Effects of nitro-L-arginine on blood pressure and cardiac index in anesthetized rats: a pharmacokinetic-pharmacodynamic analysis.
OBJECTIVE
Nitric oxide synthase (NOS) inhibitors such as Nitro-L-arginine (L-NA) are being considered for the management of hypotension observed in septic shock. However, little information is available regarding the pharmacokinetic and pharmacodynamic properties of these agents. Our objective was to examine the relationships between L-NA plasma concentration and various hemodynamic effects such as cardiac index (CI), mean arterial pressure (MAP), and heart rate (HR) elicited by L-NA administration in rats.


METHODS
L-NA was infused at doses between 2.5-20 mg/kg/hr in anesthetized rats over one hour. Hemodynamic effects and plasma L-NA levels were determined.


RESULTS
Infusion of L-NA resulted in dose-dependent increases in MAP and systemic vascular resistance (SVR), decreases in CI, and minimal change in HR. The relationships between the hemodynamic effects and plasma L-NA levels were not monotonic, and hysteresis was observed. Using nonparametric analysis, the equilibration half-time (t1/2,keo) between plasma L-NA and the hypothetical effect site was determined to be 51.5 +/- 6.6 min, 42.4 +/- 10.1 min, 43.4 +/- 9.0 min for MAP, CI, and SVR, respectively (n = 14). The Emax and EC50 values obtained were + 32.5 +/- 8.4 and 2.6 +/- 1.3 microg/ml for MAP and -52.9 +/- 15.6 and 3.7 +/- 1.8 microg/ml for CI, respectively.


CONCLUSIONS
Although L-NA can bring about beneficial elevation of MAP, such effect is always accompanied by a stronger effect on CI depression. Dose escalation of L-NA may bring about detrimental negative inotropic effect and loss of therapeutic efficacy.
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260, USA.
M A
MA
Tabrizi-Fard
H L
HL
Fung
D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000502:physiology; D002302:Cardiac Output / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects*; D007262:Infusions, Intravenous; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D019335:Nitroarginine; D019001:Nitric Oxide Synthase