Effect of captopril on vasoconstriction and Ca2+ fluxes in aortic smooth muscle.

Abstract

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...

Perivascular fat-mediated vascular dysfunction and remodeling through the AMPK/mTOR pathway in high-fat diet-induced obese rats

“…24,25 After the animals were anesthetized with pentobarbital sodium (50 mg kg À1 body mass, i.p. ), aortae were dissected and immediately placed in cold Krebs solution containing (mM): NaCl 119; NaHCO 3 25; glucose 11.1; KCl 4.7; KH 2 PO 4 1.2; MgSO 4 1.2 and CaCl 2 2.5.…”

Increased Transient Receptor Potential Canonical Type 3 Channels in Vasculature From Hypertensive Rats

“…[12][13][14][15] Although major calcium influx in VSMC is mediated by voltage-gated calcium channels, TRPC channels are important signal transducers for agonist-mediated vascular contractility. It should be noted that the increased angiotensin II-induced calcium influx in primary hypertension could also be observed in the presence of the calcium channel blocker amlodipine.…”

“…7 Increased angiotensin II-induced vasoconstriction and proliferation of VSMC, as well as augmented angiotensin II-induced intracellular signal transduction pathways and calcium influx, have frequently been observed in primary hypertension. 6,[11][12][13][14][15] Part of the action of angiotensin II may occur through TRPC channels. Although data from the literature gave evidence that calcium influx through TRPC3 channels may contribute to vasoconstriction and hypertension, this has not been tested yet using VSMC from SHR.…”

Mechanism of the Action of Angiotensin-Converting Enzyme Inhibitors on Agonist-Induced Ca²⁺ Influx

“…Furthermore, it was demonstrated that these inhibitory effects of captopril and enalaprilat on Ca2+ influx in VSMC were paralleled by a decreased 268 Zhu/Tepel/Neusser/Zidek Angiotensin-Converting Enzyme Inhibitors and Cytosolic Calcium contractile response to Ang II [23], This study also showed that the attenuation of the Ang II response is due to an inhibition of transplasma membrane Ca2+ influx. Interestingly, similar effects of captopril have also been observed in ventricular myocytes, indicating that Ca2+ influx through L-type channels as well as contraction is inhibited by captopril [24], From these results several questions arose.…”