Manuel Worcel

Differential effects of oral trandolapril and enalapril on rat tissue angiotensin-converting enzyme

Trandolapril (3-100 micrograms/kg) and enalapril (10-300 micrograms/kg) were administered orally to conscious rats. Angiotensin-converting enzyme (CE) activity was inhibited in serum, heart ventricle, renal inner cortex, lung, aorta, adrenal cortex and adrenal medulla, but not in the striatum. Inhibition was maximal at 2 h and with trandolapril was maintained for 24 h. Blood pressure and heart rate were not affected by either compound. Trandolapril was 6-10-fold more potent than enalapril. Differences between trandolapril and enalapril in CE inhibition observed in heart ventricle, adrenal cortex and medulla could be due to the presence of more than one type of CE or CE-like activity.

Angiotensin-converting enzyme inhibition, anti-hypertensive activity and hemodynamic profile of trandolapril (RU 44570)

Trandolapril (RU 44570), a new non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor chemically related to enalapril, and its diacid (RU 44403), were investigated for their ability to inhibit angiotensin-converting enzyme. Trandolapril attenuated angiotensin I (Ang I)-induced pressor responses following i.v. administration to rats and dogs with ID50 values of 13.1 +/- 1.3 and 21.1 +/- 2.3 micrograms/kg. RU 44403 produced corresponding values of 9.9 +/- 0.7 and 7.2 +/- 2.3 micrograms/kg. Trandolapril (3-300 micrograms/kg) produced a dose-related attenuation of Ang I-induced pressor responses (ID50 30 micrograms/kg) following oral administration to rats. Oral administration of trandolapril (30-1000 micrograms/kg) to dogs inhibited Ang I pressor responses for over 6 h. The depressor action of bradykinin in the rat was potentiated by i.v. trandolapril and RU 44403 with ED50 values of 5.5 +/- 0.8 and 4.9 +/- 0.3 micrograms/kg respectively. Trandolapril was 2.3-10-fold more potent than enalapril in all experiments, depending on species or route of administration. RU 44403 and MK 422 were approximately equipotent, implying that trandolapril was more readily hydrolysed than enalapril. Trandolapril (0.3-30 mg/kg) produced dose-related, long-lasting (greater than 24 h) reductions in blood pressure (BP) in spontaneously hypertensive rats (SHR) following oral administration. The anti-hypertensive effect was potentiated significantly in hydrochlorothiazide-pretreated SHR when the plasma renin activity was increased. Enalapril was 10-fold less potent than trandolapril in reducing BP. The anti-hypertensive action of trandolapril (3 mg/kg) was abolished in SHR that were bilaterally nephrectomized 24 h beforehand, but was maintained in SHR pretreated by indomethacin (5 mg/kg p.o.). Trandolapril (1 mg/kg i.v.) produced a modest and transient reduction in BP in anesthetized dogs. Trandolapril produced dose-related (30-1000 micrograms/kg) reductions in BP, total peripheral resistance and heart work in dogs pretreated with hydrochlorothiazide to increase plasma renin activity.

The effects of some slow channel blocking drugs on high affinity serotonin uptake by rat brain synaptosomes

The effects of some slow channel blocking drugs were investigated on high affinity serotonin uptake into crude rat brain synaptosomes. Serotonin uptake was sodium-dependent and competitively inhibited by imipramine (IC50 0.6 microM, Ki 0.26 microM). Bepridil, verapamil and diltiazem produced an apparent competitive inhibition of serotonin uptake with respective IC50 of 4.8, 5.2 and 308 microM. Nitrendipine and the sodium channel blocker, lidocaine, were without effect, even at 100 microM. The mechanism of the inhibitory effect is unknown but may involve an allosteric interaction with the sodium-dependent transporter.

