alpha-Hydroxy phosphinyl-based inhibitors of human renin.

The design and application of alpha-hydroxy phosphonates, a new class of transition state analogs, toward the discovery of novel and potent inhibitors of the aspartyl protease renin is described. Tripeptidic alpha-hydroxy diethyl phosphonate 3, the first example in this series, was found to be a good inhibitor of human renin (IC50 = 29 nM), and preliminary studies led to the choice of alpha-hydroxy dimethyl phosphonate 15 (IC50 = 16 nM) as a base-line compound for further structure-activity relationship study. Corresponding phosphinate (28-30) and phosphine oxide (23 and 24) analogs of 15 were prepared to assess the steric and electronic requirements around the phosphorus center. Evaluation of these analogs suggested that the presence of at least one alkoxy group on phosphorus was a critical requirement for good activity. Inhibitors with leucine at P2 possessed better in vitro activity than the corresponding P2 histidine analogs (15, IC50 = 16 nM vs 37, IC50 = 220 nM; 33, IC50 = 8.5 nM vs 40, IC50 = 41 nM). Compound 34 (IC50 = 31 nM), the P3 aminocaproic analog of 15, showed complete and long-lasting inhibition of plasma renin activity while eliciting a 10-15 mmHg drop in mean arterial pressure when administered intravenously at 1 mumol/kg in conscious, sodium-depleted, cynomolgus monkeys. In summary, the alpha-hydroxy phosphonates represent a promising and structurally novel class of transition state analog inhibitors of human renin.

Ceranapril (SQ 29,852), an orally active inhibitor of angiotensin converting enzyme (ACE).

Ceranapril (SQ 29,852) is a new inhibitor of angiotensin I (AI) converting enzyme (ACE) belonging to the hydroxylphosphonate class. The purpose of the present report is to present the in vivo pharmacology of ceranapril in conscious animal models. In conscious, normotensive rats, ceranapril administered i.v. (ED50 = 63 nmol/kg) or p.o. (ED50 = 530 nmol/kg) inhibited an AI pressor response with potency equal to that of captopril. However, in conscious dogs, ceranapril was a relatively poor inhibitor of the AI pressor response after both i.v. (ED50 = 300 nmol/kg) and p.o. (ED50 = 18 mumol/kg) administration; in monkeys ceranapril was a good inhibitor of the AI pressor response after i.v. (ED50 = 60 nmol/kg) but not p.o. (ED50 = 18 mumol/kg) administration. In rats, the duration of ceranapril's inhibition of an AI pressor response was longer than an equimolar dose of captopril. Similarly, in SHR, ceranapril's blood pressure lowering effect had a longer duration than that of captopril. Ceranapril's ACE inhibitory effects were longer lasting in anephric rats than in sham rats, suggesting a renal route of excretion for ceranapril. Ceranapril administration to conscious female dogs resulted in significant increases in renal plasma flow and GFR. In SHR, doses of 23 and 68 mumol/kg resulted in significant blood pressure lowering that lasted 24 h. Oral doses of 2.3, 6.8, 23, and 68 mumol/kg in two-kidney, one-clip hypertensive rats resulted in significant and dose-related falls in arterial pressure, which again persisted for 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood pressure lowering and renal hemodynamic effects of fosinopril in conscious animal models.

The blood pressure lowering and renal hemodynamic effects of fosinopril, the chemically novel inhibitor of angiotensin I converting enzyme (ACE), was assessed in conscious animal models. In conscious dogs, intravenous infusion of SQ 27,519 [0.5 mg/kg (1.1 mumol/kg) bolus plus 0.1 mg/kg/min (0.22 mumol/kg/min)], the active moiety of the prodrug fosinopril, increased PAH clearance and GFR by 25 and 16%, respectively (p less than 0.05, each) without changing arterial pressure (AP). Urine volume, sodium excretion, and potassium excretion were elevated, although not significantly increased. In sodium-depleted cynomolgus monkeys, 1.5 and 5.0 mumol/kg (0.88 and 2.9 mg/kg) p.o. of fosinopril lowered arterial pressure from 115 +/- 5 to 99 +/- 5 mm Hg and from 116 +/- 3 to 87 +/- 4 mmHg, respectively (p less than 0.05, each). When given orally to SHR at 10 and 30 mg/kg (5.9 and 17.6 mumol/kg), fosinopril lowered AP by 23 (183 +/- 4 to 160 +/- 5 mm Hg) and 20 mm Hg (176 +/- 4 to 156 +/- 4 mm Hg), respectively. The combination of fosinopril [10 mg/kg (5.9 mumol/kg)] plus hydrochlorothiazide (10 mg/kg) reduced AP from 206 +/- 4 to 167 +/- 2 mm Hg when given orally to SHR. Fosinopril was more effective in two-kidney, one-clip hypertensive rats relative to SHR; AP fell from 201 +/- 9 to 160 +/- 7 mm Hg after 10 mg/kg (5.9 mumol/kg), and from 205 +/- 7 to 145 +/- 7 mm Hg after 30 mg/kg (17.6 mumol/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

