Natriuretic activity

The thiazidelike compounds, including chlorthalidone Hygrown), quinethazone (Hydromox), and metolazone (Zaroxolyn) have similar mechanisms of action, but they differ substantially from one another in their duration of action, the degree of carbonic anhydrase inhibition, and the dose required for maximum natriuretic activity. 

Possibly relevant to the natriuretic activity of SK F 38393 is emerging evidence that dopamine may be a physiological regulator of aldosterone synthesis (28). Dopamine receptors in a particulate fraction of calf adrenal glomerulosa cells have been shown to bind 3H-2-amino-1,2,3,4-tetrahydro-6,7-dihydroxynaptha-lene (3H-ADTN) in a specific (displaceable by 10 pM dopamine) saturable manner (29) (Kj, 0.29 mM maximal binding capacity,... 

In the spontaneously hypertensive rat (SHR) SK F 82526 was inactive as a natriuretic, but was active as an antihypertensive agent. The weaker natriuretic activity of SK F 82526 compared to SK F 38393 was also seen in conscious dog renal clearance studies (27). SK F 82526 given 5 mg/kg p.o. increased renal plasma flow 81%, glomerular filtration rate 15%, but elevated sodium excretion only about half the amount observed with SK F 38393, and this in a somewhat delayed response. SK F 82526 when given in the drinking water at 200 mg/kg/day for 30 days in developing SHR blunted the onset of hypertension and also lowered blood pressure acutely in anesthetized SHR. It did not lower blood pressure in anesthetized Dahl salt sensitive hypertensive rats. 

The ratio Na+/K+ is calculated for natriuretic activity. Values greater than 2.0 indicate a favorable natriuretic effect. Ratios greater than 10.0 indicate a potassium-sparing effect. 

The main metabolite of /-tocopherol is 2,7,8-trimethyl-2-(/3-carboxyeth-yl) -G-hydroxychromem (/ -CEHC), which is excreted in the urine. It heis potentially physiologically significant natriuretic activity, whereas the corresponding metabolite of a-tocopherol, which is formed in increasing amounts as intake increases, is inactive (Jiang et al., 2001). 

U-Phenethylamino-lH-pyrazolo/3,h- pyrimidine hydrochloride (XVl) was reported55 to have diuretic and natriuretic activity in rats about equal to that of acetazolamidej however, it appears to be longer acting. 

Potent natriuretic activity was evident in a simple phosphate buffered saline extract of whole atria. 4 Subsequently, the material was found to be acid stable.76 7,88,100,101 while the extract is both acid and heat76.101 stable, trypsin,75,89,93 as well as other proteolytic enzymes76 such as chymotrypsin, ami nopeptidase A and carboxypeptidases B and C destroy natriuretic activity. However, treatment with carboxy-peptidase A only blunted activity,76 and concanavalin A had no effect.75 These observations are consistent with ANF being a small peptide. 

In addition to the potent natriuretic activity, ANF has significant relaxant effects on vascular and perhaps other smooth muscle tissues.84,110,113,114 Currie observed relaxation of rabbit aorta and chick rectum, which had previously been contracted with epinephrine and carbachol, respectively.8A They use this spasmolytic action to monitor ANF activity and are the first group to separate smooth muscle relaxant activity of similar peptides isolated from cardiac atria, although both peptides are natriuretic.166 A recent report by Winquist et has detailed the vascular smooth muscle relaxing effect of synthetic ANF using a variety of agonists and different vascular smooth muscle preparations.11 Based on these observations, ANF appears to have spasmolytic properties similar to sodium nitroprusside. 

Summary - In the case of natriuretic hormone, twenty-five years of research have failed to characterize a pure substance that has natriuretic activity and is an inhibitor of Na ,K -ATPase, although, a vast body of circumstantial evidence does favor the existence of such a substance. Atrial natriuretic factor, on the other hand, is a recent discovery which yielded readily to chemical characterization and synthesis. Its biological profile suggests that it may be a component of the various control systems subserving fluid volume and pressure regulation. However, no convincing evidence has yet been offered that atrial natriuretic factor plays an important physiological role in pressure or volume homeostasis. 

