PDE Inhibitors and Cardiovascular Disorders

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By virtue of their inotropic and vasorelaxant effects, PDE3 inhibitors have been widely tested for cardiovascular disorders (Beavo, 1995). They are currently used in acute settings to treat patients during cardiac surgery or for patients awaiting heart transplantation. They have been also tested as a possible replacement of, or in conjunction with, digoxin in congestive heart failure. Although a large multicentric trial with milrinone was stopped prematurely because of increased death rate in patients receiving this drug, it is felt that adjustment of the dosage and the availability of new compounds will widen the use of these PDE3 inhibitors for this indication. Because of its inhibition of PDE3 activity in platelets, the PDE3 inhibitor cilostazol is currently prescribed in Japan as an antithrombotic agent and it has been recently approved for the treatment of vascular stenosis causing claudicatio intermittens (Sorkin and Markham, 1999).

With the discovery of the second messenger nitric oxide and its link to activation of guanylyl cyclase, there has been a renewed interest in inhibition of cGMP-selective PDEs as a means to produce vascular smooth muscle relaxation. While testing several compounds that inhibit the cGMP-specific PDE5, it was discovered that the corpus cavernous of the penis was particularly sensitive to these drugs. This observation has lead to the development of drugs useful in the treatment of penile erectile dysfunction (Licht, 1999). Sildenafil citrate (Viagra) is one of the most widely publicized drugs produced at the end of this century. Another area of potential use of PDE5 inhibitors is for the treatment of pulmonary hypertension (Beavo, 1995).

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