Mechanism of α1-Adrenergic Receptor-Induced Increased Contraction of Rat Mesenteric Artery in Aging Hypertension Rats

Abstract

Introduction: Vasoconstriction is triggered by an increase in intracellular-free calcium concentration. Growing evidence indicates that contraction is also regulated by calcium-independent mechanisms involving RhoA-Rho kinase (ROCK), protein kinase C (PKC), and so on. In this study, we studied the changes of vascular reactivity as well as the underlying signaling pathways in aging spontaneously hypertensive rats (SHRs). Methods: The artery tension induced by α1-adrenergic receptor activator (α1-AR) phenylephrine (PE) was measured in the absence or presence of myosin light chain kinase (MLCK), PKC, and ROCK inhibitors. The α1-AR, PKC, ROCK, phosphorylation of myosin light chain (MLC), and PKC-potentiated phosphatase inhibitors of 17 kDa (CPI-17) of rat mesenteric arteries were analyzed at the mRNA level or protein level. Results: The vascular tension measurements showed that there was a significant increase in the mesenteric artery contraction induced by PE in old SHR. MLCK inhibitor ML-7 can similarly inhibit PE-induced vasoconstriction. PKC inhibitor GF109203X has the weakest inhibitory effect on PE-induced contraction in old SHR. At the presence of ROCK inhibitor H1152, PE-induced contraction was significantly reduced in young Wistar-Kyoto (WKY) rats, but this phenomenon disappeared in other rats. Furthermore, in old SHR the protein expression of α1-AR decreased and phosphorylation of MLC and CPI-17 were upregulated and MLC phosphatase (MLCP) activity was significantly lower. The expressions of PKC were upregulated in SHR and old rats. In addition, the expression of ROCK-1 was decreased and ROCK-2 was significantly upregulated with age in SHR. Conclusion: In aging hypertension, the expression/activity of PKC or ROCK-2/CPI-17 excessively increased, MLCP activity decreased and MLC phosphorylation enhanced, leading to increased α1-AR-induced vasoconstriction.

Thromboxane-induced contractile response of mesenteric arterioles is diminished in the older rats and the older hypertensive rats

“…As shown in Figure 1 , Emax was significantly increased in SHR compared with WKY rats ( p ＜0.01); Emax was significantly increased in OldSHR compared with OldWKY rats ( p ＜0.01). This experiment showed that the mesenteric vessels from hypertension are more sensitive to High K + in hypertension, which is consistent with other reports ( Wei et al, 2021 ; Cui et al, 2022 ).…”

“…The percentage of Emax caused by U-46619 relative to Emax caused by high K + solution (%Emax) was calculated. The vasoconstriction induced by U-46619 was different from those of vascular responses induced by high K + or PE, as previously reported ( Wei et al, 2021 ). The response of mesenteric vessels to U-46619 was significantly increased in hypertension.…”

Vascular Effects of Low-Dose ACE2 Inhibitor MLN-4760—Benefit or Detriment in Essential Hypertension?

“…Several studies confirmed that most arteries in SHRs had increased sympathetic innervation and elevated α1-adrenergic receptor-mediated contractile responses compared to normotensive rats [ 49 ]. The thoracic aorta, as a type of elastic artery, undergoes specific development during hypertension, and the hypertrophied arterial wall displays decreased contractile efficiency as a result of structural remodeling along with increased sensitivity of adrenergic receptors [ 11 ].…”

Vascular calcium signalling and ageing

“…2018) and α 1 ‐adrenoceptor‐induced (Wei et al . 2021) arterial tone. Similar to the discrepancy in rat studies, investigations of mouse small mesenteric arteries demonstrated an inconsistent impact of ageing on L‐type channel expression and function (del Corsso et al .…”

“…An enhanced myogenic tone without a change in SMC [Ca 2+ ] i at high intravascular pressure suggested an increase in SMC Ca 2+ sensitivity in middle cerebral arteries with intact endothelium from old rats (Geary & Buchholz 2003). Later studies in mouse and rat mesenteric artery implicated increased Rho kinase activity in the age-dependent increase in vascular SMC Ca 2+ sensitivity resulting in an augmentation of myogenic (Björling et al 2018) and α 1 -adrenoceptor-induced (Wei et al 2021) arterial tone. Similar to the discrepancy in rat studies, investigations of mouse small mesenteric arteries demonstrated an inconsistent impact of ageing on L-type channel expression and function (del Corsso et al 2006;DuPont et al 2016;Mikkelsen et al 2016).…”