Aged Spontaneously Hypertensive Rats Exhibit a Selective Loss of EDHF-Mediated Relaxation in the Renal Artery

Abstract

Abstract-Endothelium-dependent relaxation is frequently attenuated in hypertension. We hypothesized that the contribution of the endothelium-derived hyperpolarizing factor (EDHF) to the acetylcholine (ACh)-induced, endotheliumdependent relaxation is attenuated with aging in the renal artery of spontaneously hypertensive rats (SHR) compared with age-matched Wistar-Kyoto (WKY) rats. ACh-induced, NO-mediated relaxation was identical in young (8-weekold) WKY and SHR, whereas EDHF-mediated relaxations (assessed in the presence of N -nitro-L-arginine and diclofenac) were much more pronounced in SHR than WKY. KCl-induced relaxations were more pronounced in vessels from young WKY rats than from young SHR. The cytochrome P450 inhibitor sulfaphenazole significantly inhibited EDHF-mediated relaxation in vessels from young SHR but not WKY. Vessels from old (22 months) SHR exhibited a slightly reduced NO-mediated relaxation but a complete loss of EDHF-mediated responses. In contrast, aging did not affect EDHF-mediated responses in WKY. Moreover, ACh-induced hyperpolarization and resting membrane potential were decreased in old SHR but not in WKY. KCl-induced relaxation increased with age in WKY, whereas no response to KCl was recorded in arteries from aged SHR. In vessels from old WKY but not old SHR, mRNA expression of the Na-K-ATPase subunit ␣ 2 was increased by 2-fold compared with young animals. These data indicate that the increase in EDHF responses in renal arteries from aged WKY can be attributed to the release of K ϩ ions from the endothelium, whereas increased EDHF responses in renal arteries from young SHR can be attributed to a sulfaphenazole-sensitive cytochrome P450-dependent EDHF. Key Words: endothelium Ⅲ nitric oxide Ⅲ acetylcholine Ⅲ endothelium-derived factors Ⅲ animal models of hypertension Ⅲ renal artery T hree different endothelium-derived vasodilators, prostacyclin, nitric oxide (NO), and the endothelium-derived hyperpolarizing factor (EDHF), play an important role in the control of local vascular tone. 1 In hypertension, endotheliumdependent relaxation is attenuated (a phenomenon referred to as endothelial dysfunction) and contributes to the increased peripheral resistance. 2,3 Moreover, treatment of hypertension improves endothelium-dependent relaxation by increasing the NO-mediated and the EDHF-mediated relaxation. 4,5 Endothelial dysfunction in hypertension has been linked to a decrease in NO bioavailability reflecting the impaired generation of NO and/or the enhanced scavenging and inactivation of NO by oxygen-derived free radicals. 6,7 The mechanisms leading to the attenuation of EDHF-mediated relaxations in hypertension are poorly understood but are reportedly unrelated to enhanced vascular oxidative stress. 8 Part of the problem in addressing the factors affecting EDHF-mediated responses is that more than one EDHF may exist and that different hyperpolarizing mechanisms dominate in different arteries. There is a general consensus that EDHFmediated effects are exquisitely sensitive to the combinati...

Upregulation of endothelium-derived hyperpolarizing factor compensates for the loss of nitric oxide in mesenteric arteries of dahl salt-sensitive hypertensive rats

“…Upregulation of EDHF during hypertension has also been reported in renal arteries of SHR. 18 In that study, EDHF-mediated responses were upregulated at the age of 2 months, whereas EDHF-mediated responses were virtually abolished at the age of 22 months compared with agematched Wistar-Kyoto rats. 18 It is therefore plausible to speculate that although long-term exposure to hypertension would ultimately diminish EDHF-mediated responses, EDHF-mediated responses may be upregulated to maintain overall endothelial function in the early phase of hypertension.…”

“…18 In that study, EDHF-mediated responses were upregulated at the age of 2 months, whereas EDHF-mediated responses were virtually abolished at the age of 22 months compared with agematched Wistar-Kyoto rats. 18 It is therefore plausible to speculate that although long-term exposure to hypertension would ultimately diminish EDHF-mediated responses, EDHF-mediated responses may be upregulated to maintain overall endothelial function in the early phase of hypertension. As impairment of EDHF would induce endothelial dysfunction, which may lead to the progress of atherosclerosis, 19 it is of clinical importance to reveal the underlying mechanisms of the upregulation of EDHF during hypertension.…”

“…Such a discrepancy between EDHF-like relaxation and EDHF-mediated hyperpolarization has also been reported in renal arteries of 2-month-old SHR. 18 The apparent mismatch in the data may result from differences in experimental methodologies. The vasorelaxant effects of ACh were studied in samples preconstricted with NE, whereas the membrane potentials were recorded in the absence of NE.…”

Cellular mediators of renal vascular dysfunction in hypertension

“…Cx40-deficient mice are hypertensive, suggesting that impaired EDHF-mediated renal vasodilatation may play a role in HTN (31). Also, while EDHF-mediated renal vascular relaxation is normal in young SHR, it is reduced in aged SHR and associated with depolarized resting membrane potential of the renal artery VSM (15), suggesting that decreased EDHF may be involved in the progression of HTN.…”

Elevated pressure selectively blunts flow‐evoked vasodilatation in rat mesenteric small arteries

“…Scavenging of superoxide or inhibition of enzymatic sources of superoxide within the vascular wall has resulted in an improvement in the vasodilatator capacity of both patients with hypertension (Taddei et al, 1998) and hypertensive rats (Dobrian et al, 2001;Hamilton et al, 2002;Ulker et al, 2003), and this has been attributed to an increased bioavailability of NO (Schnackenberg et al, 1998). However, the impaired endothelium-derived hyperpolarizing factor (EDHF) type vasodilatation observed in arteries from hypertensive animals (Fujii et al, 1992;Bussemaker et al, 2003) has also been shown to be restored by scavenging of superoxide in hypertensive rats (Adeagbo et al, 2003). In rat isolated skeletal arterioles, elevated intravascular pressure through activation of protein kinase C leads to increased superoxide formation and impaired flow-evoked vasodilatation (Huang et al, 1998;Ungvari et al, 2004), suggesting that superoxide formation is due to high pressure per se.…”