Renal Vasodilation Research Articles

Attenuated diuresis and natriuresis in response to glucagon-like peptide-1 in hypertensive rats are associated with lower expression of the glucagon-like peptide-1 receptor in the renal vasculature

Accumulating evidence from clinical and experimental studies indicates that the incretin glucagon-like peptide-1 (GLP-1) elicits blood-pressure lowering effects via its diuretic, natriuretic and vasodilatory properties. The present study investigated whether acute infusion of GLP-1 induces diuresis and natriuresis in spontaneously hypertensive rats (SHRs). Additionally, we examined whether GLP-1 influences the vascular reactivity of the renal arteries of normotensive and hypertensive rats and elucidated the underlying mechanisms. We found that the increase in urinary output and urinary sodium excretion in response to systemic infusion of GLP-1 for 30min in SHRs was much less pronounced than in normotensive rats. The diuretic and natriuretic actions of GLP-1 in normotensive rats were accompanied by increases in GFR and RBF and a reduction in RVR through activation of the cAMP signaling pathway. However, no changes in renal hemodynamics were observed in SHRs. Similarly, GLP-1 induced an endothelium-independent relaxation effect in the renal arteries of normotensive rats, whereas the renal vasculature of SHRs was unresponsive to this vasodilator. The absence of a GLP-1-induced renal artery vasodilator effect in SHRs was associated with lower expression of the GLP-1 receptor, blunted GLP-1-induced increases in cAMP production and higher activity and expression of the GLP-1 inactivating enzyme dipeptidyl peptidase IV relative to the renal arteries of normotensive rats. Collectively, these results demonstrate that the renal acute responses to GLP-1 are attenuated in SHRs. Thus, chronic treatment with incretin-based agents may rely upon the upregulation of GLP-1/GLP-1 receptor signaling in the kidneys of hypertensive patients and experimental models.

Renal function and oxygenation are impaired early after liver transplantation despite hyperdynamic systemic circulation

BackgroundAcute kidney injury (AKI) occurs frequently after liver transplantation and is associated with the development of chronic kidney disease and increased mortality. There is a lack of data on renal blood flow (RBF), oxygen consumption, glomerular filtration rate (GFR) and renal oxygenation, i.e. the renal oxygen supply/demand relationship, early after liver transplantation. Increased insight into the renal pathophysiology after liver transplantation is needed to improve the prevention and treatment of postoperative AKI. We have therefore studied renal hemodynamics, function and oxygenation early after liver transplantation in humans.MethodsSystemic hemodynamic and renal variables were measured during two 30-min periods in liver transplant recipients (n = 12) and post-cardiac surgery patients (controls, n = 73). RBF and GFR were measured by the renal vein retrograde thermodilution technique and by renal extraction of Cr-EDTA (= filtration fraction), respectively. Renal oxygenation was estimated from the renal oxygen extraction.ResultsIn the liver transplant group, GFR decreased by 40% (p < 0.05), compared to the preoperative value. Cardiac index and systemic vascular resistance index were 65% higher (p < 0.001) and 36% lower (p < 0.001), respectively, in the liver transplant recipients compared to the control group. GFR was 27% (p < 0.05) and filtration fraction 40% (p < 0.01) lower in the liver transplant group. Renal vascular resistance was 15% lower (p < 0.05) and RBF was 18% higher (p < 0.05) in liver transplant recipients, but the ratio between RBF and cardiac index was 27% lower (p < 0.001) among the liver-transplanted patients compared to the control group. Renal oxygen consumption and extraction were both higher in the liver transplants, 44% (p < 0.01) and 24% (p < 0.05) respectively.ConclusionsDespite the hyperdynamic systemic circulation and renal vasodilation, there is a severe decline in renal function directly after liver transplantation. This decline is accompanied by an impaired renal oxygenation, as the pronounced elevation of renal oxygen consumption is not met by a proportional increase in renal oxygen delivery. This information may provide new insights into renal pathophysiology as a basis for future strategies to prevent/treat AKI after liver transplantation.Trial registrationClinicalTrials.gov, NCT02455115. Registered on 23 April 2015.

