Effects of Sacubitril/Valsartan on Serum Lipids in Heart Failure With Preserved Ejection Fraction.

Background Dyslipidemia is common in heart failure with preserved ejection fraction. Sacubitril/valsartan improves glycemic control and augments natriuretic peptide signaling, providing mechanisms by which sacubitril/valsartan may affect serum lipids. However, empiric data on these effects are lacking. Methods and Results We analyzed 4774 participants from PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Receptor Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction) with available screening lipids. During follow-up visits, we analyzed the treatment effect on lipid levels and assessed for interaction by baseline lipid levels. At the 16-week visit, we adjusted these treatment effects for the change in several biomarkers (including hemoglobin A1c and urinary cyclic guanosine monophosphate/creatinine [a biomarker of natriuretic peptide activation]). The average age was 73±8 years, 52% were women, 43% had diabetes mellitus, and 64% were on statin therapy. Compared with valsartan, sacubitril/valsartan reduced triglycerides -5.0% (95% CI, -6.6% to -3.5%), increased high-density lipoprotein cholesterol +2.6% (95% CI, +1.7% to +3.4%), and increased low-density lipoprotein cholesterol +1.7% (95% CI, +0.4% to +3.0%). Sacubitril/valsartan reduced triglycerides most among those with elevated baseline levels (triglycerides≥200 mg/dL) (P-interaction<0.001), and at 16 weeks by -13.0% (95% CI, -18.1% to -7.6%), or -29.9 (95% CI, -44.3 to -15.5) mg/dL, in this group. Adjusting for the change in urinary cyclic guanosine monophosphate/creatinine significantly attenuated treatment effects on triglycerides and high-density lipoprotein cholesterol, but not low-density lipoprotein cholesterol, while adjusting for other biomarkers did not significantly alter the treatment effects. Conclusions Sacubitril/valsartan significantly reduces triglycerides compared with valsartan, an effect that was nearly threefold stronger in those with elevated baseline triglycerides. Modest increases in high-density lipoprotein cholesterol and low-density lipoprotein cholesterol cholesterol were also observed with therapy. The underlying mechanism(s) of changes in high-density lipoprotein cholesterol and triglycerides are related to sacubitril/valsartan's effects on natriuretic peptide activity. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Hemodynamic, Hormonal, and Renal Actions of Phosphodiesterase-9 Inhibition in Experimental Heart Failure.

BACKGROUND: Phosphodiesterase-9 (PDE9) reduces natriuretic peptide (NP) signaling and may be involved in the pathophysiology of heart failure (HF). OBJECTIVES: This study investigated for the first time the integrated hemodynamic, endocrine, and renal effects of phosphodiesterase-9 inhibition (PDE9-I). METHODS: A total of 8 normal sheep and 8 sheep with pacing-induced HF received incremental intravenous boluses of PDE9-I (30, 100, and 300 mg PF-04749982 at 1-h intervals). RESULTS: PDE9-I dose-dependently increased plasma cyclic guanosine monophosphate (cGMP) in normal sheep (p < 0.05) while concurrently reducing circulating atrial natriuretic peptide levels (p < 0.01). Similar trends were evident in HF, resulting in significant elevations in the cGMP/NP ratio in both states (p < 0.001 and p < 0.05, respectively). PDE9-I also produced progressive falls in arterial pressure (HF: p < 0.001), atrial pressure (Normal: p < 0.001; HF: p < 0.001), and peripheral resistance (HF: p < 0.001), and transiently increased cardiac output at the top dose (Normal: p < 0.05; HF: p < 0.001). Inhibition of PDE9 had a negligible effect on circulating hormones at the lower doses, but post-high dose, acutely increased renin activity (Normal: p < 0.001; HF: p < 0.05), vasopressin (Normal: p < 0.001; HF: p < 0.01), and cyclic adenosine monophosphate (HF: p < 0.001). Plasma aldosterone increased briefly after high-dose PDE9-I in normal sheep, and fell following the top dose in HF. PDE9-I dose-dependently increased urinary cGMP in both states (both p < 0.001). In HF, this was associated with increases in urine volume (p < 0.01), sodium excretion (p < 0.01), and creatinine clearance (p < 0.001). CONCLUSIONS: PDE9-I improves NP efficacy in conjunction with beneficial hemodynamic and renal effects in experimental HF. These results support a role for PDE9 in HF pathophysiology and suggest its inhibition may constitute a novel therapeutic approach to this disease.

Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension.

