| Hypertension is a disease characterized by enhanced arterial agonist-induced contraction, reduced agonist-induced relaxation, spontaneous arterial tone and smooth muscle cell remodeling. Phosphoinositide 3-kinase (PI3-kinase) is a multi-faceted enzyme involved in a variety of biological pathways and an alteration in such a key enzyme may lead to the enhanced arterial contractility and spontaneous tone observed in hypertension. Therefore I hypothesized that spontaneous tone and agonist-induced contraction in hypertension is mediated by an up-regulation of the PI3-kinase dependent signaling pathway. This, in turn, ultimately links to an increase in intracellular calcium concentration through opening L-type calcium channels, permitting arterial contraction. Elucidation of the role of PI3-kinase in contraction in hypertension is vital to a better understanding of the pathology of hypertension, as well as for utilization as a potential therapeutic target.; Spontaneous tone is driven by alterations in available calcium and p110 PI3-kinase subunits can directly activate L-type calcium channels. Isometric contractile experiments revealed that LY294002, a PI3-kinase inhibitor, inhibited all calcium-induced spontaneous tone in aorta from hypertensive DOCA-salt, LNNA, and SHR rats; aorta from respective normotensive rats displayed no tone. LY294402 also eliminated spontaneous tone in mesenteric resistance arteries. These studies suggested that there was an alteration in PI3-kinase protein/activity in arteries from hypertensive animals; therefore biochemical assays were performed. p85α-associated PI3-kinase activity in aorta from DOCA-salt rats was 2-fold greater than sham. Western analyses revealed aorta possessed p85α, p110α, p110β and p110δ but not p110γ PI3-kinase subunits, with significantly higher p110δ protein density in aorta from hypertensive DOCA-salt, LNNA and SHR rats compared to their respective controls. Moreover, immunohistochemical studies localized p110δ to aortic smooth muscle and activity assays revealed elevated aortic p110δ-associated activity in DOCA-salt rats. LY294002 rightward shifted the enhanced contraction to norepinephrine in aorta from DOCA-salt, LNNA and SHR rats compared to control animals, demonstrating further physiological relevance of PI3-kinase. LY294002 also inhibited enhanced low-Mg2+-induced tone. Together, these data support an increase in class I PI3-kinase protein/activity in the condition of hypertension. Importantly, this increase contributes to the enhanced contractility observed in multiple models of hypertension. |
