S‐Nitrosocaptopril: in vitro characterization of pulmonary vascular effects in rats

Abstract

1 On rat isolated pulmonary arteries, vasorelaxation by S-nitrosocaptopril (SNOcap) was compared with S-nitrosoglutathione (GSNO) and nitroprusside, and inhibition by SNOcap of contractions to angiotensin I was compared with the angiotensin converting enzyme (ACE) inhibitor, captopril. 2 SNOcap was equipotent as a vasorelaxant on main (i.d. 2 ± 3 mm) and intralobar (i.d. 600 mm) pulmonary arteries (pIC 50 values: 5.00 and 4.85, respectively). Vasorelaxant responses reached equilibrium rapidly (2 ± 3 min). 3 Pulmonary vasorelaxant responses to SNOcap, like GSNO, were (i) partially inhibited by the soluble guanylate cyclase inhibitor, ODQ (1H-(1,2,4) oxadiazolo(4,3-a)-quinoxalin-1-one; 3 mM) whereas responses to nitroprusside were abolished and (ii) potentiated by hydroxocobalamin (HCOB; NO´free radical scavenger; 100 mM) whereas responses to nitroprusside were inhibited. 4 The relative potencies for pulmonary vasorelaxation compared with inhibition of platelet aggregation were: SNOcap 7 : 1; GSNO 25 : 1; nitroprusside 42000 : 1. 5 SNOcap, like captopril, concentration-dependently and time-dependently increased the EC 50 for angiotensin I but not angiotensin II. The dependence on incubation time was independent of the presence of tissue but diered for SNOcap and captopril. This dierence re¯ected the slow dissociation of SNOcap and instability of captopril, and precluded a valid comparison of the potency of the two drugs. After prolonged incubation (55.6 h) SNOcap was more eective than captopril. 6 Thus, in pulmonary arteries SNOcap (i) possesses NO donor properties characteristic of Snitrosothiols but dierent from nitroprusside and (ii) inhibits ACE at least as eectively as captopril. These properties suggest that SNOcap could be valuable in the treatment of pulmonary hypertension.

Increased Nitrosoglutathione Reductase Activity in Hypoxic Pulmonary Hypertension in Mice

“…RSNO can function as an intermediate in NO-dependent signaling pathways and has vasorelaxant properties (6,16). Studies have shown that RSNO concentration was tightly regulated but the metabolism of RSNO in vivo is not well understood (6).…”

Bronchial epithelium-associated pulmonary arterial muscle relaxation in the rat is absent in the fetus and suppressed by postnatal hypoxia

“…To assess whether the relaxing factor acted via the NO-cGMP phosphatidylinositol 3-kinase (PI3-kinase) pathway, the methacholine response was measured in the presence of the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 Ϫ5 M) or wortmannin (10 Ϫ7 M), which have been shown by others to block the NO-cGMP and PI3-kinase pathways, respectively (18,20).…”

NO-Releasing Hybrids of Cardiovascular Drugs

“…This improved mechanism of action is due not only to the sum of the two components. Recently, Ackermann et al showed that NO and NO-releasing substances can competitively inhibit ACE [201], and this finding has been confirmed by other studies on porcine iliac arteries [202] and on rat pulmonary artery [200], comparing SNOcap with the parent drug, captopril. Finally, the toxicity of SNOcap has been examined in rodents: the absence of adverse effects in subchronic toxicity studies makes SNOcap a good candidate for further clinical trials, but it could cause severe hypotension when overdosed [203].…”

“…Due to its dual mechanism of action, S-nitrosocaptopril is effective in hypertension, platelet aggregation, congestive heart failure and pulmonary hypertension, potentiating the effect of the native captopril [200]. This improved mechanism of action is due not only to the sum of the two components.…”