MANP in Hypertension With Metabolic Syndrome: Proof-of-Concept Study of Natriuretic Peptide-Based Therapy for Cardiometabolic Disease.

Hypertension and metabolic syndrome frequently coexist to increase the risk for adverse cardiometabolic outcomes. To date, no drug has been proven to be effective in treating hypertension with metabolic syndrome. M-atrial natriuretic peptide is a novel atrial natriuretic peptide analog that activates the particulate guanylyl cyclase A receptor. This study conducted a double-blind, placebo-controlled trial in 22 patients and demonstrated that a single subcutaneous injection of M-atrial natriuretic peptide was safe, well-tolerated, and exerted pleiotropic properties including blood pressure-lowering, lipolytic, and insulin resistance-improving effects. (MANP in Hypertension and Metabolic Syndrome [MANP-HTN-MS]; NCT03781739).

The Concise Guide to PHARMACOLOGY 2023/24: Catalytic receptors.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and nearly 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16180. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Sex-based differences in metabolic protection by the ANP genetic variant rs5068 in the general population.

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are produced in the heart and secreted into the circulation. As hormones, both peptides activate the guanylyl cyclase receptor A (GC-A), playing a role in blood pressure (BP) regulation. A significant role for ANP and BNP includes favorable actions in metabolic homeostasis. Sex-based high prevalence of risk factors for cardiovascular disease in males compared with females is well established, but sex-based differences on cardiometabolic protection have not been investigated in relation to ANP (NPPA) and BNP (NPPB) gene variants. We included 1,146 subjects in the general population from Olmsted County, Minnesota. Subjects were genotyped for the ANP gene variant rs5068 and BNP gene variant rs198389. Cardiometabolic parameters and medical records were reviewed. In the presence of the minor allele of rs5068, diastolic BP, creatinine, body mass index (BMI), waist measurement, insulin, and prevalence of obesity and metabolic syndrome were lower, whereas HDL was higher in males with only trends observed in females. We observed no associations of the minor allele with echocardiographic parameters in either males or females. Regarding rs198389 genotype, the minor allele was not associated with any BP, metabolic, renal, or echocardiographic parameters in either sex. In the general community, the minor allele of the ANP gene variant rs5068 is associated with a favorable metabolic phenotype in males. No associations were observed with the BNP gene variant rs198389. These studies support a protective role of the ANP pathway on metabolic function and underscore the importance of sex in relationship to natriuretic peptide responses.NEW & NOTEWORTHY Males are characterized by lower ANP and BNP with greater prevalence of cardiometabolic disease. The ANP genetic variant rs5068 was associated with less metabolic dysfunction in males, whereas no metabolic profile was related to the BNP genetic variant rs198389 in the general population. ANP may play a more biological role in metabolic homeostasis compared with BNP in the general population with greater physiological metabolic actions in males compared with females.

Evidence for Angiotensin II as a Naturally Existing Suppressor for the Guanylyl Cyclase A Receptor and Cyclic GMP Generation.

The natriuretic peptide system (NPS) and renin-angiotensin-aldosterone system (RAAS) function oppositely at multiple levels. While it has long been suspected that angiotensin II (ANGII) may directly suppress NPS activity, no clear evidence to date supports this notion. This study was designed to systematically investigate ANGII-NPS interaction in humans, in vivo, and in vitro. Circulating atrial, b-type, and c-type natriuretic peptides (ANP, BNP, CNP), cyclic guanosine monophosphate (cGMP), and ANGII were simultaneously investigated in 128 human subjects. Prompted hypothesis was validated in vivo to determine the influence of ANGII on ANP actions. The underlying mechanisms were further explored via in vitro approaches. In humans, ANGII demonstrated an inverse relationship with ANP, BNP, and cGMP. In regression models predicting cGMP, adding ANGII levels and the interaction term between ANGII and natriuretic peptides increased the predictive accuracy of the base models constructed with either ANP or BNP, but not CNP. Importantly, stratified correlation analysis further revealed a positive association between cGMP and ANP or BNP only in subjects with low, but not high, ANGII levels. In rats, co-infusion of ANGII even at a physiological dose attenuated cGMP generation mediated by ANP infusion. In vitro, we found the suppressive effect of ANGII on ANP-stimulated cGMP requires the presence of ANGII type-1 (AT1) receptor and mechanistically involves protein kinase C (PKC), as this suppression can be substantially rescued by either valsartan (AT1 blocker) or Go6983 (PKC inhibitor). Using surface plasmon resonance (SPR), we showed ANGII has low binding affinity to the guanylyl cyclase A (GC-A) receptor compared to ANP or BNP. Our study reveals ANGII is a natural suppressor for the cGMP-generating action of GC-A via AT1/PKC dependent manner and highlights the importance of dual-targeting RAAS and NPS in maximizing beneficial properties of natriuretic peptides in cardiovascular protection.