MECHANISM OF ACTION OF ANGIOTENSIN II ON EXCITATION‐CONTRACTION COUPLING IN THE RAT PORTAL VEIN

1 The action of angiotensin II (At II) has been studied on the electrical and mechanical activity of the vascular smooth muscle of the rat portal vein. 2 At low concentrations (between 5 × 10−10 and 10−9m) At II induces an acceleration of spontaneous action potential (AP) discharge without change in the resting membrane potential. The frequency and size of the associated contractions are simultaneously augmented. Under these conditions the size of the spikes is not affected, thus suggesting that At II triggers the release of Ca from internal stores. 3 The increase in AP discharge rate produced by low concentrations of At II results from an acceleration of the pacemaker potential. Furthermore, in the presence of 10 mm tetraethylammonium (TEA), there is an acceleration of the repolarizing phase of AP. 4 Ouabain (10−3 m) inhibits the increase in rhythmic activity induced by low concentrations of At II (in the presence of 10 mm TEA), thus suggesting that the Na‐K pump is directly or indirectly involved in this action of the peptide. 5 At higher concentrations, At II produces a concentration‐dependent depolarization with an EC50 of 1.2 × 10−8m and a maximum of 10−7m. The associated contraction has an EC50 of 3.3 × 10−8 m and a maximum of 3 × 10−7 m. 6 Ouabain (3 × 10−3 m) depolarizes the cell membrane. Under these conditions, At II (10−7 m) has a slight depolarizing effect, but it still produces a large tonic contraction. 7 It is concluded, that At II acts on different steps of excitation‐contraction coupling, depending on the concentration. At low levels, the peptide mainly accelerates spike discharge, through a mechanism involving the Na‐K pump. At higher concentrations, At II depolarizes the cell membrane. The contraction is then activated by the influx of Ca2+ due to secondary AP discharge and the release of Ca2+ from intracellular stores. Pharmacomechanical coupling has an important role in the triggering of contractions both at high and at low concentrations of At II.

Interactions between hydralazine, propildazine and purines on arterial smooth muscle

1 The interaction of hydralazine (Hyd) and propildazine (Pyd) with purine compounds was studied in the isolated tail artery from normotensive Wistar (NW) rats. 2 Exogenously added purines inhibit non competitively the antispasmogenic response to Hyd in denervated NW segments. The order of potency is 2‐Cl‐adenosine > adenosine > adenosine 5′‐triphosphate (ATP)> inosine. Pyd action is modified only by the most active purine 2‐C1‐> adenosine, which displaces the dose‐response curves to the right. Hyd and Pyd seem to act on the same site, since their maximal effects are not additive. 3 Theophylline (Theo) 50μm induces the appearance of the antispasmogenic effect of Hyd in the usually poorly responsive innervated proximal NW arterial segments. The potentiating action of Theo is identical to the enhancement of the Hyd response observed after 6‐hydroxydopamine denervation. This result suggests that the release of endogenous purines from sympathetic nerves is sufficient to block the smooth muscle responses to Hyd, under our experimental conditions. A similar potentiating effect is obtained with propranolol (5 μm). 4 The spontaneous release of 3H, after loading with [3H]‐noradrenaline, was considered as an indirect indication of purine leakage from nerve terminals. There is an inverse relationship between the rate of 3H release, under these conditions, and the magnitude of the relaxant response to Hyd, i.e., 3H leakage is higher in proximal NW segments. 5 The most satisfactory explanation for the interaction of Hyd and Pyd with exogenous purines, and for the modulating actions of sympathetic nerve terminals, is that both antihypertensives act on a common receptor, sensitive to endogenous ATP and adenosine.

