Background CGRP is reported to play important roles in cardiovascular regulation in human and animal models. In spite of this, its role remains controversial. We aim to clarify this by studying the autonomic cardiovascular function and vascular structure in CGRP knockout (CGRP−/−) mice. Methods Blood pressure (BP) and heart rate (HR) were assessed by telemeters. Urine (24-hr) and blood were collected for catecholamines measurements. Baroreflex sensitivity was assessed using phenylephrine and sodium nitroprusside administered in an acute study. Results Daytime mean arterial blood pressure (MAP, 12-hr period) was significantly higher in the CGRP−/− mice than in the WT mice (114.5 vs.104.5 mmHg; p=0.04). Norepinephrine was elevated in plasma and 24-hr urine in the knockouts (Urine: 956 vs. 618 pg/ml, p=0.004; Plasma: 2505 vs. 1168 pg/ml, p = 0.04). Paradoxically, cardiovagal baroreflex sensitivity was higher in CGRP−/− mice (3.2 vs.1.4 ms/mmHg, p=0.03). To increase insight, we studied aortic stiffness in CGRP−/− mice and found it increased compared to age-matched WT mice, as evidenced by the depression of the compliance curve (p<0.05). Conclusion CGRP−/− mice have higher BP due to elevated sympathetic signals and abnormalities in blood vessel structure and CGRP plays an important role in the regulation of the cardio-vagal tone.

Increased blood pressure (BP) is observed in patients with impaired baroreflexes after water drinking. The stimulus for this effect is low blood osmolality, and it has been termed the osmopressor response (OPR). The BP increase is associated with activation of the sympathetic nervous system and a requirement for transient receptor potential vanilloid 4 (TRPV4) channels. However, the mechanisms underlying the OPR are poorly understood. We tested the hypothesis that hypotonicity is sensed in the portal area to initiate the OPR. Sino-aortic denervated mice were used and BP was monitored for 30 min after fluid infusion while mice were under anesthesia. Infusion of hypotonic fluid (0.45% saline), but not of isotonic 0.9% saline, directly into the portal vein, produced an immediate OPR (increase in BP with saline 0.45%: 15 ± 13 vs. 0.9%: −7 ± 2 mm Hg, p = 0.003; AUC: 0.45%: 150 ± 99, n = 7 vs. 0.9%: −74 ± 60 mm Hg · min, n = 5, p = 0.003). However, 0.45% saline was not able to trigger a similar response in TRPV4−/− mice (ΔBPTRPV4: −2 ± 5 mm Hg, n = 8, p = 0.009). Hypotonic saline did not raise BP when infused at the same speed and volume into the jugular vein (jugular: −5 ± 6 mm Hg, p = 0.002, compared to portal). Denervation of the splanchnic nerve by celiac ganglionectomy (CGX) did not abolish the OPR (CGX: 15 ± 11 vs. Sham: 16 ± 6 mm Hg, p = 0.34). Renal denervation diminished the OPR elicited by duodenal water infusion (denervation: 9 ± 4 vs. sham: 31 ± 15 mm Hg, p = 0.016). Therefore, hypotonicity in the portal circulation, probably sensed by TRPV4 channels, triggers the OPR and intact renal nerves are needed for the full response.