title: Predicted effects of nitric oxide and superoxide on the vasoactivity of the afferent arteriole.
abstract: We expanded a published mathematical model of an afferent arteriole smooth muscle cell in rat kidney (Edwards A, Layton, AT. Am J Physiol Renal Physiol 306: F34-F48, 2014) to understand how nitric oxide (NO) and superoxide (O(2)(-)) modulate the arteriolar diameter and its myogenic response. The present model includes the kinetics of NO and O(2)(-) formation, diffusion, and reaction. Also included are the effects of NO and its second messenger cGMP on cellular Ca²⁺ uptake and efflux, Ca²⁺-activated K⁺ currents, and myosin light chain phosphatase activity. The model considers as well pressure-induced increases in O(2)(-) production, O(2)(-)-mediated regulation of L-type Ca²⁺ channel conductance, and increased O(2)(-) production in spontaneous hypertensive rats (SHR). Our results indicate that elevated O(2)(-) production in SHR is sufficient to account for observed differences between normotensive and hypertensive rats in the response of the afferent arteriole to NO synthase inhibition, Tempol, and angiotensin II at baseline perfusion pressures. In vitro, whether the myogenic response is stronger in SHR remains uncertain. Our model predicts that if mechanosensitive cation channels are not modulated by O(2)(-), then fractional changes in diameter induced by pressure elevations should be smaller in SHR than in normotensive rats. Our results also suggest that most NO diffuses out of the smooth muscle cell without being consumed, whereas most O(2)(-) is scavenged, by NO and superoxide dismutase. Moreover, the predicted effects of superoxide on arteriolar constriction are not predominantly due to its scavenging of NO.
authors.affiliation: Department of Mathematics, Duke University, Durham, North Carolina; and.
authors.forename: Anita T
authors.initials: AT
authors.lastname: Layton
authors.affiliation: Sorbonne Universités, UPMC Université Paris 06, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMRS 1138, CNRS ERL 8228, Centre de Recherche des Cordeliers, Paris, France aurelie.edwards@crc.jussieu.fr.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Edwards
mesh_terms: D000465:Algorithms; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy; D007668:Kidney / Q000187:drug effects; D008297:Male; D015233:Models, Statistical; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009218:Myosins / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D011918:Rats, Inbred SHR; D012079:Renal Circulation / Q000187:drug effects; D013113:Spin Labels; D013481:Superoxides / Q000494:pharmacology*
chemical_list: D020746:Calcium Channels, L-Type; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D013113:Spin Labels; D013481:Superoxides; D000804:Angiotensin II; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D009218:Myosins; D006152:Cyclic GMP; C001803:tempol
keywords: afferent arteriole; mathematical model; myogenic response; nitric oxide; reactive oxygen species