Abstract
Soluble guanylate cyclase‐ stimulating compounds that are either independent of nitric oxide and of the redox status of the haem‐group of the enzyme are being developed. In the present work we synthesized and probed several metalo‐based complexes (iron and ruthenium‐based drugs). The compounds were probed in rat aortic thoracic rings, rat, rabbit and human corpora cavernosa. Tissues were pre‐contracted with phenylephrine and then concentration‐response curves (10−12 to 10−4M)were evaluated in the absence or presence of a soluble guanylate cyclase inhibitor [1,2,4]oxalodiazolo[4,3]oxonalina (ODQ; 10 μM). RU‐ Indazol induced relaxation of strips of rat corpora cavernosa with an IC50 of 8.9 μM (n=5). The smooth muscle relaxation induced by Indazol increased 33 % in tissues pre‐treated during 30 minutes with ODQ (n=5). The results were similar for rabbit and human corpora cavernosa. The compounds relaxed aortic rings. An Iron‐ Indazole compound (FE‐IN) promoted maximal relaxation of 106.5 ± 14.3% (PD2 of 7.6 [7.8–7.4] being 21.9‐fold more potent than BAY‐412272. The compound, Ru‐5‐AIN induced maximal relaxation of 121,4±7,6% (PD2 of 7,2[7,7–6,8]) being 8‐fold more potent than BAY‐412272. Both compounds were insensitive to ODQ. The metal‐based derivatives of YC‐1 are effective relaxants of smooth muscle by a ODQ‐insensitive mechanism.
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