Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Abstract

BackgroundCyclic guanosine monophosphate‐protein kinase G‐phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl‐peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function.Methods and ResultsWe assessed LV hypertrophy and function at the organ and cellular level in aortic‐banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end‐systolic pressure‐volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil‐treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening‐frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium‐retention capacity and Complex II‐dependent respiratory control, was present in both HF and tadalafil‐treated animals.ConclusionsBoth saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

Loss of Female Sex Hormones Exacerbates Cerebrovascular and Cognitive Dysfunction in Aortic Banded Miniswine Through a Neuropeptide Y–Ca 2+ ‐Activated Potassium Channel–Nitric Oxide Mediated Mechanism

“…Heart failure was induced with AB over a period of 24 weeks, as previously reported by our laboratory, in AB and AB‐OVX miniature swine at 8 months of age. The AB was placed around the ascending aorta, and a systolic transstenotic gradient of ≈70 mm Hg was achieved (73±3 and 72±3 mm Hg for AB and AB‐OVX, respectively; P =0.83).…”

“…Vena cava occlusion was performed to induce central hypovolemia, as previously described . MAP and carotid artery blood flow were recorded at baseline, during balloon inflation/vena cava occlusion, at the end of inflation, and for 60 seconds after deflation.…”

“…Heart failure was induced with AB over a period of 24 weeks, as previously reported by our laboratory, 5,22,23 in AB and AB-…”

“…31 Vena cava occlusion was performed to induce central hypovolemia, as previously described. 5,22,23 MAP and carotid artery blood flow were recorded at baseline, during balloon inflation/vena cava occlusion, at the end of inflation, and for 60 seconds after deflation. Data during the inflation and deflation were averaged across quintiles based on time (ie, 5 12-second averages were calculated for the 60-second period after recovery from vena cava occlusion).…”

Regulation of Intracellular Calcium by Carbon Monoxide in Human Bronchial Epithelial Cells

“…Protein (50 µg) was added to each well for further assay. The PKG activity assay was performed using the Cylex cyclic GMP-dependent protein kinase assay kit (MBL, USA) as previously described [33]. …”