Drugs that activate specific nitric oxide sensitive guanylyl cyclase isoforms independent of nitric oxide release.

Nitric oxide (NO) releasing drugs have helped patients suffering from angina pectoris for more than a century. In the 1970s NO-sensitive guanylyl cyclase was identified as the target of NO. Since then, three different isoforms of the enzyme have been identified. All NO-releasing drugs act by binding of NO to the prosthetic heme group common to all three isoforms. They thus act all as isoform-unspecific substances. This review addresses recently developed drugs that activate NO-sensitive guanylyl cyclase independent of NO-release. They have great potential in the treatment of angina pectoris, hypertension and erectile dysfunction. The molecular target has been validated by the successful clinical use of NO-releasing drugs for more than a century. At the same time the mode of action of these drugs is entirely new. The development of highly isoform-specific derivatives with distinct pharmacological profiles is now an open possibility with great potential.