Selective Enhancement of Contractions to α1-adrenergic Receptor Activation in the Aorta of Mice With Sickle Cell Disease

Abstract

Sickle cell disease (SCD), the most common inherited hematologic disorder in the United States and the most common single gene disorder in the world, causes substantial morbidity and mortality. The major pathobiologic processes that underlie SCD include vaso-occlusion, inflammation, procoagulant processes, hemolysis, and altered vascular reactivity. The present study examined the vasoactive response to α-adrenergic activation in a murine model of SCD. Isolated aortas from sickle mice as compared with wild-type mice exhibit heightened contractions to norepinephrine and phenylephrine; such responses were completely blocked by an α1-receptor antagonist, prazosin. Aortas from either group exhibited comparable contractile responses to potassium chloride and the thromboxane agonist U46619 and no contractile response to an α2-adrenergic receptor agonist, UK14304. We conclude that there is an exaggerated vasoconstrictive response to α1-receptor agonists in SCD. Because sickle crisis is induced by diverse forms of stress, the latter attended by increased adrenergic activity, our findings may be relevant to the occurrence of sickle crisis. We also suggest that such heightened reactivity may contribute to vaso-occlusive processes that underlie ischemic injury in SCD. Finally, our findings urge caution in the use of phenylephrine in patients with SCD.

Dexmedetomidine ameliorates nocifensive behavior in humanized sickle cell mice

“…This possibility is supported by ex-vivo studies showing that aortas of SCD mice have enhanced contraction response to α 1 agonists, such as phenylephrine and norepinephrine(Juncos et al, 2011). Further, human studies suggest that SCD patients might have autonomic nervous system alterations and resultant sympathetic/parasympathetic imbalances that correlate with clinical SCD severity(Connes and Coates, 2013; Hedreville et al, 2014; Pearson et al, 2005).…”

Reconstructing sickle cell disease: A data‐based analysis of the “hyperhemolysis paradigm” for pulmonary hypertension from the perspective of evidence‐based medicine

“…Sickle patients exhibit abnormal autonomic function (increase of sympathetic versus parasympathetic activity) [198]. Interestingly, sickle transgenic mice exhibit an exaggerated vasoconstrictive response, tested ex vivo on aortic rings, to a1 receptor agonists [199]. It should be considered whether this is relevant to the pulmonary arterial wall as well.…”

Fentanyl Buccal Tablet: A New Breakthrough Pain Medication in Early Management of Severe Vaso‐Occlusive Crisis in Sickle Cell Disease

“…In addition, the accelerated clearance of morphine observed in SCD patients requires the development of alternative or additional therapeutic strategies in controlling acute pain of VOCs . In SCD, VOCs are characterized by severe continuous pain with exacerbation of acute pain most likely due to sudden temporary local enhanced vasoconstriction phenomena that are favored by abnormal parasympathetic vascular response, promoting acute ischemic pain . The temporal characteristics, the intensity, and the mechanism of this type of pain might be considered as a breakthrough pain as defined by the literature (Davies et al., 2009) (Figure ).…”