Adverse cardiac effects of exogenous angiotensin 1-7 in rats with subtotal nephrectomy are prevented by ACE inhibition

Abstract

We previously reported that exogenous angiotensin (Ang) 1–7 has adverse cardiac effects in experimental kidney failure due to its action to increase cardiac angiotensin converting enzyme (ACE) activity. This study investigated if the addition of an ACE inhibitor (ACEi) to Ang 1–7 infusion would unmask any beneficial effects of Ang 1–7 on the heart in experimental kidney failure. Male Sprague–Dawley rats underwent subtotal nephrectomy (STNx) and were treated with vehicle, the ACEi ramipril (oral 1mg/kg/day), Ang 1–7 (subcutaneous 24 μg/kg/h) or dual therapy (all groups, n = 12). A control group (n = 10) of sham-operated rats were also studied. STNx led to hypertension, renal impairment, cardiac hypertrophy and fibrosis, and increased both left ventricular ACE2 activity and ACE binding. STNx was not associated with changes in plasma levels of ACE, ACE2 or angiotensin peptides. Ramipril reduced blood pressure, improved cardiac hypertrophy and fibrosis and inhibited cardiac ACE. Ang 1–7 infusion increased blood pressure, cardiac interstitial fibrosis and cardiac ACE binding compared to untreated STNx rats. Although in STNx rats, the addition of ACEi to Ang 1–7 prevented any deleterious cardiac effects of Ang 1–7, a limitation of the study is that the large increase in plasma Ang 1–7 with ramipril may have masked any effect of infused Ang 1–7.

Clinical Implications of SARS-CoV-2 Interaction With Renin Angiotensin System

“…Treatment with ramipril and valsartan resulted in increased plasma Ang I and Ang II and suppression in plasma ACE and ACE2 activity, however, neither monotherapy nor combination therapy affected ACE2 or AT1 receptor expression, both of which remained at levels comparable to non-myocardial infarction control [48]. However, a prior study in the same murine model showed ACE and ACE2 upregulation in the border, infarct zones and in viable myocardium after myocardial infarction, and treatment with ramipril reduced ACE expression while ACE2 remained elevated compared to non-infarcted control [49]. A recent study in the same murine model demonstrated that treatment with olmesartan or telmisartan increased both cardiac ACE2 mRNA and protein expression while augmenting plasma Ang 1-7/Ang II ratios resulting in improved cardiac function and alleviated collagen disposition [40].…”

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

“… Male Wistar rats/ Doxorubicin-induced cardiomyopathy model No change in cardiac ACE2 protein expression in doxorubicin treated rats H. Ma et al (2017) Ramipril/ ACE-Inh. Male Sprague Dawley rats/ Subtotal nephrectomy induced kidney disease model No effect on cardiac ACE2 activity in subtotal nephrectomized rats Burrell, Gayed, Griggs, Patel, & Velkoska (2017) Captopril/ ACE-Inh. Female Wistar rats/ Ovariectomized rat model for osteoporosis Increased bone ACE2 protein expression in osteoporotic rats.…”

Morphological and Functional Characteristics of Animal Models of Myocardial Fibrosis Induced by Pressure Overload

“…However, in other experiments, myocardial fibrosis on histology was first detected at 5 weeks (mortality unknown) [78]. Similarly, myocardial fibrosis can also be induced after 10 days of right nephrectomy, which is consistent with an increase in collagen content [74]. But Chang et al observed only impaired cardiac relaxation without myocardial fibrosis 8 weeks after left nephrectomy [79].…”

“…Nephrectomy causes water and sodium excretion disorders, resulting in increased blood volume, extracellular fluid volume, ventricular pressure, and volume overload; this ultimately leads to cardiac disease. Activation of RASS system [74] and parasympathetic disorder [75] are considered to be the pathogenic factors of nephropathy and its cardiovascular complications. e 5/6 nephrectomy model is considered a classic model for studying cardiovascular complications of kidney disease.…”