Low-Dose C-Type Natriuretic Peptide Does Not Affect Cardiac and Renal Function in Humans

Barletta, Giuseppe; Lazzeri, Chiara; Vecchiarino, Sabrina; Bene, Riccarda Del; Messeri, Gianni; Sbarba, Antonio Dello; Mannelli, Massimo; Villa, Giorgio La

doi:10.1161/01.hyp.31.3.802

Cited by 43 publications

(38 citation statements)

References 59 publications

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“…This finding is in accordance with previously published data showing that CNP does not influence renal function in humans and dogs after i.v. administration at low dosages (33,34). It has been demonstrated that systemic infusion or bolus administration of supraphysiological CNP concentrations in dogs increased aldosterone release and distal nephron sodium reabsorption, suggesting that CNP regulates tubular reabsorption and not glomerular filtration rate (35).…”

Section: Discussionmentioning

confidence: 99%

Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B

Langenickel

Buttgereit

Pagel-Langenickel

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

115

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Natriuretic peptides (NP) mediate their effects by activating membrane-bound guanylyl cyclase-coupled receptors A (NPR-A) or B (NPR-B). Whereas the pathophysiological role of NPR-A has been widely studied, only limited knowledge on the cardiovascular function of NPR-B is available. In vitro studies suggest antiproliferative and antihypertrophic actions of the NPR-B ligand C-type NP (CNP). Because of the lack of a specific pharmacological inhibitor, these effects could not clearly be attributed to impaired NPR-B signaling. Recently, gene deletion revealed a predominant role of NPR-B in endochondral ossification and development of female reproductive organs. However, morphological abnormalities and premature death of NPR-B-deficient mice preclude detailed cardiovascular phenotyping. In the present study, a dominant-negative mutant (NPR-B⌬KC) was used to characterize CNP-dependent NPR-B signaling in vitro and in transgenic rats. Here we demonstrate that reduced CNP-but not atrial NP-dependent cGMP response attenuates antihypertrophic potency of CNP in vitro. In transgenic rats, NPR-B⌬KC expression selectively reduced NPR-B but not NPR-A signaling. NPR-B⌬KC transgenic rats display progressive, blood pressure-independent cardiac hypertrophy and elevated heart rate. The hypertrophic phenotype is further enhanced in chronic volume overload-induced congestive heart failure. Thus, this study provides evidence linking NPR-B signaling to the control of cardiac growth.C-type natriuretic peptide ͉ knockdown

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Section: Discussionmentioning

confidence: 99%

Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B

Langenickel

Buttgereit

Pagel-Langenickel

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

115

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“…Charles et al 19 performed the same experiments in conscious sheep and found only decreased cardiac output with increased natriuresis but no influence on blood pressure. In addition, Barletta et al 20 systemically infused low-dose CNP in humans and found no cardiovascular or renal effects.…”

Section: Discussionmentioning

confidence: 99%

C-Type Natriuretic Peptide–Induced Vasodilation Is Dependent On Hyperpolarization in Human Forearm Resistance Vessels

Honing¹,

Smits²,

Morrison³

et al. 2001

Hypertension

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Abstract-Animal studies have demonstrated that CNP causes endothelium-independent vasodilation, which is limited by neutral endopeptidase (NEP) activity. However, the vasodilating mechanism of CNP in humans is still unknown. Therefore, we investigated the vasodilator actions of CNP in human forearm resistance vessels before and after inhibition of nitric oxide (NO) and then prostacyclin production and after inhibition of Ca 2ϩ -dependent potassium channel activation and NEP activity. Three separate studies were performed. In each study, forearm blood flow was recorded by venous occlusion plethysmography in 8 healthy nonsmoking subjects. Brachial artery infusion of CNP (70, 140, 280, and 560 ng per 100 mL forearm volume per minute) caused significant forearm vasodilation in all studies (forearm blood flow from 3.94 to 8.50 mL per 100 mL forearm volume per minute). Inhibition of the endogenous generation of NO by L-N G -monomethyl arginine (by use of the NO-clamp technique) did not block the maximal vasodilating effects of CNP (forearm blood flow from 3.69 to 6.93). In addition, when the cyclooxygenase system was inhibited by 600 mg of acetylsalicylic acid (aspirin) administered orally 30 minutes before start of measurements, the rise in forearm blood flow remained intact (forearm blood flow from 3.31 to 8.27 mL per 100 mL forearm volume per minute). However, inhibition of Ca 2ϩ -dependent potassium channels with tetraethylammonium chloride (0.1 mg per 100 mL forearm volume per minute) significantly attenuated vasodilation caused by CNP (forearm blood flow from 2.28 to 3.06 mL per 100 mL forearm volume per minute), which suggests that CNP opens vascular potassium channels. Vasodilation to all doses of CNP was significantly increased when activity of NEP was blocked with thiorphan (30 nmol/min), which suggests that NEP activity limits vasodilation of CNP. CNP is a dilator of human resistance vessels that mediates its effects through hyperpolarization of the vessel wall independent of the NO and prostaglandin system. Inhibition of local NEP activity increases CNP bioavailability. This may be of relevance to cardiovascular disease, given that vascular tone is well balanced between NO and an endothelium-derived hyperpolarizing factor, which suggests that in pathological situations, impaired NO activity can be compensated for by enhanced endothelium-derived hyperpolarizing factor release to maintain vascular homeostasis. (Hypertension. 2001;37:1179-1183.)

