HIV-1 infection can infect and replicate in human macrophages undetected by the host innate immune system

Abstract

Abstract Introduction: A key element in the management of septic shock is maintenance of a blood pressure adequate for organ perfusion. Patients in prolonged septic shock have impaired pressor responses to norepinephrine (NE) yet enhanced sensitivity to vasopressin (VP). As both cause vasoconstriction through G protein-coupled receptors, activating the inositol phosphate cascade to increase vascular smooth muscle Ca2+ levels, the reason for this disparity is uncertain. We postulated that these drugs may have diverse effects on different Ca2+ mobilisation pathways during sepsis. We investigated this hypothesis using specific modulators of Ca2+ release and influx on the contractile responses to VP and NE in mesenteric arteries taken from septic and sham-operated rats. Methods: Sepsis was induced in 6 awake, fluid-resuscitated Wistar rats by i.p. injection of faecal slurry. Paired sham controls received no injection. Rats were sacrificed after 24 hours, and mesenteric arteries mounted on a wire myograph to measure isometric tension responses to VP and NE. The contributions of sarcoplasmic reticulum Ca2+ release and Ca2+ entry through the store-operated channel (SOC) were assessed by removing and returning extracellular Ca2+ respectively. The contribution of the voltage-gated Ca2+ channel (VGCC) was assessed by applying VP/NE in the presence of nifedipine. Results: Mimicking the clinical scenario, contractions were significantly enhanced to VP but depressed to NE in septic vessels (p<0.05). In all arteries, constriction to both agonists relied predominantly on extracellular Ca2+ influx rather than Ca2+ release from sarcoplasmic reticulum. The Ca2+ influx in response to NE was almost entirely VGCC-mediated, with a negligible contribution from SOCs in both sham and septic arteries. On the other hand, SOCs contributed significantly to VP-induced contraction, and SOCrather than VGCC-mediated influx of Ca2+ predominated in septic arteries. Discussion: Despite coupling to similar 2nd messenger systems, VP and NE appear to differentially activate SOCand VGCC-mediated Ca2+ entry. In sepsis, hyperpolarisation of the vascular smooth muscle membrane may impair VGCC activity. The ability of VP to preferentially activate SOCs may explain its preserved vasoconstrictor function in septic shock. Ca2+ channel modulation in this context is a potential new therapeutic paradigm.