Abstract 1574: Inhibition Of Extracellular Ca2+ Influx And Rho Kinase Mediate Hypoxic Dilation Of Human Mammary Artery
Objective: Systemic artery dilates in response to decrease in Po2, to maintain blood supply to stressed organ. However, the mechanism of hypoxic dilation is still unknown and the effect of hypoxia on human systemic arteries is infrequently studied. Since the internal mammary artery (IMA), a routinely used bypass conduit, is often exposed to low Po2 that evokes vasospasm and leads to hypo-perfusion of myocardium in peri- and post-operative conditions, we initiated this study to elucidate the mechanism of hypoxic dilation in IMA.
Methods & Results: The distal IMA was collected during a CABG surgery in a blinded-fashion and 2–3 mm rings were used in the isometric tone study. The IMA rings pre-contracted with either KCl (30 mM; n=7), a depolarizing agent, or phenylephrine (PE: 10 μM; n=7), a α-adrenergic agonist, relaxed to 34 ± 12% and 10±7%, respectively, of the steady-state pre-hypoxic contraction, in a time-dependent manner by decreasing Po2 from 140 to 30 torr. The initiation of hypoxic dilation was mediated by opening of K+ channels, because IMA pre-contracted with PE relaxed (P=0.027) to 74±12% of the steady-state pre-hypoxic contraction @ 3 minutes by hypoxia and tetraethylammonium acetate (TEA; 10 mM), a K+ channel blocker, suppressed (P=0.059) relaxation (97.4±1.6% @ 3 minutes). More interestingly pretreatment of IMA with Y-27362 (10 μM), a Rho kinase inhibitor, shifted Ca2+ sensitivity to the right, since [Ca2+]o required to induce 50% contraction of IMA by KCl (30 mM) was shifted from 0.3±0.1 mM (control) to 1.1±0.1 mM (Y-27362), and decreased (P=0.043) hypoxic dilation (Y-27362+KCl: 74±14%; n=5 versus KCl: 34±12%; n=7; @ 3 minutes). Hypoxia also shifted Ca2+ sensitivity and suppressed (P<0.005) steady-state contraction (Normoxia: 4.3±0.1g versus Hypoxia: 1.2±0.6g) evoked by 1.5 mM [Ca2+]o.
Conclusion: Our results, therefore, demonstrate that inhibition of extracellular Ca2+ influx and Rho kinase plays a major role in hypoxic dilation of human artery and we propose that response of IMA conduits to hypoxia could be compromised in hypertension and diabetes in which the Ca2+ handling and Rho kinase is modulated, leading to hypo-perfusion of myocardium in hypertensive/diabetic patients undergoing CABG surgery.
(Supported by AHA Grant #0435070N)