The detailed integrated renal, hormonal, and hemodynamic effects of acute (first dose) and established (4 days) inhibition of endopeptidase 24.11 by SCH 42495 (200 mg, every 12 hours) were documented in eight patients with essential hypertension in a double-blind, balanced random-order, crossover study. SCH 42495 suppressed plasma endopeptidase activity (> 90%, P < .001) for the duration of the dosing period. Initially, plasma atrial natriuretic factor levels increased markedly (+123%, P < .01) and remained elevated, although to a lesser extent (+34%, P < .01), with established enzyme inhibition. Cyclic guanosine monophosphate in both plasma and urine remained elevated throughout the treatment period. Significant augmentation of sodium excretion in excess of placebo values (96 +/- 27 mmol sodium, P < .001) was established in the initial 24 hours of dosing but later became attenuated, with a mild antinatriuresis (P < .01) in the latter 3 days of treatment. Blood pressure, heart rate, the renin-angiotensin-aldosterone system, and plasma norepinephrine levels were all initially (first dose) unchanged. With established enzyme inhibition (day 4), however, blood pressure was significantly lower (mean 24-hour values, 9.3 +/- 3/-3.8 +/- 1 mm Hg, P < .05 for both systolic and diastolic pressures) than matched placebo values, whereas heart rate was higher (2.7 +/- 1 beats per minute, P < .01). Mean 24-hour values of plasma renin activity (+33%, P < .05), aldosterone (+36%, P < .05), and norepinephrine (+40%, P < .001) were all clearly increased above placebo values with established enzyme inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined inhibition of neutral endopeptidase and angiotensin-converting enzyme by sampatrilat in essential hypertension.

BACKGROUND: The antihypertensive response to angiotensin-converting enzyme (ACE) inhibitors may be attenuated by a compensatory decrease in atrial natriuretic factor production. If so, inhibition of atrial natriuretic factor breakdown by neutral endopeptidase (NEP) may enhance the antihypertensive effects of ACE inhibition. We compared effects of the combined ACE-NEP inhibitor sampatrilat, lisinopril, and placebo on blood pressure, plasma ACE, and renin activity and urinary cyclic guanosine monophosphate (cGMP) of patients with hypertension. METHODS AND RESULTS: After a 4-week placebo run-in period, 124 patients with a mean blood pressure of 162/102 mm Hg were randomized in a double-blind parallel-group design to 1 of 5 treatments, given once daily for 10 days: 50 mg, 100 mg, or 200 mg sampatrilat; 20 mg lisinopril; or placebo. The first dose of sampatrilat did not lower clinic or ambulatory blood pressure. Lisinopril had an immediate antihypertensive effect that differed significantly from all doses of sampatrilat. After 10 days of treatment, sampatrilat lowered clinic and ambulatory blood pressure significantly at all doses, with a trend toward a dose response for systolic ambulatory blood pressure. Sampatrilat inhibited plasma ACE in a dose-dependent fashion but significantly less so than lisinopril on days 1 and 10 of treatment. Lisinopril but not sampatrilat significantly increased plasma renin activity, whereas sampatrilat but not lisinopril significantly increased urinary cGMP excretion. CONCLUSION: The increasing efficacy of sampatrilat compared with lisinopril over 10 days could not be attributed to an increase in plasma ACE inhibition, suggesting that the NEP inhibitor activity of sampatrilat may have contributed to its antihypertensive action. NEP inhibition may enhance the antihypertensive effect of ACE inhibition.

Atriopeptin regulation and renal function in conscious spontaneously hypertensive rats.

We examined the interaction of a non-guanylate cyclase-linked atriopeptin (AP) binding site ligand, SC-46542 (des[Phe106,Gly107,Ala115,Gln116]AP-(103-126], and an endopeptidase 24.11 inhibitor, thiorphan, on mean arterial pressure, urinary sodium excretion, urinary cyclic guanosine monophosphate (cGMP) excretion, plasma cGMP concentration, and plasma AP immunoreactivity (ir) in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Compared to vehicle control rats, coadministration of SC-46542 and thiorphan increased urinary sodium excretion in SHR from 2.1 +/- 0.3 to 11.6 +/- 0.7 microEq/min/100 g body weight and in WKY from 1.6 +/- 0.4 to 4.4 +/- 0.4 microEq/min/100 g body weight, and increased urinary cGMP excretion in SHR from 2.7 +/- 0.5 to 79.0 +/- 17.5 pmol/min/100 g body weight and in WKY from 7.0 +/- 3.0 to 72.4 +/- 10.6 pmol/min/100 g body weight. The change in urinary sodium excretion was greater in SHR than WKY. The coadministration of SC-46542 and thiorphan had greater effects on urinary sodium excretion and urinary cGMP excretion than administration of either compound alone. Coadministration of thiorphan and SC-46542 had no effect on glomerular filtration rate or plasma cGMP concentration, suggesting that the urinary cGMP excretion response was nephrogenous. Compared to vehicle control rats, plasma APir was increased during coadministration of SC-46542 and thiorphan in both SHR (998 +/- 76 v 5.10 +/- 116 pg/mL) and WKY (775 +/- 36 v 414 +/- 36 pg/mL).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of ecadotril, a neutral endopeptidase inhibitor, on myocardial hypertrophy in the rat aortic insufficiency model.

