Regionally-selective hyper-responsiveness to KATP channel-mediated vasodilatation during lipopolysaccharide (LPS) infusion in conscious rats

T Bennett, J E March, P A Kemp & S M Gardiner, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, UK.

An enhanced hypotensive response to K ATP channel activation 24h after a bolus dose of LPS has been reported (Sorrentino et al., 1999), but the time course of change, and the accompanying regional vascular responses have not been assessed. We have now measured the regional and temporal changes in haemodynamic responses to KATP channel activation with levcromakalim (LCK) during LPS infusion.

Male, Sprague-Dawley rats (380-450g) underwent a two-stage procedure for the implantation of pulsed Doppler flow probes (renal (R), mesenteric (M), hindquarters (H)) and, subsequently, intravascular catheters (jugular vein, caudal artery). All surgery was under general anaesthesia (fentanyl and medetomidine, 300 μg kg-1 of each i.p.) with post-operative anaesthetic reversal and analgesia provided by atipamezole and nalbuphine (1 mg kg-1 of each s.c.). At least 24h after catheter implantation, heart rate (HR), mean blood pressure (BP) and regional vascular conductances (VC) were measured in conscious, unrestrained animals with free access to food and water.

Responses to LCK (10 m g kg-1 i.v.: 5 minute infusion) were assessed 2h and 6h after the onset of saline (0.4 ml h-1, n=7) or LPS (150 m g kg-1 h-1, n=8) infusion. During the 6h infusion of saline, there were no significant changes in the measured cardiovascular variables, and the cardiovascular responses to LCK were consistent (Table 1). Two and 6h after the onset of LPS infusion, there was significant (P<0.05, Friedman’s test) tachycardia (+119 ± 17 and 120 ± 14 beats min-1, respectively), and renal vasodilatation (RVC +46 ± 8 and +82 ± 11 %), with no change in BP or HVC; there was a fall in MVC at 2h (-25 ± 5%) but not at 6h (+19 ± 18%). The hypotensive responses to LCK were enhanced at both time points during LPS infusion, accompanied by a selective augmentation of the mesenteric vasodilatation, but with some inhibition of the renal and hindquarters vasodilatations (Table 1).

Table 1. Changes in cardiovascular variables in response to LCK (10 m g kg-1) during infusion of saline (Sal) or LPS. Values are mean ± s.e. mean. * P<0.05 vs corresponding Sal (Mann-Whitney test)

The present results show that hyper-responsiveness to the vasodilator effects of LCK during LPS infusion is selective for the mesenteric vascular bed, at a time when there is no resting mesenteric vasodilatation. These findings indicate that either there is no activation of KATP channels by endogenous processes in that region, and/or any effects of the latter are opposed by concurrent activation of vasoconstrictor mechanisms.

Sorrentino, R. et al. (1999). Br. J. Pharmacol., 127, 1447-1453.