Endothelium‐Dependent Agonists Interact to Augment Vasodilation and Limit α1‐Adrenergic Vasoconstriction in Humans
Authors: Terwoord Janee D. , Racine Matthew L. , Hearon Christopher M. , Luckasen Gary J. , Dinenno Frank A. 
Published: November 2023

We have recently demonstrated that vasodilation to the endothelium‐dependent agonist acetylcholine (ACh) is amplified in mildly contracting compared with quiescent skeletal muscle, and further, that this can limit sympathetically‐mediated vasoconstriction similar to what is observed during higher intensity exercise. In contrast, this does not occur when endothelium‐independent vasodilation is stimulated via the nitric oxide donor sodium nitroprusside (SNP). These observations highlight the endothelium as a critical site for the integration of vasomotor signals, and further suggest that net vascular tone is regulated in a highly specific manner. In the present study, we tested the hypothesis that combined action of the endothelium‐dependent agonists ATP and ACh would result in greater vasodilation than the combined action of either dilator with SNP, which acts directly on vascular smooth muscle. Additionally, we hypothesized that the combination of endothelium‐dependent vasodilators would further limit α1‐adrenergic vasoconstriction. We measured forearm blood flow (FBF; Doppler ultrasound) and calculated changes in vascular conductance (FVC: FBF/mean arterial pressure) in 12 young adults (5 M, 7 F) during local, intra‐arterial infusion of endothelium‐dependent and ‐independent vasodilators alone and in combination. Each substance was infused separately for 4 minutes to observe the normal vasodilatory response, then the following combinations of vasodilators were tested: 1) ATP + ACh, 2) ATP + SNP, and 3) SNP + ACh. In the combination trials, the second dilator was infused for 4 minutes after steady‐state blood flow was attained with the first dilator. After the vascular response to each dilator alone or in combination reached steady‐state, we assessed vasoconstriction during infusion of phenylephrine (PE; α1‐agonist) for 2 minutes. As intended, each vasodilator evoked a similar vascular response from rest (FVC: ~22 ml·min−1·100 mmHg−1) when infused individually (FVC: ATP: 64 ± 5; ACh: 73 ± 6; SNP: 73 ± 6 ml·min−1·100 mmHg−1; P = 0.22). Combined infusion of ATP + ACh resulted in greater FVC than combined infusion of either ATP + SNP or SNP + ACh (104 ± 11 vs. 83 ± 7 and 80 ± 8 ml·min−1·100 mmHg−1, respectively; P < 0.05). When infused separately, PE elicited less vasoconstriction during infusion of ATP or ACh vs. SNP (Δ FVC: −24 ± 4 and −30 ± 4 vs. −49 ± 3%; P < 0.05). Combination of ATP + ACh further diminished vasoconstrictor responsiveness (Δ FVC: −16 ± 4%; P < 0.05 vs. ACh alone), and the constriction to PE was lower than that observed during the other combinations (Δ FVC: ATP + SNP: −31 ± 4%; SNP + ACh: −24 ± 3; P < 0.05) and during a higher dose of SNP intended to match the higher steady‐state FVC of the ATP + ACh trial (Δ FVC: −41 ± 6%, P < 0.05). We conclude that endothelium‐dependent agonists can interact to augment vasodilation and limit α1‐adrenergic vasoconstriction. How such interactions occur to regulate vascular tone and thus tissue blood flow in humans under physiological conditions remains to be determined.Support or Funding InformationSupported by NIH HL119337