CYP4A/CYP2C Modulation of the Interaction of Calcium Channel Blockers with Cyclosporine on EDHF‐Mediated Renal Vasodilations in Rats

The endothelium‐derived hyperpolarizing factor (EDHF) is a back‐up mechanism that compensates for reduced nitric oxide (NO)/prodtanoids bioavailability. Here we investigated whether (i) cyclosporine (CSA, immunosuppressant drug) upregulates EDHF‐dependent renal vasodilations through altering CYP4A/CYP2C signaling, and (ii) calcium channel blockers modulate the CSA/EDHF/CYP interaction. Rats were treated with CSA, verapamil, nifedipine, or their combination for 7 days. Systolic blood pressure (SBP) was measured by Tail‐cuff plethysmography. Kidneys were then isolated, perfused with physiological solution containing L‐NAME (NOS inhibitor) and diclofenac (cyclooxygenase inhibitor), and preconstricted with phenylephrine. Carbachol vasodilations were established before and after the inhibition of 20‐HETE or EETs. CSA (25 mg.kg−1.day−1 for 7 days) increased SBP and augmented carbachol renal vasodilations. The concurrent administration of verapmil (2 mg.kg−1.day−1) or nifedipine (3 mg.kg−1.day−1) abolished the hypertensive effect of CSA and produced divergent effects on carbachol vasodilations (increases versus decreases). The infusion of MSPPOH (EETs inhibitor) reduced carbachol vasodilations in perfused kidneys of all rat groups, suggesting the importance of EETs in these responses. Moreover, HETE‐20 inhibition by HET0016 increased carbachol vasodilations in control rats, an effect that disappeared in CSA‐treated, and reappeared in rats treated with CSA/verapamil or CSA/nifedipine. The renal protein expression of CYP2C and CYP4A as well as their vasoactive products (EETs and 20‐HETE) were increased in CSA‐treated rats. Whereas the CYP2C/EETs effects of CSA were abolished by verapamil and intensified by nifedipine, the CYP4A/20‐HETE effects were reduced by verapamil only. Overall, CYP2C/EETs and CYP4a/20‐HETE pathways variably modulate the contracting effects of nifedipine and verpamil on CSA‐evoked facilitation of EDHF‐dependent renal vasodilations. These effects may not be related to changes in SBP.Support or Funding InformationSupported by the Lebanese National Council for Scientific Research (CNRS) Grant Award for Lebanese graduates (Awardee: Safaa Hammoud).

Vasodilatory responses of renal interlobular arteries to epoxyeicosatrienoic acids analog are not enhanced in Ren-2 transgenic hypertensive rats: evidence against a role of direct vascular effects of epoxyeicosatrienoic acids in progression of experimental heart failure.

Pathophysiological mechanisms underlying the development of renal dysfunction and progression of congestive heart failure (CHF) remain poorly understood. Recent studies have revealed striking differences in the role of epoxyeicosatrienoic acids (EETs), active products of cytochrome P-450-dependent epoxygenase pathway of arachidonic acid, in the progression of aorto-caval fistula (ACF)-induced CHF between hypertensive Ren-2 renin transgenic rats (TGR) and transgene-negative normotensive Hannover Sprague-Dawley (HanSD) controls. Both ACF TGR and ACF HanSD strains exhibited marked intrarenal EETs deficiency and impairment of renal function, and in both strains chronic pharmacologic inhibition of soluble epoxide hydrolase (sEH) (which normally degrades EETs) normalized EETs levels. However, the treatment improved the survival rate and attenuated renal function impairment in ACF TGR only. Here we aimed to establish if the reported improved renal function and attenuation of progression of CHF in ACF TGR observed after she blockade depends on increased vasodilatory responsiveness of renal resistance arteries to EETs. Therefore, we examined the responses of interlobar arteries from kidneys of ACF TGR and ACF HanSD rats to EET-A, a new stable 14,15-EET analog. We found that the arteries from ACF HanSD kidneys rats exhibited greater vasodilator responses when compared to the ACF TGR arteries. Hence, reduced renal vasodilatory responsiveness cannot be responsible for the lack of beneficial effects of chronic sEH inhibition on the development of renal dysfunction and progression of CHF in ACF HanSD rats.

Renal Artery Vasodilation May Be An Indicator of Successful Sympathetic Nerve Damage During Renal Denervation Procedure.

