Henderson Kyle K, Byron Kenneth L
Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Maywood, Illinois 60153, USA.
J Appl Physiol (1985). 2007 Apr;102(4):1402-9. doi: 10.1152/japplphysiol.00825.2006. Epub 2007 Jan 4.
Current scientific literature generally attributes the vasoconstrictor effects of [Arg(8)]vasopressin (AVP) to the activation of phospholipase C (PLC) and consequent release of Ca(2+) from the sarcoplasmic reticulum. However, half-maximal activation of PLC requires nanomolar concentrations of AVP, whereas vasoconstriction occurs when circulating concentrations of AVP are orders of magnitude lower. Using cultured vascular smooth muscle cells, we previously identified a novel Ca(2+) signaling pathway activated by 10-100 pM AVP. This pathway is distinguished from the PLC pathway by its dependence on protein kinase C (PKC) and L-type voltage-sensitive Ca(2+) channels (VSCC). In the present study, we used isolated, pressurized rat mesenteric arteries to examine the contributions of these different Ca(2+) signaling mechanisms to AVP-induced vasoconstriction. AVP (10(-14)-10(-6) M) induced a concentration-dependent constriction of arteries that was reversible with a V(1a) vasopressin receptor antagonist. Half-maximal vasoconstriction at 30 pM AVP was prevented by blockade of VSCC with verapamil (10 microM) or by PKC inhibition with calphostin-C (250 nM) or Ro-31-8220 (1 microM). In contrast, acute vasoconstriction induced by 10 nM AVP (maximal) was insensitive to blockade of VSCC or PKC inhibition. However, after 30 min, the remaining vasoconstriction induced by 10 nM AVP was partially dependent on PKC activation and almost fully dependent on VSCC. These results suggest that different Ca(2+) signaling mechanisms contribute to AVP-induced vasoconstriction over different ranges of AVP concentration. Vasoconstrictor actions of AVP, at concentrations of AVP found within the systemic circulation, utilize a Ca(2+) signaling pathway that is dependent on PKC activation and can be inhibited by Ca(2+) channel blockers.
当前的科学文献普遍将[精氨酸（8）]血管加压素（AVP）的血管收缩作用归因于磷脂酶C（PLC）的激活以及随后肌浆网中Ca（2 +）的释放。然而，PLC的半数最大激活需要纳摩尔浓度的AVP，而当AVP的循环浓度低几个数量级时就会发生血管收缩。我们之前使用培养的血管平滑肌细胞，鉴定出了一种由10 - 100 pM AVP激活的新型Ca（2 +）信号通路。该通路与PLC通路的区别在于它依赖蛋白激酶C（PKC）和L型电压敏感性Ca（2 +）通道（VSCC）。在本研究中，我们使用分离的、加压的大鼠肠系膜动脉来研究这些不同的Ca（2 +）信号机制对AVP诱导的血管收缩的作用。AVP（10（-14）- 10（-6）M）诱导动脉出现浓度依赖性收缩，这种收缩可被V（1a）血管加压素受体拮抗剂逆转。用维拉帕米（10 microM）阻断VSCC或用钙泊三醇 - C（250 nM）或Ro - 31 - 8220（1 microM）抑制PKC可阻止30 pM AVP时的半数最大血管收缩。相比之下，由10 nM AVP（最大）诱导的急性血管收缩对VSCC阻断或PKC抑制不敏感。然而，30分钟后，由10 nM AVP诱导的剩余血管收缩部分依赖于PKC激活，几乎完全依赖于VSCC。这些结果表明，不同的Ca（2 +）信号机制在不同的AVP浓度范围内对AVP诱导的血管收缩起作用。在体循环中发现的AVP浓度下，AVP的血管收缩作用利用了一种依赖PKC激活且可被Ca（2 +）通道阻滞剂抑制的Ca（2 +）信号通路。
