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Patients with cirrhosis often exhibit cardiac autonomic dysfunction (CAD), characterized by enhanced cardiac sympathetic activity and diminished cardiac vagal tone, leading to increased morbidity and mortality. This study delineates the cellular and molecular mechanisms associated with altered neuronal activities causing cirrhosis-induced CAD. Biliary and nonbiliary cirrhotic rats were produced by common bile duct ligation (CBDL) and intraperitoneal injections of thioacetamide (TAA), respectively. Three weeks after CBDL or TAA injection, the assessment of heart rate variability revealed autonomic imbalance in cirrhotic rats. We observed increased excitability in stellate ganglion (SG) neurons and decreased excitability in intracardiac ganglion (ICG) neurons in cirrhotic rats compared to sham-operated controls. Additionally, threshold, rheobase, and action potential duration exhibited opposite alterations in SG and ICG neurons, along with changes in afterhyperpolarization duration. A- and M-type K⁺ channels were significantly downregulated in SG neurons, while M-type K⁺ channels were upregulated, with downregulation of the N- and L-type Ca2⁺ channels in the ICG neurons of cirrhotic rats, both in transcript expression and functional activity. Collectively, these findings suggest that cirrhosis induces an imbalance between cardiac sympathetic and parasympathetic neuronal activities via the differential regulation of K+ and Ca2+ channels. Thus, cirrhosis-induced CAD may be associated with impaired autonomic efferent functions within the homeostatic reflex arc that regulates cardiac functions. [ABSTRACT FROM AUTHOR]

Voltage-dependent (VD) inhibition of N-type [Ca.sup.2+] channels is mediated primarily by neurotransmitter receptors that couple to pertussis toxin (PTX)-sensitive G proteins (such as [G.sub.o] and [G.sub.i]). To date, however, the composition of heterotrimeric complexes, i.e., specific G [Alpha] [Beta] [Gamma] combinations, capable of coupling receptors to N-type [Ca.sup.2+] channels has not been defined. We addressed this question by heterologously expressing identified G [Alpha] [Beta] [Gamma] combinations in PTX-treated rat sympathetic neurons and testing for reconstitution of agonist-mediated VD inhibition. The heterologously expressed G [Alpha] subunits were rendered PTX-insensitive by mutating the codon specifying the ADP ribosylation site. The following results were obtained from this approach. (i) Expression of G [[Alpha].sub.oA], G [[Alpha].sub.oB], and G [[Alpha].sub.i2] (along with G [[Beta].sub.1][Gamma].sub.2]]) reconstituted VD inhibition mediated by [[Alpha].sub.2]-adrenergic, adenosine, somatostatin, and prostaglandin [E.sub.2] receptors. Conversely, expression of G [Alpha].sub.i1] and G [[Alpha].sub.i3] was ineffective at restoring coupling. (ii) Coupling efficiency, as determined from the magnitude of reconstituted [Ca.sup.2+] current inhibition, depended on both the receptor and Ga subtype. The following rank order of coupling efficiency was observed: G [[Alpha].sub.oA] = G [Alpha].sub.oB] [is greater than] G [[Alpha.sub.oB] for [[Alpha].sub.2]-adrenergic receptor; = G [[Alpha].subi2] [is greater than] G [[Alpha].sub.oA] = G [[Alpha] sub.oB] for adenosine and prostaglandin [E.sub.2] receptors; and G [[Alpha].sub.oB] = G [[Alpha].sub .i2] [is greater than] G [[Alpha].sub.oA] for the somatostatin receptor. (iii) In general, varying the G [Beta] [Gamma] composition of G [[Alpha].sub.oA]-containing heterotrimers had little effect on the coupling of [Alpha] 2- adrenergic receptors to the VD pathway. Taken together, these results suggest that multiple, diverse G [Alpha]/[Beta] combinations are capable of coupling neurotransmitter receptors to VD inhibition of N-type [Ca.sup.2+] channels. Thus, if exquisite G [Alpha] [Beta] [Gamma]-coupling specificity exists in situ, it cannot arise solely from the inherent inability of other G [Alpha] [Beta] [Gamma] combinations to form functional signaling complexes.

Background: This study determined whether changes in the expression of neuregulin (NRG) 1, erbB2 tyrosine kinase (ErbB2) and the M2 muscarinic receptor in the urothelium and detrusor muscle of the rat bladder were associated with partial bladder outlet obstruction (PBOO).Methods: Male Sprague-Dawley rats (body weight 250-300 g) were used and subdivided into control (n = 10) and PBOO groups (n = 20). PBOO was induced for 21 days, and the expression of NRG1, ErbB2 and M2 muscarinic receptor mRNA and protein was evaluated using reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting, respectively.Results: In the urothelium of rat bladder samples, protein expression and mRNA expression of NRG1, ErbB2 and M2 muscarinic receptor were significantly increased in the PBOO group compared to the control group (p < 0.05). Only mRNA expression levels of NRG1/ ErbB2 were higher in the detrusor muscle of the PBOO group compared to the control group (p < 0.05).Conclusions: Our study demonstrated remarkable changes in the expression of NRG1/ErbB2 receptor mRNA and protein in the urothelium and muscle layer. These results suggest that NRG1 overexpression plays some kind of role against the PBOO-induced upregulated muscarinic receptors in detrusor overactivity. [ABSTRACT FROM AUTHOR]