Functional pharmacological characterization of SER100 in cardiovascular health and disease.
SER100 is a selective nociceptin (NOP) receptor agonist with sodium-potassium-sparing aquaretic and anti-natriuretic activity. This study was designed to characterize the functional cardiovascular pharmacology of SER100 in vitro and in vivo, including experimental models of cardiovascular disease.



Haemodynamic, ECG parameters and heart rate variability (HRV) were determined using radiotelemetry in healthy, conscious mice. The haemodynamic and vascular effects of SER100 were also evaluated in two models of cardiovascular disease, spontaneously hypertensive rats (SHR) and murine hypoxia-induced pulmonary hypertension (PH). To elucidate mechanisms underlying the pharmacology of SER100, acute blood pressure recordings were performed in anaesthetized mice, and the reactivity of rodent aorta and mesenteric arteries in response to electrical- and agonist-stimulation assessed.



SER100 caused NOP receptor-dependent reductions in mean arterial blood pressure and heart rate that were independent of NO. The hypotensive and vasorelaxant actions of SER100 were potentiated in SHR compared with Wistar Kyoto. Moreover, SER100 reduced several indices of disease severity in experimental PH. Analysis of HRV indicated that SER100 decreased the low/high frequency ratio, an indicator of sympatho-vagal balance, and in electrically stimulated mouse mesenteric arteries SER100 inhibited sympathetic-induced contractions.



SER100 exerts a chronic hypotensive and bradycardic effects in rodents, including models of systemic and pulmonary hypertension. SER100 produces its cardiovascular effects, at least in part, by inhibition of cardiac and vascular sympathetic activity. SER100 may represent a novel therapeutic candidate in systemic and pulmonary hypertension.
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Inmaculada C
IC
Villar
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Kristen J
KJ
Bubb
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Amie J
AJ
Moyes
Serodus ASA, Oslo, Norway.
Eva
E
Steiness
Serodus ASA, Oslo, Norway.
Trygve
T
Gulbrandsen
Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
Finn Olav
FO
Levy
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Adrian J
AJ
Hobbs
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000503:physiopathology; D002319:Cardiovascular System / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists*; D000094942:Nociceptin Receptor
D009842:Oligopeptides; D011957:Receptors, Opioid; C473470:ZP120; D000094942:Nociceptin Receptor
Exp Physiol. 2013 Oct;98(10):1432-45
23748904
Eur J Pharmacol. 2009 Jul 1;614(1-3):50-7
19445927
Exp Physiol. 2008 Jan;93(1):83-94
17911354
Br J Pharmacol. 2010 Aug;160(7):1577-9
20649561
Hypertension. 1983 Nov-Dec;5(6):881-6
6654451
Nucleic Acids Res. 2016 Jan 4;44(D1):D1054-68
26464438
Peptides. 2000 Jul;21(7):1081-99
10998543
Life Sci. 1997;60(8):PL141-5
9042395
J Neurosci. 1996 Nov 1;16(21):6657-64
8824306
Peptides. 2000 Jul;21(7):961-7
10998529
J Pharmacol Exp Ther. 2005 Aug;314(2):652-60
15855355
Antioxid Redox Signal. 2002 Oct;4(5):833-43
12470512
Br J Pharmacol. 2015 Dec;172(24):5979-6023
26650444
Peptides. 2009 Feb;30(2):248-55
18992780
J Pharmacol Exp Ther. 1997 Nov;283(2):735-41
9353393
Proc Natl Acad Sci U S A. 1997 May 13;94(10):5450-5
9144258
Br J Pharmacol. 2016 Dec;173(23):3386-3401
27667485
Circ J. 2009 Dec;73(12):2337-41
19822980
Pharmacol Ther. 2013 Oct;140(1):10-25
23711793
Circulation. 2004 Sep 7;110(10):1308-12
15337703
Life Sci. 2000;66(6):PL99-104
10794074
Br J Pharmacol. 2011 Sep;164(2b):584-97
21457229
Br J Pharmacol. 2000 Apr;129(7):1261-83
10742280
Circulation. 2012 Jun 12;125(23):2922-32
22572914
Clin Exp Pharmacol Physiol. 2008 Apr;35(4):454-7
18307740
Circ Res. 2003 May 16;92(9):984-91
12690034
Br J Pharmacol. 2006 Jul;148(5):703-13
16715120
Am J Physiol Regul Integr Comp Physiol. 2008 Dec;295(6):R1822-30
18832081
J Clin Invest. 1997 Apr 1;99(7):1500-5
9119993
Br J Pharmacol. 2015 Dec;172(24):5904-41
26650441
Br J Pharmacol. 2015 Jul;172(14):3461-71
26114403
PLoS One. 2013 May 07;8(5):e60850
23667430
Respir Res. 2009 Oct 13;10:95
19825167
Br J Pharmacol. 2015 Dec;172(24):5744-869
26650439
Circulation. 2001 Oct 30;104(18):2242-8
11684638
Brain Res. 1999 May 22;829(1-2):134-42
10350539
Br J Pharmacol. 1987 Jan;90(1):147-50
3814916
Circulation. 2004 Jan 20;109(2):159-65
14734504
Br J Pharmacol. 2015 Dec;172(24):5942-55
26650442
Am J Physiol Heart Circ Physiol. 2007 Nov;293(5):H2977-85
17766480
Am J Respir Crit Care Med. 2011 Nov 15;184(10):1171-82
21868504
J Pharmacol Exp Ther. 2009 Feb;328(2):533-9
19028991
Am J Physiol Lung Cell Mol Physiol. 2012 Aug 15;303(4):L343-53
22683574
Cardiovasc Res. 2007 Jun 1;74(3):515-25
17391657
PLoS One. 2013 Sep 23;8(9):e74943
24086402
Diagn Pathol. 2013 Nov 25;8:193
24274330
Circ Res. 2007 Mar 30;100(6):782-94
17395884
Br J Pharmacol. 2015 Dec;172(24):6024-109
26650445
Br J Pharmacol. 2002 Oct;137(3):369-74
12237257
Am J Physiol Renal Physiol. 2004 Jul;287(1):F160-8
15010357
J Pharmacol Exp Ther. 2007 Jul;322(1):324-31
17452419
Am J Physiol Lung Cell Mol Physiol. 2000 May;278(5):L867-79
10781416
Br J Pharmacol. 1996 Apr;117(8):1609-11
8732266
Circ Res. 1977 Jul;41(1):19-26
862138
Am J Physiol Renal Physiol. 2007 May;292(5):F1443-51
17229677
Hypertension. 2006 Jul;48(1):157-64
16682607
Br J Pharmacol. 2008 Mar;153(6):1185-94
18193068
Eur J Pharmacol. 1997 Aug 27;333(2-3):177-9
9314032
Brain Res. 1999 Jul 24;835(2):315-23
10415388
Clin Exp Pharmacol Physiol. 2002 Mar;29(3):229-32
11906489
Arterioscler Thromb Vasc Biol. 2007 Sep;27(9):1877-85
17541026
Br J Pharmacol. 2015 Jul;172(13):3189-93
25964986
Circulation. 2014 Aug 5;130(6):496-507
24899690
Am J Respir Cell Mol Biol. 2014 Jun;50(6):1010-20
24328827