Acute Systemic Rho‐kinase Inhibition Reduces Blood Pressure and Influences Peripheral Vascular Tone in Healthy Older Adults

Abstract

Aging is the primary risk factor for cardiovascular disease (CVD), and Rho‐kinase has emerged as an important contributor to the pathogenesis of CVD in preclinical and clinical studies. Therefore, we tested the hypothesis that acute, systemic Rho‐kinase inhibition would improve measures of CVD risk in older adults. We studied healthy young (YA; 25 ± 1 yrs; 6M/6F) and older adults (OA; 65 ± 1 yrs; 6M/7F) under control conditions (CON, intravenous saline) and during inhibition of Rho‐kinase via intravenous fasudil administration (60 mg) in a double‐blind, randomized, crossover design. In separate visits to the laboratory, saline and fasudil were infused over the course of 1 h, after which we measured blood pressure, carotid‐femoral pulse wave velocity (cfPWV; index of arterial stiffness), and central augmentation index (AIx; SphygmoCor XCEL). In a subset of participants (YA: 5M/5F; OA: 6M/3F), we assessed reactive hyperemia (RH) and flow‐mediated dilation (FMD) to evaluate microvascular function and conduit artery endothelial function, respectively. We measured brachial artery diameter and mean blood velocity (MBV; Doppler ultrasound) to calculate forearm vascular conductance (FVC; forearm blood flow/mean arterial pressure · 100). FMD was quantified as the percent change in brachial artery diameter following 5 min of forearm ischemia. Shear rate (8 · MBV/diameter) was expressed as area under the curve (SRAUC) from cuff release to peak diameter to quantify the stimulus for FMD. In OA, fasudil reduced systolic (SBP, 127 ± 4 vs. CON: 134 ± 4 mmHg, P < 0.05), diastolic (DBP, 76 ± 2 vs. CON: 79 ± 1 mmHg, P < 0.05), and mean arterial pressure (MAP, 93 ± 2 vs. CON: 97 ± 2 mmHg, P < 0.05), and BP remained lower 1 and 2 h postinfusion. Although fasudil initially reduced SBP (114 ± 2 vs. CON: 119 ± 2 mmHg, P < 0.05), DBP (68 ± 2 vs. CON: 72 ± 2 mmHg, P < 0.05), and MAP (84 ± 2 vs. CON: 88 ± 2 mmHg, P < 0.05) in YA, BP returned to control levels and was not different from CON at 1 or 2 h post‐infusion. Fasudil lowered cfPWV in OA (7.6 ± 0.4 vs. CON: 7.8 ± 0.4 m/s, P < 0.05) and tended to lower cfPWV in YA (5.2 ± 0.2 vs. CON: 5.4 ± 0.2 m/s, P = 0.07). However, AIx was unchanged by the fasudil treatment in both OA (27 ± 2 vs. CON: 31 ± 2%, P = NS) and YA (−2 ± 2 vs. CON: −5 ± 5%, P = NS). Baseline brachial diameter increased with fasudil in OA (3.29 ± 0.23 vs. CON: 3.16 ± 0.20 mm, P < 0.05), whereas fasudil had no effect on baseline diameter in YA (3.19 ± 0.19 vs. CON: 3.16 ± 0.17 mm, P = NS). Similarly, resting FVC was elevated under fasudil conditions in OA (36 ± 4 vs. CON: 25 ± 3 ml/min/100 mmHg, P < 0.05), while FVC was unchanged with fasudil in YA (36 ± 9 vs. CON: 32 ± 5 ml/min/100 mmHg, P = NS). Following forearm ischemia, there was no effect of fasudil on peak blood flow (OA, 288 ± 30 vs. CON: 286 ± 31 ml/min, P = NS; YA, 346 ± 65 vs. CON: 346 ± 45 ml/min, P = NS) or on FMD (OA, 6.2 ± 1.1 vs. CON: 7.0 ± 1.1%, P = NS; YA, 6.5 ± 1.1 vs. CON: 7.9 ± 1.4%, P = NS). Fasudil did not affect SRAUC (OA, 29 ± 5 vs. CON: 29 ± 4 s−1 · 103, P = NS; YA, 32 ± 5 vs. CON: 36 ± 5 s−1 · 103) in either group. Collectively, these data suggest Rho‐kinase contributes to the age‐related elevation in blood pressure potentially via greater peripheral vasoconstrictor tone in healthy older adults.Support or Funding InformationHL119337