Autonomic nervous system plays a crucial role in maintaining and regulating vessel tension. Renal denervation (RDN) may induce renal artery vasodilation by damaging renal sympathetic fibers. We conducted this animal study to evaluate whether renal artery vasodilation could be a direct indicator of successful RDN. Twenty-eight Chinese Kunming dogs were randomly assigned into three groups and underwent RDN utilizing temperature-controlled catheter (group A, n = 11) or saline-irrigated catheter (group B, n = 11) or sham procedure (group C, n = 6). Renal angiography, blood pressure (BP) and renal artery vasodilation measurements were performed at baseline, 30-minute, 1-month, and 3-month after interventions. Plasma norepinephrine concentrations were tested at baseline and 3-month after intervention. Results showed that, in addition to significant BP reduction, RDN induced significant renal artery vasodilation. Correlation analyses showed that the induced renal artery vasodilation positively correlated with SBP reduction and plasma norepinephrine reduction over 3 months after ablation. Post hoc analyses showed that saline-irrigated catheter was superior to TC catheter in renal artery vasodilation, especially for the acute dilatation of renal artery at 30-minute after RDN. In conclusion, renal artery vasodilation, induced by RDN, may be a possible indicator of successful renal nerve damage and a predictor of blood pressure response to RDN.

The Efficacy of Niacin-Bound Chromium to Slow the Progression of Diabetic Nephropathy in Type II Diabetic Rats

Animal and clinical studies suggest niacin-bound chromium (NBC) added to the diet improves glucose-insulin sensitivity, the ability to ameliorate inflammation, hypertension, and proteinuria. In addition to its lipid-lowering actions, NBC possesses potent antioxidant and anti-inflammatory properties. Rat studies demonstrated that T2DM decreases both the production and bioavailability of nitric oxide (NO), and we hypothesized that NBC supplementation will preserve NO production via increased endothelial nitric oxide synthase (eNOS) and decreased neuronal nitric oxide synthase (nNOS). NBC supplementation decreased levels of plasma creatinine in the treated diabetic rats compared to the untreated diabetic rats, and therefore preserved glomerular filtration rate (GFR). We provide evidence that this effect may also be due to increased levels of eNOS, which leads to renal microvascular vasodilation. Supplementation of NBC also lowered nNOS levels, which is a significant finding when considering the role of nNOS in T2DM. Marked improvements in fasting glucose and lower body weights were observed in the treated diabetic rats compared to the untreated diabetic rats. Therefore, these results demonstrate that NBC supplementation slows the progression of diabetic nephropathy (DN) in type 2 diabetic rats.

Reversal of acute kidney injury after peritoneal dialysis in a dog: a case report

Acute kidney injury is characterised by a sudden injury to the renal parenchyma and causes defects in its excretory, metabolic and endocrine function. Dialysis therapy has been instituted in small animal clinics with the aim of removing the metabolic waste and correcting the electrolyte disturbances stemming from renal dysfunction. Peritoneal dialysis is a therapy based on the use of the peritoneum as a semipermeable membrane through which solutes and fluids are exchanged between blood from the peritoneal capillaries and the dialysis solution. This report describes a case of acute kidney injury stemming from drug therapy in a 13-year-old female mongrel canine. The patient exhibited anorexia, emesis, prostration and anuria and had a history of prolonged treatment with meloxicam. The patient also presented with azotaemia and metabolic acidosis. When anuria continued to persist after drug therapy (volume restoration, chemical and osmotic diuresis and renal vasodilation), peritoneal dialysis was instituted. Three cycles of peritoneal dialysis were performed; during the second cycle, the patient’s anuria was reversed, and at the end of the third cycle she showed a significant reduction in azotaemia, hyperkalaemia and an improved metabolic acidosis. Therefore, peritoneal dialysis showed satisfactory clinical results and reversed anuria, reduced azotaemia and electrolyte disturbances, thereby providing clinical improvement.

