Dependence of Ca2+sensitivity of arterial contractions on history of receptor activation

Abstract

Stimulation of receptors causing arterial contraction may also cause attenuation of cell responsiveness to stimuli. This study tested the hypothesis that attenuation of receptor-induced contractions involves Ca2+ desensitization. Renal artery rings were pretreated with 10 μM phenylephrine (PE), relaxed with PE washout (plus phentolamine), and then activated by histamine (HA). Pretreatment for 30 min resulted in a rightward shift in the concentration-contraction curve to HA by ∼½ log without a reduction in the slope or maximum response. For example, control and PE-pretreated tissues responded to 0.56 μM HA with strong (0.95 F/ F o) and weak (0.16 F/ F o) contractions, respectively, where F/ F orepresents contractile force. This reduced reactivity was completely reversed within 90 min. In fura-loaded tissues, PE pretreatment caused less of a rightward shift in the HA concentration-intracellular free Ca2+ concentration ([Ca2+]i) curve than in the HA concentration-contraction curve. A dissociation between force and [Ca2+]iwas also produced when KCl was used instead of HA. These data suggest that the reduced reactivity produced by PE pretreatment involved, in part, a reduction in the ability of HA to increase the Ca2+ sensitivity of contractions. These data support the hypothesis that the degree of stimulus-induced Ca2+ sensitization of contractions is dependent on the history of receptor activation.