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, 142 (3), 453-60

Vasoactive Properties of CORM-3, a Novel Water-Soluble Carbon Monoxide-Releasing Molecule

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Vasoactive Properties of CORM-3, a Novel Water-Soluble Carbon Monoxide-Releasing Molecule

Roberta Foresti et al. Br J Pharmacol.

Abstract

1 Carbon monoxide (CO), one of the end products of heme catabolism by heme oxygenase, possesses antihypertensive and vasodilatory characteristics. We have recently discovered that certain transition metal carbonyls are capable of releasing CO in biological fluids and modulate physiological functions via the delivery of CO. Because the initial compounds identified were not water soluble, we have synthesized new CO-releasing molecules that are chemically modified to allow solubility in water. The aim of this study was to assess the vasoactive properties of tricarbonylchloro(glycinato)ruthenium(II) (CORM-3) in vitro and in vivo. 2 CORM-3 produced a concentration-dependent relaxation in vessels precontracted with phenylephrine, exerting significant vasodilatation starting at concentrations of 25-50 microm. Inactive CORM-3, which does not release CO, did not affect vascular tone. 3 Blockers of ATP-dependent potassium channels (glibenclamide) or guanylate cyclase activity (ODQ) considerably reduced CORM-3-dependent relaxation, confirming that potassium channels activation and cGMP partly mediate the vasoactive properties of CO. In fact, increased levels of cGMP were detected in aortas following CORM-3 stimulation. 4 The in vitro and in vivo vasorelaxant activities of CORM-3 were further enhanced in the presence of YC-1, a benzylindazole derivative which is known to sensitize guanylate cyclase to activation by CO. Interestingly, inhibiting nitric oxide production or removing the endothelium significantly decreased vasodilatation by CORM-3, suggesting that factors produced by the endothelium influence CORM-3 vascular activities. 5 These results, together with our previous findings on the cardioprotective functions of CORM-3, indicate that this molecule is an excellent prototype of water-soluble CO carriers for studying the pharmacological and biological features of CO.

Figures

Figure 1
Figure 1
Vasodilatation induced by CORM-3. Isometric recordings of aortic rings precontracted with phenylephrine (Phe, 1 μM) and subsequently subjected to a bolus addition of CORM-3 (100 μM) or iCORM-3 (100 μM). Typically, CORM-3 was added to the water bath containing aortic rings once phenylephrine had produced a stable contraction; CORM-3 caused relaxation within few minutes of addition whereas iCORM-3 was ineffective.
Figure 2
Figure 2
Effect of CORM-3 on vascular tone: involvement of cGMP and KATP channels. (a) Vasodilatory responses of aortic rings subjected to three consecutive bolus additions of CORM-3 at different concentrations (25–100 μM). iCORM-3 (100 μM), the negative control, did not cause any evident relaxation. Vasodilatation is expressed as percentage of the maximal preconstriction. Data represent the mean±s.e.m. of 6–8 independent experiments. *P<0.05 compared to iCORM-3. (b) Vasodilatory responses of aortic rings subjected to three consecutive bolus additions of CORM-3 in the presence of ODQ (10 μM) or glibenclamide (Gli, 10 μM). ODQ and glibenclamide were added to the water bath 15 or 30 min prior to the addition of phenylephrine, respectively. Dilatations are expressed as percentage of preconstriction. Data represent the mean±s.e.m. of 6–8 independent experiments. *P<0.05 compared to 100 μM CORM-3 alone.
Figure 3
Figure 3
YC-1 potentiates CORM-3-mediated vasodilatation. (a) Isometric recordings of aortic rings pretreated with 1 μM YC-1 (30 min prior to phenylephrine). As shown, the presence of YC-1 potentiated the dilatory responses of CORM-3 (50 μM). (b–d) Vasodilatory responses of aortic rings subjected to three consecutive bolus additions of CORM-3 (25, 50 and 100 μM, respectively) in the presence of 1 μM YC-1. Data represent the mean±s.e.m. of 6–8 independent experiments. *P<0.05 compared to CORM-3 alone.
Figure 4
Figure 4
Changes in MAP in vivo following administration of CORM-3 in the presence or absence of YC-1. Animals were anesthetized and chronically catheterized as described in Methods. CORM-3 (30 μmol kg−1, i.v.) caused a sustained decrease in MAP that was potentiated by YC-1 (1.2 μmol kg−1, i.v.). Data represent the mean±s.e.m. of three independent experiments. *P<0.05 compared to control; **P<0.05 compared to CORM-3 alone.
Figure 5
Figure 5
cGMP levels in aortas treated with CORM-3. Aortas were extracted and subjected to the same treatments with CORM-3 as for measurements of isometric tension. At 8 min after the first, second or third addition of CORM-3 (100 μM), aortas were snap-frozen and subsequently processed for cGMP assay. Control aortas (CON) were treated with vehicle (water). Data represent the mean±s.e.m. of four different aortas per group. *P<0.05 compared to control.
Figure 6
Figure 6
Effect of CORM-3 on purified guanylate cyclase activity. The activity of purified guanylate cyclase was measured following addition of increasing concentrations of CORM-3 (10–3000 μM) in the presence or absence of YC-1 (200 μM). As shown, CORM-3 was able to activate the enzyme only in the presence of YC-1. Data represent the mean±s.e.m. of five independent experiments (s.e.m. not showing because values are smaller than the size of the symbols).
Figure 7
Figure 7
Blockade of NO production or removal of the endothelium reduces CORM-3-mediated dilatory responses. (a) Aortic rings were incubated with the inhibitor of NO synthase activity L-NAME (100 μM) for 30 min prior to contraction with phenylephrine. L-NAME markedly prevented relaxation caused by 100 μM CORM-3, and higher concentrations of the CO carrier (200 or 400 μM) were required to induce dilatation in the presence of L-NAME. Data represent the mean±s.e.m. of 6–8 independent experiments. *P<0.05 compared to 100 μM CORM-3 alone. (b) The endothelium of aortic rings was gently removed (−E) as described in Methods and the response to CORM-3 was compared to that of intact rings (+E). The absence of the endothelium markedly reduced CORM-3-mediated vasodilatation and higher CORM-3 concentrations were required to produce relaxation. Data represent the mean±s.e.m. of 6–8 independent experiments. *P<0.05 compared to 100 μM CORM-3 alone.

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