Abstract 292: The Role of the ATF6 Branch of the ER Stress Response in the Endocrine Heart

Rationale: Atrial natriuretic peptide (ANP) is stored in the heart in large dense core granules of atrial myocytes as a biologically inactive precursor, pro-ANP. Hemodynamic stress and atrial stretch stimulate coordinate secretion and proteolytic cleavage of pro-ANP to its bioactive form, ANP, which promotes renal salt excretion and vasodilation, which, together contribute to decreasing blood pressure. While the ATF6 branch of the ER stress response has been studied in ventricular tissue mouse models of myocardial ischemia and pathological hypertrophy, roles for ATF6 and ER stress on the endocrine function of atrial myocytes have not been studied. Objective/Methods: To address this gap in our knowledge, we knocked down ATF6 in primary cultured neonatal rat atrial myocytes (NRAMs) using a chemical inhibitor of the proteolytic cleavage site enabling ATF6 activation and siRNA and measured ANP expression and secretion basally and in response to alpha- adrenergic agonist stimulation using phenylephrine. We also compared the ANP secretion from wild- type mice and ATF6 knockout mice in an ex vivo Langendorff model of the isolated perfused heart. Results: ATF6 knockdown in NRAMs significantly impaired basal and phenylephrine-stimulated ANP secretion. ATF6 knockout mice displayed lower levels of ANP in atrial tissue at baseline as well as after phenylephrine treatment. Similarly, in the ex vivo isolated perfused heart model, less ANP was detected in effluent of ATF6 knockout hearts compared to wild-type hearts. Conclusions: The ATF6 branch of the ER stress response is necessary for efficient co-secretional processing of pro-ANP to ANP and for agonist-stimulated ANP secretion from atrial myocytes. As ANP is secreted in a regulated manner in response to a stimulus and pro-ANP is synthesized and packaged through the classical secretory pathway, we posit that ATF6 is required for adequate expression, folding, trafficking, processing and secretion of biologically active ANP from the endocrine heart.

Reversal of acute kidney injury after peritoneal dialysis in a dog: a case report

Acute kidney injury is characterised by a sudden injury to the renal parenchyma and causes defects in its excretory, metabolic and endocrine function. Dialysis therapy has been instituted in small animal clinics with the aim of removing the metabolic waste and correcting the electrolyte disturbances stemming from renal dysfunction. Peritoneal dialysis is a therapy based on the use of the peritoneum as a semipermeable membrane through which solutes and fluids are exchanged between blood from the peritoneal capillaries and the dialysis solution. This report describes a case of acute kidney injury stemming from drug therapy in a 13-year-old female mongrel canine. The patient exhibited anorexia, emesis, prostration and anuria and had a history of prolonged treatment with meloxicam. The patient also presented with azotaemia and metabolic acidosis. When anuria continued to persist after drug therapy (volume restoration, chemical and osmotic diuresis and renal vasodilation), peritoneal dialysis was instituted. Three cycles of peritoneal dialysis were performed; during the second cycle, the patient's anuria was reversed, and at the end of the third cycle she showed a significant reduction in azotaemia, hyperkalaemia and an improved metabolic acidosis. Therefore, peritoneal dialysis showed satisfactory clinical results and reversed anuria, reduced azotaemia and electrolyte disturbances, thereby providing clinical improvement.

Relaxin for the Treatment of Acute Decompensated Heart Failure: Pharmacology, Mechanisms of Action, and Clinical Evidence.

Acute heart failure remains a major cause of morbidity, and its treatment requires an increasing investment of the health care system. Whereas success in treating chronic heart failure has been achieved over the last decades, several pharmacological approaches for acute heart failure have been introduced but have failed to demonstrate any clinical benefit. Serelaxin is a recombinant human relaxin-2 vasoactive peptide that causes systemic and renal vasodilation. Data suggest that the clinical benefits may be attributable to a potential combination of multiple actions of serelaxin, including improving systemic, cardiac, and renal hemodynamics, and protecting cells and organs from damage via neurohormonal, anti-inflammatory, antiremodeling, antifibrotic, anti-ischemic, and proangiogenic effects. Recently, a number of clinical trials have demonstrated that serelaxin infusion over 48 hours improved dyspnea with more rapid relief of congestion during the first days after admission for heart failure. In addition, administration of serelaxin diminished cardiac, renal, and hepatic damage, which were associated with improved long-term mortality. Available data support substantial clinical benefits and significant promise for serelaxin as a treatment option for patients with acute heart failure. This review focuses on the pharmacology and mechanisms of action of serelaxin and provides a detailed discussion of the clinical evidence for this novel therapy in acute heart failure.

Contribution of K(+) channels to endothelium-derived hypolarization-induced renal vasodilation in rats in vivo and in vitro.