Cardiac hypertrophy develops to compensate for hemodynamic overload of the myocardium. However, cardiac hypertrophy itself poses a serious risk to patients with heart failure. Whether natriuretic peptides enhanced by ecadotril, a neutral endopeptidase inhibitor, suppress the increase of left ventricular mass in the rat aortic insufficiency model was investigated. Ecadotril suppressed the increase of the left ventricular mass without affecting blood pressure (710.9 +/- 15.6 mg in the group treated with ecadotril and 865.0 +/- 27.3 mg in the control group, P < 0.01). Although the increase of atrial natriuretic peptide in the left ventricle was trivial and did not reach statistical significance (406.5 +/- 62.2 pg/mg in the ecadotril-treated group versus 269.8 +/- 35.7 pg/mg in the control group), urinary cGMP excretion was greater in the group given ecadotril than in the control group (10.6 +/- 2.5 pmol/mL and 1.7 +/- 0.6 pmol/mL, respectively, P < 0.01). Plasma angiotensin II concentration also decreased in the group treated with ecadotril compared with the control group (116.6 +/- 25.4 pg/mL versus 358.7 +/- 98.7 pg/mL, P < 0.05). In conclusion, ecadotril suppressed the increase of left ventricular mass in the overloaded heart. In ecadotril-treated rats, cGMP synthesis was augmented and angiotensin II concentration was reduced.

The role of nitric oxide metabolites during pregnancy.

Nitric Oxide (NO) is a potent vascular endothelial cell derived vasorelaxant with important effects on vascular tone. This study was initiated to clarify the role of urinary metabolites of nitric oxide (NOx) during pregnancy. Twenty four normal pregnant women and 12 patients with preeclampsia were studied. Urinary NOx levels were determined with the Greiss reagent and spectrophotometry methods after enzymatic reduction of nitrate to nitrite in the samples. Urinary excretion of nitric oxide (NOx) were elevated in normal pregnant women and decreased in preeclamptic women. A significant correlationship was observed in the urinary excretion of cyclic guanosine monophosphate (cGMP) level in between the normal and preeclamptic puerperial groups (p < 0.05). Positive correlationships were found between urinary excretion of nitrate level and either of fractional excretion of sodium (FENa) (r = 0.702, p < 0.005) or fractional excretion of calcium (FECa) (r = 0.570, p < 0.04) in normal and preeclamptic subjects. Also a positive correlationship was observed between the level of urinary NOx excretion and high density lipoprotein cholesterol (HDL-cholesterol) (r = 0.681, p < 0.005). Our results suggest that nitric oxide may play an important role in the mechanism to modulate circulatory physiology of normal and preeclamptic pregnant women.

Impaired natriuretic and renal endocrine response to acute volume expansion in pre-clinical systolic and diastolic dysfunction.

OBJECTIVES: We hypothesized an impaired renal endocrine and natriuretic response to volume expansion (VE) in humans with pre-clinical systolic dysfunction (PSD) and pre-clinical diastolic dysfunction (PDD). We further hypothesized that exogenous B-type natriuretic peptide (BNP) could rescue an impaired natriuretic response in PSD and PDD. BACKGROUND: Recent reports suggest that in early systolic heart failure (HF), there is an impaired natriuretic response to acute VE. METHODS: PSD was defined as left ventricular ejection fraction <40% without HF symptoms. PDD was defined as ejection fraction >50%, moderate to severe diastolic dysfunction by Doppler criteria, and no HF symptoms. A double-blinded, placebo-controlled, crossover study was employed to determine the renal response to VE (0.25 ml/kg/min of normal saline for 60 min) in the presence and absence of exogenous BNP. Twenty healthy control subjects, 20 PSD subjects, and 18 PDD subjects participated. RESULTS: In healthy control subjects, urinary cyclic guanosine monophosphate (cGMP) and natriuresis increased after VE. In contrast, among PSD and PDD subjects, there was a paradoxical decrease in urinary cGMP and attenuated natriuresis. Pre-treatment with subcutaneous BNP resulted in similar increases in both urinary cGMP and natriuresis among healthy normal, PSD, and PDD subjects. CONCLUSIONS: In PSD and PDD, there is impaired renal cGMP activation, which contributes to impaired natriuresis in response to VE. Impaired activation of urinary cGMP and reduced natriuresis may contribute to volume overload and the progression of HF among PSD and PDD subjects. Importantly, the impaired renal excretory response to VE is rescued by exogenous BNP in PSD and PDD.

