Effect of angiotensin II-induced arterial hypertension on the voltage-dependent contractions of mouse arteries

Abstract

Arterial hypertension (AHT) affects the voltage dependency of L-type Ca(2+) channels in cardiomyocytes. We analyzed the effect of angiotensin II (AngII)-induced AHT on L-type Ca(2+) channel-mediated isometric contractions in conduit arteries. AHT was induced in C57Bl6 mice with AngII-filled osmotic mini-pumps (4 weeks). Normotensive mice treated with saline-filled osmotic mini-pumps were used for comparison. Voltage-dependent contractions mediated by L-type Ca(2+) channels were studied in vaso-reactive studies in vitro in isolated aortic and femoral arteries by using extracellular K(+) concentration-response (KDR) experiments. In aortic segments, AngII-induced AHT significantly sensitized isometric contractions induced by elevated extracellular K(+) and depolarization. This sensitization was partly prevented by normalizing blood pressure with hydralazine, suggesting that it was caused by AHT rather than by direct AngII effects on aortic smooth muscle cells. The EC50 for extracellular K(+) obtained in vitro correlated significantly with the rise in arterial blood pressure induced by AngII in vivo. The AHT-induced sensitization persisted when aortic segments were exposed to levcromakalim or to inhibitors of basal nitric oxide release. Consistent with these observations, AngII-treatment also sensitized the vaso-relaxing effects of the L-type Ca(2+) channel blocker diltiazem during K(+)-induced contractions. Unlike aorta, AngII-treatment desensitized the isometric contractions to depolarization in femoral arteries pointing to vascular bed specific responses of arteries to hypertension. AHT affects the voltage-dependent L-type Ca(2+) channel-mediated contraction of conduit arteries. This effect may contribute to the decreased vascular compliance in AHT and explain the efficacy of Ca(2+) channel blockers to reduce vascular stiffness and central blood pressure in AHT.

Isometric Stretch Alters Vascular Reactivity of Mouse Aortic Segments

“…In mesenteric arteries of hypertensive rats, it has been described that the density of VGCC Ca 2+ current, and large conductance Ca 2+ -dependent K + current as well, are elevated, since the sensitivity to nifedipine and the Ca 2+ dependent K + channel agonist NS11021 is increased (Shi et al, 2015). Comparable results were obtained in Angiotensin II-treated hypertensive mice (Fransen et al, 2016). Moreover, hypertension depolarized VSMC from −50 to −37 mV (Pesic et al, 2004).…”

“…In hypertensive animals, VSMC are depolarized and the density of voltage-gated Ca 2+ channels (VGCC) is increased (Pesic et al, 2004; Shi et al, 2015). The voltage-dependence of VGCC window contractions is altered (Fransen et al, 2016) and the preparations spontaneously develop tension (Sekiguchi et al, 1996). Furthermore, the release of endothelium-derived NO is diminished (Sekiguchi et al, 2001) and a pressure- and stretch-activated constrictor response that relies on increased calcium influx through VGCC is elicited (Rapacon-Baker et al, 2001).…”

LC-MS analysis ofMyrica rubraextract and its hypotensive effectsviathe inhibition of GLUT 1 and activation of the NO/Akt/eNOS signaling pathway

“…Thus, increase in Ang II signaling is considered to be a strong stimulus for arterial aging, and Ang II affects the structural, molecular, functional, and biomechanical properties of the arterial wall. [9][10][11] Blood pressure (BP) is controlled by the renin-angiotensin system, in which the renin-derived, renin-catalyzed rate of angiotensinogen conversion to angiotensin I (AT-I) is limited by an inactive decapeptide. Angiotensin-converting enzyme (ACE) plays a crucial role in the regulation of blood pressure, and catalyzes the cleavage of the carboxy-terminal His-Leu dipeptide of AT-1 into angiotensin II, which is an effective octapeptide vasopressor.…”

Potassium channels in vascular smooth muscle: a pathophysiological and pharmacological perspective

“…Chronic hypertension is accompanied by a continuous increase in arterial tone resulting from coronary artery dysfunction. The increase in the arterial tone is mainly related to depolarization, which may be due to dysfunction of ion channels responsible for hyperpolarization of VSMCs . The VSM has a great significance in relation to the pathogenesis of hypertension .…”