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Vasopressor effects of NG-substituted arginine analogs in the anesthetized guinea pig
1615 O.we.24.8 [
Vasopressor effects of NG-substitutedarginine analogs in the anesthetized guinea pig Steinberg, C., A i s a k a *, K., Gross *, S.S., Griffith * *, O.W. a n d Levi *, R. • Departments of Pediatrics, Division of Pediatric Critical Care Medicine, Pharmacology and * * Bic.-~emistry, Cornell University Medical College, 1300 York Avenue, New York, N Y 10021, U.S.A.
L-N°-methyl arginine (NMA) competitively inhibits the synthesis of endothefium-derived relaxing factor/nitric oxide ( E D R F / N O ) from L-arginine (ARG) in guinea pig pulmonary artery (Sakuma et al., 1988). Furthermore, NMA is a potent vasopressor agent in the anesthetized guinea pig, an effect reversed by ARG (Aisaka et al., 1989). We have now assessed the systemic vasopressor effects of other N-guanido substituted ARG analogs (NG-ARGs) and their reversibility by ARG. Methods: Male Hartley guinea pigs were anesthetized with pentobarbital and instrumented with jugular venous and carotid arterial catheters. Blood pressure was recorded continuously. NC3-ARGs with the following substituents: methyl (NMA), dimethyi (NDA), ethyl (NEA), propyl (NPA), butyl (NBA), amino (NAA) and nitro (NNA) were administered in doses of 0.1, 1.0 and 10.0 mg/kg i.v., followed after 20 min by 30 m g / k g of ARG. Results: Vasopressor effects and their reversibility are shown in Table 1. Results are expressed as increases in diastolic blood pressure (DBP) in mm Hg (mean + SEM) from baseline. A sustained ( > 20 min) dose-dependent •Jasopressor response was seen with all compounds except NBA, which had no pressor effect. Time-to-peak action was within 2 min for NMA, NDA, and NE, within 5 min for NAA and NPA, and 20 rain for NNA. The pressor effect of each compound except NNA was rapidly and completely reversed by L-ARG. Conclusions: N ° - A R G s elicit pressor effects with varying degrees of potency. Propyl- and butyl-substituted NC3-ARGs are less potent than those with shorter alkyl groups. NNA differs from the other analogs in its slower onset of action and incomplete reversibility by ARG. NNA and NAA are the most potent vasopressors, perhaps because the small size of the NC3-ARG substituents allows tight binding to the E D R F / N O synthetic enzyme(s). The fact that NAA is the most potent vasopressor agent may be due to its chemical as well as steric resemblance to NG-hydroxyARG, a likely intermediate in the NO biosynthetic pathway. Table 1 Increase from baseline in DBP following administration of NC'-ARG and ARG. N°-ARG NMA NDA NEA NPA NBA NAA NNA
R -Me -(Me)2 -Et -nPr - nBu -NH 2 -NO2
N 8 4 6 4 4 4 4
NG-ARG dose (mg/kg, i.v.)
+ ARG (30 mg/kg, i.v.)
0.1
1.0
10
3 +1 2 _+1 4 -+1 2 _+1 1 _+1 4 _+1 0.5_+0.5
11+1 6_+1 10_+2 3+2 1 _+0.5 20_+5 6_+3
26 +3 16 +3 31 _+1 9 _+1 0.5 _+0.5 39 +5 32 +4
Supported by USPHS grants No. HL34215 and DK37116. References Aisaka et al. (1989), Biochem. Biophys Res. Con'an., 160, 881-886. Sakuma et al. (1988), Procs. Natl. Acad. Sci. USA, 85, 8664-8667.
2 _+4 - 2 -+1 1 _+2 0.3_+0.3 1 _+1 1 -+3 19 -+5
Vasopressor effects of NG-substitutedarginine analogs in the anesthetized guinea pig Steinberg, C., A i s a k a *, K., Gross *, S.S., Griffith * *, O.W. a n d Levi *, R. • Departments of Pediatrics, Division of Pediatric Critical Care Medicine, Pharmacology and * * Bic.-~emistry, Cornell University Medical College, 1300 York Avenue, New York, N Y 10021, U.S.A.
L-N°-methyl arginine (NMA) competitively inhibits the synthesis of endothefium-derived relaxing factor/nitric oxide ( E D R F / N O ) from L-arginine (ARG) in guinea pig pulmonary artery (Sakuma et al., 1988). Furthermore, NMA is a potent vasopressor agent in the anesthetized guinea pig, an effect reversed by ARG (Aisaka et al., 1989). We have now assessed the systemic vasopressor effects of other N-guanido substituted ARG analogs (NG-ARGs) and their reversibility by ARG. Methods: Male Hartley guinea pigs were anesthetized with pentobarbital and instrumented with jugular venous and carotid arterial catheters. Blood pressure was recorded continuously. NC3-ARGs with the following substituents: methyl (NMA), dimethyi (NDA), ethyl (NEA), propyl (NPA), butyl (NBA), amino (NAA) and nitro (NNA) were administered in doses of 0.1, 1.0 and 10.0 mg/kg i.v., followed after 20 min by 30 m g / k g of ARG. Results: Vasopressor effects and their reversibility are shown in Table 1. Results are expressed as increases in diastolic blood pressure (DBP) in mm Hg (mean + SEM) from baseline. A sustained ( > 20 min) dose-dependent •Jasopressor response was seen with all compounds except NBA, which had no pressor effect. Time-to-peak action was within 2 min for NMA, NDA, and NE, within 5 min for NAA and NPA, and 20 rain for NNA. The pressor effect of each compound except NNA was rapidly and completely reversed by L-ARG. Conclusions: N ° - A R G s elicit pressor effects with varying degrees of potency. Propyl- and butyl-substituted NC3-ARGs are less potent than those with shorter alkyl groups. NNA differs from the other analogs in its slower onset of action and incomplete reversibility by ARG. NNA and NAA are the most potent vasopressors, perhaps because the small size of the NC3-ARG substituents allows tight binding to the E D R F / N O synthetic enzyme(s). The fact that NAA is the most potent vasopressor agent may be due to its chemical as well as steric resemblance to NG-hydroxyARG, a likely intermediate in the NO biosynthetic pathway. Table 1 Increase from baseline in DBP following administration of NC'-ARG and ARG. N°-ARG NMA NDA NEA NPA NBA NAA NNA
R -Me -(Me)2 -Et -nPr - nBu -NH 2 -NO2
N 8 4 6 4 4 4 4
NG-ARG dose (mg/kg, i.v.)
+ ARG (30 mg/kg, i.v.)
0.1
1.0
10
3 +1 2 _+1 4 -+1 2 _+1 1 _+1 4 _+1 0.5_+0.5
11+1 6_+1 10_+2 3+2 1 _+0.5 20_+5 6_+3
26 +3 16 +3 31 _+1 9 _+1 0.5 _+0.5 39 +5 32 +4
Supported by USPHS grants No. HL34215 and DK37116. References Aisaka et al. (1989), Biochem. Biophys Res. Con'an., 160, 881-886. Sakuma et al. (1988), Procs. Natl. Acad. Sci. USA, 85, 8664-8667.
2 _+4 - 2 -+1 1 _+2 0.3_+0.3 1 _+1 1 -+3 19 -+5