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Kinetensin Increases Blood Pressure by Activation of Angiotensin‐II Type 1 Receptors, in Isoflurane Anesthetized Male Mice
Author(s) -
Mohammed Mazher,
Filipeanu Catalin,
Lazartigues Eric
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04168
Subject(s) - neurotensin , angiotensin ii , in vivo , chemistry , jugular vein , blood pressure , endocrinology , saline , medicine , heart rate , cannula , receptor , renin–angiotensin system , pharmacology , neuropeptide , biology , surgery , microbiology and biotechnology
Kinetensin, a peptide consisting of nine amino acids, originally isolated from pepsin‐treated human plasma, shows sequence homology with serum albumin, angiotensin (Ang)‐II and neurotensin (Mogard et al., 1986). Due to its interesting homology with the C‐terminal end of neurotensin and Ang‐II, it was earlier suggested that this peptide might have neurotensin‐ or Ang‐II‐like biological activity. Earlier, in‐vitro studies revealed the functional role of kinetensin in releasing histamine from mast cells (Sydbom et al., 1989); however, the cardiovascular role of kinetensin, in‐vivo , has never been established. In the present study, we investigated first the functional role of kinetensin on blood pressure (BP) and heart rate (HR) variables in mice. Under isoflurane anaesthesia, 12 male C57Bl6/J mice (30‐33 g) were implanted with a Millar catheter into their left common carotid artery for continuous recording of BP and HR. The right jugular vein was implanted with flexible cannula for intravenous administration of drugs or saline. Raw traces were obtained using PowerLab (ADInstruments) and analogue signals were digitized using LabChart8 software. Under stable baselines, kinetensin was administered intravenously (1, 10, 100 μg in 0.1 mL of saline). In comparison to vehicle, kinetensin dose‐dependently increased BP (2 ±0, 8 ±1, 29 ±4 mmHg, respectively) with a variable response in HR (‐6 ±6, ‐7 ±16, 2 ±11 bpm, respectively), log‐dose regression R 2 = 0.77, p<0.001 for BP and R 2 = 0.001, p<0.91 for HR, n=6. BP responses were precisely reproducible at approximately 10 min intervals and there was no desensitization effect observed for the highest kinetensin dose of 100 μg, 29±4 and 33±4, p=0.268 , n=6. Interestingly, pre‐treatment with an AT1‐receptor antagonist (losartan, 15 mg/kg, i.v.), completely eliminated the kinetensin‐mediated (100 μg dose) BP increase (pre‐losartan 29±4 versus post‐losartan ‐3±1 mmHg, respectively, p<0.001). In another cohort (n=6), pre‐treatment with a ganglionic‐blocker (chlorisondamine, 5 mg/kg) substantially reduced baseline BP, however subsequent administration of kinetensin i.v. produced delayed (~ 1 min) with much bigger and prolonged increases in BP responses (55±5 mmHg; p<0.001) compared to untreated mice (~ 5 sec, 29 ±4 mmHg, p<0.001). Our preliminary results show for the first time that kinetensin increases BP in a dose‐dependent manner via activation of AT1 receptors, similar to Ang‐II. Blockade of autonomic nervous control innervating vasculature produces similar increases in BP with much longer latencies strongly suggests a potential neuropeptide secretion role, such as arginine vasopressin. Further studies are needed to explore the kinetensin role in the central nervous system‐mediated autonomic and neuroendocrine functions.