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Cyclic nucleotides (cyclic AMP and cyclic GMP) and the enzymes involved in their synthesis, (cyclases), metabolism (diesterases) and actions (protein kinases and phosphatases) regulate a host of cellular functions involved in signal transduction pathways. Several drugs and hormones modify physiological and pathological processes by causing changes in the steady-state levels of cyclic nucleotides. Current evidence indicates that there are at least ten distinct families of cyclic nucleotide phosphodiesterases, one of the two main mechanisms by which the content of cyclic nucleotides is controlled in the cell. These enzymes are regulated by different mechanisms, and many drugs are known to exhibit tissue specificity and/or pharmacological selectivity towards them. Complementary approaches are used to determine what role these genetically, pharmacologically, and biochemically distinct phosphodiesterase isozymes play in the regulation of cyclic nucleotide metabolism, normal physiology mechanisms and pathophysiological models of disease, e.g. diabetes, cardiac failure, ischemia, pulmonary hypertension and cancer. Protein purification, cell culture, and molecular biology are among the research tools used to investigate these enzymes at the cellular and molecular levels.

Proposed mechanism of cGMP cross-communicating with cAMP through the cGMP-inhibitable cAMP PDE. ANF, atrial natriuretic factor; EDRF, endothelial-derived relaxing factor; -, inhibitory; +, excitatory. Refer to Reference No. 5 for details.

Relationship between the ability of a series of cardiotonic vasodilators to relax serotonin-contracted rat aortic strips (ordinate) and IC50 values for inhibition of SR-PDE (abscissa). A statistically significant correlation occurred with a correlation coefficient of 0.87. See Reference No. 5 for details.

1. Strada SJ and Hidaka H (Editors). The Biology of Cyclic Nucleotide Phosphodiesterases. In: "Advances in Second Messenger and Phosphoprotein Research," 25:416 (1992).

2. Haynes Jr. J, Kithas PA, Taylor AE, and Strada SJ. Selective inhibition of cGMP-inhibitable cAMP phosphodiesterase decreases pulmonary vasoreactivity. Amer. J. Physiol. 261 (Heart Circ. Physiol. 30): H487-492 (1992).

3. Haynes Jr. J, Robinson J, Saunders L, Taylor AE, and Strada SJ. The role of cAMP dependent protein kinase in cAMP mediatede vasodilation. Amer. J. Physiol. 262 (Heart Circ. Physiol. 31): H511-516 (1992).

4. Diwan AH, Thompson WJ, Lee AK, and Strada SJ. Cyclic GMP-dependent protein kinase activity in rat pulmonary microvascular endothelial cells. Biochem. Biophys. Res. Comm. 202:728-735 (1994).

5. Polson JB and Strada SJ. Cyclic nucleotide phophodiesterases and smooth muscle. Ann Rev. Pharmacolo. Toxicol. 36:403-427, (1996).

6.T. Ashikaga, D.W. Robertson, R.J. Sportsman, S.J. Strada, and W.J. Thompson.Comparison of Indolidan Analog Binding Sites of Drug Antibody and Sarcoplasmic Reticulum with Inhibition Cyclic AMP Phosphodiesterase.J. of Recept. Signal Transduct. Res. 16:315-325 (1996).

7. Diwan AH, Honkanen RE, Schaeffer RC, Jr, Strada SJ and Thompson WJ. Inhibition of serine-threonine protein phosphatatases decreases barrier function of rat pulmonary microvascular endothelial cells. J. Cell. Physiol., 171:259-270, (1997).

8. Ashikaga T., Strada SJ, and Thompson WJ. Altered expression of cyclic nucleotdie phosphodiesterase isozymes during culture of aortic endothelial cells. Biochem Pharmacol. 54:1071-1079, (1997).

9. P.D. Reynolds, S.J. Strada, and W.J. Thompson.Utilization of a New Prelabelling Technique to Measure Cyclic GMP Accumulation in Rat Pulmonary Microvascular Endothelial Cells. Life Sciences 60:909-918 (1997).

10. W.J. Thompson, T. Ashikaga, J.F. Kelly, L. Liu, B. Zhu, L. Vemavarapu, and S.J. Strada. Regulation of Cyclic AMP in Rat Pulmonary Microvascular Endothelial Cells by Rolipram-Sensitive Cyclic AMP phosphodiesterase (PDE4). Biochemical Pharmacology 63:797-807 (2002).