We investigated the mechanisms behind the endothelial-derived hyperpolarization (EDH)-induced renal vasodilation in vivo and in vitro in rats. We assessed the role of Ca(2+)-activated K(+) channels and whether K(+) released from the endothelial cells activates inward rectifier K(+) (Kir) channels and/or the Na(+)/K(+)-ATPase. Also, involvement of renal myoendothelial gap junctions was evaluated in vitro. Isometric tension in rat renal interlobar arteries was measured using a wire myograph. Renal blood flow was measured in isoflurane anesthetized rats. The EDH response was defined as the ACh-induced vasodilation assessed after inhibition of nitric oxide synthase and cyclooxygenase using L-NAME and indomethacin, respectively. After inhibition of small conductance Ca(2+)-activated K(+) channels (SKCa) and intermediate conductance Ca(2+)-activated K(+) channels (IKCa) (by apamin and TRAM-34, respectively), the EDH response in vitro was strongly attenuated whereas the EDH response in vivo was not significantly reduced. Inhibition of Kir channels and Na(+)/K(+)-ATPases (by ouabain and Ba(2+), respectively) significantly attenuated renal vasorelaxation in vitro but did not affect the response in vivo. Inhibition of gap junctions in vitro using carbenoxolone or 18α-glycyrrhetinic acid significantly reduced the endothelial-derived hyperpolarization-induced vasorelaxation. We conclude that SKCa and IKCa channels are important for EDH-induced renal vasorelaxation in vitro. Activation of Kir channels and Na(+)/K(+)-ATPases plays a significant role in the renal vascular EDH response in vitro but not in vivo. The renal EDH response in vivo is complex and may consist of several overlapping mechanisms some of which remain obscure.

Renal endothelial function is associated with the anti-proteinuric effect of ACE inhibition in 5/6 nephrectomized rats.

In healthy rats, the physiological variation of baseline endothelial function of intrarenal arteries correlates with the severity of renal damage in response to a subsequent specific renal injury. However, whether such a variation in endothelial function may also condition or predict the variable response to angiotensin-converting enzyme-inhibiting treatment in these individuals has not been addressed before. To study this, 5/6 nephrectomy was performed to induce renal injury and chronic kidney disease in a group of healthy Wistar rats. At the time of nephrectomy, interlobar arteries were obtained from the extirpated right kidney and studied in vitro for endothelium-dependent relaxation to acetylcholine. Six weeks thereafter, treatment with lisinopril was started (n = 11) and continued for 9 wk. Proteinuria (metabolic cages) and systolic blood pressure (SBP; tail cuff) were evaluated weekly, and these were analyzed in relation to renal endothelial function at baseline. 5/6 Nephrectomy induced an increase in SBP and progressive proteinuria. Treatment with lisinopril reduced SBP and slowed proteinuria, albeit to a variable degree among individuals. The acetylcholine-induced renal artery dilation at baseline negatively correlated with lisinopril-induced reduction of proteinuria (r(2) = 0.648, P = 0.003) and with the decrease in SBP (r(2) = 0.592, P = 0.006). Our data suggest that angiotensin-converting enzyme-inhibitor attenuates the progression of renal damage the most in those individuals with decreased basal renal endothelial-mediated vasodilation.

Contrast induced nephropathy in vascular surgery

Contrast induced nephropathy (CIN) is traditionally associated with outpatient imaging studies. More recently, patients afflicted with vascular pathologies are increasingly undergoing endovascular treatments that require the use of iodinated contrast media (CM) agents, thus placing them as risk of developing CIN. As perioperative physicians, anaesthetists should be aware of the risk factors and measures that might minimize acute kidney injury caused by CM. This review evaluates recent data regarding preventive measures against CIN and where possible, places the evidence in the context of the patient receiving endovascular surgical treatment. Measures including the use of peri-procedural hydration, N-acetylcysteine, statins, remote ischaemic preconditioning, renal vasodilators and renal replacement therapy and the use of alternatives to iodinated contrast agents are discussed. It should be noted that most of the available data regarding CIN are from non-surgical patients.

