Enhanced production of angiotensin II and excessive release of norepinephrine in the ischemic heart are major causes of arrhythmias and sudden cardiac death. Mast cell-dependent mechanisms are pivotal in the local formation of angiotensin II and modulation of norepinephrine release in cardiac pathophysiology. Cardiac mast cells increase in number in myocardial ischemia and are located in close proximity to sympathetic neurons expressing angiotensin AT1- and histamine H3-receptors. Once activated, cardiac mast cells release a host of potent pro-inflammatory and pro-fibrotic cytokines, chemokines, preformed mediators (e.g., histamine) and proteases (e.g., renin). In myocardial ischemia, angiotensin II (formed locally from mast cell-derived renin) and histamine (also released from local mast cells) respectively activate AT1- and H3-receptors on sympathetic nerve endings. Stimulation of angiotensin AT1-receptors is arrhythmogenic whereas H3-receptor activation is cardioprotective. It is likely that in ischemia/reperfusion the balance may be tipped toward the deleterious effects of mast cell renin, as demonstrated in mast cell-deficient mice, lacking mast cell renin and histamine in the heart. In these mice, no ventricular fibrillation occurs at reperfusion following ischemia, as opposed to wild-type hearts which all fibrillate. Preventing mast cell degranulation in the heart and inhibiting the activation of a local reninangiotensin system, hence abolishing its detrimental effects on cardiac rhythmicity, appears to be more significant than the loss of histamine-induced cardioprotection. This suggests that therapeutic targets in the treatment of myocardial ischemia, and potentially congestive heart failure and hypertension, should include prevention of mast cell degranulation, mast cell renin inhibition, local ACE inhibition, ANG II antagonism and H3-receptor activation.

Renin, the rate-limiting enzyme in the activation of the reninangiotensin system (RAS), is synthesized and stored in cardiac mast cells. In ischemia/reperfusion, cardiac sensory nerves release neuropeptides such as substance P that, by degranulating mast cells, might promote renin release, thus activating a local RAS and ultimately inducing cardiac dysfunction. We tested this hypothesis in whole hearts ex vivo, in cardiac nerve terminals in vitro, and in cultured mast cells. We found that substance P-containing nerves are juxtaposed to renin-containing cardiac mast cells. Chemical stimulation of these nerves elicited substance P release that was accompanied by renin release, with the latter being preventable by mast cell stabilization or blockade of substance P receptors. Substance P caused degranulation of mast cells in culture and elicited renin release, and both of these were prevented by substance P receptor blockade. Ischemia/reperfusion in ex vivo hearts caused the release of substance P, which was associated with an increase in renin and norepinephrine overflow and with sustained reperfusion arrhythmias; substance P receptor blockade prevented these changes. Substance P, norepinephrine, and renin were also released by acetaldehyde, a known product of ischemia/reperfusion, from cardiac synaptosomes and cultured mast cells, respectively. Collectively, our findings indicate that an important link exists in the heart between sensory nerves and renin-containing mast cells; substance P released from sensory nerves plays a significant role in the release of mast cell renin in ischemia/reperfusion and in the activation of a local cardiac RAS. This culminates in angiotensin production, norepinephrine release, and arrhythmic cardiac dysfunction.

We previously showed that activation of G i/o -coupled histamine H 3 -receptors (H 3 R) is cardioprotective because it attenuates excessive norepinephrine release from cardiac sympathetic nerves. This action is characterized by a marked decrease in intraneuronal Ca 2ϩ ([Ca 2ϩ ] i ), as G␣ i impairs the adenylyl cyclasecAMP-protein kinase A (PKA) pathway, and this decreases Ca 2ϩ influx via voltage-operated Ca 2ϩ channels (VOCC). Yet, the G i/oderived ␤␥ dimer could directly inhibit VOCC, and the subsequent reduction in Ca 2ϩ influx would be responsible for the H 3 Rmediated attenuation of transmitter exocytosis. In this study, we tested this hypothesis in nerve-growth factor-differentiated rat pheochromocytoma cells (PC12) stably transfected with H 3 R (PC12-H 3 ) and with the G␤␥ scavenger ␤-adrenergic receptor kinase 1 (␤-ARK1)-(495-689)-polypeptide (PC12-H 3 /␤-ARK1). Thus, we evaluated the effects of H 3 R activation directly on the following: 1) Ca 2ϩ current (I Ca ) using the whole-cell patchclamp technique; and 2) K ϩ -induced exocytosis of endogenous dopamine. H 3 R activation attenuated both peak I Ca and dopamine exocytosis in PC12-H 3 but not in PC12-H 3 /␤-ARK1 cells. Moreover, a membrane permeable phosducin-like G␤␥ scavenger also prevented the antiexocytotic effect of H 3 R activation. In contrast, the H 3 R-induced attenuation of cAMP accumulation and dopamine exocytosis in response to forskolin were the same in both PC12-H 3 and PC12-H 3 /␤-ARK1 cells. Our findings reveal that although G␣ i participates in the H 3 -mediated antiexocytotic effect when the adenylyl cyclase-cAMP-PKA pathway is stimulated, a direct G␤␥-induced inhibition of VOCC, resulting in an attenuation of I Ca , plays a pivotal role in the H 3 R-mediated decrease in [Ca 2ϩ ] i and associated cardioprotective antiexocytotic effects. The discovery of this H 3 R-signaling step may offer new therapeutic approaches to cardiovascular diseases characterized by hyperadrenergic activity.

This editorial celebrates the launch of BMC Pharmacology and Toxicology within the BMC series of journals published by BioMed Central. The scope of the journal is interdisciplinary encompassing toxicology, experimental and clinical pharmacology including clinical trials. In this editorial we discuss the origins of this new journal and the ethos and policies under which it will operate.

Background To assess patient outcomes after the introduction of a regular orthopaedic‐specific trauma list (OTL). Methods A retrospective analysis of 422 trauma cases was performed comparing patient outcomes after the introduction of the OTL. Four common traumatic injuries requiring operative intervention were considered; closed tibial fractures, intra‐capsular neck of femur fractures, displaced paediatric supracondylar humeral fractures and hand tendon injuries. The outcomes assessed included time from patient referral to theatre, time from admission to theatre, operative times, time of day operation commenced, consultant involvement, hospital length of stay (LOS), returns to theatre and mortality. Results Tibial fractures had an increased time from admission to theatre (0.46 days pre‐OTL versus 1.21 days post‐OTL, P = 0.01), hand tendons injuries had an increase in time from referral to theatre (1.06 days pre‐OTL versus 2.82 days post‐OTL, P = 0.001). Consultant involvement increased for supracondylar procedures (27% pre‐OTL versus 61% post‐OTL, P < 0.001) and tendinous hand injury repairs (5% pre‐OTL versus 37% post‐OTL, P < 0.001). There was a decrease in cases starting after 17:00 hours; however, no group reached statistical significance. There was a reduction in complications and shorter inpatient LOS, however; these were not statistically significant. There was no difference in overall operative times after OTL implementation; however, individual group differences existed between registrars and consultants. Conclusion Implementing regular orthopaedic trauma lists resulted in greater consultant involvement and was associated with decreased after‐hours operating. Delays to theatre increased from both time of referral and admission; however, this was not correlated with increases in significant harm.