Age-related impairment of conducted dilation in human coronary arterioles

Abstract

Conducted vasodilation is essential to coordinate vascular resistance along distances to ensure adequate tissue perfusion. We hypothesized that conducted vasodilation of coronary resistance arteries declines with age. Coronary arterioles were dissected from right atrial appendage of patients (n = 27) undergoing cardiac surgery. Arterioles (~100 μm) were cannulated and pressurized (80 mmHg), and developed spontaneous myogenic tone. Conducted vasodilation was initiated by locally administering the endothelium-dependent agonist bradykinin (BK; 100 μM) ejected from a glass micropipette (~3 μm tip opening, positioned in close proximity to the vessel wall). Diameter changes were measured at local and upstream sites (500 and 1,000 μm from the stimulus) with videomicroscopy. Local administration of BK elicited vasodilation, the magnitude of which increased with the duration of stimulus (69 ± 6, 81 ± 6, 90 ± 2%, after 1, 3, and 5 × 100 ms, respectively). BK-induced dilation remained substantial at upstream sites (500 μm: 53 ± 7%; 1,000 μm: 46 ± 9%). The gap junction uncoupler carbenoxolone or 18-α-glycyrrhetinic acid did not affect local responses, but diminished conducted vasodilation. Inhibitors of small/intermediate conductance calcium-activated potassium channels (SKCa/IKCa), apamin and TRAM34, reduced dilations both at local and remote sites. We found that conducted dilation, but not the local response, was significantly reduced in older (≥64 yr) patients. The nitric oxide (NO) synthesis inhibitor N(ω)-nitro-l-arginine methyl ester did not affect local responses, but markedly reduced conducted dilation in younger (<64 yr) individuals. Collectively, we show that human coronary arterioles exhibit SKCa/IKCa-mediated hyperpolarization spread through gap junctions, which contributes to conducted vasodilation initiated by focal application of BK. We demonstrate that conducted dilation declines with age, likely due to reduced NO availability, which plays a permissive role in propagating longitudinal vasomotor signaling.

Regulation of Coronary Blood Flow

“…The role of ion channels in endothelial regulation of coronary vascular tone is impacted by disease, cardiovascular risk factors, and the degree of physical fitness. For example, SK Ca , IK Ca , and gap junctions contribute to conducted vasodilation in human coronary arterioles, a response that is impaired by aging (327). Similarly, impairments in SK Ca and IK Ca channels contribute to the endothelial dysfunction of coronary arterioles from diabetic patients (623).…”

SK channels and ventricular arrhythmias in heart failure

“…SK channels contribute to repolarization of action potential in atrial cardiomyocytes and diseased ventricular cells (Bonilla et al, 2014; Chang et al, 2013a; Chua et al, 2011; Lee et al, 2013; Xu et al, 2003). The activation of SK channels also plays important roles in the function of a range of other tissues, such as the endothelium, intestine and urinary bladder (Feher et al, 2014; Hougaard et al, 2009; Ro et al, 2001). The SK channel family consists of 3 major subtypes: SK1, SK2 and SK3.…”

“…Endothelial SK channel activation leads to hyperpolarization, and contributes to the conducted dilatation of coronary arteries. Dysfunction of SK channels in endothelial cells, such as that occurs during aging, may contribute to impaired myocardial flow reserve (Feher et al, 2014). The SK channels in cardiac stellate ganglia are associated with sympathetic outflow.…”

The effect of aging on the cutaneous microvasculature

“…For example, acetylcholine-induced endothelium-dependent vasodilatation declines with advancing age (although vasodilatation in response to bradykinin, substance P and isoproterenol is preserved) (DeSouza et al, 2002). Aging is also associated with deficits in endothelial nitric oxide availability (Feher et al, 2014) and nitric oxide synthase-dependent vasodilation of arterioles (Mayhan et al, 2008). Replacement of low estrogen levels in aged female rats can restore impairments of vasodilation (Kang et al, 2011).…”