One mechanism of erythropoietin induced hypertension may be an increase in [Ca2+]i in vascular smooth muscle cells.
Changes in cytosolic free calcium concentration ([Ca2+]i) induced by angiotensin II (ANG II), arginine vasopressin (AVP), angiotensin III (ANG III), norepinephrine (NE), or thapsigargin were investigated after inhibition of the Na(+)-Ca2+ exchange in vascular smooth muscle cells (VSMC) from Wistar-Kyoto rats by use of the fluorescent dye technique. The ANG II-induced peak [Ca2+]i increase was significantly enhanced after inhibition of Na(+)-Ca2+ exchange by NiCl2 or 1,3-dimethyl-2-thiourea (DMTU): control, 99 +/- 9 (SE) nM (n = 64); NiCl2, 181 +/- 23 nM (n = 23; P < 0.01); DMTU, 182 +/- 35 nM (n = 10; P < 0.05). In the absence of external calcium, the inhibition of the Na(+)-Ca2+ exchange by NiCl2 also enhanced the ANG II-induced [Ca2+]i increase. Inhibition of Na(+)-Ca2+ exchange by removal of external sodium, which was replaced by choline, augmented the ANG II-induced [Ca2+]i increase to 174 +/- 26 nM (n = 11; P < 0.05 compared with control). The inhibition of the protein kinase C activity by isoquinoline-sulfonyl-O-2-methylpiperazine blocked the enhancing effect of NiCl2 on ANG II-induced [Ca2+]i increase. The inhibition of the Na(+)-Ca2+ exchange did not enhance the increase in [Ca2+]i induced by ANG III, NE, or thapsigargin. The AVP-induced changes in [Ca2+]i were not significantly different in the presence or absence of NiCl2. It is concluded that the recovery of resting [Ca2+]i after stimulation by ANG II is mediated by calcium efflux via the Na(+)-Ca2+ exchange.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of captopril on the response of cytosolic free Ca 2+ concentration in cultured vascular smooth muscle cells of aortas from Wistar-Kyoto and spontaneously hypertensive rats to angiotensin II (Ang II) and bradykinin were studied using fura 2. Incubation with captopril for longer than 10 minutes caused a decreased response of cytosolic free Ca 2+ to Ang II and bradykinin. Maximal effects of captopril were observed after a 40-minute incubation. The inhibitory effect of captopril was abolished in Ca 2+ -free medium, suggesting that captopril acts by blocking Ca 2+ influx. Similar effects were observed with enalaprilat. Isometric contraction of aortic strips induced by Ang II in normotensive rats was reduced from 6.5±2.5 to 1.8±0.6 mN by a 40-minute incubation with 1 /tmol/L captopril (P=.O16). Enalaprilat similarly decreased the Ang II-induced contraction. Besides the inhibition of the angiotensin converting enzyme, direct effects of Ang II converting enzyme inhibitors on vascular contraction and Ca 2+ influx in vascular smooth muscle cells may be of therapeutic relevance. (Hypertension. 1993;22:806-811.) KEY WORDS • calcium channel • captopril • angiotensin converting enzyme inhibitors • muscle, smooth, vascular A ngiotensin converting enzyme (ACE) inhibitors / \ were introduced in antihypertensive therapy in A. A . 1977.' The main mechanism of action is lowering the angiotensin II (Ang II) production in both plasma and tissues containing renin and the ACE. The long-term antihypertensive action of ACE inhibitors is not strictly correlated with inhibition of circulating ACE.2 -3 Although the inhibition of tissue ACE 4 and possibly the accumulation of bradykinin by inhibition of kininase II 5 may help to explain the antihypertensive effects, other non-ACE-dependent mechanisms cannot be excluded. Among those, a postjunctional blockade of a-adrenergic vasoconstriction, 6 an inhibition of norepinephrine release from sympathetic neurons, 7 and an inhibition of Na + ,K + -ATPase 8 have been demonstrated. However, these effects were found with concentrations of an ACE inhibitor far exceeding those effective in blocking ACE. Furthermore, long-term ACE inhibition in spontaneously hypertensive rats (SHR) was found to affect Ca 2+ handling in vascular smooth muscle cells (VSMCs).9 Because this was observed after intact animals had been treated with an ACE inhibitor, the question remained open as to whether ACE inhibitors can affect Ca 2+ handling in VSMCs directly. To examine this question, we studied the effect of ACE inhibitors on agonist-induced Ca 2+ transients in cultured VSMCs and on isometric contraction of aortic strips. Methods Cell CultureAll experiments were carried out using rat thoracic aortas isolated from 6-month-old male SHR (weight, 300 to 400 g; systolic blood pressure, 195 ±4 mm Hg, mean±SEM) of the Munster strain (Medizinische Universitats-PolikJinik, Munster, Germany) as previously described 10 and age-matched male normotensive Wistar-Kyoto (WKY) rats (systolic blood pressure, 116±3 mm Hg ). V...
To evaluate the influence of the sarcoplasmic Ca(2+)-ATPase, isometric vasoconstrictions of aortic strips from spontaneously hypertensive rats from the Münster strain (SHR) and normotensive Wistar-Kyoto rats (WKY) were measured after inhibition of Ca(2+)-ATPase by thapsigargin. Inhibition of Ca(2+)-ATPase by thapsigargin caused a biphasic contractile response of the aorta in both SHR and WKY (maximum increase of tension: 1.7 +/- 0.3 x 10(-3) Newton and 2.1 +/- 0.3 x 10(-3) Newton, respectively; mean +/- SE). The second peak of the contractile response was abolished in the absence of external calcium or by inhibition of transplasmamembrane calcium influx by nifedipine, indicating that the second peak occurs as a consequence of calcium influx from the extracellular space. The initial peak of the contractile response after thapsigargin administration was abolished in the presence of an intracellular calcium antagonist, 8-(diethylamino-)-octyl-3,4,5-trimethoxybenzoate (TMB-8), indicating that the initial response was due to calcium release from intracellular stores. Measurements using the fluorescent dye fura2 showed that thapsigargin increased the cytosolic free calcium concentration ([Ca2+]i) in SHR by 72.6 +/- 7.3 nmol/l (n = 34) and in WKY by 53.3 +/- 6.6 nmol/l (n = 39), showing no significant differences between the two strains. The inhibition of Ca(2+)-ATPase increases [Ca2+]i and causes vasoconstriction. The vasoconstriction produced by thapsigargin is not significantly different between SHR and WKY.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.