We recently described dose-dependent cardiovascular effects of a 6h infusion of hUII in conscious rats, comprising tachycardia, modest hypertension and marked hindquarters vasodilatation (Bennett et al., 2004), and have now investigated the effects of indomethacin or L-NAME thereupon.

Under anaesthesia (fentanyl and medetomidine, 300 µg kg^-1 of each i.p.), male Sprague-Dawley rats (450-480g) had pulsed Doppler flow probes (renal (R), mesenteric (M), distal aortic (hindquarters (H))) and intravascular catheters (distal aorta via caudal artery, jugular vein) implanted in a 2-stage procedure separated by at least 10 days. On day 1, 24 h after the last procedure (catheterisation), mean arterial blood pressure (BP), heart rate (HR), and R, M and H vascular conductances (VC) were measured in conscious animals (2 groups, n=8 in each) before and during a 6h infusion of hUII (300 pmol kg ^-1 h^-1). On day 3, animals were given infusions of either indomethacin (5 mg kg^-1 h^-1, n=8) or L-NAME (3 mg kg^-1 h^-1, n=8) starting 90 min before the administration of hUII (as above). Some of the results are shown in Table 1.

Table 1. Cardiovascular variables and changes () before (0) and 120 min after the onset of infusion of hUII in the absence or presence of indomethacin or L-NAME. Values are mean ± s.e.mean. * P 0.05 vs time 0 (Friedman’s test). † P 0.05 vs control condition (Wilcoxon’s test). Units for VC
are [kHz mmHg^-1]10³

Time (min)	0	120		0	120
	Control for indomethacin +			indomethacin
HR (beats min-1)	347 ± 5	427 ± 13	+80 ± 11*	308 ± 7	312 ± 6	+4 ± 7†
BP (mmHg)	108 ± 2	123 ± 2	+15 ± 1*	102 ± 2	106 ± 2	+4 ± 2†
HVC (units)	40 ± 3	49 ± 4	+9 ± 1*	36 ± 4	34 ± 2	-3 ± 2†
	Control for L-NAME			+ L-NAME
HR (beats min-1)	322 ± 6	397 ± 7	+76 ± 12*	285 ± 7	327 ± 11	+42 ± 12*†
BP (mmHg)	104 ± 2	126 ± 3	+22 ± 4*	125 ± 3	140 ± 4	+15 ± 5*†
HVC (units)	46 ± 6	56 ± 7	+11 ± 3*	25 ± 3	25 ± 3	0 ± 2†

Under control conditions, infusion of hUII caused tachycardia, a rise in BP and hindquarters vasodilatation (Table 1) with no consistent changes in RVC or MVC (data not shown). Indomethacin had no effect on baseline cardiovascular variables but abolished all the haemodynamic actions of hUII. L-NAME caused hypertension, bradycardia and widespread vasoconstriction, abolished the hindquarters vasodilator effect of hUII and attenuated the tachycardia and the hypertension.

It is possible that during hUII infusion, the primary event is an increase in cyclooxygenase activity which, directly and/or indirectly, stimulates NO synthesis (Madrigal et al., 2003). It was notable that no underlying vasoconstrictor response to hUII was uncovered when the vasodilator effects were inhibited.

Bennett, T. et al. (2004). Br. J. Pharmacol. (in press)
Madrigal, J.L.M. et al. (2003). Eur. J. Neurosci., 18, 1701-1705

This work was supported by the British Heart Foundation