Background-Impaired ␤-adrenergic receptor (AR)-mediated vasorelaxation in hypertension plays a role in increased peripheral vascular resistance and blood pressure. Because the ␤ 2 AR is the most abundant vascular AR subtype, we sought to enhance ␤AR vasorelaxation by overexpressing ␤ 2 ARs via adenoviral-mediated gene transfer (AD␤ 2 AR) to the vascular endothelium of the carotid artery. Methods and Results-In normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, we exposed the right common carotid artery to AD␤ 2 AR in situ for 15 minutes by injection into the lumen while the blood flow was interrupted. Control carotids received an empty vector (ADempty). Three days later, transgene expression and selective endothelial localization were confirmed in infected vessels. Vasoregulation after ␤ 2 AR overexpression (2-fold) was studied in isolated organ baths. AD␤ 2 AR carotid responses to ␣ 1 AR and ␣ 2 AR agonists were not affected, whereas responses to epinephrine were altered and ␤AR-mediated vasorelaxation was enhanced after ␤ 2 AR overexpression. As expected, ␤AR-mediated vasodilatation in control carotids of SHR rats was significantly less than in similar control WKY carotid arteries. AD␤ 2 AR treatment enhanced ␤AR vasorelaxation in SHR to levels similar to those seen in AD␤ 2 AR WKY carotids. Conclusions-Our results demonstrate a critical role for the endothelium in ␤AR-mediated vasorelaxation and suggest that impaired ␤AR signaling may account for dysfunctional ␤AR vasorelaxation in hypertension rather than impaired endothelium-dependent nitric oxide metabolism.

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Abstract-The ␤-adrenergic receptor (␤AR) kinase (␤ARK1) is a G protein-coupled receptor kinase (GRK) that controls cardiac ␤AR signaling via receptor phosphorylation, leading to desensitization. We have observed in mice that chronic isoproterenol administration results in increased myocardial levels of ␤ARK1 activity, suggesting that adrenergic activation can regulate cardiac ␤ARK1 expression. Thus, we evaluated left ventricular (LV) ␤ARK1 levels and activity in response to 3 weeks of a low-sodium (0.05%) diet, which is known to chronically activate the sympathetic nervous system. Wistar-Kyoto rats were subjected to either low or regular sodium (2%) intake. To prove the association of ␤ARK1 expression and low sodium-induced adrenergic activation, a group of rats was subjected to atenolol treatment (1 mg/kg per day) during the low-sodium diet. LV ␤ARK1 expression was assessed by protein immunoblotting and ␤ARK1 activity by in vitro GRK phosphorylation assays. We verified the LV protein levels of GRK5, which is abundantly expressed in the heart. A low-sodium diet reduced body weight and cardiac size so that the heart-to-body weight ratio did not change. On the contrary, low-sodium diet increased by 50% both LV ␤ARK1 Key Words: G proteins Ⅲ kinases Ⅲ receptors, adrenergic, beta Ⅲ heart Ⅲ rats Ⅲ signal transduction Ⅲ diet ␤ -Adrenergic receptors (␤ARs) represent the major determinant of inotropic and chronotropic regulation of the heart. Two classes of ␤AR receptor are represented in the heart, ␤ 1 and ␤ 2 . ␤ 1 is the most abundant type in the normal heart.After stimulation with the agonist norepinephrine, 1 both ␤ARs activate adenylyl cyclase via coupling to the heterotrimeric G protein G s , stimulating the production of the second messenger, cAMP. 2 Moreover, agonist occupancy of ␤ARs also triggers a series of events that leads to the inactivation of ␤AR signaling, known as desensitization, which allows the fine regulation of ␤AR signaling. 3 The molecules involved in desensitization include the G protein-coupled receptor kinase (GRK) family, which in the heart is represented by GRK2, GRK3, GRK4, and GRK5 and the 2 ␤-arrestins. 3 A pivotal role in this mechanism is played by the GRK2, better known as the ␤AR kinase 1 (␤ARK1). 3 This GRK can phosphorylate the active form of both ␤ 1 AR and ␤ 2 AR in the heart and uncouples the receptor from the production of the second messenger, preventing further signaling. Another GRK that is abundant in the heart is GRK5. Like ␤ARK1, GRK5 can phosphorylate the active form of myocardial ␤AR. 4 By causing ␤AR desensitization, ␤ARK1 plays a crucial role in pathological conditions in which it is found at increased levels. In fact, several reports have shown that cardiac ␤ARK1 levels are increased in heart failure, 5,6 myocardial ischemia, 7 hypertension, 8,9 and pressure overload left ventricular (LV) hypertrophy. 10 The mechanisms that cause the increase in cardiac ␤ARK1 expression in these conditions are not completely understood. A common feature of cardiovascular diseases ass...