Question9

=Text of the Question:= toc A) Viagra operates via a particular signal transduction cascade. Draw a detailed cartoon showing how viagra operates at the molecular level, including downstream signaling relevant to vasomodulaiton. B) One of our other fine Texas institutions has spun out a company, Neogenis. The product of this company, Neo40, acts on the same pathway you just drew, but by a very different mechanism. Draw the mechanism on the same diagram (hint: NO is a gas, but they aren't packaging it). C) Upstream of the Neogenis mechanism is another trendy thing, the "Mediterranean diet." How might it provide vasomodulation.

=Definitions of the Terms:= Viagra:

Signal transduction cascade:

Downstream signaling:

Vasomodulation:

Neo40:

Upstream signaling:

=Part A Diagram:=

TODO: put picture here

=Part B Mechanism:=

Neo40 is a proprietary blend including beetroot and Hawthorne berry. The beetroot apparently provides nitrates, while the Hawthorne berry provides an effective nitrite reductase.[9.b.1] The body naturally converts nitrates to nitrites by absorbing them in the small intestine, then concentrating them in the saliva, where facultative anaerobic bacteria reduce them to nitrites (using the nitrate as a final electron acceptor).[9.b.1]

The apparent effect of Neo40 results from it increasing the amount of NO available to the soluble Guanyl Cyclase (sGC, or type II Guanyl Cyclase, BRENDA 4.6.1.2, PDB 2WZ1).

TODO: put picture here

=Part C Mediterranean Diet:=

Endothelial nitric oxide synthase (eNOS) activity in cultured cells is increase in response to addition of thyme and wild artichoke extracts added //in vitro//. The presence of these extracts also increases the expression of eicosanoid prostacyclin.[9.c.1]

Prostacyclin is a prostoglandin which acts by exerting its influence against PGI receptor, a G-protein coupled receptor (resulting in modulation of cAMP, upregulation of inositol triphosphate). It is a potent vasodilator, plays a role in the inflammation responses and is a factor in edema, as well as acting to prevent thrombosis. It also inhibits platelet aggregation.[9.c.2]

The effect on eNOS apparently not due to an increase in the expression of eNOS, but rather due to an increase in its effectiveness. Curiously, this appears to only have resulted in a modest increase in cGMP expression within the cell.[9.c.1]

=Relevant Literature:=

9.a.1. [|Feil, R., S. M. Lohmann, et al. (2003). "Cyclic GMP-dependent protein kinases and the cardiovascular system: insights from genetically modified mice." Circ Res. 93(10): 907-916.] 9.b.1. [|Zand, J., F. Lanza, et al. (2011). "All-natural nitrite and nitrate containing dietary supplement promotes nitric oxide production and reduces triglycerides in humans." Nutrition Research 31(4): 262-269.] 9.c.1. [|Grande, S., P. Bogani, et al. (2004). "Vasomodulating Potential of Mediterranean Wild Plant Extracts." Journal of Agricultural and Food Chemistry 52(16): 5021-5026.] 9.c.2. [|Ricciotti, E. and G. A. FitzGerald (2011). "Prostaglandins and Inflammation." Arteriosclerosis Thrombosis and Vascular Biology 31(5): 986-1000.]