John P. Koepke

Thiorphan, an inhibitor of endopeptidase 24.11, potentiates the natriuretic activity of atrial natriuretic peptide

To evaluate the role of endopeptidase 24.11 in metabolism of atrial natriuretic peptide (ANP) in vivo, we examined the effect of thiorphan, an inhibitor of this enzyme, on plasma ANP concentrations and the cardiovascular and renal actions of ANP(99–126). Thiorphan alone produced a modest increase in urinary sodium excretion in anesthetized rats; however, urine flow, arterial pressure, and basal plasma ANP concentrations were unchanged. When administered during an infusion of ANP(99–126) (330 ng/kg/min i.v.), thiorphan increased the plasma concentration of ANP and enhanced the diuretic and natriuretic activity of this hormone. The effects on urine flow and urinary sodium excretion were most pronounced immediately after the inhibitor was administered and later diminished in magnitude. Thiorphan did not alter the depressor activity of exogenous ANP(99–126). These data suggest that endopeptidase 24.11 participates in metabolism of ANP(99–126) and that thiorphan potentiates the renal actions of this hormone by inhibiting its degradation.

Central and peripheral actions of a nonpeptidic angiotensin II receptor antagonist.

Nonpeptidic imidazole derivatives were recently reported to be angiotensin II receptor antagonists with acute blood pressure-lowering activity. In the present study, we characterized the angiotensin II receptor antagonist properties of one such derivative, 4′-{[2-butyl-4-chloro-5-(hydroxymethyl)- lH-imidazol-l-yl]methyl}-[l,l′-biphenyl]-2-carboxylic acid (IMI). In receptor binding studies, IMI displaced bound [125I] angiotensin II from rat uterine membranes with an IC50 of 0.17 μM. In isolated rabbit aortic rings, IMI shifted the angiotensin II concentration-response curve to the right in a parallel and concentration-dependent manner. A Schild plot of these data indicated a pA2o of 7.13±0.16 and a slope of 0.94±0.06. In rat kidney slices, IMI shifted the concentration-response curve for angiotensin II-induced inhibition of renin release to the right Antagonism of the angiotensin II pressor response by IMI was dose dependent and reversible in ganglion-blocked, anesthetized rats. The water intake and pressor responses to intracerebroventricular angiotensin II (100 pmol) were inhibited by intracerebroventricular IMI (25 or 50 nmol) in conscious Sprague-Dawley rats. Similarly, the drinking and pressor responses to intravenous angiotensin II were blocked by intravenous IMI in conscious rats. IMI alone had no effects on mean arterial pressure or drinking when administered either intravenously or intracerebroventricularly. IMI decreased mean arterial pressure throughout 5 days of infusion in spontaneously hypertensive rats. In summary, IMI was a full competitive antagonist without partial agonist activity in peripheral tissues and the central nervous system. Moreover, the chronic administration of this angiotensin II receptor antagonist was antihypertensive in spontaneously hypertensive rats.

Chronic atriopeptin regulation of arterial pressure in conscious hypertensive rats.

Acute coadministrations of an inhibitor of endopeptidase 24.11 (thiorphan) and a ligand (SC-46542) selective for the non-guanylate cyclase-llnked atriopeptin binding sites increases urinary sodium excretion to a greater degree in conscious spontaneously hypertensive rats than in normotensive Wistar-Kyoto rats. In the present study, we examined the effects of chronic 10-day intravenous infusions of SC-46542 (des[Phe106,Gly107,Ala116Gln116] atriopeptin-(103–126)) (0.1 mg/kg/hr), thiorphan (1.5 mg/kg/hr), and atriopeptin-(103–126) (100 ng/hr) alone or in combination on direct recording of mean arterial pressure in conscious spontaneously hypertensive rats. During an 11-day time-control infusion of isotonic saline vehicle (100 μl/hr), mean arterial pressure remained stable. Chronic infusion of atriopeptin-(103–126) decreased mean arterial pressure progressively over the first 3 days; then mean arterial pressure progressively rose to control level over the following 3 days and remained at control level for the remainder of the experiment Similarly, coinfusions of atriopeptin-(103–126) and SC-46542 or thiorphan, SC-46542 and thiorphan, or the triple infusion of atriopeptin-(103–126), SC-46542, and thiorphan had only transient effects on mean arterial pressure during 10-day infusions. SC-46542 alone had no effect on mean arterial pressure. Similarly, thiorphan alone had no effect on mean arterial pressure except at doses that blocked the acute pressor response to angiotensin I. Chronic infusions of atriopeptin-(103–126), SC-46542, and thiorphan alone or in combination are not effective long-term treatments for hypertension in spontaneously hypertensive rats.

Pharmacology of SC-52458, an orally active, nonpeptide angiotensin AT1 receptor antagonist

Summary We describe the pharmacologic properties of SC-52458, 5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine, a novel nonpeptide angiotensin II (AH) receptor antagonist. SC-52458 was a potent inhibitor of [125I]AII binding to AT, receptors in rat adrenal cortex and uterine smooth muscle membranes (IC50 values of 2.8 and 6.9 nM, respectively). Contraction of rabbit aortic rings by AII was antagonized by SC-52458 in a competitive and reversible manner (pA2 of 8.18). SC-52458 had no effect on the activity of angiotensin converting enzyme (ACE) or renin in vitro. In normotensive rats, administration of SC-52458, either intravenously (i.v.) or by gavage, inhibited the pressor response to AH. Daily treatment with SC-52458 at 20, 30, and 50 mg/kg by gavage for 4 days decreased blood pressure (BP) in conscious, spontaneously hypertensive rats (SHR). Further studies in renal-artery ligated rats and sodium-deficient dogs demonstrated that oral administration of SC-52458 decreased BP and that this activity was correlated with significant plasma levels of the compound. SC-52458 is an orally active, competitive AT1-receptor antagonist with antihypertensive properties.

Role of renal nerves in the potentiation of atriopeptin-induced natriuresis by vasopressin.

Previous studies have shown that vasopressin potentiates the natriuresis produced by atriopeptin. In five anesthetized dogs of this study, we found that the potentiation was proportional to the dose of vasopressin infused. Sodium excretion was 46±16 μeq/min with atriopeptin (103-126) (AP24) alone (0.36 nmol/kg ± min), was increased to 127±29 by concomitant intravenous infusion of 0.4 mU/kg-mln vasopressin, was further increased to 301±75 by 1.2 μ/kg-min vasopressin and leveled off at 328±37 with 3.6 mU/kg ± min vasopressin. To investigate whether the potentiation by vasopressin was due to an intrarenal action, we infused three doses of vasopressin (0.04, 0.12, and 0.36 mU/kg±min) into the renal artery during intravenous AP24 infusion in a second group of five dogs. The natriuresis, 128±18 μeq/min, was unaffected by any intrarenal dose of vasopressin. In a third group, we determined whether the potentiation produced by vasopressin was mediated by a mechanism involving the renal nerves by denervating the left kidney before AP24 infusion. In the denervated kidneys, sodium excretion was increased from a control value of 33 ±5 μeq/min to 303 ±38 with AP24 alone and was unresponsive to subsequent intravenous vasopressin administration. The exaggerated natriuresis with AP24 alone was of the same magnitude as that produced by AP24 plus the highest doses of intravenous vasopressin in the innervated kidneys of the first group. From these results we conclude that the potentiation of AP-induced natriuresis by vasopressin is mediated by a mechanism involving the renal nerves and probably results from the known effect of vasopressin to inhibit renal nerve activity.