Alpha Calcitonin gene-related peptide protects the vasculature in L-NAME-induced hypertension

F. Argunhan¹, X. Kodji¹, A. A. Aubdool¹, M. Nandi², J. E. Clark³, S. D. Brain¹. ¹Vascular Biology Group, King\'s College London, London, United Kingdom, ²Institute of Pharmaceutical Science, King\'s College London, London, United Kingdom, ³The Rayne Institute, King\'s College London, London, United Kingdom.

Introduction: Alpha Calcitonin Gene-Related Peptide (αCGRP) is a potent vasodilator neuropeptide that has recently been shown to be protective in AngII-induced hypertension (1,2). The current study aimed to characterize L-NAME-induced experimental model of hypertension and elucidate whether αCGRP’s protective mechanism involves nitric oxide (NO) and ATP-sensitive K⁺ channels.

Method: All in vivo procedures were carried out in accordance to the UK Home Office Animals (Scientific Procedures) Act 1986. L-NAME (1mg/ml) was administered in drinking water of age matched (8-10 weeks) male C57BL/6J wild type (WT) and αCGRP knock-out (KO) mice. After 14 days, the left carotid artery was cannulated under terminal anaesthesia (Isoflurane; 5% induction, 2% maintenance) for measurement of mean arterial blood pressure (MAP) (2). A subcohort of L-NAME treated WT mice were cannulated and received intravenous (i.v.) injection of the CGRP receptor antagonist BIBN 4096 BS (0.3mg/kg). Additionally, a selective ATP-sensitive potassium channel (K_ATP) inhibitor PNU 37883 (2mg/kg, i.v.) was used to investigate the role K_ATP channels play in blood pressure regulation. Data is expressed as mean ± SEM (n=5-7) and analysis was performed using 2-way ANOVA followed by Bonferroni post hoc test.

Results: Figure 1 shows that control WT and αCGRP KO mice had similar MAP whereas the L-NAME treated WT mice developed significantly higher MAP, as expected. MAP was further exacerbated in αCGRP KO mice and in WT mice injected with the antagonist BIBN 4096 BS. The K_ATP inhibitor, PNU 37883, did not show a significant difference in mean arterial blood pressure across groups.

Conclusion: Chronic treatment with L-NAME induced hypertension in αCGRP WT mice, as expected, which was further exacerbated in αCGRP KO mice or with CGRP antagonist treatment. In conclusion, a model of hypertension has been established and novel data suggests that the protective role of αCGRP is independent of endogenous NO formation. The protective mechanism does not appear to be mediated by ATP- sensitive potassium channels. Thus, the actual protective mechanism of αCGRP is presently unclear.

References:

1. Smillie SJ et al. (2014). Hypertension 63(5): 1056-1062.

2. Aubdool AA et al. (2017). Circulation 136(4):367-383.

Acknowledgements and Funding Sources FA is supported by an MRC studentship.