Coronary and Systemic Hemodynamic Effects of Sustained Inhibition of Nitric Oxide Synthesis in Conscious Dogs

Abstract

Sustained inhibition of NO synthesis ( N ^ω -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 <.01). 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 _1α 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 (1) 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.