EVIDENCE FOR ANGIOTENSIN II AS A NATURALLY EXISTING SUPPRESSOR FOR THE NATRIURETIC PEPTIDE SYSTEM.

Background: Natriuretic peptide system (NPS) and renin angiotensin aldosterone system (RAAS) function oppositely at multiple levels. While it has long been suspected that angiotensin II (ANGII) may directly suppress NPS activity, no clear evidence to date support this notion. Objectives: This study was designed to systematically investigate ANGII-NPS interaction in humans, in vivo, and in vitro for translational insights. Methods: Circulating atrial, b-type, and c-type natriuretic peptides (ANP, BNP, CNP), cyclic guanosine monophosphate (cGMP), and ANGII were simultaneously investigated in 128 human subjects. Prompted hypothesis was validated in rat model to determine influence of ANGII on ANP actions. Multiple engineered HEK293 cells and surface plasmon resonance (SPR) technology were leveraged for mechanistic exploration. Results: In humans, ANGII showed inverse relationship with ANP, BNP, and cGMP. In regression models predicting cGMP, adding ANGII levels and interaction term between ANGII and natriuretic peptide increased predicting accuracy of base models constructed with either ANP or BNP, but not CNP. Importantly, stratified correlation analysis further revealed positive association between cGMP with ANP or BNP only in subjects with low, but not high, ANGII levels. In rats, co-infusion of ANGII even at physiological dose attenuated blood pressure reduction and cGMP generation triggered by ANP infusion. In vitro, we showed that the suppression effect of ANGII on ANP-stimulated cGMP requires the presence of ANGII type-1 (AT1) receptor and mechanistically involves protein kinase C (PKC), which can be substantially rescued by either valsartan (AT1 blocker) or Go6983 (PKC inhibitor). Using SPR, we showed ANGII has low affinity for particulate guanylyl cyclase A (GC-A) receptor binding compared to ANP or BNP. Conclusions: Our study reveals ANGII as a natural suppressor for cGMP-generating action of GC-A via AT1/PKC dependent manner and highlights importance of dual-targeting RAAS and NPS in maximizing beneficial properties of natriuretic peptides in cardiovascular disease.

Natriuretic peptide pathways in heart failure: further therapeutic possibilities.

The discovery of the heart as an endocrine organ resulted in a remarkable recognition of the natriuretic peptide system (NPS). Specifically, research has established the production of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) from the heart, which exert pleiotropic cardiovascular, endocrine, renal, and metabolic actions via the particulate guanylyl cyclase A receptor (GC-A) and the second messenger, cGMP. C-type natriuretic peptide (CNP) is produced in the endothelium and kidney and mediates important protective auto/paracrine actions via GC-B and cGMP. These actions, in part, participate in the efficacy of sacubitril/valsartan in heart failure (HF) due to the augmentation of the NPS. Here, we will review important insights into the biology of the NPS, the role of precision medicine, and focus on the phenotypes of human genetic variants of ANP and BNP in the general population and the relevance to HF. We will also provide an update of the existence of NP deficiency states, including in HF, which provide the rationale for further therapeutics for the NPS. Finally, we will review the field of peptide engineering and the development of novel designer NPs for the treatment of HF. Notably, the recent discovery of a first-in-class small molecule GC-A enhancer, which is orally deliverable, will be highlighted. These innovative designer NPs and small molecule possess enhanced and novel properties for the treatment of HF and cardiovascular diseases.

Purification, characterization, and preliminary serial crystallography diffraction advances structure determination of full-length human particulate guanylyl cyclase A receptor.

