Coronary and systemic hemodynamic effects of sustained inhibition of nitric oxide synthesis in conscious dogs - Evidence for cross talk between nitric oxide and cyclooxygenase in coronary vessels

Sustained inhibition of NO synthesis (N(o)mega-nitro-L-arginine [L-NNA], 20 mg . kg(-1). d(-1), 7 days) was investigated at rest and during exercise in conscious dogs. At rest, L-NNA did not alter mean arterial blood pressure but markedly increased total peripheral resistance (+ 73+/-14%, P<.01). Exaggerated hypertension was observed during exercise (+ 132+/-5 mm Hg after L-NNA versus + 113+/-5 mm Hg before L-NNA, P<.0.1), L-NNA decreased the resting coronary artery diameter by 6+/-1% and suppressed its exercise-induced dilation but had no effect on coronary blood flow and resistance. L-NNA decreased flow repayment volumes during reactive hyperemia, but corresponding flow debt volumes remained unchanged. The cyclooxygenase inhibitor diclofenac (10 mg/kg) had no effect on reactive hyperemia parameters before L-NNA but reduced flow repayment volumes, durations, and corresponding debt-to-repayment ratios in L-NNA-treated dogs (all P<.05). In vitro, indomethacin blunted the residual relaxation to bradykinin of large coronary arteries taken from L-NNA-treated, but not from control, dogs. Bradykinin-induced increase in 6-ketoprostaglandin F-1 alpha production was greater in coronary arteries taken from L-NNA-treated dogs (+ 179+/-41 pg/mm(2)) than from control dogs (+ 66+/-18 pg/mm(2)) (P<.05). These results indicate that (i) NO is of major importance in the control of systemic but not coronary resistance vessels at rest and during exercise, and (2) after L-NNA, the cyclooxygenase pathway is involved in myocardial reactive hyperemia and in the residual relaxation to bradykinin of isolated coronary arteries. Thus, in conscious dogs, the cyclooxygenase pathway might act as a protective mechanism of the coronary circulation when endothelial nitric oxide synthesis is altered.