Effects of indomethacin on systemic and renal haemodynamics in conscious lambs

Abstract

Both prostaglandins (PGs) PGE 2 and PGI 2 can act as renal vasodilators, these effects being exacerbated when the renin-angiotensin system is activated. Therefore, we hypothesized that PGs would play a more predominant role in modulating renal haemodynamics in the newborn period, when the renin-angiotensin system is activated. To this end, the role of endogenously produced PGs in modulating systemic and renal haemodynamics was investigated in two groups of conscious lambs aged ∼1 and ∼6 weeks. Arterial pressure, venous pressure and renal blood flow were measured for 5 min before (control) and for 20 min after intravenous injection of vehicle (experiment 1). Twenty-four hours later, this protocol was repeated with intravenous injection of the non-selective cyclo-oxygenase inhibitor indomethacin (1 mg kg −1 , experiment 2). Heart rate was calculated from the systolic peak of the arterial pressure waveform, and renal vascular resistance (RVR) was calculated from the measured variables. In response to indomethacin but not vehicle, in both age groups of lambs there was an increase in mean arterial pressure and pulse interval, as well as a marked increase in RVR. These responses to indomethacin were, however, transient, with baseline levels being resumed within minutes. Although the hypothesis that PGs play a greater role in modulating renal haemodynamics early in life is not supported, these data do provide evidence that endogenously produced PGs modulate systemic and renal haemodynamics during postnatal maturation. It is apparent, however, that other vasoactive factors must be rapidly recruited in order to buffer the circulatory responses to removal of vasodilatory PGs in the developing newborn.

Haemodynamic responses to angiotensin II in conscious lambs: role of nitric oxide and prostaglandins

“…More recently, we showed that there is an interaction between ANG II and NO in influencing cardiovascular homeostasis as well as the arterial baroreflex of heart rate early in life, which appears to be developmentally regulated [46]. We have also previously reported on the haemodynamic responses to INDO alone [12,13,39], as well as L-NAME alone [30][31][32]46] in conscious lambs at different stages of post-natal maturation. To these findings, the present observations support a further modulatory role for PGs in influencing the vasoconstrictor effects of ANG II soon after birth.…”

“…We also showed that endogenously produced prostaglandins (PGs) influence baseline renal haemodynamics early in life [12] but do not buffer the renal vasoconstrictor effects of endothelin-1 in the newborn period [13]. More recently, we demonstrated that NO and ANG II work synergistically to modulate cardiovascular homeostasis as well as the arterial baroreflex control of heart rate in the newborn period [46], which may help to explain the activation of these two systems early in life.…”

“…The dose of L-NAME was selected from previous experiments as that which inhibits intrarenal production of NO for 2 h[32]. The dose of INDO was selected from previous experiments as that which inhibits intrarenal production of PGE[12] for a minimum of 24 h.…”

Indomethacin abolishes core temperature, but not cardiovascular or renal, responses to lipopolysaccharide in conscious lambs

“…As previously described, we established an indomethacin dose-urinary prostaglandin excretion rate response relationship and showed that a dose of 1 mg ⁄ kg indomethacin is the EC 100 (i.e. the minimum dose required to inhibit, by 100%, the intrarenal production of prostaglandins of the E series) for a minimum of 24 h. 10 In the aforementioned study by Azab et al, 36 LPS administration was also associated with a significant incrase in HR (approximately 50 b.p.m.) measured 6 h later and, as in the present study, this HR response was not altered significantly by indomethacin.…”

“…10 More recently, Furtado et al 11 measured the effects of indomethacin on systemic and renal haemodynamics in anaesthetized, paralysed and ventilated piglets that were administered Escherichia coli. In these experiments, endotoxin alone elicited a renal vasoconstriction; this response was attenuated by indomethacin.…”