The role pleiotropic effects of calcium channel blocker lercanidipine in perioperative therapy of arterial hypertension

This review presents the data of assessing antihypertensive efficacy and tolerability vasoselective high-lipophilic the 3d generations calcium channel blocker lercanidpine. The inhibition of the calcium ions flow through the membranes of smooth muscle cells of blood vessels causes peripheral, cerebral, renal and coronary vasodilation decreasing total peripheral vascular resistance and, consequently, blood pressure (BP) lowering and improve regional circulation. During reception of lercanidipine the level of norepinephrine remains the same even when using high doses of the drug. Negative inotropic effect does not occur therefore, lercanidipine can be used in the treatment of myocardial ischemia. Renal protection properties slow down the development and progression ofchronic renalfailure (CRF). The drug can be successfully used in patients with arterial hypertension, chronic renalfailure, diabetic and non-diabetic nephropathy. Lercanidpine also may be effectively used in the treatment of hypertension with associated clinical conditions: bronchial asthma, chronic obstructive pulmonary disease, bradiarrythmias, atrioventricular blockade 2-3 degree, sinus node dysfunction, peripheral arteries deseases with symptoms of the extremities ischemia, sleep disturbance, depression, dystonia, asthenic and cephalgic syndme in the frame of the cerebrovascular insufficiency manifestations. Therapy with lercanidpine, in addition to lowering blood pressure, can help to nephroprotection, neuroprotection, antianginal effect, the regression of left ventricular hypertrophy, improvement of lipid metabolism and glucose tolerance. With over 30 years experience in the application and modification of the molecular structure, slow the onset of action and superior long-lasting effect reception of letranidipine well-tolerated and provides a high adherence ofpatients to the treatment of hypertension.

Dopamine: Receptors, Functions, Synthesis, Pathways, Locations and Mental Disorders: Review of Literatures

Dopamine is monoamine neurotransmitter. Dopamine is produced in the dopaminergic neurons in the ventral tegmental area of the substantia nigra, midbrain and the arcuate nucleus of the hypothalamus. In the periphery, dopamine is found in the kidney where it functions to produce renal vasodilation, diuresis, and natriuresis. Dopamine neurons are more widely distributed than those of other monamines and it is found in hypothalamus, olfactory bulb, the midbrain substantia nigra and ventral tegmental area and in the periaqueductal gray and retina. There are five subtypes of dopamine receptors, D1, D2, D3, D4, and D5, which are members of the large G-protein coupled receptor super family. The dopamine receptor subtypes are divided into two major subclasses: types 1 and 5 are similar in structure and drug sensitivity, and these two receptors are referred to as the D1like group or class of receptors. Dopamine receptor types 2, 3, and 4 are called the D2like group. Dopamine plays central role in pleasurable reward behavior, inhibition of prolactin production (involved in lactation), sleep, mood, attention, learning, behavior, control of nausea and vomiting and pain processing. In addition it also involved in controlling movement, emotion and cognition. Due to extensive localization of dopamine receptor to brain areas and its role in wide range of functions, dopaminergic dysfunction has been implicated in the pathophysiology of schizophrenia, mood disorders, obsessive compulsive disorder (OCD), autism spectrum disorders, attention deficit–hyperactivity disorder (ADHD), tourette's syndrome, substance dependency, Parkinson's disease and other disorders.

5-HT2 receptor blockade exhibits 5-HT vasodilator effects via nitric oxide, prostacyclin and ATP-sensitive potassium channels in rat renal vasculature

The aim of this study was to determine whether orally sarpogrelate (selective 5-HT2 antagonist) treatment (30mg/kg/day; 14days) could modify 5-HT renal vasoconstrictor responses, characterizing 5-HT receptors and mediator mechanisms involved in serotonergic responses in the in situ autoperfused rat kidney. Intra-arterial (i.a.) injections of 5-HT (0.00000125 to 0.1μg/kg) decreased renal perfusion pressure (RPP) but did not affect the mean blood pressure (MBP). i.a. agonists 5-CT (5-HT1/7), CGS-12066B (5-HT1B), L-694,247 (5-HT1D) or AS-19 (5-HT7) mimicked renal 5-HT vasodilator effect. However, neither 8-OH-DPAT (5-HT1A) nor 1-phenylbiguanide (5-HT3) modified RPP. Moreover: (i) GR-55562 (5-HT1B antagonist) and L-NAME (nitric oxide synthase [NOS] inhibitor) blocked CGS-12066B-induced vasodilator response, (ii) LY310762 (5-HT1D antagonist) and indomethacin (non-selective cyclooxygenase inhibitor) blocked L-694,247-induced vasodilator response; (iii) SB-258719 (5-HT7 antagonist) and glibenclamide (ATP-sensitive K+ channel blocker) blocked AS-19-induced vasodilator response; and (iv) 5-HT- or 5-CT-elicited renal vasodilation was significantly blocked by the mixture of GR-55562+LY310762+SB-258719. Furthermore, eNOS and iNOS proteins and prostacyclin levels are overexpressed in sarpogrelate-treated rats. Our data suggest that 5-HT exerts renal vasodilator effect in the in situ autoperfused sarpogrelate-treated rat kidney, mediated by 5-HT1D, 5-HT1B and 5-HT7 receptors, involving cyclooxygenase-derived prostacyclin, nitric oxide synthesis/release and ATP-sensitive K+ channels, respectively.

