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Aspects of autoregulation: the effects of mitogen-activated protein kinase and gap junction communication inhibition on myogenic tone

University of British Columbia

Autoregulation of blood flow in small arteries and arterioles is a combination of myogenic, neural, humoral and metabolic effects. The interaction between these effects allows capillary blood flow to remain relatively constant in spite of changes in blood pressure. And, myogenic or pressure-induced tone significantly contributes to the overall contractile state of many vascular beds for example, in the coronary, mesenteric, skeletal muscle and cerebral circulations. Cytosolic calcium concentration is the primary factor that governs the contractility during the myogenic response. However, several cellular events can modulate the reactivity of smooth muscle cells. Two such processes include the mitogen-activated protein (MAP) kinase and intercellular communication mediated via gap junctions. Two inhibitors of MAP kinase, U0126 and PD98059, were used to determine the effects of MAP kinase inhibition on myogenic tone in the rat middle cerebral artery. In addition, their inhibitory effects on vasopressin- and depolarization-induced constrictions were determined. PD98059 was nonselective and partially inhibited the three forms of vasoconstriction. U0126 (at 10µM) selectively inhibited myogenic tone and agonist-induced tone but not depolarization-induced tone. Furthermore, indolactam, an activator of protein kinase C, was not affected at this concentration. These results suggest that MAP kinase may be involved in the regulation of myogenic and agonist-induced tone. Two inhibitors of gap junction coupling, heptanol and α-glycyrrhetinic acid (α-GA) were used to determine the role of cell-to-cell communication in myogenic tone. Both inhibitors exhibited similar trends in inhibiting myogenic and vasopressin-induced tone. However, heptanol also inhibited depolarization-induced tone but not a-GA indicating that heptanol may inhibit voltage-gated Ca2+ channels. These results suggest that myogenic tone may be mediated through a similar signaling cascade as the receptor-mediated vasopressin response. Also, the selectivity of α- GA suggests that a significant proportion of smooth muscle cells are insensitive to agonist or pressure stimulation and require gap junction-coupled cells for activation.

Thesis/Dissertation

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2009-07-13

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http://hdl.handle.net/2429/10678

Pharmacology

University of British Columbia

UBCV

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