Sphingosine-1-Phosphate (S1P) Lyase Inhibition Causes Increased Cardiac S1P Levels and Bradycardia in Rats

Abstract

Inhibition of the sphingosine-1-phosphate (S1P)-catabolizing enzyme S1P lyase (S1PL) elevates the native ligand of S1P receptors and provides an alternative mechanism for immune suppression to synthetic S1P receptor agonists. S1PL inhibition is reported to preferentially elevate S1P in lymphoid organs. Tissue selectivity could potentially differentiate S1PL inhibitors from S1P receptor agonists, the use of which also results in bradycardia, atrioventricular block, and hypertension. But it is unknown if S1PL inhibition would also modulate cardiac S1P levels or cardiovascular function. The S1PL inhibitor 6-[(2R)-4-(4-benzyl-7-chlorophthalazin-1-yl)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile was used to determine the relationship in rats between drug concentration, S1P levels in select tissues, and circulating lymphocytes. Repeated oral doses of the S1PL inhibitor fully depleted circulating lymphocytes after 3 to 4 days of treatment in rats. Full lymphopenia corresponded to increased levels of S1P of 100-to 1000-fold in lymph nodes, 3-fold in blood (but with no change in plasma), and 9-fold in cardiac tissue. Repeated oral dosing of the S1PL inhibitor in telemeterized, conscious rats resulted in significant bradycardia within 48 hours of drug treatment, comparable in magnitude to the bradycardia induced by 3 mg/kg fingolimod. These results suggest that S1PL inhibition modulates cardiac function and does not provide immune suppression with an improved cardiovascular safety profile over fingolimod in rats.

Overexpression of sphingosine-1-phosphate lyase protects insulin-secreting cells against cytokine toxicity

“…SPL deficiency in mice has been shown to induce systemic inflammation (27). SPL inhibition or knockdown contributes to deleterious inflammatory responses in the brain, heart, colon, and lungs (27,30,31) and can cause cardio-and neurotoxicity (32)(33)(34). So far, very little is known about the role of SPL in insulin-secreting cells.…”

Sphingolipid metabolism and signaling in cardiovascular diseases

“…A shortening of the ERP may predispose to the development of reentry arrhythmias, such as atrial fibrillation ( 178 ). Moreover, in Sprague Dawley rats, pharmacological inhibition of S1P lyase caused bradycardia ( 179 ).…”

The role of sphingosine 1‐phosphate and its receptors in cardiovascular diseases

“… 17 Varying S1P plasma concentrations are closely related to multiple cardiovascular diseases, including heart rate change, coronary heart disease (CAD), atherosclerosis, heart failure and myocardial infarction (MI) 18‐21 . Therefore, the S1PL inhibitor, 6‐[(2R)‐4‐(4‐benzyl‐7‐chlorophthalazin‐1‐yl)‐2‐methylpiperazin‐1‐yl] pyridine‐3‐carbonitrile, has been applied to increase S1P plasma concentrations and slow down heart rate and consequently improve heart function 18 . In patients with CAD, the severity of stenosis is positively associated with the increased serum S1P concentrations.…”

“…17 Varying S1P plasma concentrations are closely related to multiple cardiovascular diseases, including heart rate change, coronary heart disease (CAD), atherosclerosis, heart failure and myocardial infarction (MI). [18][19][20][21] Therefore, the S1PL inhibitor,…”