(Phosphinyloxy)acyl amino acid inhibitors of angiotensin converting enzyme. 2. Terminal amino acid analogues of (S)-1-[6-amino-2 [[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline.

Analogues of (S)-1-[6-amino-2[[hydroxy(4-phenylbutyl)phosphinyl] oxy]-1-oxohexyl]-L-proline (1, SQ 29,852) in which the terminal proline residue has been replaced by a variety of substituted and heteroatom-substituted prolines, N-arylglycines, N-cycloalkylglycines, and bicyclic amino acids have been synthesized and evaluated as inhibitors of angiotensin converting enzyme in vitro and in vivo. In general, the addition of lipophilic substituents to the 4-position of proline of the parent phosphonate 1 resulted in substantial increases in in vitro activity. The largest improvements were observed in the case of cis-benzyl (36-fold) and dithioketal (24-fold) analogues 2r and 2x, respectively. These enhancements of in vitro activity were accompanied by modest increases (2-3.5-fold) in in vivo (iv) activity. Among the various terminal amino acid replacements examined in this study, the indoline-based analogue 2i was by far the most potent compound on iv administration in the normotensive rat.

Fosinopril, a phosphinic acid inhibitor of angiotensin I converting enzyme: in vitro and preclinical in vivo pharmacology.

Fosinopril is the first member of a new chemical class of angiotensin I (AI) converting enzyme (ACE) inhibitors, the phosphinic acids. In vitro, SQ 27,519, the active moiety of the prodrug fosinopril, was a more potent inhibitor of purified rabbit lung ACE- (IC50 = 11 vs. 23 nM) and bradykinin-induced contractions of guinea pig ileum than captopril. In vivo, SQ 27,519 was equipotent to captopril as an inhibitor of an AI pressor response after intravenous (i.v.) administration to conscious rats and monkeys but appeared to be less potent in conscious dogs. After oral administration, fosinopril again was equipotent to captopril as an inhibitor of an AI pressor response in rats and monkeys and slightly less potent in dogs. However, both SQ 27,519 (i.v. studies) and fosinopril (oral studies) had a longer effect than captopril in all three species. When fosinopril was administered orally for 5 days, its effects on an AI pressor response were the same on days 1 and 5, suggesting lack of tolerance to the compound. The ACE inhibitory effect of captopril, but not fosinopril, was prolonged in conscious rats with glycerol-induced acute renal failure, suggesting that fosinopril is excreted by an extrarenal route. Finally, fosinopril had no effect on the pressor or chronotropic effects of norepinephrine (NE) or 1,1-dimethyl-4-phenylpiperinium (DMPP) or electrical stimulation of the sympathetic ganglia of pithed rats. Fosinopril attenuated the pressor, but not the chronotropic effects of tyramine. We conclude that fosinopril is a potent and long-lasting inhibitor of ACE in conscious animal models that does not impair adrenergic function or reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Perinephritis hypertension in Macaca fascicularis (cynomolgus monkey): studies of the renin-angiotensin-aldosterone axis and renal hemodynamic function.

The purpose of the present study was to characterize the etiology of bilateral perinephritis hypertension in the non-human primate. Hypertension was induced in female cynomolgus (Macaca fascicularis) monkeys by wrapping both kidneys under sterile surgical procedures. Mean arterial pressure (MAP), plasma renin activity (PRA), plasma aldosterone concentration (ALDO), para-aminohippurate (PAH) clearance, glomerular filtration rate (GFR), urine volume, and sodium and potassium excretion were measured before and weekly after induction of the hypertension. MAP increased progressively from 108 +/- 1 to 135 +/- 4 mmHg during the first 6 weeks; thereafter, MAP remained at this elevated level, PRA was elevated two- to fivefold for up to 10 weeks after the hypertension and ALDO was elevated during 1 (139%), 4 (60%), 6 (196%), 8 (249%) and 10 (148%) weeks of the hypertension. PAH clearance and GFR were significantly reduced during week 1 of the hypertension, but returned to control values by week 2. Urine volume was increased significantly during the first week of the hypertension, while sodium and potassium excretion were not changed. Captopril (15 mumol/kg, intravenously) normalized the blood pressure regardless of the severity or duration of the disease. Additionally, captopril lowered ALDO and increased PRA. It is concluded that bilateral perinephritis hypertension in the monkey is dependent on increased activity of the renin-angiotensin-aldosterone axis.

