A comparative study of alpha-adrenergic receptor mediated Ca(2+) signals and contraction in intact human and mouse vascular smooth muscle.
In many vascular smooth muscle cells, physiological and pharmacological agonists initiate oscillatory fluctuations in intracellular Ca(2+) to initiate and maintain vasoconstriction. These oscillations are supported by the underlying cellular ultrastructure, particularly the close apposition between the plasma membrane (PM) and superficial sarcoplasmic reticulum (SR), the so-called PM-SR junctions, which are important for SR Ca(2+) refilling. We hypothesize that the disappearance of PM-SR junctions during aging and/or disease is directly related to the disappearance of agonist-induced Ca(2+) oscillations. We compared phenylephrine-mediated Ca(2+) signals and contraction in human and murine smooth muscle cells in small mesenteric arteries and also employed electron microscopy to examine the cytoplasmic distribution of the SR. Phenylephrine elicited tonic contractions in both types of vessels, asynchronous Ca(2+) oscillations in the mouse mesenteric smooth muscle cells, but only single transient Ca(2+) signals in the human mesenteric smooth muscle cells. While nifedipine inhibited 90% of the phenylephrine-induced tonic contraction in mouse mesenteric arteries, it only slightly attenuated tonic contraction in human mesenteric arteries, although the nifedipine-resistant component was abolished by the Rho-kinase blocker 1-(5-Isoquinolinylsulfonyl)homopiperazine dihydrochloride (HA-1077). Furthermore, superficial SR was found to be abundant in the mouse vessels and many PM-SR junctions were observed, but the smooth muscle of human mesenteric arteries had far less peripheral SR and was almost devoid of PM-SR junctions. As PM-SR junctions are essential for the maintenance of Ca(2+) oscillations, the change in Ca(2+) signalling pattern in the relatively old human patients was due to impaired SR refilling.
Dai
Jiazhen Minnie
JM
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
Syyong
Harley
H
Navarro-Dorado
Jorge
J
Redondo
Santiago
S
Alonso
Mauricio
M
van Breemen
Cornelis
C
Tejerina
Teresa
T
D000005:Abdomen / Q000601:surgery; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010656:Phenylephrine / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D014652:Vascular Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014661:Vasoconstriction / Q000187:drug effects; D055815:Young Adult
D011942:Receptors, Adrenergic, alpha; D010656:Phenylephrine