compared to baseline, there were no significant differences after treatment in body mass index, glycosylated haemoglobin (HbA(1c)), systolic blood pressure and diastolic blood pressure. In type 2 diabetic patients with LVH, treatment with a low dose of valsartan, an angiotensin II receptor antagonist, for 12 months, reduced LVMI, with no reduction in systemic blood pressure. This drug may be safely administered to type 2 diabetic patients with LVH. The long-term risk-reduction effects will have to be evaluated in further trials.

A method for determining whether hypotension caused by novel compounds in preclinical development results from histamine release

Introduction: Many therapeutic agents stimulate histamine release from mast cells, which results in a decrease in blood pressure. The purpose of this study is to establish a method to determine if the mechanism of action, or one of the mechanisms, of hypotensive compounds is related to the release of histamine. The method was developed using a novel hypotensive compound, SC-372. Methods: In Inactin anesthetized rats, after intravenous administration of SC-372 (0.3-7 mg/kg), the 2 and 7 mg/kg resulted in a dose-dependent decrease in blood pressure. Histamine (0.1 and 1 mg/kg) was injected intravenously to establish whether histamine release was the mechanism of action for the hypotension induced by SC-372. Compound 48/80 (0.1 mg/kg, promotes histamine release) and Cromolyn (1 mg/kg/min, [5 min], prevents histamine release from mast cells) were characterized and used intravenously in combination with/or compared to SC-372. Results: Histamine resulted in a decrease in blood pressure that was unaffected by Cromolyn (1 mg/kg). Administration of Compound 48/80 resulted in a rapid reduction of systemic blood pressure. Intravenous infusion of Cromolyn prior to the injection of Compound 48/80 significantly attentuated the hypotensive response and the increase in histamine levels in the plasma. Intravenous administration of SC-372 resulted in a rapid reduction in blood pressure with a profile similar to that of Compound 48/80. When the rats were treated with Cromolyn prior to the administration of SC-372, both the blood pressure and plasma histamine levels were maintained at their pretreatment control levels. Discussion: These data indicate that Compound 48/80 and Cromolyn can be used in rats to screen for histamine release-dependent drug-induced hypotension and suggest that the rapid decrease in blood pressure caused by SC-372 may result from histamine release from mast cells.

Microalbuminuria and diabetic cardiovascular disease.

Microalbuminuria is an important clinical finding in patients with diabetes because of its established association with progressive renal disease. However, it is also becoming increasingly recognized as an independent risk factor for cardiovascular disease in patients with or without diabetes. The pathogenesis of microalbuminuria in this context is still poorly understood. In patients at risk of cardiovascular disease, it is thought to reflect widespread endothelial dysfunction. There is accumulating evidence to suggest that the use of antihypertensive agents that target the renin-angiotensin system (RAS) provide cardioprotection and slow the progression of renal disease in patients with diabetes and microalbuminuria. Antihypertensive agents that target the RAS also appear to have advantages over and above reductions in systemic blood pressure. The recent Steno-2 study has demonstrated that multifactorial interventions can significantly reduce cardiovascular events in microalbuminuric patients with type 2 diabetes.

Long-term antiproteinuric and renoprotective efficacy and safety of losartan in children with proteinuria

Background Angiotensin receptor antagonists are effective in reducing proteinuria by an action independent of blood pressure. As a consequence, such agents retard progressive renal dysfunction in adults with chronic proteinuria. Long-term efficacy and tolerability data in children are unavailable.Methods Efficacy of losartan in reducing proteinuria and in preserving renal function was prospectively assessed in 52 consecutive children under 18 years of age with chronic proteinuric renal disorders, an initial creatinine clearance ≥25 mL/min/1.73 m2, and a minimum of two or more follow-up visits. Thirty had proteinuria (P), and 22 had proteinuria combined with hypertension (P+H). Adverse effects were also evaluated.Results Proteinuria had persisted or increased during a mean interval of 8.5 months before initiation of losartan at a mean dosage of 0.8 mg/kg/d. Mean protein excretion before starting losartan was 2453 mg/m2/d and fell by 34% at a mean follow-up time of six weeks (visit I, P<.05), and between 64% and 67% at mean follow-up periods of 0.38, 0.71, and 2.48 years corresponding to visits II, III, and IV (all P<.001 compared with baseline). The proportion of children with protein excretion exceeding 40 mg/m2/h (nephrotic range proteinuria) or nephrotic syndrome (>3500 mg/1.73 m2/d) fell from 42% and 40% at the start, to 24% and 8%, respectively, at visit IV (P<.01). Mean creatinine clearance as well as serum potassium and total CO2 levels remained unchanged during the time of follow-up. Reduction in proteinuria in the P subgroup alone correlated with lowering in diastolic blood pressure at visit II and with both diastolic and systolic blood pressure at visits III and IV (all P<.05); it was largely independent of reduction in blood pressure in the P+H subgroup. The concomitant use of immunosuppressive agents in 28 of the 52 children had an influence on proteinuria only at baseline and at visit I (P<.05). There was no significant change in height or body mass index Z scores. Thirteen children had adverse effects potentially ascribed to losartan; most of these either improved or resolved with dosage adjustment or resulted in its discontinuation in 9 of the 52 children (17%).Conclusion Losartan therapy was associated with a marked and sustained reduction in proteinuria and in preservation of GFR in children with chronic proteinuric disorders. The association between proteinuria and systemic blood pressure reduction was complex: it was largely limited to the first year of losartan therapy and was more pronounced in the normotensive subgroup. Losartan was generally well tolerated.

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy.

Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury. Diabetic spontaneously hypertensive rats were treated with the ACE inhibitor perindopril (mg.kg(-1).day(-1)) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg.kg(-1).day(-1) for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor beta, beta-inducible gene-h3 and nephrin were also quantitated. Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGFbeta and betaig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs. These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease.

Basal and nitroglycerin-induced exhaled nitric oxide before and after cardiac surgery with cardiopulmonary bypass

Exhaled nitric oxide (NO) may reflect NO production and consumption but the pulmonary origin of NO in exhaled gas is not clear. There are also conflicting data on exhaled NO after cardiopulmonary bypass (CPB). Because intravenous nitrovasodilators increase exhaled NO by conversion to NO in the lung, we measured basal and nitroglycerin (GTN)-induced exhaled NO in patients having low-risk coronary artery bypass graft (CABG) operations using routine CPB. We reasoned that GTN-induced exhaled NO would be a primarily vascular mechanism, which would contrast with the airway epithelial origin of basal exhaled NO, and that they might be differentially influenced by CPB. Breath-to-breath concentrations of gas phase NO were measured in 12 CABG patients before and 1, 3 and 6 h after CPB. After the baseline measurements, three increasing doses of 1, 2 and 3 micro g kg(-1) intravenous GTN were given by a central venous catheter and exhaled NO and haemodynamic responses were recorded. Intravenous administration of 1, 2 and 3 micro g kg(-1) doses of GTN produced a dose-dependent increase in exhaled NO and a reduction in systemic blood pressure. Baseline exhaled NO remained unchanged. Exhaled NO but not blood pressure responses were reduced 1 and 3 h after CPB. The capacity of the lungs to increase exhaled NO in response to intravenous GTN is reduced after CPB, suggesting microvascular injury and/or atelectasis after routine open-heart surgery.