From the FDA Drug Label
Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina.
The most important types of second messenger cellular pathways mentioned are:
- cGMP pathway: involved in the relaxation of pulmonary vascular smooth muscle cells, leading to vasodilation.
- PDE3 pathway: involved in the control of cardiac contractility.
- PDE6 pathway: involved in the phototransduction pathway of the retina. These pathways are relevant to the mechanism of action of sildenafil 1 1.
From the Research
The most important types of second messenger cellular pathways include cyclic AMP (cAMP), calcium, cyclic GMP (cGMP), inositol trisphosphate (IP3), and diacylglycerol (DAG) signaling systems, as highlighted in the study by 2. These pathways are critical for translating extracellular signals into intracellular responses.
- The cAMP pathway, activated when G-protein coupled receptors stimulate adenylyl cyclase, regulates numerous cellular processes including metabolism, gene expression, and cell growth.
- Calcium signaling is versatile, with calcium ions serving as second messengers that activate calmodulin and protein kinases to control muscle contraction, secretion, and neuronal activity, as described in the study by 3.
- The cGMP pathway, often activated by nitric oxide, regulates smooth muscle relaxation and visual phototransduction.
- IP3 and DAG are generated when phospholipase C hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2), with IP3 triggering calcium release from intracellular stores while DAG activates protein kinase C. These pathways don't operate in isolation but form complex networks with extensive crosstalk, allowing cells to integrate multiple signals and produce appropriate responses, as demonstrated in the studies by 4, 5, and 6. Understanding these pathways is fundamental to comprehending cellular communication, physiological processes, and the mechanisms of many drugs that target these signaling systems. The study by 2 provides the most recent and highest quality evidence, and therefore, its findings are prioritized in this recommendation.