Search

AimsST-elevation myocardial infarction is associated with high levels of cardiac sympathetic drive and release of the co-transmitter neuropeptide Y (NPY). We hypothesized that despite beta-blockade, NPY promotes arrhythmogenesis via ventricular myocyte receptors.Methods and resultsIn 78 patients treated with primary percutaneous coronary intervention, sustained ventricular tachycardia (VT) or fibrillation (VF) occurred in 6 (7.7%) within 48 h. These patients had significantly (P

The inhibition of Nav1.7 is a promising strategy for the development of analgesic treatments. Spider venom‐derived peptide toxins are recognized as significant sources of Nav1.7 inhibitors. However, their development has been impeded by limited selectivity. In this study, eight peptide toxins from three distinct spider venom Nav channel families demonstrated robust inhibition of hNav1.7, rKv4.2, and rKv4.3 (rKv4.2/4.3) currents, exhibiting a similar mode of action. The analysis of structure and function relationship revealed a significant overlap in the pharmacophore responsible for inhibiting hNav1.7 and rKv4.2 by HNTX‐III, although Lys25 seems to play a more pivotal role in the inhibition of rKv4.2/4.3. Pharmacophore‐guided rational design is employed for the development of an mGpTx1 analogue, mGpTx1‐SA, which retains its inhibition of hNav1.7 while significantly reducing its inhibition of rKv4.2/4.3 and eliminating cardiotoxicity. Moreover, mGpTx1‐SA demonstrates potent analgesic effects in both inflammatory and neuropathic pain models, accompanied by an improved in vivo safety profile. The results suggest that off‐target inhibition of rKv4.2/4.3 by specific spider peptide toxins targeting hNav1.7 may arise from a conserved binding motif. This insight promises to facilitate the design of hNav1.7‐specific analgesics, aimed at minimizing rKv4.2/4.3 inhibition and associated toxicity, thereby enhancing their suitability for therapeutic applications. [ABSTRACT FROM AUTHOR]

Elevated levels of brain natriuretic peptide (BNP) are regarded as an early compensatory response to cardiac myocyte hypertrophy, although exogenously administered BNP shows poor clinical efficacy in heart failure and hypertension. We tested whether phosphodiesterase 2A (PDE2A), which regulates the action of BNP-activated cyclic guanosine monophosphate (cGMP), was directly involved in modulating Ca2+ handling from stellate ganglia (SG) neurons and cardiac norepinephrine (NE) release in rats and humans with an enhanced sympathetic phenotype. SG were also isolated from patients with sympathetic hyperactivity and healthy donor patients. PDE2A activity of the SG was greater in both spontaneously hypertensive rats (SHRs) and patients compared with their respective controls, whereas PDE2A mRNA was only high in SHR SG. BNP significantly reduced the magnitude of the calcium transients and ICaN in normal Wistar Kyoto (WKY) SG neurons, but not in the SHRs. cGMP levels stimulated by BNP were also attenuated in SHR SG neurons. Overexpression of PDE2A in WKY neurons recapitulated the calcium phenotype seen in SHR neurons. Functionally, BNP significantly reduced [3H]-NE release in the WKY rats, but not in the SHRs. Blockade of overexpressed PDE2A with Bay 60-7550 or overexpression of catalytically inactive PDE2A reestablished the modulatory action of BNP in SHR SG neurons. This suggests that PDE2A may be a key target in modulating the action of BNP to reduce sympathetic hyperactivity.

Let k be a positive integer. A signed Roman k-dominating function (SRkDF) on a digraph D is a function f : V (D) → {−1, 1, 2} satisfying the conditions that (i) Σx∈N−[v]f(x) ≥ k for each v ∈ V (D), where N−[v] is the closed in-neighborhood of v, and (ii) each vertex u for which f(u) = −1 has an in-neighbor v for which f(v) = 2. The weight of an SRkDF f is Σv∈V (D)f(v). The signed Roman k-domination number γksR(D) of a digraph D is the minimum weight of an SRkDF on D. We determine the exact values of the signed Roman k-domination number of some special classes of digraphs and establish some bounds on the signed Roman k-domination number of general digraphs. In particular, for an oriented tree T of order n, we show that γ2sR(T) ≥ (n + 3)/2, and we characterize the oriented trees achieving this lower bound.

A vertex subset S of a digraph D is called a dominating set of D if every vertex not in S is adjacent from at least one vertex in S. The domination number of a digraph D, denoted by γ(D), is the minimum cardinality of a dominating set of D. A Roman dominating function (RDF) on a digraph D is a function f : V (D) → {0, 1, 2} satisfying the condition that every vertex v with f(v) = 0 has an in-neighbor u with f(u) = 2. The weight of an RDF f is the value ω (f) =Σv∈V(D)f(v). The Roman domination number of a digraph D, denoted by γR(D), is the minimum weight of an RDF on D. In this paper, for any integer k with 2 ≤ k ≤ γ(D), we characterize the digraphs D of order n ≥ 4 with δ−(D) ≥ 1 for which γR(D) = (D) + k holds. We also characterize the digraphs D of order n ≥ k with γR(D) = k for any positive integer k. In addition, we present a Nordhaus-Gaddum bound on the Roman domination number of digraphs.