In the case of the related compound 6,7-dichloro-2,3-dihydro-5-(2-thienylcarbonyl)-2-benzofurancarboxylic acid (Fig. 10), the diuretic and uricosuric properties are essentially completely separated. The (+)-5 -enan-tiomer, possessing the natriuretic activity, is twice as active as the racemate, with the uricosuric activity residing in the (—)-i -enantiomer [75,76]. It was postulated that a mixture of the two enantiomers could be prepared to yield an appropriate balance between the two actions [76]. Examination of nonracemic mixtures of the individual enantiomers in the chimpanzee resulted in the conclusion that the racemate possesses the optimal therapeutic ratio of the diuretic and uricosuric properties [75]. However, compared to humans the chimpanzee is a hyperresponder to uricosuric compounds and thus it may not be possible to extend this observation to man. A similar differentiation in enantiomeric activity has also been observed for the related compound 5-dimethylsulphamyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (DBCA) (Fig. 10), the uricosuric and diuretic activities being associated with the (+)-7 - and (—)-5-enantiomers, respectively [77]. 

Hypotensive, diuretic, and natriuretic activity of an aqueous extract of stinging nettle leaf was observed in anesthetized rats intravenously administered a continuous perfusion at a rate of 4 mg/kg per hour or 24 mg/kg per hour for 1.25 h. The decrease in arterial blood pressure was reduced by 15% at the lower dose and 38% at the higher dose (Tahri et al. 2000). A rapid but transient blood pressure decrease of 37% in rats was observed after intravenous administration of an aqueous extract of 25 mg/kg stinging nettle leaf (Lasheras 1986). In cats, administration of 26.6 mg/kg produced a hypotensive effect and bradycardia that was not compensated by administration of adrenaline (Broncano 1983). 

Pyridyl)-4ff-l,2,4-triazole-3-thiol [l,2-Dihydro-5-(4-pyridinyl)-3H-l,2y4-triazole-3-thlone] [14910-06-6] M 178.2, m 301-303 (dec), 305-308 (dec), 308-313 , 320-322 (dec), 321-322 (dec), pKes,(d 3.5 (py N), pKj stp) 9 (SH). This thio-l,2,4-triazole was prepared and purified as for the 3-pyridyl-isomer above but by using isonicotinic acid derivatives. It has mild diuretic and natriuretic activity. [Blackman et al. J Chem Soc C 661 1967, Beyerman et al. Rec Trav Chim Pays Bas 73 109 1954, Yale Piala JMeJ Chem 9 42 1966, Yoshida Asai J Pharm Soc Jpn 74 948 1954, Chem Abstr 49 10937 1955, Beilstein 26 IV 2129], 5-(4-Pyridyl)-4H-l,2,4-triazole-3-sulfonic add hydrate was obtained by oxidising the 3-thiol with saturated aqueous KMn04 25° (1 hour), decomposed with EtOH, filtered, precipitated as the Ag salt, filtered off, and decomposed with 5% HCl, then evaporated, and the residue was recrystallised from H2O. It decomposed on heating. [Blackman et al. J Chem Soc C 661 19677 ... 

The 6-unsubstituted derivatives, VIII and IX, caused the greatest Increases in urinary Na+ excretion in rats and produced favorable Na+/K+ ratios. 6-Substitution with SH or OH was usually detrimental although X retained appreciable natriuretic activity. 

Most studies of mechanisms by which reduced RVR leads to increased sodium excretion have involved agents which have no Independent natriuretic activity. Dopamine, for example, produces natriuresis by interacting with dopamine specific receptors to dilate the renal vasculature. Likewise, acetylcholine. Infused into the renal artery, dilates kidney blood vessels... 

Leu2, Leu ]oxytocin, which has natriuretic activity and weak diuretic effects, is also an inhibitor of oxytocic activltyl in contrast to [Leu ]oxytocin which has considerable diuretic and natriuretic effects as well as anti-ADH activity (inhibiting the antidiuretic effect of vasopressin) other 4-substituted oxytocins have been reported to have anti-ADH... 

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