Cyclic GMP reduces myocardial stunning through non-cyclic GMP protein kinase mechanisms.

We tested the hypothesis that myocardial stunning would be reduced by increased cyclic GMP and cGMP protein kinase activity. Hearts were instrumented in eight open-chest anesthetized dogs. The left anterior descending coronary artery (LAD) was occluded for 15 minutes followed by a 30-minute recovery and infusion of 8-Bromo-cGMP (0.1 and 1 microg/kg/min) during functional and metabolic data collection. Myocytes from circumflex and LAD regions were then used to obtain data at baseline, with 8-Br-cGMP (10(-7, -6, -5) M) and KT5823 10(-6) M, cGMP protein kinase inhibitor. The in vivo time delay of regional shortening increased significantly from 55 +/- 12 to 99 +/- 3 msec following stunning, but was reduced to 81 +/- 2 by 1 microg/kg/min 8-Br-cGMP. The % regional work during systole decreased during stunning (93 +/- 2 to 76 +/- 8%), but was restored by 8-Br-cGMP (91 +/- 7). Stunning lengthened the time of myocyte contraction and relaxation and reduced baseline shortening. 8-Br-cGMP reduced myocyte shortening in both regions. However, KT5823 only restored myocyte shortening in controls. These data indicated that regional myocardial stunning could be reduced by cyclic GMP but this appeared to be through non-cGMP protein kinase mechanisms.

Cyclic nucleotide analogs as biochemical tools and prospective drugs.

Cyclic AMP (cAMP) and cyclic GMP (cGMP) are key second messengers involved in a multitude of cellular events. From the wealth of synthetic analogs of cAMP and cGMP, only a few have been explored with regard to their therapeutic potential. Some of the first-generation cyclic nucleotide analogs were promising enough to be tested as drugs, for instance N(6),O(2)'-dibutyryl-cAMP and 8-chloro-cAMP (currently in clinical Phase II trials as an anticancer agent). Moreover, 8-bromo and dibutyryl analogs of cAMP and cGMP have become standard tools for investigations of biochemical and physiological signal transduction pathways. The discovery of the Rp-diastereomers of adenosine 3',5'-cyclic monophosphorothioate and guanosine 3',5'-cyclic monophosphorothioate as competitive inhibitors of cAMP- and cGMP-dependent protein kinases, as well as subsequent development of related analogs, has proven very useful for studying the molecular basis of signal transduction. These analogs exhibit a higher membrane permeability, increased resistance against degradation, and improved target specificity. Furthermore, better understanding of signaling pathways and ligand/protein interactions has led to new therapeutic strategies. For instance, Rp-8-bromo-adenosine 3',5'-cyclic monophosphorothioate is employed against diseases of the immune system. This review will focus mainly on recent developments in cyclic nucleotide-related biochemical and pharmacological research, but also highlights some historical findings in the field.