Preclinical pharmacology of zofenopril, an inhibitor of angiotensin I converting enzyme.

Zofenopril calcium (one-half calcium salt) is a prodrug ester analog of captopril whose biological effects are manifested by its active component, SQ 26,333. Because of the relative insolubilities of both zofenopril calcium and SQ 26,333, zofenopril potassium salt and SQ 26,703, the arginine salt of the active ACE (angiotensin I converting enzyme) inhibitory moiety of zofenopril, were employed in many of the following studies. The in vitro and in vivo pharmacological effects of zofenopril have been evaluated and comparisons have been made to captopril. In vitro, SQ 26,703 was more potent than captopril as an inhibitor of rabbit lung ACE (IC50 = 8 vs. 23 nM). SQ 26,703 was also a potent inhibitor of angiotensin I (AI)-induced contractions (EC50 = 3 nM) and a potentiator of bradykinin-induced contractions (EC50 = 1 nM) of isolated guinea pig ileum, while it had no effect on the inotropic effects of angiotensin II, BaCl2, PGE1, histamine, serotonin, or acetycholine in the same tissue, signifying that zofenopril is a specific inhibitor of ACE. In vivo, the potency of SQ 26,703 was equal to or greater than that of captopril as an inhibitor of an AI pressor response when given intravenously to rats, dogs, and monkeys. After oral administration of equimolar doses, zofenopril was the more effective and longer lasting ACE inhibitor in all three species. In SHR, doses of 6.6 and 22.0 mg/kg, p.o. lowered pressure by 20 and 33 mm Hg, respectively, while 30 mg/kg of captopril lowered pressure by 25 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacology of novel imidazole alcohol inhibitors of primate renin.

SQ 30,774 and SQ 31,844 are representatives of a novel class of renin inhibitors, the imidazole alcohols. These compounds, which contain an imidazole ring as part of their active site binding group are potent in vitro inhibitors of primate renin, but not rat, hog of dog renin. In conscious, sodium-depleted cynomolgus monkeys both compounds produced a dose-related inhibition of plasma renin activity (PRA) at doses ranging between 0.001 and 1.0 mumol/kg, intravenously, and total inhibition was observed after the highest dose. However, a reduction in blood pressure was observed only after an intravenous dose of 10 mumol/kg or when the compounds were administered by infusion. In sodium-replete monkeys, SQ 30,774 inhibited the rise in arterial pressure and PRA following administration of exogenous monkey renin. When the compounds were administered orally at 50 mumol/kg, only SQ 31,844 significantly inhibited PRA (80%). It is concluded that representatives of the imidazole alcohol class of renin inhibitors are potent inhibitors of renin in vitro and inhibit PRA and lower arterial pressure in vivo.

Differentiation of angiotensin-converting enzyme (ACE) inhibitors by their selective inhibition of ACE in physiologically important target organs.