Particulate Guanylyl Cyclase Receptor A (pGC-A) is a natriuretic peptide membrane receptor, playing a vital role in controlling cardiovascular, renal, and endocrine functions. The extracellular domain interacts with natriuretic peptides and triggers the intracellular guanylyl cyclase domain to convert GTP to cGMP. To effectively develop methods to regulate pGC-A, structural information on the full-length form is needed. However, structural data on the transmembrane and intracellular domains are lacking. This work presents expression and optimization using baculovirus, along with the first purification of functional full-length human pGC-A. In vitro assays revealed the pGC-A tetramer was functional in detergent micelle solution. Based on our purification results and previous findings that dimer formation is required for functionality, we propose a tetramer complex model with two functional subunits. Previous research suggested pGC-A signal transduction is an ATP-dependent, two-step mechanism. Our results show the binding ligand also moderately activates pGC-A, and ATP is not crucial for activation of guanylyl cyclase. Furthermore, crystallization of full-length pGC-A was achieved, toward determination of its structure. Needle-shaped crystals with 3 Å diffraction were observed by serial crystallography. This work paves the road for determination of the full-length pGC-A structure and provides new information on the signal transduction mechanism.

MANP Activation Of The cGMP Inhibits Aldosterone Via PDE2 And CYP11B2 In H295R Cells And In Mice.

BACKGROUND: Aldosterone is a critical pathological driver for cardiac and renal diseases. We recently discovered that mutant atrial natriuretic peptide (MANP), a novel atrial natriuretic peptide (ANP) analog, possessed more potent aldosterone inhibitory action than ANP in vivo. MANP and natriuretic peptide (NP)-augmenting therapy sacubitril/valsartan are under investigations for human hypertension treatment. Understanding the elusive mechanism of aldosterone inhibition by NPs remains to be a priority. Conflicting results were reported on the roles of the pGC-A (particulate guanylyl cyclase A receptor) and NP clearance receptor in aldosterone inhibition. Furthermore, the function of PKG (protein kinase G) and PDEs (phosphodiesterases) on aldosterone regulation are not clear. METHODS: In the present study, we investigated the molecular mechanism of aldosterone regulation in a human adrenocortical cell line H295R and in mice. RESULTS: We first provided evidence to show that pGC-A, not NP clearance receptor, mediates aldosterone inhibition. Next, we confirmed that MANP inhibits aldosterone via PDE2 (phosphodiesterase 2) not PKG, with specific agonists, antagonists, siRNA silencing, and fluorescence resonance energy transfer experiments. Further, the inhibitory effect is mediated by a reduction of intracellular Ca2+ levels. We then illustrated that MANP directly reduces aldosterone synthase CYP11B2 (cytochrome p450 family 11 subfamily b member 2) expression via PDE2. Last, in PDE2 knockout mice, consistent with in vitro findings, embryonic adrenal CYP11B2 is markedly increased. CONCLUSIONS: Our results innovatively explore and expand the NP/pGC-A/3',5', cyclic guanosine monophosphate (cGMP)/PDE2 pathway for aldosterone inhibition by MANP in vitro and in vivo. In addition, our data also support the development of MANP as a novel ANP analog drug for aldosterone excess treatment.

Pre-clinical data supporting immunotherapy for HIV using CMV-HIV-specific CAR T cells with CMV vaccine.

T cells engineered to express HIV-specific chimeric antigen receptors (CARs) represent a promising strategy to clear HIV-infected cells, but to date have not achieved clinical benefits. A likely hurdle is the limited T cell activation and persistence when HIV antigenemia is low, particularly during antiretroviral therapy (ART). To overcome this issue, we propose to use a cytomegalovirus (CMV) vaccine to stimulate CMV-specific T cells that express CARs directed against the HIV-1 envelope protein gp120. In this study, we use a GMP-compliant platform to engineer CMV-specific T cells to express a second-generation CAR derived from the N6 broadly neutralizing antibody, one of the broadest anti-gp120 neutralizing antibodies. These CMV-HIV CAR T cells exhibit dual effector functions upon in vitro stimulation through their endogenous CMV-specific T cell receptors or the introduced CARs. Using a humanized HIV mouse model, we show that CMV vaccination during ART accelerates CMV-HIV CAR T cell expansion in the peripheral blood and that higher numbers of CMV-HIV CAR T cells were associated with a better control of HIV viral load and fewer HIV antigen p24+ cells in the bone marrow upon ART interruption. Collectively, these data support the clinical development of CMV-HIV CAR T cells in combination with a CMV vaccine in HIV-infected individuals.

