Clinical Assistant Professor, Anesthesiology, Perioperative and Pain Medicine
Aging is associated with alterations in the responses to several important vasoactive drugs. We have investigated histamine-mediated venodilation across the adult age range using the human hand vein compliance technique. Histamine produces dilation in human veins by activating both H1- and H2-receptors.Full dose-response curves to histamine were constructed in 16 healthy volunteers (mean age, 47 +/- 20 years; age range, 21 to 80 years) by infusing histamine (2 to 136 ng/min) into dorsal hand veins preconstricted with the alpha-adrenergic selective agonist phenylephrine.Histamine was an efficacious venodilator across the age range; the average maximal response (Emax) was 122 +/- 45% and the geometric mean ED50 (the dose producing half-maximal response) was 16.6 ng/min for all subjects. Dose-response curves to histamine were repeated after infusion of the H2-selective antagonist cimetidine at a dose sufficient to completely block the H2-mediated response (49 micrograms/min). Cimetidine did not inhibit the Emax in the elderly as much as it did in the young subjects. The Emax to histamine in the presence of cimetidine plotted against age showed a significant relationship (r = 0.62, p = 0.02).These results suggest that, although the overall histamine-induced venodilation is conserved in aging, there is a loss of the signal transduction pathway activated by way of H2-receptors but no loss in function of H1-receptors. Consequently, these results suggest differential changes in function of H1- versus H2-histamine receptors with aging. Because H1-receptors are coupled to endothelial-derived relaxing factor release and because H2-receptors activate cyclic adenosine monophosphate in smooth muscle, the results are compatible with hypothesis that there are specific changes in these signal transduction pathways with aging.
View details for Web of Science ID A1995RL59000009
View details for PubMedID 7628185
Hypercholesterolemia impairs endothelium-dependent dilation in arteries. We tested the hypothesis that hypercholesterolemia impairs endothelium-dependent vasodilation by an interaction between elevated plasma lipoproteins and a presumably normal endothelium using human veins in vivo; veins do not generally develop atherosclerosis and are appropriate for testing functional alterations.Full dose-response curves were constructed in 13 hypercholesterolemic and 12 normocholesterolemic subjects by infusing bradykinin (0.25 to 508 ng/min) into hand veins preconstricted with the alpha-adrenergic agonist phenylephrine. The maximal relaxation induced by bradykinin was 80 +/- 38% in the controls and 103 +/- 40% in subjects with hypercholesterolemia (P = .08). Responsiveness to bradykinin was also determined after infusion of indomethacin (5.4 micrograms/min), a cyclooxygenase inhibitor, to block the contribution of prostaglandins; maximal responsiveness was greater in hypercholesterolemic subjects (112 +/- 41%) than in controls (81 +/- 31%) (P = .03). Hypercholesterolemic subjects were more sensitive to bradykinin, with an ED50 of 4.2 ng/min versus 10.9 ng/min in controls (P = .05); a similarly increased sensitivity was found in the presence of indomethacin. The response to a maximally effective dose of nitroglycerin was greater in hypercholesterolemic subjects (142 +/- 31%) versus 106 +/- 28% in controls (P = .007). In five hypercholesterolemic subjects, treated with lovastatin to normalize serum cholesterol concentrations, maximal responsiveness to bradykinin decreased from 103 +/- 52% to 80 +/- 28%.These results demonstrate that hypercholesterolemia in humans does not impair endothelium-derived relaxing factor-mediated venodilation.
View details for Web of Science ID A1993ML69900034
View details for PubMedID 8252688