Neostigmine and pilocarpine attenuated tumour necrosis factor [alpha] expression and cardiac hypertrophy in the heart with pressure overload

The inflammatory cytokine tumour necrosis factor [alpha] (TNF[alpha]) is known to be a major factor contributing to cardiac remodelling and dysfunction. Parasympathetic nervous system cholinergic function can inhibit TNF[alpha] expression during systemic infection. In the present study, we tested the effects of a cholinesterase inhibitor, neostigmine, and a muscarinic cholinergic agonist, pilocarpine, on cardiac hypertrophy and TNF[alpha] levels during pressure overload. Rats with transverse aortic constriction exhibited elevated TNF[alpha] protein levels in the heart, increased heart weight to body weight ratios (an index of cardiac hypertrophy) and decreased left ventricular diastolic function. Two weeks of infusion with neostigmine (6 [mu]g kg-1 day-1) or pilocarpine (0.3 mg kg-1 day-1) significantly reduced cardiac hypertrophy, reduced TNF[alpha] levels and elevated interleukin-10 levels in heart tissues, and improved ventricular function in rats with transverse aortic constriction. Neither of these treatments significantly changed ventricular pressure load. Furthermore, in primary cultured neonatal cardiac cells, treatment with pilocarpine attenuated adrenergic agonist phenylephrine-induced increased TNF[alpha] expression and [3H]leucine (a marker of protein synthesis) incorporation in the cells. Collectively, both cholinergic agents decreased TNF[alpha] levels and attenuated cardiac hypertrophy. Since both agents potentially enhanced cholinergic function, the anti-inflammatory action may be involved in the cardioprotective effect of the treatments with these agents.