CRISPR-Cas9-mediated gene disruption of HIV-1 co-receptors confers broad resistance to infection in human T cells and humanized mice.

In this preclinical study, we evaluated the efficacy and feasibility of creating broad human immunodeficiency virus (HIV) resistance by simultaneously disrupting the human CCR5 and CXCR4 genes, which encode cellular co-receptors required for HIV-1 infection. Using a clinically scalable system for transient ex vivo delivery of Cas9/guide RNA (gRNA) ribonucleoprotein (RNP) complexes, we demonstrated that CRISPR-mediated disruption of CCR5 and CXCR4 in T lymphocyte cells significantly reduced surface expression of the co-receptors, thereby establishing resistance to HIV-1 infection by CCR5 (R5)-tropic, CXCR4 (X4)-tropic, and dual (R5/X4)-tropic strains. Similarly, disruption of CCR5 alleles in human CD34+ hematopoietic stem and progenitor cells (HSPCs) successfully led to the differentiation of HIV-resistant macrophages. In a humanized mouse model under HIV-1 challenge, CXCR4-disrupted CD4+ T cells were enriched in the peripheral blood and spleen, indicating survival advantage because of resistance to viral infection. However, in human CD4+ T cells with both CCR5 and CXCR4 disruption, we observed poor engraftment in bone marrow, although significant changes were not observed in the lung, spleen, or peripheral blood. This study establishes a clinically scalable strategy for the dual knockout of HIV-1 co-receptors as a therapeutic strategy, while also raising caution of disrupting CXCR4, which may abate engraftment of CD4+ T cells in bone marrow.

MANP (M-Atrial Natriuretic Peptide) Reduces Blood Pressure and Furosemide-Induced Increase in Aldosterone in Hypertension.

BACKGROUND: cGMP MANP (M-atrial natriuretic peptide) is a best-in-class activator of the pGC-A (particulate guanylyl cyclase A) receptor. Furosemide increases the effectiveness of antihypertensive agents, but activates renin-angiotensin-aldosterone system. We aimed to investigate for the first time cardiorenal and neurohumoral actions of MANP in a genetic model of hypertension in spontaneously hypertensive rats. We also assessed how MANP would potentiate the blood pressure (BP)-lowering actions of furosemide while reducing the production of aldosterone. METHODS: Spontaneously hypertensive rats (N=60) were randomized in vehicle, MANP, furosemide, or MANP+furosemide groups. Furosemide (1, 5, 10 mg/kg) was given as a single bolus which in MANP+furosemide groups was followed by a 60-minute infusion of MANP. RESULTS: BP was reduced in MANP300 (300 pmol/[kg·min]) and MANP600 (600 pmol/[kg·min]) groups (P<0.05) and was accompanied by significant increase in plasma cyclic guanosine monophosphate. Furosemide alone reduced BP but less compared with MANP with no change in plasma cyclic guanosine monophosphate. MANP+furosemide resulted in the greatest BP reduction and significant increase in plasma cyclic guanosine monophosphate in Fs5+MANP300, Fs10+MANP300, and Fs10+MANP600. Plasma aldosterone increased in furosemide groups, which was significantly attenuated in MANP+furosemide groups. Natriuresis and diuresis increased in all treated groups (P<0.05) with no significant differences between furosemide and furosemide+MANP. In vitro, MANP increased cyclic guanosine monophosphate level in human vascular cells. CONCLUSIONS: We provide novel evidence that MANP potentiates the BP-lowering actions of furosemide, suppresses the activation of renin-angiotensin-aldosterone system, and preserves renal function. These data are highly relevant to clinical needs in the treatment of hypertension and heart failure.

Cardiorenal Effects of Long-Term Phosphodiesterase V Inhibition in Pre-Heart Failure.

