Intermedin/Adrenomedullin 2 (IMD/AM2) is a potent vasodilator in chronic hypoxia induced pulmonary hypertensive isolated rat lungs
Authors: Telli Gökçen , Kandilci H. Burak , Tel Banu C. , Gümüşel Bülent 
Published: November 2023

Intermedin/Adrenomedullin 2 (IMD/AM2) is an endogenous peptide which is a member of calcitonin gene‐related peptide family (calsitonin, CGRPα, CGRPβ, adrenomedullin, amiline). Due to our previous findings, IMD/AM2 is a potent endothelium‐dependent and nitric oxide‐(NO) mediated vasodilator in pulmonary vascular bed (1, 2). It has been reported that ACh‐induced vasodilation is impaired in chronic hypoxia induced pulmonary hypertension (PHT) since hypoxia claimed to disrupt NO synthesis, release, and activity (3–5). Furthermore, NO‐dependent vasodilation pathways and its proteins may also alter due to hypoxia (6, 7). Therefore, we wondered whether IMD/AM2 is still responsive in PHT. For this purpose, adult male SD rats (300–350 g) were exposed to 3 weeks hypobaric hypoxia (Hacettepe University Animal Experimentations Local Ethics Board, 2015/02). In chronic hypoxic rats, development of PHT was assessed by right ventricular hypertrophy (LV+S/RV; PHT: 4,24±0,41 vs normoxia: 8,2±0,05 n=4–5, p<0.05), polycythemia (hematocrit: PHT: 58,7±1,4 vs normoxia: 40,2±0,8 n=4, p<0.05) and increased lung baseline perfusion pressure (PHT: 3,37± 0,46 mmHg vs normoxia: 1,58±0,19 mmHg, n=8–10 p<0.05). In PHT group rats, IMD/AM2 (10−9–3×10−7 M) and ACh (10−8–10−5 M) cumulatively relaxed U46619 (10−9–6×10−8 M) precontracted main pulmonary artery rings and they were not different from their normoxic controls (Table 1, p>0.05). These responses were blocked by L‐NAME (10−4 M) in each group (Table 1, p<0.05). Moreover, bolus injections (2μg/100μl) of IMD/AM2 and ACh decreased perfusion pressure similarly both in isolated buffer perfused PHT or normoxic rat lungs (Table 2, p>0.05). These vasodilations were still NO mediated since they were also blocked by L‐NAME (10−4 M; Table 2, p<0.05). Vascular smooth muscle response to papaverine (10−4 M or 1.8 μg bolus) did not alter by chronic hypoxia in all experimental groups (Table 1 and 2, p>0.05). These results firstly suggest that endothelium function remains intact in PHT. Secondly, there is no evidence for a shift in IMD/AM2 receptor coupling mechanism due to PHT. In conclusion, IMD is a promising potent therapeutic agent as adrenomedullin in vasodilator therapy of PHT.Support or Funding Information
The vasodilatory responses of IMD/AM2 and ACh in U46619 precontracted normoxic and chronic hypoxia induced pulmonary hypertensive (PHT) rat main pulmonary artery rings.

Normoxia (Emax)
PHT (Emax)
n

IMD/AM2 (3×10−7 M)
43,1±3,8
40±2,8
3–4

IMD/AM2 (3×10−7 M) + L‐NAME (10−4 M)
9,1±1,1
10,5±0,5
2–3

ACh (10−5 M)
68,6±6
68,3±3,2
3

ACh (10−5 M) +L‐NAME (10−4 M)
11±2,1
12,3±1,6
2–3

Papaverine (10−4 M)
98±5,2
96±2,5
2–3

The vasodilatory responses to bolus injections of IMD/AM2 and ACh when perfussion pressure was raised by U46619 in isolated normoxic or chronic hypoxia induced pulmonary hypertensive (PHT) rat lungs.

Normoxia
PHT
n

IMD/AM2 (2 μg/100 μl)
27,8±2,5
30,87±1,9
6–8

IMD/AM2 (2 μg/100 μl) +L‐NAME) (10−4 M)
6,83±3,3
11,72±1,7
3–5

ACh (2 μg/100 μl)
23,44±5,4
30,21±4,1
6–7

ACh (2 μg/100 μl) + L‐NAME(10−4 M)
10±4,7
12,10±1,1
4–6

Papaverine (1,8 μg/100 μl)
70,27±5,5
78,93±4,3
6–7