An antihypertensive opioid: Biphalin, a synthetic non-addictive enkephalin analog decreases blood pressure in spontaneously hypertensive rats.

Bądzyńska B1, Lipkowski AW2, Sadowski J3.
  • 1Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Centre, Polish Academy of Science, Warszawa, Poland. Electronic address:
  • 2Department of Neuropeptides, Mossakowski Medical Research Centre, Polish Academy of Science, Warszawa, Poland.
  • 3Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Centre, Polish Academy of Science, Warszawa, Poland.



BACKGROUND: Endogenous opioid systems may be engaged in the control of arterial pressure (MAP), however, given the risk of addiction, opioid receptor agonists are not used in antihypertensive therapy. We examined cardiovascular effects of biphalin, a potentially non-addictive dimeric enkephalin analog, an agonist of opioid μ and δ receptors.

METHODS: Biphalin was infused iv at 150μg/kg/h to anesthetized spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Along with MAP and heart rate (HR), renal blood flow (RBF) and iliac blood flow (IBF, a measure of hind limb perfusion) were measured using Transonic probes on renal and iliac artery, respectively. The effects of biphalin were compared with those of intravenous morphine (1.5mg/kg/h).

RESULTS: In two SHR groups biphalin decreased MAP from 143±2 to 130±2 and from 177±4 to 167±3mmHg (p<0.001) while HR did not change or modestly decreased. The renal blood flow (RBF) increased modestly and both renal and hind limb vascular resistances decreased significantly (p<0.001). The responses were blocked by inhibition of peripheral opioid receptors with naloxone methiodide. Unlike in SHR, in WKY rats biphalin did not change MAP or vascular resistances. Morphine infusion decreased MAP in SHR from 169±6 to 150±6mmHg (less decrease in WKY) and significantly decreased RBF and IBF.

CONCLUSION: Since biphalin, a non-addictive synthetic opioid, lowers MAP in SHR, a model of hypertension with pronounced neurogenic component, such analogs might find therapeutic application in human stress-induced hypertensive states. Biphalin’s advantage is no associated reduction of renal perfusion.

KEYWORDS: Biphalin; Blood pressure; Naloxone; Opioid receptors; Renal blood flow

PMID: 26721351



How select opioids for the fight against  arterial hypertension:

Why not use morphine  (known to decrease blood pressure)?

(1)   Morphine circulating in blood enters the brain and causes addiction

(2)   Morphine has serious untoward effects (side-effects): one is a reduction of blood supply to the kidneys, which presents a danger of kidney failure and fatal consequences


Why  biphalin or biphalin-like compounds might be useful in combatting hypertension?

(1)   Biphalin a peripherally acting opioid, only poorly penetrates to the brain and is unlikely to cause addiction

(2)   In general, with peripherally acting opioids side-effects are fewer and less severe

(3)   Important: our study proved that in hypertensive rats Biphalin decreased blood pressure but definitely did not reduce blood supply to the kidneys, or even tended to increase it. Thus, kidney function is not endangered

(4)   Wide application potential:  Biphalin’s  hypotensive action was shown in spontaneously hypertensive rats, the strain which closely resembles essential hypertension, a most common form of human hypertension