Background Phosphodiesterase V (PDEV) is upregulated in heart failure, leading to increased degradation of cGMP and impaired natriuresis. PDEV inhibition improves the renal response to B-type natriuretic peptide in animal models. We tested the hypothesis that long-term PDEV inhibition would improve renal function and cardiorenal response after short-term volume load in subjects with pre-heart failure. Methods and Results A total of 20 subjects with pre-heart failure (defined as an ejection fraction ≤45% without previous diagnosis of heart failure) and renal impairment were randomized in a 2:1 manner to tadalafil or placebo. Baseline echocardiography and renal clearance study were performed, followed by a short-term saline load and repeated echocardiography and renal clearance study. Subjects then received either tadalafil at a goal dose of 20 mg daily or placebo, and the study day was repeated after 12 weeks. Long-term tadalafil did not improve glomerular filtration rate (median increase of 2.0 mL/min in the tadalafil group versus 13.5 mL/min in the placebo group; P=0.54). There was no difference in urinary sodium or cGMP excretion with PDEV inhibition following short-term saline loading. Conclusions Glomerular filtration rate and urinary sodium/cGMP excretion were not significantly different after 12 weeks of tadalafil compared with placebo. These results do not support the use of PDEV inhibition to improve renal response in patients with pre-heart failure. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01970176.

Cyclic GMP modulating drugs in cardiovascular diseases: mechanism-based network pharmacology.

Mechanism-based therapy centred on the molecular understanding of disease-causing pathways in a given patient is still the exception rather than the rule in medicine, even in cardiology. However, recent successful drug developments centred around the second messenger cyclic guanosine-3'-5'-monophosphate (cGMP), which is regulating a number of cardiovascular disease modulating pathways, are about to provide novel targets for such a personalized cardiovascular therapy. Whether cGMP breakdown is inhibited or cGMP synthesis is stimulated via guanylyl cyclases or their upstream regulators in different cardiovascular disease phenotypes, the outcomes seem to be so far uniformly protective. Thus, a network of cGMP-modulating drugs has evolved that act in a mechanism-based, possibly causal manner in a number of cardiac conditions. What remains a challenge is the detection of cGMPopathy endotypes amongst cardiovascular disease phenotypes. Here, we review the growing clinical relevance of cGMP and provide a glimpse into the future on how drugs interfering with this pathway may change how we treat and diagnose cardiovascular diseases altogether.

Novel Humanized Peripheral Blood Mononuclear Cell Mouse Model with Delayed Onset of Graft-versus-Host Disease for Preclinical HIV Research.

Humanized mouse models are based on the engraftment of human cells in immunodeficient mouse strains, most notably the NSG strain. Most used models have a major limitation in common, the development of graft-versus-host disease (GVHD). GVHD not only introduces variabilities into the research data but also leads to animal welfare concerns. A new mouse strain, B6.129S-Rag2tm1Fwa CD47tm1Fpl Il2rgtm1Wjl/J, which lacks Rag1, IL2rg, and CD47 (triple knockout [TKO]), is resistant to GVHD development. We transplanted TKO mice with human peripheral blood mononuclear cells (PBMCs) to establish a new humanized PBMC (hu-PBMC) mouse model. A cohort of these mice was infected with HIV-1 and monitored for plasma HIV viremia and CD4+ T cell depletion. The onset and progression of GVHD were monitored by clinical signs. This study demonstrates that TKO mice transplanted with human PBMCs support engraftment of human immune cells in primary and secondary lymphoid tissues, rectum, and brain. Moreover, the TKO hu-PBMC model supports HIV-1 infection via the intraperitoneal, rectal, or vaginal route, as confirmed by robust plasma HIV viremia and CD4+ T cell depletion. Lastly, TKO mice showed a delayed onset of GVHD clinical signs (∼24 days) and exhibited significant decreases in plasma levels of tumor necrosis factor beta (TNF-ß). Based on these results, the TKO hu-PBMC mouse model not only supports humanization and HIV-1 infection but also has a delayed onset of GVHD development, making this model a valuable tool in HIV research. IMPORTANCE Currently, there is no cure or vaccine for HIV infection; thus, continued research is needed to end the HIV pandemic. While many animal models are used in HIV research, none is used more than the humanized mouse model. A major limitation with current humanized mouse models is the development of graft-versus-host disease (GVHD). Here, we describe a novel humanized-PBMC mouse model that has a delayed onset GVHD development and supports and models HIV infection comparably to well-established humanized mouse models.