Involvement of sinoaortic afferents in renal sympathoinhibition and vasodilation induced by acute hypernatremia.

Despite the abundance of evidence that supports the important role of aortic and carotid afferents to short-term regulation of blood pressure and detection of variation in the arterial PO2 , PCO2 and pH, relatively little is known regarding the role of these afferents during changes in the volume and composition of extracellular compartments. The present study sought to determine the involvement of these afferents in the renal vasodilation and sympathoinhibition induced by hypertonic saline (HS) infusion. Sinoaortic-denervated and sham male Wistar rats were anaesthetised with intravenous (i.v.) urethane (1.2g/kg body weight (bw)) prior to the measurement of the mean arterial pressure (MAP), renal vascular conductance (RVC) and renal sympathetic nerve activity (RSNA). In the sham group, the HS infusion (3mol/L NaCl, 1.8mL/kg bw, i.v.) induced transient hypertension (12±4 mmHg from baseline, peak at 10min; P<0.05), an increase in RVC (127±9% and 150±13% from baseline, at 20 and 60min respectively; P<0.05) and a decrease in RSNA (-34±10% and -29±5% from baseline, at 10 and 60min respectively; P<0.05). In sinoaortic-denervated rats, HS infusion promoted a sustained pressor response (30±5 and 17±6mmHg of baseline values, at 10 and 30min respectively; P<0.05) and abolished the increase in RVC (85±8% from baseline, at 10min) and decrease in RSNA (-4±3% from baseline, at 10min). These results suggest that aortic and carotid afferents are involved in cardiovascular and renal sympathoinhibition responses induced by acute hypernatremia.

Pro–Atrial Natriuretic Peptide: A Novel Guanylyl Cyclase-A Receptor Activator That Goes Beyond Atrial and B-Type Natriuretic Peptides

ObjectivesThe aim of this study was to determine if the atrial natriuretic peptide (ANP) precursor proANP is biologically active compared with ANP and B-type natriuretic peptide (BNP). BackgroundProANP is produced in the atria and processed to ANP and activates the guanylyl cyclase receptor–A (GC-A) and its second messenger, cyclic guanosine monophosphate (cGMP). ProANP is found in the human circulation, but its bioavailability is undefined. MethodsThe in vivo actions of proANP compared with ANP, BNP, and placebo were investigated in normal canines (667 pmol/kg, n = 5/group). cGMP activation in human embryonic kidney 293 cells expressing GC-A or guanylyl cyclase receptor–B was also determined. ProANP processing and degradation were observed in serum from normal subjects (n = 13) and patients with heart failure (n = 14) ex vivo. ResultsProANP had greater diuretic and natriuretic properties, with more sustained renal tubular actions, compared with ANP and BNP in vivo in normal canines, including marked renal vasodilation not observed with ANP or BNP. ProANP also resulted in greater and more prolonged cardiac unloading than ANP but much less hypotensive effects than BNP. ProANP stimulated cGMP generation by GC-A as much as ANP. ProANP was processed to ANP in serum from normal control subjects and patients with heart failure ex vivo. ConclusionsProANP represents a novel activator of GC-A with enhanced diuretic, natriuretic, and renal vasodilating properties, and it may represent a key circulating natriuretic peptide in cardiorenal and blood pressure homeostasis. These results support the concepts that proANP may be a potential innovative therapeutic beyond ANP or BNP for cardiorenal diseases, including heart failure.

