. 2019 Jul 31;24(15):2778. doi: 10.3390/molecules24152778

Table 1.

Snake venom proteins and peptides expressing hypotensive effects through various mechanisms of action.

Protein/Peptide	Source	Mechanism of Hypotensive Effect	Ref.
Bradykinin Potentiating Peptides (BPP)/Proline-Rich Oligopeptides (PRO) *
Bj-PRO-5a	Bothrops jararaca	Increases urinary flow rate and sodium excretion. Vasodilation is achieved through the inhibition of the angiotensin-converting enzyme (ACE), along with the activation of bradykinin B₂ and muscarinic M₁ receptors. Lowers cardiac output by inducing bradycardia.	[34,35]
Bj-PRO-7a	Bothrops jararaca	Acts as an M₁ muscarinic receptor agonist, thus mobilizes intracellular Ca²⁺ in various cell types and induces vasodilation through vascular endothelial cells.	[36]
Bj-PRO-9a	Bothrops jararaca	Inhibits ACE and increases the effect of endogenous bradykinin (BK).	[37]
Bj-PRO-10c (Bj-BPP-10c)	Bothrops jararaca	Activates argininosuccinate synthetase (AsS) at kidney level, increasing l-arginine and consecutive nitric oxide (NO) production. Increases production of NO through gene expression of AsS and nitric oxide synthase (NOS) in the endothelium. Improves baroreflex sensitivity in the central nervous system and increases the release of gamma-aminobutyric acid (GABA) and glutamate mediators, involved in the regulation of the autonomic nervous system. Lowers cardiac output by inducing bradycardia. Increases urinary flow rate and sodium excretion. Inhibits the angiotensin-converting enzyme (ACE).	[34,38,39,40]
Bj-PRO-11e Bj-PRO-12b	Bothrops jararaca	Lowers cardiac output by inducing bradycardia. Induces Ca²⁺ mobilization in different tissues, possibly interacting with regulators of the cardiovascular system, such as the Ca²⁺/calmodulin-dependent kinase II (CaMK-II). Increases the effect of endogenous BK.	[37]
Bj-PRO-13a	Bothrops jararaca	Increases AsS activity, NO production and Ca²⁺ mobilization. Agonist on M3 muscarinic receptors (mAChR), possibly inducing smooth muscle relaxation and negative cardiac chronotropy.	[37]
Bn-PRO-10a, Bn-PRO-10a-MK, Bn-PRO-10b-MK, Br-PRO-10a, Bg-PRO-11a, Bn-PRO-10c	Bitis spp.	Inhibits the enzymatic activity of ACE with some minor differences regarding modulation of angiotensin I conversion and BK degradation.	[41]
BPP-Cdc	Crotalus durissus cascavella	Inhibits BK degradation and conversion of AT I into AT II by inhibiting the enzymatic activity of ACE	[42]
LmrBPP9	Lachesis muta rhombeata	Inhibits the enzymatic activity of ACE.	[43]
PRO synthetic analogues	Agkistrodon bilineatus	Inhibits the enzymatic activity of ACE.	[44]
Natriuretic Peptides (NP)
Coa_NP	Crotalus oreganus abyssus	Induces endothelium dependent vasodilatation through NO formation.	[45,46]
DNP	Dendroaspis angusticeps	Phosphorylates Ca²⁺ channel proteins via protein kinase G (PKG) activation, inhibiting L-type Ca²⁺ channel activity in the hearth, modulating contractility.	[47]
NP2_Casca	Crotalus durissus cascavella	Increases NO production and consequent vasodilation, also causes increase in urinary flow, glomerular filtration rate and sodium excretion, thus resulting a strong diuretic effect.	[48]
PNP	Pseudocerastes persicus	Increases urine flow and sodium excretion thus decreasing blood pressure. It exerts ANP-like activity as it induces cGMP activity and binds to natriuretic peptide receptor (NPR)-A.	[49]
PtNP-a	Pseudonaja textilis	Increases intracellular cGMP levels similarly to ANP and BNP while inhibiting ACE activity.	[50]
Phospholipases A₂ (PLA₂)
BmooPLA2-I	Bothrops moojeni	Decreases blood pressure through an unreported mechanism.	[51]
BthA-I-PLA2	Bothrops jararacussu	Decreases blood pressure due to its phospholipase activity.	[52]
OSC3a, OSC3b	Oxyuranus scutellatus	Hypotensive effect induced through cyclooxygenase metabolites (dilator prostaglandins or prostacyclin). Possible involvement in the release of endogenous mediators, such as histamine and bradykinin. Both direct (OSC3a) and endothelium-dependent (OSC3a, OSC3b) vasodilator effect.	[53]
Snake Venom Serine-Proteases (SVSP)
AHP-Ka	Agkistrodon halys pallas	Possible hypotensive effect, due to its kallikrein-like activity.	[54]
Harobin	Lapemis hardwickii	Degrades angiotensin I to angiotensin II and angiotensin II to tetrapeptides lacking hypertensive activity. Releases BK with vasodilator effect, due to its kallikrein-like activity. Decreases blood fibrinogen levels, altering the blood rheology.	[55]
Kn-Ba	Bitis arietans	Releases BK and Met-Lys-bradykinin from kininogen, the latter has equivalent biological activity with BK at B1 and B2 receptors causing vasodilation.	[56]
LV-Ka	Lachesis muta	Decreases blood pressure through its kallikrein-like activity.	[57]
Rhinocerase	Bitis gabonica rhinoceros	Possible hypotensive effect, due to its kallikrein-like activity.	[58]
Tm-VIG and Tm-IIG	Trimeresurus mucrosquamatus	Degrades angiotensin I and releases bradykinin from plasma kininogen with potent vasodilator effect.	[59]
Vascular endothelial Growth Factor Like (VEGF-like) Peptides
TfsvVEGF	Trimeresurus flavoviridis	Possible hypotensive effect, due to VEGF-like mechanism of action.	[60]
VEGF-F (VR-1’)	Daboia russelli siamensis	Possible hypotensive effect, due to VEGF-like mechanism of action.	[61]
Other Hypotensive Snake Venom Components
Calciseptine FS-2 toxin	Dendroaspis polylepis	Act as l-Type Ca²⁺ channel blockers.	[62,63]
Heparin-binding dimeric hypotensive factor (HF)	Vipera aspis	Exhibits potent hypotensive effect, due to VEGF-like mechanism of action (vasodilation and hyperpermeability).	[64]
Nucleotidases	Bothrops asper	Degrades adenosine triphosphate (ATP) to adenosine, which exerts hypotensive activity through vasodilation.	[65]

* While “Bradykinin potentiating peptides” is the well-established name for these proteins, recent publications use the “Proline-rich oligopeptides” expression (based on structure, rather than effect). This is due the fact, that not all known proteins in this class have a bradykinin potentiating effect.