Abstract
L-type Ca2+ channel (VGCC) mediated Ca2+ influx in vascular smooth muscle cells (VSMC) contributes to the functional properties of large arteries in arterial stiffening and central blood pressure regulation. How this influx relates to steady-state contractions elicited by α1-adrenoreceptor stimulation and how it is modulated by small variations in resting membrane potential (Vm) of VSMC is not clear yet. Here, we show that α1-adrenoreceptor stimulation of aortic segments of C57Bl6 mice with phenylephrine (PE) causes phasic and tonic contractions. By studying the relationship between Ca2+ mobilisation and isometric tension, it was found that the phasic contraction was due to intracellular Ca2+ release and the tonic contraction determined by Ca2+ influx. The latter component involves both Ca2+ influx via VGCC and via non-selective cation channels (NSCC). Influx via VGCC occurs only within the window voltage range of the channel. Modulation of this window Ca2+ influx by small variations of the VSMC Vm causes substantial effects on the contractile performance of aortic segments. The relative contribution of VGCC and NSCC to the contraction by α1-adrenoceptor stimulation could be manipulated by increasing intracellular Ca2+ release from non-contractile sarcoplasmic reticulum Ca2+ stores. Results of this study point to a complex interactions between α1-adrenoceptor-mediated VSMC contractile performance and Ca2+ release form contractile or non-contractile Ca2+ stores with concomitant Ca2+ influx. Given the importance of VGCC and their blockers in arterial stiffening and hypertension, they further point toward an additional role of NSCC (and NSCC blockers) herein.
Highlights
Arterial stiffness and hypertension are common clinical conditions in the elderly that lead to increased cardiovascular risk
Results of this study extend our knowledge of the important role of VGCC and non-selective cation channels (NSCC) in arterial stiffening and hypertension, which is of major importance to develop therapeutical strategies for the treatment of arterial stiffness, hypertension and closely associated cardiovascular risk [4,20,21]
When the segments were incubated with a combination of 50 μM 2-aminoethoxydiphenyl borate (2-APB) with 35 μM diltiazem, 1 μM PE caused a transient contraction, which was not increased upon subsequent addition of 10 μM cyclopiazonic acid (CPA) (Figs. 9C and D)
Summary
Arterial stiffness and hypertension are common clinical conditions in the elderly that lead to increased cardiovascular risk. The physiological significance of this background window Ca2+ influx in multicellular preparations, and in mouse aortic segments was evident in segments depolarised with elevated extracellular K+ [9,10,11] How it contributes to contractions induced by α1-adrenoceptor stimulation is not clear. Elevated extracellular K+ and α1-adrenoceptor stimulation of VSMC causes contraction initially by intracellular Ca2+ release via IP3-receptor-mediated Ca2+ release from sarcoplasmic reticulum (SR) Ca2+ stores, followed by Ca2+ influx via Ca2+ permeable ion channels and concomitant Ca2+ sensitization [12,13,14] Even these contractions are associated with depolarisation [15,16,17,18,19]. Results of this study extend our knowledge of the important role of VGCC and NSCC (and their blockers) in arterial stiffening and hypertension, which is of major importance to develop therapeutical strategies for the treatment of arterial stiffness, hypertension and closely associated cardiovascular risk [4,20,21]
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