Influence of CGRP (8-37), but not adrenomedullin (22-52), on the haemodynamic responses to lipopolysaccharide in conscious rats

Abstract

1. The functional involvement of the vasodilator peptides, adrenomedullin (ADM) and calcitonin gene-related peptide (CGRP), in the haemodynamic sequelae of continuous infusion of lipopolysaccharide (LPS) was assessed in conscious, male, Long Evans rats, by the use of peptide antagonists. 2. It was demonstrated that ADM (22-52) at a dose of 500 nmol kg-1 h-1 caused significant inhibition of the effects of ADM (1 nmol kg-1), without affecting responses to CGRP (0.1 or 1 nmol kg-1). 3. Even when the regional vasodilator responses to LPS infusion were enhanced (by pre-treatment with dexamethasone and the endothelin antagonist, SB 209670, or by pretreatment with SB 209670 and the AT1-receptor antagonist, losartan), ADM (22-52) had no significant cardiovascular effects. In contrast, the CGRP1-receptor antagonist, CGRP (8-37), caused small, but significant, inhibitions of the hypotensive and renal and mesenteric vasodilator effects of LPS, but only 6 h after onset of infusion in the presence of dexamethasone and SB 209670. 4. The results indicate that, in this model of endotoxaemia, the marked regional vasodilatations seen in the presence of dexamethasone and SB 209670 do not involve ADM, but do involve CGRP, albeit only to a small extent.

Figure 1

Integrated (areas over or under curves; t=0–15 min) cardiovascular responses to adrenomedullin (1 nmol kg⁻¹) in the absence or in the presence of adrenomedullin (22-52) (20 min after the start of infusion at 500 nmol kg⁻¹ h⁻¹) in the same conscious, Long Evans rats (n=11). Values are mean and vertical bars show s.e.mean; ^*P<0.05 versus corresponding value in the absence of adrenomedullin (22-52).

Figure 2

Cardiovascular responses to CGRP at 0.1 nmol kg⁻¹ (n=8) or 1 nmol kg⁻¹ (n=6) in the absence or presence of ADM (22-52) (500 nmol kg⁻¹ h⁻¹) in conscious Long Evans rats. The mesenteric vasoconstrictor effect of the higher dose of CGRP was enhanced in the presence of ADM (22-52), possibly due to the mesenteric vasodilator influence of the latter. Values are mean and vertical bars show s.e.mean.

Figure 3

Cardiovascular responses to infusion of LPS (150 μg kg⁻¹ h⁻¹) in the presence of dexamethasone and SB 209670 in conscious Long Evans rats. At 6 h, the animals were infused with ADM (22-52) (500 nmol kg⁻¹ h⁻¹) (n=7) or saline (n=7). The tachycardia, hypotension and renal, mesenteric and hindquarters vasodilatations were not affected significantly by ADM (22-52). Values are mean and vertical bars show s.e.mean.

Figure 4

Cardiovascular responses to infusion of LPS (150 μg kg⁻¹ h⁻¹) in the presence of dexamethasone and SB 209670 in conscious Long Evans rats. At 6 h, animals were infused with CGRP (8-37) (6 μmol kg⁻¹ h⁻¹) (n=9) or saline (n=7; data as in Figure 3). CGRP (8-37) caused small, but significant inhibitions of the hypotension and renal, mesenteric and hindquarters vasodilatations. In animals receiving saline infusions (n=6), CGRP (8-37) at 6 h had no effects. Values are mean and vertical bars show s.e.mean. ^*P<0.05 versus the 6 h value (Friedman's test).

Figure 5

Cardiovascular responses to infusion of LPS (150 μg kg⁻¹ h⁻¹) in conscious Long Evans rats pretreated with SB 209670, and infused with CGRP (8-37) (6 μmol kg⁻¹ h⁻¹) at 6 h (n=6), or pretreated with losartan and SB 209670, and infused with CGRP (8-37) at 6 h (n=3), or pretreated with losartan and SB 209670 and infused with saline at 6 h (n=6). Values are mean and vertical bars show s.e.mean. ^*P<0.05 versus the 6 h value (Friedman's test).

Figure 6

Cardiovascular responses to infusion of LPS (150 μg kg⁻¹ h⁻¹) in conscious Long Evans rats (n=3) pretreated with losartan and SB 209670, and given CGRP (8-37) starting 40 min after the onset of LPS infusion. For comparison, the data from animals infused with LPS following pretreatment with losartan and SB 209670 (from Figure 5) are included. Values are mean and vertical bars show s.e.mean. CGRP (8-37) did not reverse the hypotension or vasodilatations associated with LPS infusion.