Endothelium-Dependent Vasodilation and Tissue-Type Plasminogen Activator Release in Borderline Hypertension

Abstract

Abstract We recently showed that muscarinic receptor stimulation causes a marked increase in the net release of tissue-type plasminogen activator (TPA) antigen and activity across the human forearm in vivo, in conjunction with endothelium-dependent vasodilation. Because hypertension has been associated with endothelial dysfunction, the aim of the study was to compare forearm TPA release and vasodilation in response to muscarinic stimulation in normotensive (NC) and borderline hypertensive (BH) subjects. The study was performed in 10 apparently healthy young men with BH and 10 male NC subjects. Methacholine (MCh: 0.1, 0.8, and 4.0 μg/min) and sodium nitroprusside (SNP: 0.5, 2.5, and 10 μg/min) were administered in randomized order as double-blind, stepwise, intrabrachial artery infusions. Forearm blood flow was assessed by plethysmography. Net release/uptake was calculated as the product of the arteriovenous concentration gradient and forearm plasma flow. Vasodilator responses to MCh were similar in both groups ( P =NS), whereas the decrease in forearm vascular resistance in response to SNP was somewhat less in BH subjects ( P =.005). At rest, both groups showed a significant arteriovenous gradient and net release of TPA antigen across the forearm ( P <.05 throughout). However, in contrast to the significant net increment in TPA activity across the forearm in the NC group ( P <.018), BH subjects had no basal forearm increment in TPA activity (NC vs BH, P =.006). Arterial and venous plasma levels of plasminogen activator inhibitor 1 (PAI-1) antigen and activity were higher in BH subjects ( P ≤.05 throughout), who in contrast to NC subjects, also had a significant forearm net release of PAI-1 antigen ( P =.006). Across the whole group, there was a significant inverse relation between arterial PAI-1 antigen levels and increment in TPA activity across the forearm ( r =−.57, P =.008) but no relation to TPA antigen release. In response to MCh infusion, both the net release of TPA antigen and increment in TPA activity increased markedly and to similar extents in both groups ( P <.01 throughout). SNP infusion had no effect on either TPA antigen release or increment in TPA activity in the NC group but elicited a significant net release of TPA antigen and increase in TPA activity in the BH group ( P <.05). Both circulating levels and local release of PAI-1 antigen were significantly correlated to fasting plasma insulin. Endothelium-dependent vasodilation and endothelial TPA release in response to muscarinic receptor stimulation were preserved in BH subjects. At rest, BH subjects had higher circulating PAI-1 antigen levels and a corresponding decrease in circulating levels and local increment of TPA activity. In contrast to NC subjects, BH subjects responded with a TPA release also in response to increased flow, which may indicate an enhanced endothelial cell responsiveness to fluid shear stress.