Interactions of sildenafil with various coronary vasodilators in isolated porcine coronary artery

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Abstract

There are reports of serious hypotension or circulatory shock when sildenafil citrate, a selective cyclic nucleotide phosphodiesterase type 5 inhibitor, which was developed for the treatment of erectile dysfunction, is given to patients taking certain coronary vasodilators. We thus examined the interaction of sildenafil with various coronary vasodilators including nitric oxide (NO) donors in isolated porcine coronary artery. Sildenafil caused concentration-dependent relaxations of the artery precontracted with U46619 (9,11-dideoxy-9α,11α-methanoepoxy-prostaglandin F). Incubation with the NO synthase inhibitor NG-nitro-l-arginine or the soluble guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one) significantly shifted the concentration–response curve for sildenafil to the right without affecting the maximum response, indicating that some part of the relaxant response to sildenafil may be the result of the inhibition of phosphodiestrase type 5-induced degradation of cyclic GMP (cGMP) that is produced through guanylate cyclase activation by NO released spontaneously. The relaxant effects of the vasodilators with an NO donor property, isosorbide dinitrate, sodium nitroprusside, nicorandil and nipradilol, were significantly enhanced by sildenafil, as shown by a significant leftward shift of their concentration–response curves. In contrast, the relaxant responses to the drugs without a property as an NO donor, diltiazem, celiprolol and pinacidil, were not affected by sildenafil. The cGMP level of the tissue was elevated after adding sildenafil, and the cGMP-generating effect of a combination of sildenafil and sodium nitroprusside was higher than that of each drug alone. The cyclic AMP level determined simultaneously was not changed by sildenafil. These results suggest that sildenafil potentiates specifically the relaxant responses of porcine coronary artery to the drugs which behave as an NO donor, providing basic evidence that the benefit of sildenafil in the treatment of erectile dysfunction can be limited by a risk of marked vasodilation when used together with NO-related coronary vasodilators.

Introduction

Nitric oxide (NO), through activation of soluble guanylate cyclase, induces the formation of intracellular cyclic GMP (cGMP) from GTP to elicit relaxation of smooth muscle cells Moncada et al., 1991, Umans and Levi, 1995. Upon penile erection, NO is released from nonadrenergic-noncholinergic neurons and vascular endothelial cells, and cGMP content is elevated in the corpora cavernosa. The accumulated cGMP in turn leads to relaxation of vascular and trabecular smooth muscle of the penis, and the resultant increase in blood flow and engorgement of the trabecular spaces result in pinile erection Boolell et al., 1996, Burnett, 1997, Ballard et al., 1998.

Sildenafil (Viagra™) is now popularly used for the treatment of patients with erectile dysfunction. This agent is a highly selective inhibitor of phosphodiesterase type 5 (Ballard et al., 1998), the predominant isozyme responsible for the degradation of cGMP in the corpus cavernosum Boolell et al., 1996, Moreland et al., 1998. Selective inhibition by sildenafil of phosphodiesterase type 5 accelerates NO-induced accumulation of cGMP during penile erection, leading to the enhancement of relaxation of both vascular and trabecular smooth muscle in the corpus cavernosum Waldman and Murad, 1987, Jeremy et al., 1997. This mode of action suggests that sildenafil may synergistically interact with NO donors, which cause potent vasodilation. Indeed, clinical data have shown that severe hypotension or circulatory shock often occurs when sildenafil is given to the patients taking NO-related coronary vasodilators Webb et al., 1999, Zusman et al., 1999, Kloner, 2000. To our knowledge, however, only a few studies using isolated arteries have been done to provide basic evidence for the interaction of sildenafil or other phosphodiesterase type 5 inhibitors and NO donors Medina et al., 2000, Takagi et al., 2001. Furthermore, the interactions of sildenafil and other coronary vasodilators as non-NO donors remain unknown.

The present study was undertaken to examine how sildenafil can modify the relaxant effects of various coronary vasodilators, including NO donors, Ca2+ channel blocker, K+ channel openers and β-adrenoceptor-acting agents, which can be currently available for the treatment of coronary heart disease, in isolated porcine coronary artery. We also investigated the effect of sildenafil on the changes in cGMP and cyclic AMP (cAMP) contents caused by some vasodilators in this tissue to determine whether sildenafil has a synergistic action on the relaxant responses to the vasodilators in relation to its effect on cyclic nucleotide metabolism.

Section snippets

Tension measurement

Porcine hearts were obtained from a slaughterhouse and transported in ice-cold oxygenated physiological salt solution (PSS). The composition of PSS was as follows (in mM): NaCl 118.2, KCl 4.7, MgCl2 1.2, CaCl2 2.5, KH2PO4 1.2, NaHCO3 25.0 and glucose 10.0. The left circumflex coronary artery (outer diameter, ∼2 mm) was dissected from the heart in oxygenated PSS. The isolated artery was trimmed of fat and connective tissues under a dissecting microscope and cut into rings 4 mm in length. Care

Relaxant response to sildenafil

Fig. 1 shows the concentration–response curve for sildenafil-induced relaxation, which was obtained from the experiments where sildenafil was cumulatively given to porcine coronary artery precontracted with 100 nM U46619. Sildenafil revealed a concentration-dependent relaxant effect with a pD2 value of 5.7±0.2 (n=9). Preincubation of the artery with maximally effective concentration of the NO synthase inhibitor l-NNA (100 μM) significantly shifted the concentration curve for the relaxant effect

Discussion

In this study, we demonstrated that sildenafil by itself produced a concentration-dependent relaxation of porcine coronary artery. Incubation with the NO synthase inhibitor l-NNA caused a decrease in the sensitivity to sildenafil. A similar rightward shift of the sildenafil concentration–response curve was observed in the presence of the soluble guanylate cyclase inhibitor ODQ. In view of strong evidence that sildenafil is a highly selective inhibitor of phosphodiesterase type 5 that is

Acknowledgements

This work was supported in part by a Grant-in-Aid for Science Research from the Ministry of Education, Science, Sports and Culture of Japan, and by Health Sciences Research Grants for Comprehensive Research on Aging and Health from the Ministry of Health and Welfare of Japan.

References (33)

  • M. Boolell et al.

    Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction

    Int. J. Impot. Res.

    (1996)
  • O.E. Brodde et al.

    β-Adrenoceptor antagonists (non-selective as well as β1-selective) with partial agonistic activity decrease β2-adrenoceptor density in human lymphocytes: evidence for a β2-agonistic component of the partial agonistic activity

    Naunyn-Schmiedeberg's Arch. Pharmacol.

    (1986)
  • A.L. Burnett

    Nitric oxide in the pennis: physiology and pathology

    J. Urol.

    (1997)
  • S. Dhein et al.

    Celiprolol exerts microvascular dilatation by activation of β2-adrenoceptors

    Naunyn-Schmiedeberg's Arch. Pharmacol.

    (1992)
  • P. Geelen et al.

    Sildenafil (Viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current

    Circulation

    (2000)
  • T. Hayashi et al.

    Nipradilol: a β-adrenoceptor antagonist with nitric oxide releasing action

    Cardiovasc. Drug Rev.

    (1998)
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