Presynaptic stimulus-release and postsynaptic compensatory changes in mice lacking the N-type calcium channel α(1B)-subunit.

N-type (Ca(v)2.2) voltage-dependent calcium channels (VDCC) play an important role in presynaptic neurotransmitter release in the autonomic nervous system and may be clinically relevant in the treatment of cardiovascular diseases. The physiological impact of N-type VDCC ablation on cardiac function, stimulus-release coupling and cardiac autonomic regulation was studied using mice deficient in the α(1B) subunit of the N-type channel (N-type-/-).The positive inotropic effect (increase in +dP/dt) secondary to high frequency field stimulation (HFFS), mediated by the sympathetic nervous system, was decreased by 33 ± 12.6% in N-type-/- versus 89 ± 11.4% in Wild-Type (WT)(P<0.01), whereas the negative inotropic response (decrease in +dP/dt) following HFFS in the presence of propranolol, mediated by the parasympathetic nervous system, was similar to that in Wild-type (WT) animals 34 ± 5.0% and 35 ± 5.4%, respectively. There were no changes in the postsynaptic β-adrenergic responsiveness, β-adrenoreceptor density or adenylyl cyclase activity. N-type-/- hearts demonstrated an increased contractile response to α(1)-adrenoreceptor (α(1)-ADR) stimulation with 10(-5)M phenylephrine in the presence of the β-blocker propranolol, which might be attributed to an increased expression of PLCβ1. Protein abundance of other signal transducers for α(1) ADR transduction protein was not changed in the N-type-/- hearts. These results suggest that selective impairment of sympathetic inflow does not modulate postsynaptic β-adrenergic responsiveness, but causes increased functional response to α(1)-adrenergic stimulation.