Prevention of hemorrhage-induced renal vasoconstriction and hypoxia by angiotensin II type 1 receptor antagonism in pigs

Abstract

Angiotensin II (AngII) is a potent vasoconstrictor and may reduce renal blood flow (RBF), causing renal hypoxia. Hypotensive hemorrhage elevates plasma AngII levels and is associated with increased risk of acute kidney injury. We hypothesized that AngII antagonism prevents renal vasoconstriction and hypoxia caused by hemorrhage. Pigs were anaesthetized, surgically prepared and randomized to intravenous losartan (1.5 mg kg-1 h-1, n=8) or an equal volume of intravenous Ringer's acetate (vehicle-treated, n=8). Hemorrhage was induced by continuous aspiration of blood to reach and sustain mean arterial blood pressure of <50 mmHg for 30 minutes. Plasma AngII levels, hemodynamics and oxygenation were assessed 60 minutes pre-hemorrhage, 30-minutes after the start of hemorrhage and 60 minutes post-hemorrhage. Erythropoietin mRNA was analyzed in cortical and medullary tissue sampled at the end of the experiment. Hypotensive hemorrhage increased plasma AngII levels and decreased RBF and oxygen delivery in both groups. Losartan-treated animals recovered in RBF and oxygen delivery, whereas vehicle-treated animals had persistently reduced RBF and oxygen delivery. In accordance, renal vascular resistance increased over time post hemorrhage in vehicle-treated animals but was unchanged in losartan-treated animals. Renal oxygen extraction rate and cortical erythropoietin mRNA levels increased in the vehicle group but not in the losartan group. In conclusion, AngII antagonism alleviates prolonged renal vasoconstriction and renal hypoxia in a large animal model of hypotensive hemorrhage.

Oxygen saturation in intraosseous sternal blood measured by CO-oximetry and evaluated non-invasively during hypovolaemia and hypoxia – a porcine experimental study

“…A urinary catheter was introduced by a small vesicotomy after a mini-laparotomy. Doppler flow probes were applied to the left renal vein and left carotid artery for a separate study investigating renal function, which is reported elsewhere [16].…”

Reducing Oxygen Demand to Alleviate Acute Kidney Injury

“…Not surprisingly, angiotensin II increases oxygen consumption by renal mitochondria [134]. While angiotensin receptor blockers (ARBs) have repeatedly shown benefits in animal models of AKI [135][136][137][138] and CKD in humans [139][140][141], the results from clinical trials of AKI with ARBs and angiotensin converting enzyme inhibitors (ACEIs) have had mixed results (Table 1). One potential adverse impact of ACEIs and ARBs in the setting of AKI is that they could worsen renal hypoperfusion.…”

Anesthesia and the renal sympathetic nervous system in perioperative AKI

“…100 We have recently conducted two experimental studies with results indicating that the increased activity of the renin-angiotensin system following propofol-induced hypotension and major hemorrhage mediates renal vasoconstriction, ultimately resulting in renal hypoxia. 11,12 These studies were performed during barbiturate anesthesia (known to suppress RSNA), thus minimizing the role of RSNA. 68 Thus, the risk for renal ischemia might be even higher during sevoflurane anesthesia (with its independent mechanisms to increase RSNA and plasma renin concentration), but this remains to be investigated.…”

“…10 If the arterial blood pressure falls below the autoregulatory threshold, RBF is reduced in parallel to the reduction in pressure. 11,12 Even short-term hypotension (1−5 minutes) with mean arterial pressure below 55 mmHg has been associated with increased incidence of postoperative AKI. 9 It remains unclear how RBF and the autoregulatory threshold in humans is affected by anesthesia, but it is likely that major reductions in arterial blood pressure significantly impair RBF.…”