Abstract P607: Deletion of GPER Protects from Age-related Renovascular Dysfunction and Tubulo-interstitial Injury

Aging is associated with reduced vasodilatory capacity in renal arteries. Activation of the G protein-coupled estrogen receptor (GPER) induces vasodilation and improves hypertensive renal injury in rats. Moreover, GPER, as observed with many G protein-coupled receptors, likely exhibits “basal activity” independent of ovarian estrogen production, which may become relevant in disease-like states such as aging. We hypothesized that deletion of basal GPER activity would further aggravate vasodilatory dysfunction in renal arteries and the associated tubulo-interstitial injury. In young (4 month-old) and senescent (24 month-old) male wild-type and GPER-deficient ( Gper -/- ) mice, blood pressure and endothelium-dependent vasodilation to acetylcholine in renal arteries were determined. In addition, vascular injury (VIS score) and tubulo-interstitial injury (TIS score) including staining for amyloid were quantified in histologic sections. In wild-type mice, aging markedly reduced renal artery vasodilation to acetylcholine (from 77±5% to 28±4% of precontraction, n=4-5, p&lt;0.001 vs. young mice), and increased vascular injury (VIS: 0.42±0.07 vs. 0.04±0.03), tubulo-interstitial injury (TIS: 2.9±0.6 vs. 0.3±0.1), and amyloid staining (2.8±0.7 vs. 0±0, all n=6-8, p&lt;0.001 vs. young mice). Contrary to our hypothesis, vasodilatory responses to acetylcholine were largely preserved in renal arteries from senescent Gper -/- mice (63±4 vs. 28±4% of precontraction, n=4-5, p&lt;0.001 vs. wild-type mice). Similarly, in senescent Gper -/- mice, vascular injury (VIS) was reduced by 46% (n=6-7, p=0.09 vs. wild-type mice), as were tubulo-interstitial injury (TIS) and amyloid staining by 77% and 92%, respectively (both n=6-7, p&lt;0.01 vs. wild-type mice). Deletion of Gper had no effect on blood pressure in either senescent (110±5/83±1 vs. 114±2/87±2 mmHg) or young animals (117±2/90±1 vs. 119±2/91±2 mmHg, both n=5-12, p=n.s. vs. wild-type mice). These results indicate a novel role for GPER expression in age-related impaired vasodilatory capacity in renal arteries and the associated tubulo-interstitial injury independent of blood pressure, as well as a pathophysiologically relevant activity of GPER in male mice, possibly independent of estrogen.

Ethnopharmacological investigation of the diuretic and hemodynamic properties of native species of the Brazilian biodiversity

Ethnopharmacological relevanceAlthough Echinodorus grandiflorus, Cuphea carthagenensis, and Phyllanthus tenellus infusions are used in Brazilian folk medicine due to their possible diuretic effect, none of these species was critically investigated as a diuretic drug. So, the aim of this study was to evaluate the possible acute diuretic activity of ethanol soluble fractions (ES) obtained from these species and assess the relationship between renal cortical blood flow and their antioxidant and hypotensive activity using normotensive Wistar rats. Material and methodsThe preparation obtained from E. grandiflorus (ES-EG), C. carthagenensis (ES-CC), and P. tenellus (ES-PT) infusions was orally administered in a single dose to rats. Urine excretion rate, pH, density, conductivity and Na+, K+, Cl− and HCO3− contents were measured in the urine of saline-loaded animals. Concentration of electrolytes, total protein, urea, creatinine, and angiotensin converting enzyme (ACE) activity were evaluated in collected serum. The involvement of the renal cortical blood flow and antioxidative activity in the hypotensive and diuretic effects was also determined. ResultsWater and Na+, Cl− and Na+ excretion rates were significantly increased by ES-EG, while urinary bicarbonate excretion was reduced. Moreover, ES obtained from E. grandiflorus was able to significantly increase renal blood flow and reduce mean arterial pressure and oxidative stress in “in vitro” and “in vivo” models. All other parameters evaluated were not affected by any treatment. ConclusionThe results presented here shown that the ES-EG obtained from E. grandiflorus leaves shown a significant diuretic and hypotensive activity and suggest that these effects could be related with an important renal and systemic vasodilator effect. In addition, it was shown for the first time that the pharmacological effects of ES obtained from P. tenellus and C. carthagenensis do not support its popular use as a diuretic agent.