Angiotensin 1/2 (5-7)

N-[[4'-[(2-Ethyl-5,7-dimethyl-3 H-imidazo[4,5-b]pyridine-3-yl)methyl][1,1'-biphenyl]-2-yl]sul-fonyl]-4-[11C]methoxybenzamide

Angiotensin II (Ang II), an octapeptide, plays an important role in the regulation of cardiovascular, renal, and endocrine functions (1, 2). Ang II induces a variety of physiologic changes, such as constriction of vascular smooth muscle cells, modulation of glomerular filtration rate, and sodium retention, resulting in an increase in blood pressure. Two subtypes of Ang II receptors, AT1 and AT2, have been well characterized pharmacologically and biochemically (3, 4). AT1 is indicated in all known pressor effects of Ang II, whereas no direct Ang II biological functions have been found for AT2. The AT1 receptor subtype is found mainly in all vascular tissues and the pituitary gland and is the only subtype in the liver. The AT2 receptor subtype is found mainly in the rat adrenal medulla, human uterus, rat ovarian granulosa cells, and rat striatum (4-6). In other tissues, such as the adrenal cortex, kidneys, heart, and brain, there is a mixture of both subtypes.

The AT1 nonpeptide antagonist losartan (MK-954 or DuP753) has been shown to be an effective antihypertensive agent (7). MK-996 (L-159,282), a losartan analog, was found to be a potent and selective AT1 antagonist with high affinity (inhibitory concentration (IC50) = 0.15 nM for AT1 and >300 nM for AT2) (8). L-159,884, the methoxyl analog of MK-996 (IC50 = 0.08 nM) (9), has been synthesized as [11C]L-159,884 (N-[[4?[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl][1,1?-biphenyl]-2-yl]sulfonyl]-4-[11C]methoxybenzamide) for in vivo investigation of AT1 expression by positron emission tomography (PET) in the kidneys, adrenal glands, and heart.

Association of Serum Potassium with All-Cause Mortality in Patients with and without Heart Failure, Chronic Kidney Disease, and/or Diabetes

Background: The relationship between serum potassium, mortality, and conditions commonly associated with dyskalemias, such as heart failure (HF), chronic kidney disease (CKD), and/or diabetes mellitus (DM) is largely unknown.
Methods: We reviewed electronic medical record data from a geographically diverse population (n = 911,698) receiving medical care, determined the distribution of serum potassium, and the relationship between an index potassium value and mortality over an 18-month period in those with and without HF, CKD, and/or DM. We examined the association between all-cause mortality and potassium using a cubic spline regression analysis in the total population, a control group, and in HF, CKD, DM, and a combined cohort.
Results: 27.6% had a potassium <4.0 mEq/L, and 5.7% had a value ≥5.0 mEq/L. A U-shaped association was noted between serum potassium and mortality in all groups, with lowest all-cause mortality in controls with potassium values between 4.0 and <5.0 mEq/L. All-cause mortality rates per index potassium between 2.5 and 8.0 mEq/L were consistently greater with HF 22%, CKD 16.6%, and DM 6.6% vs. controls 1.2%, and highest in the combined cohort 29.7%. Higher mortality rates were noted in those aged ≥65 vs. 50-64 years. In an adjusted model, all-cause mortality was significantly elevated for every 0.1 mEq/L change in potassium <4.0 mEq/L and ≥5.0 mEq/L. Diuretics and renin-angiotensin-aldosterone system inhibitors were related to hypokalemia and hyperkalemia respectively.
Conclusion: Mortality risk progressively increased with dyskalemia and was differentially greater in those with HF, CKD, or DM.

Neprilysin Is Required for Angiotensin-(1-7)'s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1-2)

Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve β-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1-7) by ACE2 and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that, although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1-7)-mediated GSIS. However, a more widely expressed islet peptidase, neprilysin, degrades angiotensin-(1-7) into several peptides. In neprilysin-deficient mouse islets, angiotensin-(1-7) and neprilysin-derived degradation products angiotensin-(1-4), angiotensin-(5-7), and angiotensin-(3-4) failed to enhance GSIS. Conversely, angiotensin-(1-2) enhanced GSIS in both neprilysin-deficient and wild-type islets. Rather than mediating this effect via activation of the G-protein-coupled receptor (GPCR) MasR, angiotensin-(1-2) was found to signal via another GPCR, namely GPCR family C group 6 member A (GPRC6A). In conclusion, in islets, intact angiotensin-(1-7) is not the primary mediator of beneficial effects ascribed to the ACE2/angiotensin-(1-7)/MasR axis. Our findings warrant caution for the concurrent use of angiotensin-(1-7) compounds and neprilysin inhibitors as therapies for diabetes.

Vasodilator effect of angiotensin-(1-7) in mature and sponge-induced neovasculature

Angiotensin-(1-7) (Ang-(1-7)), a peptide constituent of the renin-angiotensin system, has been shown to act as a vasodilator mediator in pre-existing (skin) and newly formed vasculatures (14-day-old sponge implants). Blood flow was determined by the outflow rate of sodium fluorescein applied intradermally or intraimplant and the results were expressed in t(1/2) values (time taken for the fluorescence to reach 50% of the peak in the systemic circulation). We showed that the t(1/2) value was significantly lower (4.1+/-0.46) in the implants compared with the cutaneous vasculature (5.7+/-0.5). Ang-(1-7) 20 ng was able to decrease t(1/2) values in both vasculatures. The specific receptor antagonist, D-Ala7-Ang-(1-7) (A-779), prevented Ang-(1-7)-induced vasodilation and altered the basal vascular tone of the implants. The vasodilator effect was also abolished by nitric oxide (NO) synthase inhibitors in both vasculatures and by indomethacin in the implant. Selective AT(1) and AT(2) receptor antagonists did not alter the vasodilation induced by the peptide. These results establish the vasodilator effect of Ang-(1-7) in the cutaneous and implant vasculature and that the peptide is produced endogenously by the fibrovascular tissue, and suggest that this peptide contributes for the vasodilation found in newly formed vascular beds (wound healing, chronic inflammatory processes and tumors).