PDE-5 inhibitors:
PDE-5 inhibitors & nitrates synergistically contribute to endothelial vasodilation, thereby promoting hypotension.
Thank you for making me think more deeply about this with your question, @Knight9 ; this post is partly self-serving because typing it up is helping me appreciate the mechanisms more deeply.
To delve a little more into how the mechanisms interact:
Endothelial cells function to prevent intravascular coagulation under normal conditions, yet promoting blood clotting and inflammation at sites of vessel damage. To achieve these opposite functions, endothelial cells secrete several proteins that regulate blood clotting, blood flow, and local immune responses. In response to endothelial cell activation, several important vasoactive molecules are released, including nitric oxide (NO).
L-arginine increases NO via nitric oxide synthase & synthetase enzyme activity (here, eNOS [endothelial nitric oxide synthase], the constitutive NOS isoform in the vascular endothelium).
NO released by endothelial cells functions largely via cyclic GMP. NO via guanylate cyclase yields GTP that yields cyclic GMP (cGMP).
There is another source of nitrates: dietary food sources. Here, nitrate (and nitrite) are physiologically recycled in blood & tissue to form NO, and serve as storage pools for NO bioactivity, complementing the aforementioned (eNOS-dependent) pathway. From this pool, a series of oxygen-independent and eNOS-independent single-electron transfer reactions occur, ultimately ⇒ vasodilation.
With respect to PDE-5 inhibitors: PDE-5 breaks cGMP's phosphodiester bond, attenuating the PKG cascade (the signaling system involved in NO & cGMP synthesis). Thus, PDE-5 inhibitors abrogate (prevent) this breaking of the cGMP phosphodiester bond, increasing the synthesis of NO & cGMP.
In endothelial cells then, increased NO levels (by L-arginine, nitrates from food & PDE-5 inhibitors) ⇒ ↑↑vasodilation (greater than additively via ↑NO by different pathways; specifically, the eNOS -dependent [L-arginine] & -independent [dietary nitrates], with disinhibition of cGMP activity & the PKG cascade [PDE-5 inhibitor]) ⇒ hypotension
P.S., ARBs, ACE inhibitors, & β-antagonists (β blockers) further promote hypotension and are an additional consideration for those using them.
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