Arterial effects of aldosterone and antimineralocorticoid compounds mechanism of action

The aim of our work was to study the mechanism of action of aldosterone and antialdosterone compounds on Na+ and K+ fluxes in vascular smooth muscle. In the long term, regulation of salt metabolism depends on aldosterone effects on Na+, K+, H+ and H2O transport by the renal tubules. Furthermore, it has been shown that aldosterone modifies several epithelial transports, inducing a positive sodium balance. The chronic in vivo administration of aldosterone modifies transmembrane ionic fluxes in vascular smooth muscle. Garwitz and Jones suggested that aldosterone may enhance net Na+ transport through the stimulation of the sodium pump. The results obtained in our laboratory indicate that aldosterone has a direct stimulatory action on ouabain-dependent and on ouabain-independent Na efflux. Furthermore, the mineralocorticoid enhances passive K permeability, as well as the Na pump dependent K influx. Both effects are blocked by antimineralocorticoid compounds. Recent experiments have shown that vasopressin potentiates some of the in vivo effects of aldosterone.

Mode of action of cyclothiazide and triamterene. Ex vivo effect on 22Na and 86Rb efflux from arterial smooth muscle

Acute oral cyclothiazide treatment of conscious rats increased ex vivo 86Rb efflux from tail artery smooth muscle. This effect was blocked by oral triamterene. Identical results were obtained in binephrectomized rats, suggesting that the two drugs had a direct effect on smooth muscle K+ (86Rb) permeability. Decreased ex vivo smooth muscle 22Na efflux induced by oral cyclothiazide and triamterene is probably secondary to their renal actions, since there was no effect in binephrectomized rats.

Comparison of the effects of the ace inhibitors trandolapril and enalapril on phlogogen induced foot pad oedema in the rat

Two angiotensin converting enzyme (ACE) inhibitors, trandolapril and enalapril, were compared for their effects on rat food-pad oedema induced by carrageenin, bradykinin dextran and platelet activating factor (PAF). Trandolapril (0.03–30.0 mg/kg, per os) potentiated carrageenin-induced oedemas. Enalapril produced the same effect at 3–10 fold higher doses (0.3–30.0 mg/kg per os). Both ACE inhibitors were equiactive in potentiating bradykinin-induced oedema. Neither compound affected dextran-induced oedema. In marked contrast PAF-induced oedema was reduced by both ACE inhibitors, trandolapril being approximately 10 fold more active than enalapril. The observed differences in potency between the two ACE inhibitors corresponded with their previously described actions on inhibition of plasma and tissue ACE and in inducing hypotension. The results suggest a crucial role of kinins in the oedemagenic response to carrageenin. The reason why the ACE inhibitors reduced PAF-induced oedema is not clear, but could involve peripheral vasodilation.

Arterial smooth muscle effects of aldosterone and vasopressin: Action on ionic fluxes

We have shown previously that aldosterone injected s.c. to adrenalectomized rats has a mineralocorticoid specific action on the transmembrane movements of sodium and potassium from the rat tail artery. These effects appeared to be partly due to an unknown humoral factor. Indeed, the late in vivo effects of aldosterone on 22Na and 86Rb effluxes are suppressed or reduced after in vitro exposure to the hormone. In rats perfused with a specific antagonist of the pressor effect of vasopressin, the in vitro administration of aldosterone induced a kinetic action similar to that observed after in vitro exposure to the mineralocorticoid. Vasopressin exerts a direct action on 22Na and 86Rb effluxes. These effects were correlated in the time with the late in vivo effects of aldosterone. Moreover, vasopressin appears to potentiate the in vitro effects of aldosterone on 22Na and 86Rb effluxes. It is not yet possible to ascertain if this effect is additive or permissive.

Interaction between aldosterone and vasopressin on vascular smooth muscle permeability to sodium

The s.c. injection of aldosterone (10 micrograms/kg) induces a release of vasopressin. The peak of plasma vasopressin level occurs at the same time as the late in vivo effect of aldosterone on passive 22Na efflux from arterial smooth muscle. These results indicate that vasopressin mediates the delayed in vivo effects of aldosterone on ouabain-insensitive 22Na efflux, since on the other hand, it has been possible to show that the action of the peptide is accelerated by a previous exposure to the mineralocorticoid. Indeed, after a 120-min pretreatment with 10(-8) M aldosterone, vasopressin induces an effect on 22Na efflux in 30 min, as opposed to the 120 min needed in the absence of the steroid.