Effects of chronic treatment with a low dose of nicorandil on the function of the rat aorta during ageing

Raveaud, Stéphanie; Mézin, P.; Lavanchy, N; Starcher, Barry; Mecham, Robert P.; Verdetti, Jean; Faury, Gilles

doi:10.1111/j.1440-1681.2009.05174.x

Cited by 15 publications

(8 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, we see that passive vessel compliance is increased in both genotypes. Increased vessel compliance may reflect increased elastin production in smooth muscle, as has been reported in response to pharmacological activators of K ATP channels in cultured smooth muscle cells (34), and in the rat aorta (35). It should be noted that endothelial K ATP channels have also been implicated in blood pressure control (36,37), and in angiogenesis (38)(39)(40).…”

Section: Discussionmentioning

confidence: 80%

Cardiovascular consequences of KATP overactivity in Cantu syndrome

Huang¹,

McClenaghan²,

Harter³

et al. 2018

JCI Insight

View full text Add to dashboard Cite

Cantu syndrome (CS) is characterized by multiple vascular and cardiac abnormalities including vascular dilation and tortuosity, systemic hypotension, and cardiomegaly. The disorder is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits. However, there is little understanding of the link between molecular dysfunction and the complex pathophysiology observed, and there is no known treatment, in large part due to the lack of appropriate preclinical disease models in which to test therapies. Notably, expression of Kir6.1 and SUR2 does not fully overlap, and the relative contribution of KATP GOF in various cardiovascular tissues remains to be elucidated. To investigate pathophysiologic mechanisms in CS we have used CRISPR/Cas9 engineering to introduce CS-associated SUR2[A478V] and Kir6.1[V65M] mutations to the equivalent endogenous loci in mice. Mirroring human CS, both of these animals exhibit low systemic blood pressure and dilated, compliant blood vessels, as well dramatic cardiac enlargement, the effects being more severe in V65M animals than in A478V animals. In both animals, whole-cell patch-clamp recordings reveal enhanced basal KATP conductance in vascular smooth muscle, explaining vasodilation and lower blood pressure, and demonstrating a cardinal role for smooth muscle KATP dysfunction in CS etiology. Echocardiography confirms in situ cardiac enlargement and increased cardiac output in both animals. Patch-clamp recordings reveal reduced ATP sensitivity of ventricular myocyte KATP channels in A478V, but normal ATP sensitivity in V65M, suggesting that cardiac remodeling occurs secondary to KATP overactivity outside of the heart. These SUR2[A478V] and Kir6.1[V65M] animals thus reiterate the key cardiovascular features seen in human CS. They establish the molecular basis of the pathophysiological consequences of reduced smooth muscle excitability resulting from SUR2/Kir6.1-dependent KATP GOF, and provide a validated animal model in which to examine potential therapeutic approaches to treating CS.

show abstract

Section: Discussionmentioning

confidence: 80%

Cardiovascular consequences of KATP overactivity in Cantu syndrome

Huang¹,

McClenaghan²,

Harter³

et al. 2018

JCI Insight

View full text Add to dashboard Cite

show abstract

“…Thoracic aortas were stretched to 2 grams tension over a series of three adjustments in tension taking a total of 10 minutes. Resting tension was chosen based on published literature [ 41 – 44 ]. Following a 30-minute equilibration period, vascular integrity in all vessels was confirmed by exposing them to Phe (10μM) followed by MCh (3 μM).…”

Section: Methodsmentioning

confidence: 99%

Postpartum Vascular Dysfunction in the Reduced Uteroplacental Perfusion Model of Preeclampsia

et al. 2016

View full text Add to dashboard Cite

Preeclampsia is a disorder affecting 2–8% of all pregnancies, characterized by gestational hypertension (≥ 140/90 mmHg) and proteinuria (≥300 mg over 24 hours) diagnosed following the 20th week of pregnancy, and for which there is currently no available treatment. While the precise cause of preeclampsia is unknown, placental ischemia/hypoxia resulting from abnormal trophoblast invasion and maternal endothelial dysfunction are central characteristics. Preeclampsia is a major cause of both maternal and fetal morbidity and mortality in the perinatal period. In addition, women who have experienced preeclampsia are more likely to suffer cardiovascular disease later in life. The cause of this elevation in cardiovascular risk postpartum, however, is unknown. We hypothesize that there may be lasting vascular dysfunction following exposure to reduced uteroplacental perfusion during pregnancy that may contribute to increased cardiovascular risk postpartum. Using the rat reduced utero-placental perfusion pressure (RUPP) model of preeclampsia, blood pressure was assessed in dams at gestational day 20, one and three months postpartum. Mesenteric artery and aortic function were assessed using wire myography. We demonstrated hypertension and increased mesenteric artery responses to phenylephrine at gestational day 20, with the latter due to a decreased contribution of nitric oxide without any change in methylcholine-induced relaxation. At one month postpartum, we demonstrated a small but significant vasoconstrictive phenotype that was due to an underlying loss of basal nitric oxide contribution. At three months postpartum, endothelium-dependent relaxation of the aorta demonstrated sensitivity to oxLDL and mesenteric arteries demonstrated decreased nitric oxide bioavailability with impaired methylcholine-induced relaxation; indicative of an early development of endothelial dysfunction. In summary, we have demonstrated impaired vascular function following exposure to a RUPP pregnancy that continued into the postpartum period; suggesting that a pregnancy complicated by preeclampsia may predispose women to later life cardiovascular disease via ongoing vascular dysfunction.

show abstract

“…Chronic treatment of mice with minoxidil also results in improvements of the arterial mechanics and cerebral perfusion and, at least in aged animals, in neosynthesis of elastic fibers and protection of pre-existing elastic fibers [157][158][159]. Other KATP channel openers, like diazoxide or nicorandil, exert an effect on in vivo elastin synthesis similar to those induced by minoxidil [156,160], while pinacidil and some cromakalim or diazoxide derivatives have also been shown to induce elastin production by cultured VSMCs in rats [156,161,162]. However, treatment of animals with other antihypertensive drugs, either angiotensin-II type 1 receptor blocker, beta blocker or calcium channel blocker, does not modify the elastin content in arteries [163].…”

Section: Pharmacological Reinitiation Of Elastin or Elastic Fiber Synthesis In Aged Patients Or Animalsmentioning

confidence: 98%

Rise and fall of elastic fibers from development to aging. Consequences on arterial structure-function and therapeutical perspectives

et al. 2019

Self Cite

View full text Add to dashboard Cite

Effects of chronic treatment with a low dose of nicorandil on the function of the rat aorta during ageing

Cited by 15 publications

References 43 publications

Cardiovascular consequences of KATP overactivity in Cantu syndrome

Cardiovascular consequences of KATP overactivity in Cantu syndrome

Postpartum Vascular Dysfunction in the Reduced Uteroplacental Perfusion Model of Preeclampsia

Rise and fall of elastic fibers from development to aging. Consequences on arterial structure-function and therapeutical perspectives

Contact Info

Product

Resources

About