Discovery of small molecule guanylyl cyclase A receptor positive allosteric modulators.

The particulate guanylyl cyclase A receptor (GC-A), via activation by its endogenous ligands atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), possesses beneficial biological properties such as blood pressure regulation, natriuresis, suppression of adverse remodeling, inhibition of the renin-angiotensin-aldosterone system, and favorable metabolic actions through the generation of its second messenger cyclic guanosine monophosphate (cGMP). Thus, the GC-A represents an important molecular therapeutic target for cardiovascular disease and its associated risk factors. However, a small molecule that is orally bioavailable and directly targets the GC-A to potentiate cGMP has yet to be discovered. Here, we performed a cell-based high-throughput screening campaign of the NIH Molecular Libraries Small Molecule Repository, and we successfully identified small molecule GC-A positive allosteric modulator (PAM) scaffolds. Further medicinal chemistry structure-activity relationship efforts of the lead scaffold resulted in the development of a GC-A PAM, MCUF-651, which enhanced ANP-mediated cGMP generation in human cardiac, renal, and fat cells and inhibited cardiomyocyte hypertrophy in vitro. Further, binding analysis confirmed MCUF-651 binds to GC-A and selectively enhances the binding of ANP to GC-A. Moreover, MCUF-651 is orally bioavailable in mice and enhances the ability of endogenous ANP and BNP, found in the plasma of normal subjects and patients with hypertension or heart failure, to generate GC-A-mediated cGMP ex vivo. In this work, we report the discovery and development of an oral, small molecule GC-A PAM that holds great potential as a therapeutic for cardiovascular, renal, and metabolic diseases.

First-in-Human Study of MANP: A Novel ANP (Atrial Natriuretic Peptide) Analog in Human Hypertension.

[Figure: see text].

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Catalytic receptors.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15541. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Effects of phosphodiesterase V inhibition alone and in combination with BNP on cardiovascular and renal response to volume load in human preclinical diastolic dysfunction.

Preclinical diastolic dysfunction (PDD) results in impaired cardiorenal response to volume load (VL) which may contribute to the progression to clinical heart failure with preserved ejection fraction (HFpEF). The objective was to evaluate if phosphodiesterase V inhibition (PDEVI) alone or combination PDEVI plus B-type natriuretic peptide (BNP) administration will correct the impaired cardiorenal response to VL in PDD. A randomized double-blinded placebo-controlled cross-over study was conducted in 20 subjects with PDD, defined as left ventricular ejection fraction (LVEF) >50% with moderate or severe diastolic dysfunction by Doppler echocardiography and without HF diagnosis or symptoms. Effects of PDEVI with oral tadalafil alone and tadalafil plus subcutaneous (SC) BNP, administered prior to acute volume loading, were assessed. Tadalafil alone did not result in improvement in cardiac response to VL, as measured by LVEF, LV end diastolic volume, left atrial volume (LAV), or right ventricular systolic pressure (RVSP). Tadalafil plus SC BNP resulted in improved cardiac response to VL, with increased LVEF (4.1 vs. 1.8%, p = 0.08) and heart rate (4.3 vs. 1.6 bpm, p = 0.08), and reductions in both LAV (-4.3 ± 10.4 vs. 2.8 ± 6.6 ml, p = 0.03) and RVSP (-4.0 ± 3.0 vs. 2.1 ± 6.0 mmHg, p < 0.01) versus tadalafil alone. Plasma and urinary cyclic guanosine monophosphate (cGMP) excretion levels were higher (11.3 ± 12.3 vs. 1.7 ± 3.8 pmol/ml, 1851.0 ± 1386.4 vs. 173.4 ± 517.9 pmol/min, p < 0.01) with tadalafil plus SC BNP versus tadalafil alone. There was no improvement in renal response as measured by GFR, renal plasma flow, sodium excretion, and urine flow with tadalafil plus SC BNP compared to tadalafil alone. In subjects with PDD, tadalafil alone resulted in no improvement in cardiac adaptation, while tadalafil and SC BNP resulted in enhanced cardiac adaptation to VL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01544998.