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“…Echocardiographic assessment of cardiovascular function and systemic hemodynamics was performed by one investigator using a SSA 270 HG Toshiba (Tokyo, Japan) echocardiograph, as previously reported. 22,24 LV volumes and cardiac output were determined from LV diameters and heart rate using the Teichholz formula. 25 Antero-posterior left atrial diameters were obtained in the standard parasternal long-axis projection.…”

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confidence: 99%

“…Longitudinal and transversal diameters of the left and the right atria were measured in the apical 4-chamber view. 24 Atrial emptying fraction was calculated as (systolic atrial volume Ϫ diastolic atrial volume)/systolic atrial volume. Cardiac volumes and cardiac output were normalized by body surface area and expressed as the corresponding indexes (I).…”

mentioning

confidence: 99%

Hemodynamic, renal, and endocrine effects of acute inhibition of nitric oxide synthase in compensated cirrhosis

et al. 2001

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To assess whether an increased production of nitric oxide is involved in the circulatory and renal alterations of cirrhosis, we evaluated systemic hemodynamics (echocardiography), renal hemodynamics, and sodium handling (lithium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 ؎ 2 years) with compensated cirrhosis, portal hypertension, and hyperdynamic circulation during intravenous N Gmonomethyl-L-arginine (L-NMMA) (3 mg/kg bolus plus 0.05 mg/kg ⅐ min for 120 minutes) or placebo (the vehicle) in a randomized, placebo-controlled, crossover study. Administration of L-NMMA resulted in significant reductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synthase. L-NMMA also significantly reduced cardiac index (؊13%) and increased systemic vascular resistance (؉26%), arterial pressure (؉9%), renal blood flow (؉12%), glomerular filtration rate (؉12%), and sodium excretion (؉25%). Changes in sodium excretion were caused by both enhanced filtered sodium load and reduced sodium reabsorption in the proximal tubule. Plasma norepinephrine significantly decreased in response to L-NMMA, and there was a trend for reductions in PRA and PAC. Placebo had no appreciable effect on any of the measured parameters. These results indicate that in patients with compensated cirrhosis, portal hypertension and hyperdynamic circulation inhibition of nitric oxide synthase corrects the altered systemic hemodynamics and improves re- Patients with cirrhosis and portal hypertension eventually develop a hyperdynamic circulation, with high cardiac output, reduced systemic vascular resistance, and a trend towards arterial hypotension. 1 This abnormality, that contributes to worsen portal hypertension and plays a major role in the pathogenesis of other complications, including ascites and renal failure, has been related to peripheral arterial vasodilation, mainly occurring in the splanchnic circulation. 2 The cause(s) and mechanism(s) of arterial vasodilation are still unknown, but available evidence suggests that an increased synthesis of nitric oxide (NO) participates in the pathogenesis of the altered systemic hemodynamics in cirrhosis. 3,4 Animals with experimental cirrhosis have increased expression of nitric oxide synthase (NOS) and increased synthesis of NO in the vasculature. 5-9 They also have impaired response to vasoconstrictors in isolated aortic rings or splanchnic vasculature preparations, which is reversed by NOS inhibitors, 10,11 and increased pressor response to systemic administration of NOS inhibitors. 12,13 In addition, normalization of NO production by low-dose N G -nitro-L-arginine methyl ester, a NOS inhibitor, corrected the altered systemic hemodynamics, normalized the activity of the main vasoconstricting and sodiumretaining systems, 14 and improved renal sodium and water excretion in cirrhotic rats with ascites. 15 Evidence of an increased synthesis of NO has also ...

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Low-Dose C-Type Natriuretic Peptide Does Not Affect Cardiac and Renal Function in Humans

Cited by 43 publications

References 59 publications

Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B

Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B

C-Type Natriuretic Peptide–Induced Vasodilation Is Dependent On Hyperpolarization in Human Forearm Resistance Vessels

Hemodynamic, renal, and endocrine effects of acute inhibition of nitric oxide synthase in compensated cirrhosis

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