Increased Activation of the Rho-A/Rho-Kinase Pathway in the Renal Vascular System Is Responsible for the Enhanced Reactivity to Exogenous Vasopressin in Endotoxemic Rats*

Abstract

Our data suggest that activation of Rho-kinase potentiates the vascular effects of vasopressin in the kidneys, contributing to the maintenance of the hypertensive effects of this agent during septic shock.

Reduction in renal blood flow following administration of norepinephrine and phenylephrine in septic rats treated with Kir6.1 ATP-sensitive and KCa1.1 calcium-activated K+ channel blockers

“…Using kidneys from rats subjected to CLP -an experimental model of sepsis able to reproduce several aspects associated with human sepsis, including hypotension and systemic refractoriness to vasoconstrictors ( Supplementary Fig. S1) -we confirmed that the renal vascular bed displays a sustained reduction in the reactivity to both phenylephrine and norepinephrine after the induction of sepsis, as previously demonstrated for α 1A -adrenergic receptor agonists in experimental models of sepsis (Chen et al, 1994;Guarido et al, 2014). Most importantly, in spite of the lack of effects in control preparations, we found that at 18 h after the induction of sepsis, continuous perfusion of kidneys with the non-selective K + channel blocker tetraethylammonium was able to normalize phenylephrine-increased RVPP.…”

“…It was previously described that exposure of in vitro blood-perfused juxtamedullary nephron preparations to endotoxin results in sustained vasoconstriction (van 5 Lambalgen et al, 1996), a finding that was reproduced in in vivo studies, revealing increased renal vascular resistance in endotoxemic animals (Lugon et al, 1989). In addition, the reactivity of the renal vascular bed in response to pressor agents in endotoxemic rats was found to be unchanged in response to norepinephrine and angiotensin II (Boffa and Arendshorst, 2005), reduced to phenylephrine (Guarido et al, 2014), and enhanced to vasopressin (Boffa and Arendshorst, 2005;Guarido et al, 2014). Together, these findings suggest that impairments in the functionality of the renal vascular bed contribute to the changes in arterial pressure during sepsis.…”

Vasopressin, Sepsis, and Renal Perfusion—A VASST Deficit in Our Understanding*

“…This is a key insight for interpreting the work by Cuarido et al (1). It may simply be the innate differences in humans versus other animals.…”

“…I n this issue of Critical Care Medicine, Guarido et al (1) present their fascinating work in a model of endotoxemia in rats. Consistent with prior studies, they found that vasopressin could increase blood pressure in animals refractory to phenylephrine.…”

“…Notably, the VASST trial did not examine a cohort of patients that could be considered a corollary to the refractory shock model reported by Cuarido et al (1). Civen that the mean arterial blood pressures in both arms at baseline of the VASST trial were approximately 70 mm Hg, vasopressin was examined as a "catecholamine-sparing drug," not necessarily as a therapy for refractory shock.…”