Vascular hypo-responsiveness to intermedin (IMD) following lipopolysaccharide (LPS) adminstration in conscious rats

L Jolly, JE March, PA Kemp, T Bennett & SM Gardiner, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, UK

Recently, a novel member of the calcitonin superfamily, IMD, was identified and shown to elicit a hypotensive response comparable to adrenomedullin (Roh et al., 2004). Here, we describe regional haemodynamic effects of IMD before and after bolus administration of LPS, since others (Wang et al., 1999) have shown a change in responsiveness to adrenomedullin in disease states such as sepsis.
Male, Sprague-Dawley rats (400-500g) were implanted with pulsed Doppler flow probes to measure renal (R), mesenteric (M) and hindquarters (H) blood flows. At least 10 days later, catheters were implanted in the jugular vein, caudal artery and intra-peritoneally. All surgery was carried out under general anaesthesia (fentanyl and medetomidine 300μg kg-1 of each i.p.). Experiments began at least 24h after catheter implantation, in unrestrained, conscious animals. Responses to IMD (1nmol kg-1 i.v.) were assessed 1.5h, 6h and 25h after bolus administration of saline (0.5ml i.p.) on Day 1, and LPS (E.coli serotype 0127:B8, 1mg kg-1 i.p.) on Day 3.
Baseline data after saline and LPS administration are shown in Table 1. After saline, cardiovascular responses to IMD were consistent and reproducible across time; comprising tachycardia, a decrease in blood pressure (BP) and an increase in R, M and H vascular conductances (VC) (Table 2). Following LPS administration, there was a marked loss of responsiveness to IMD in all 3 vascular beds at 1.5h, with some recovery at 6h. At 25h after LPS administration, IMD-induced increases in R, M and HVC were not different from control (Table 2).



Table 1. Resting cardiovascular variables after saline or LPS. Values are mean ± s.e mean; n=9. Units for VC are (kHz mmHg-1)103. *P<0.05 vs saline (Wilcoxon test).

Table 2. Integrated responses (mean ± s.e mean; n=9) 0-5min after administration of IMD (1nmol kg-1) following saline or LPS. *P<0.05 vs saline (Wilcoxon test).

The present results show that, under normal conditions, IMD is a potent vasodilator. The mechanisms responsible for the loss of vasodilator responsiveness to IMD following LPS administration remain to be determined.


Roh, J. et al. (2004). J. Biol. Chem.279, 8, 7264-7274.
Wang et al. (1999). J. Surg. Res. 85, 59-65.



Research supported by a British Heart Foundation grant.