Ionic mechanisms mediating the myogenic response in newborn porcine cerebral arteries

Mechanisms that underlie autoregulation in the newborn vasculature are unclear. Here we tested the hypothesis that in newborn porcine cerebral arteries intravascular pressure elevates wall tension, leading to an increase in intracellular calcium concentration ([Ca²⁺]_i) and a constriction that is opposed by pressure-induced K⁺ channel activation. Incremental step (20 mmHg) elevations in intravascular pressure between 10 and 90 mmHg induced an immediate transient elevation in arterial wall [Ca²⁺]_i and a short-lived constriction that was followed by a smaller steady-state [Ca²⁺]_i elevation and sustained constriction. Pressures between 10 and 90 mmHg increased steady-state arterial wall [Ca²⁺]_i between ∼142 and 299 nM and myogenic (defined as passive-active) tension between 25 and 437 dyn/cm. The relationship between pressure and myogenic tension was strongly Ca²⁺ dependent until forced dilation. At low pressure, 60 mM K⁺ induced a steady-state elevation in arterial wall [Ca²⁺]_i and a constriction. Nimodipine, a voltage-dependent Ca²⁺ channel blocker, and removal of extracellular Ca²⁺ similarly dilated arteries at low or high pressures. 4-Aminopyridine, a voltage-dependent K⁺ (K _v) channel blocker, induced significantly larger constrictions at high pressure, when compared with those at low pressure. Although selective Ca²⁺-activated K⁺ (K_Ca) channel blockers and intracellular Ca²⁺ release inhibitors induced only small constrictions at low and high pressures, a low concentration of caffeine (1 μM), a ryanodine-sensitive Ca²⁺ release (RyR) channel activator, increased K_ca channel activity and induced dilation. These data suggest that in newborn cerebral arteries, intravascular pressure elevates wall tension, leading to voltage-dependent Ca²⁺ channel activation, an increase in wall [Ca²⁺]_i and Ca²⁺-dependent constriction. In addition, pressure strongly activates K_v channels that opposes constriction but only weakly activates K_ca channels.