Seven ACE inhibitors were studied for possible differences in distribution to aorta, brain, heart, lung, and kidney after administration of single oral doses to spontaneously hypertensive rats (SHR). Doses, normalized for differences in inhibitory potency and molecular weight, were expected to deliver equivalent levels of ACE-inhibitory activity to the circulation, and this was confirmed by preliminary dose-response studies. The relative potencies of the active moieties of the seven drugs and the normalized oral doses used were: SQ 29,852 (1.0), 100 mg/kg; captopril (3.5), 30 mg/kg; enalapril (12), 20 mg/kg; fosinopril (13), 25 mg/kg; zofenopril (20), 10 mg/kg; lisinopril (24), 10 mg/kg; and ramipril (51), 5 mg/kg. In these ex vivo studies, ACE activities were determined fluorometrically in SHR sera and in uncentrifuged homogenates of the solid tissues at various times after oral dosing with the ACE inhibitors. As expected, the normalized oral doses of the seven inhibitors had equivalent effects on serum ACE. In lung, where ACE has a vascular endothelial localization, and in aorta, where ACE inhibition correlates with antihypertensive action, ramipril, lisinopril, and zofenopril were distinguished by the magnitude and duration (three to four days) of their effects. In the brain, where ACE may affect central regulation of blood pressure and participate in the degradation of certain neuropeptides, ramipril and enalapril had no effect; captopril and zofenopril had modest, short-lasting effects, and fosinopril, lisinopril, and SQ 29,852 had delayed but long-lasting inhibitory actions. In the kidney, where ACE inhibition may have positive or negative effects on renal function, ramipril and fosinopril could be distinguished by their weak actions, perhaps associated with biliary routes of excretion. In the heart, where ACE inhibitors may prevent ischemic damage to the myocardium, single oral doses of captopril, fosinopril, and particularly zofenopril produced striking and long-lasting inhibition, whereas equivalent doses of ramipril and enalapril produced barely detectable inhibition.

Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE).

1. Seven drugs (captopril, zofenopril, enalapril, ramipril, lisinopril, fosinopril, and SQ 29,852) were compared in vitro in homogenates of aorta, brain, heart, lung, and kidney and in sera of spontaneously hypertensive rats (SHR) both with respect to potencies of their active moieties as inhibitors of angiotensin-converting enzyme (ACE), and, where applicable, rates of hydrolysis of their prodrug ester functions. 2. In ex vivo dose-response and time-course studies, the inhibitory effects of the seven drugs on tissue ACEs and their relative distributions to SHR tissues were compared following oral administration. 3. The relative potencies of the inhibitory moieties of the drugs (in parentheses) and the normalized 'equiactive' oral doses employed for time-course studies were: SQ 29,852 (1.0), 100 mg kg-1; captopril (3.5), 30 mg kg-1; enalapril (12), 20 mg kg-1; fosinopril (13), 25 mg kg-1; zofenopril (20), 10 mg kg-1; lisinopril (24), 10 mg kg-1; and ramipril (51), 5 mg kg-1. 4. Following oral administration of the drugs to SHR, the degree and duration of ACE inhibition in aorta and lung correlated with the antihypertensive actions, with ramipril, lisinopril, and zofenopril producing effects of the greatest magnitude and duration. 5. Ramipril and enalapril did not inhibit brain ACE ex vivo; captopril and zofenopril had modest but short-lasting effects; and fosinopril, lisinopril, and SQ 29,852 had long-lasting inhibitory actions, which, with the latter two, were delayed in onset. 6. All of the drugs produced significant inhibition of kidney ACE, with ramipril and fosinopril having somewhat weaker effects, perhaps due to biliary routes of excretion. 7. Captopril, fosinopril, and particularly zofenopril inhibited cardiac ACE ex vivo with degrees and durations that were marked compared with those of the other drugs; preliminary studies with isolated hearts suggest a possible relationship between inhibition of cardiac ACE and preservation of cardiac function subsequent to ischaemia.

Biology of a novel class of potent long-acting angiotensin converting enzyme inhibitors: the acyl lysinamido phosphonates.

The acyl lysinamido phosphonates represent a novel class of angiotensin I converting enzyme (ACE) inhibitors. Representatives of this class produce 50% inhibition of purified rabbit lung ACE at concentrations less than 8 nmol/l. After intravenous and oral administration to normotensive rats the phosphonates inhibited an angiotensin I pressor response by 50% at doses less than or equal to enalapril (oral studies) or its free acid, MK-422 (intravenous studies); however, the duration of effect was much longer after the phosphonates. In conscious cynomolgus monkeys, representatives of the phosphonate class showed greater inhibition of an angiotensin I pressor response and for a much longer period of time than enalapril, fosinopril and lisinopril. Similarly, in sodium-depleted monkeys the blood pressure lowering effects of enalapril, lisinopril and fosinopril were of short duration compared with those of the phosphonates. It is concluded that the acyl lysinamido phosphonates represent a potent and long-acting class of ACE inhibitors in vitro and in vivo.

Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.

Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.

Ketomethylureas. A new class of angiotensin converting enzyme inhibitors.

