Prostacyclin analogs stimulate receptor-mediated cAMP synthesis and ATP release from rabbit and human erythrocytes

Objectives: The purpose of this study was to establish that the prostacyclin (PGI₂) receptor (IP receptor) is present on rabbit and human erythrocytes and that its activation stimulates cyclic adenosine monophosphate (cAMP) synthesis and adenosine triphosphate (ATP) release. Methods: The effect of incubation of erythrocytes with the active PGI₂ analogs, iloprost or UT‐15C, on cAMP levels and ATP release was determined in the absence and presence of the IP receptor antagonist, CAY10441. Western analysis was used to determine the presence of the IP receptor on isolated membranes. To establish that effects of PGI₂ analogs were not due to prostaglandin E₂(PGE₂) receptor activation, the effect of PGE₂ on cAMP levels and ATP release was determined. Results: Rabbit and human erythrocytes possess IP receptors. Iloprost and UT‐15C stimulated increases in cAMP and ATP release that were prevented by the IP receptor antagonist, CAY10441. PGE₂ did not stimulate cAMP accumulation or ATP release and did not inhibit iloprost‐induced increases in cAMP. Conclusions: This study establishes that the IP receptor is present on rabbit and human erythrocytes and that its activation results in increases in cAMP and ATP release. These results suggest a novel mechanism by which PGI₂ and its active analogs, when administered pharmacologically, could produce vasodilation.     

Relation of silent myocardial ischemia after coronary artery bypass grafting to angiographic completeness of revascularization and long-term prognosis

The prevalence and characteristics of silent myocardial ischemia as detected by 24-hour ambulatory electrocardiography ST-segment depression were prospectively assessed in 94 patients examined early (1 to 3 months) and 184 patients examined late (12 months) after coronary artery bypass grafting (CABG), and followed for a mean of 48 +/- 11 (range 4 to 62) months. The relation of ambulatory electrocardiographic silent ischemia to evidence of completeness of revascularization as defined by cardiac angiography performed 1 and 12 months after CABG, and to prognosis by follow-up of adverse clinical events was analyzed. Silent ischemia was detected early in 20% (19 of 94) and late in 27% (50 of 184) of patients, and showed a mean frequency of episodes ranging from 6 to 10 episodes/24 hours with a mean duration ranging from 15 to 23 minutes. The circadian distribution of episodes disclosed a significant peak of ischemic activity during the period of 6 A.M. to noon and a secondary peak between 6 P.M. and midnight (p less than 0.01 and p less than 0.001, respectively). Silent ischemia was not found by univariate analysis to be associated with graft or anastomotic site occlusions, low graft flow rates, grafted arteries with significant distal residual stenoses or ungrafted stenotic native coronary arteries. Kaplan-Meier analysis of time to cardiac event showed that silent ischemia was not predictive of an adverse clinical event in the early years after CABG. Cox regression analysis of 30 covariates only disclosed age (relative risk 1.06 [95% confidence interval, 1.01 to 2.94]) as having an effect on time to adverse clinical event.(ABSTRACT TRUNCATED AT 250 WORDS)     

Editorial: The search for core symptoms – will this help clinical decision‐making?

Diagnosis is an important component of our clinical roles, and should also lead to particular treatment pathways. The diagnostic process may be challenged by co‐occurring deficits that are neither specific nor universal to the diagnosis under consideration and may well be evident across a range of other clinical conditions. How important is it to refine our instruments so that they measure unique symptoms? Will this alter or improve intervention choices? This Editorial focuses on the extent to which fine tuning diagnostic instruments improves our decisions about treatment, in the context of articles published in this issue of JCPP.     

The role of platelet CD154 in the modulation in adaptive immunity

Platelets’ primary role is hemostasis. However, a growing body of research has demonstrated that platelets are integral to the initiation of an inflammatory response and are potent effector cells of the innate immune response. Activated platelets express CD154, a molecule critical to adaptive immune responses, which has been implicated in platelet-mediated modulation of innate immune responses and inflammation. Recent studies utilizing CD154 knockout mice extend the role of platelet-derived CD154 to the modulation of adaptive immune response by enhancing antigen presentation, improving CD8⁺ T cell responses, and playing a critical function in T-dependent humoral immunity under physiological conditions. Together these data provide a basis for the expansion of the current paradigm of B cell activation and germinal center formation to include a role for platelets.     

Restoration of acoustic orienting into a cortically deaf hemifield by reversible deactivation of the contralesional superior colliculus: the acoustic "Sprague Effect"

Removal of all contiguous visual cortical areas of one hemisphere results in a contralateral hemianopia. Subsequent deactivation of the contralesional superior colliculus (SC) nullifies the effects of the visual cortex ablation and restores visual orienting responses into the cortically blind hemifield. This deficit nullification has become known as the "Sprague Effect." Similarly, in the auditory system, unilateral ablation of auditory cortex results in severe sound localization deficits, as assessed by acoustic orienting, to stimuli in the contralateral hemifield. The purpose of this study was to examine whether auditory orienting responses can be restored into the impaired hemifield during deactivation of the contralesional SC. Three mature cats were trained to orient toward and approach an acoustic stimulus (broadband, white noise burst) that was presented centrally, or at one of 12 peripheral loci, spaced at 15 degrees intervals. After training, a cryoloop was chronically implanted over the dorsal surface of the right SC. During cooling of the cooling loop to temperatures sufficient to deactivate the superficial and intermediate layers (SZ, SGS, SO, SGI), auditory orienting responses were eliminated into the left (contracooled) hemifield while leaving acoustic orienting into the right (ipsicooled) hemifield unimpaired. This deficit was temperature-dependently graded from periphery to center. After the effectiveness of the SC cooling loop was verified, auditory cortex of the middle and posterior ectosylvian and anterior and posterior sylvian gyri was removed from the left hemisphere. As expected, the auditory cortex ablation resulted in a profound deficit in orienting to acoustic stimuli presented at any position in the right (contralesional) hemifield, while leaving acoustic orienting into the left (ipsilesional) hemifield unimpaired. The ablations of auditory cortex did not have any impact on a visual detection and orienting task. The additional deactivation of the contralesional SC to temperatures sufficient to cool the superficial and intermediate layers nullified the deficit caused by the auditory cortex ablation and acoustic orienting responses were restored into the right hemifield. This restoration was temperature-dependently graded from center to periphery. The deactivations were localized and confirmed with reduced uptake of radiolabeled 2-deoxyglucose. Therefore deactivation of the right superior colliculus after the ablation of the left auditory cortex yields a fundamentally different result from that identified during deactivation of the right superior colliculus before the removal of left auditory cortex in the same animal. Thus the "Sprague Effect" is not unique to a particular sensory system and deactivation of the contralesional SC can restore either visual or acoustic orienting responses into an impaired hemifield after cortical damage.     

A content review of online naloxone Continuing Education courses for pharmacists in states with standing orders

Background

Many community pharmacists are uncomfortable educating patients about naloxone, an opioid reversal agent.