Excessive vasoconstriction after stress by the aging kidney: inadequate prostaglandin modulation of increased endothelin activity.

The adaptive capacity of the aging kidney to stimulation of the sympathetic nervous system, as induced by a 30-minute mental stress (MS), was assessed in 8 elderly healthy women (68 to 82 years of age) and compared with that of 8 younger women (24 to 40 years of age). The study encompassed 4 consecutive 30-minute periods (baseline, mental stress, recovery 1, and recovery 2). In the elderly subjects, baseline effective renal plasma flow (ERPF)(iodine 131-labeled hippurate clearance) was lower and glomerular filtration rate (GFR)(iodine 125-labeled iothalamate clearance) was proportionally less reduced than in the younger group; the filtration fraction (FF) was higher. The elderly group excreted more endothelin 1 (ET-1) (P < .05), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1alpha (6-keto PGF1alpha)(P < .001 for both)(radioimmunoassay). Mental stress induced similar increases in blood pressure, heart rate, and plasma catecholamines in the 2 age groups, limited to the stimulation period. In the elderly group, mental stress caused a prolonged decrease in ERPF that reached its maximum 60 minutes after mental stress (-33%, P < .05), while GFR remained constant during the whole experiment, so that FF increased. In the younger subjects, renal hemodynamic changes were limited to the mental stress period. ET-1 increased during mental stress and the first recovery period in the elderly group (+50% and +25%, P < .05) as it did in the younger group, but the elderly group differed from the younger in that vasodilating prostaglandins increased only during mental stress. In conclusion, the aging kidney reacts to adrenergic stimulation with more-pronounced and -prolonged vasoconstriction that is probably caused by a defect in prostaglandin modulation of endothelin activity. Autoregulation of GFR is maintained at the expense of increased intraglomerular pressure.

Sub-antihypertensive doses of ramipril normalize sarcoplasmic reticulum calcium ATPase expression and function following cardiac hypertrophy in rats.

We examined the hypothesis that the angiotensin converting enzyme inhibitor ramipril at sub-antihypertensive concentrations could improve sarcoplasmic reticulum (SR) CaATPase expression and function in compensated hypertrophied rat hearts. Five weeks after abdominal aortic constriction, rats received a daily dose (50 micrograms/kg/day) of ramipril or vehicle for 4 weeks. Cardiac angiotensin-converting enzyme (ACE) activity increased with cardiac hypertrophy (CH) but returned to normal following ramipril treatment. SR CaATPase protein levels and activity decreased with CH (P < 0.05) and were normalized following ramipril treatment (P < 0.05 for protein and activity). No change in phospholamban (PLB) protein levels could be demonstrated between any of the groups. In contrast, ramipril treatment specifically increased control SR CaATPase and PLB mRNA levels by > 60% (P < 0.01) and > 30%, respectively. In the hypertrophied group, SR CaATPase increased by 35% (P < 0.05 n = 6) after ramipril treatment. Calsequestrin mRNA levels were unaffected by ramipril administration. In conclusion, ramipril normalizes SR CaATPase protein expression and function in pressure-overloaded and compensated CH. The effects of ramipril are however multifaceted, affecting RNA and protein expression differentially.

Blockade of endothelium-dependent responses in conscious rats by cyclosporin A: effect of L-arginine.

This study was undertaken to examine the effect of the major immunosuppressive drug, cyclosporin A (CyA), on endothelial function. Conscious Wistar rats, treated with CyA (25 mg.kg-1 x day-1 im for 15 days), developed an inhibition of the endothelium-dependent acetylcholine (ACh)-mediated vasodilation, diuresis, natriuresis, and guanosine 3',5'-cyclic monophosphate excretion. The response to two endothelium-independent agents, i.e., sodium nitroprusside and atrial natriuretic peptide was preserved in similarly treated rats. The toxic effects of CyA were acutely overcome by the administration of the amino acid L-arginine (L-Arg), a source of substrate for nitric oxide. Moreover, the simultaneous administration of L-Arg (200 mg/kg ip for 15 days) significantly prevented the functional effects of CyA toxicity. The present data suggest that, in early stages of CyA toxicity, the predominant functional alteration occurs at the endothelial level. The reversibility of such alteration by L-Arg opens the possibility for further strategies aimed to reduce the harmful effects of CyA.