The design rationale for a new series of tripeptide derived angiotensin converting enzyme (ACE) inhibitors, which we term "ketomethylureas", is described. Analogs of tripeptide substrates (i.e. N-benzoyl-Phe-Ala-Pro) in which the nitrogen atom of the scissile amide bond and the adjacent asymmetric carbon atom of the penultimate amino acid residue are formally transposed give rise to this novel class of inhibitors. The most potent ketomethylureas inhibit ACE with I50 values in the nM range.

(Phosphinyloxy)acyl amino acid inhibitors of angiotensin converting enzyme (ACE). 1. Discovery of (S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L -proline a novel orally active inhibitor of ACE.

The synthesis of a series of orally active, phosphinyloxyacyl proline inhibitors of angiotensin converting enzyme (ACE) is described. The in vitro and in vivo ACE inhibitory activities are reported for each compound. The structure-activity relationship for this series of compounds in relation to the carboxyalkyl dipeptide ACE inhibitors as well as other types of hydroxyphosphinyl-containing ACE inhibitors (e.g., the corresponding nitrogen and carbon isosteres) is discussed. Within an isosteric series of phosphorus-containing inhibitors based on the lysylproline terminal dipeptide sequence, only the phosphonates (oxygen isosteres) show a high level of oral activity. Optimum potency and oral activity in the phosphonate series occurs with the (phenylbutyl)- and n-hexylphosphonate side chains. An aminobutyl side chain in the P1' residue is an absolute requirement for full expression of oral activity. The most potent of these compounds, 8b (SQ 29,852), has intravenous and oral activities superior in potency to those of captopril in the normotensive rat.

Relationship between metabolism and pharmacologic activity of SQ 27,786, an angiotensin converting enzyme inhibitor with potent diuretic activity.

SQ 27,786 is a sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor, which also possesses potent diuretic activity in dogs after intravenous administration. The absorption, distribution, metabolism and elimination of 35S-labeled SQ 27,786 was studied in dogs to determine if the observed pharmacologic activities were intrinsic to this compound or the result of metabolism to separate ACE-inhibitory and diuretic moieties. The poor pharmacologic activity observed after oral administration was found to be due to poor absorption of the ACE-inhibitory-diuretic compound. The results of this study indicated that SQ 27,786 was excreted largely intact, either as the parent compound, the symmetrical disulfide of the parent compound, or as mixed disulfides of the parent compound with endogenous sulfhydryl compounds (e.g., SQ 27,786-L-cysteine) in a manner similar to captopril. It was concluded that the observed diuretic and ACE inhibitory activities were the result of intact SQ 27,786 and not of metabolites resulting from cleavage of the molecule to separate diuretic and ACE inhibitory moieties.

SQ 27,786 and SQ 28,853: two angiotensin converting enzyme inhibitors with potent diuretic activity.

SQ 27,786 and SQ 28,853 were designed to possess both angiotensin converting enzyme (ACE) inhibitory and diuretic properties. Both compounds were given to conscious male Sprague-Dawley rats and mongrel female dogs to determine ACE inhibitory and diuretic activities. All animals had previously been equipped with indwelling arterial and venous catheters. Both compounds resulted in dose-related inhibition of an angiotensin I pressor response in rats after i.v. administration. The maximum response and duration of effect of both compounds were similar to that seen with equimolar doses of captopril. Oral doses of SQ 28,853 (50.0 mumol/kg) and SQ 27,786 (15.0 mumol/kg) resulted in 15 and 64% inhibition of ACE, respectively. In conscious normotensive dogs, both compounds (2.0 mg/kg, i.v.) resulted in complete inhibition of ACE. Urine volume was increased by 153 and 667% after SQ 27,786 and SQ 28,853, respectively. Similarly, sodium excretion was increased by 336% after SQ 27,786 and by 650% after SQ 28,853. SQ 27,786 and SQ 28,853 increased potassium excretion by 54 and 115%, respectively. No significant changes in blood pressure were observed with either compound in either species. These results demonstrate that both SQ 27,786 and SQ 28,853 are potent ACE inhibitors and diuretic agents in vivo.

Antihypertensive effects of 12 beta adrenoceptor antagonists in conscious spontaneously hypertensive rats: relationship to changes in plasma renin activity, heart rate and sympathetic nerve function.

Twelve beta adrenoceptor antagonists were examined for their effects on mean blood pressure (MBP), heart rate (HR), plasma renin activity (PRA) and sympathetic nerve function in spontaneously hypertensive rats (SHR). The selected drugs included cardioselective agents (acebutolol, atenolol and metoprolol), agents with intrinsic sympathomimetic activity (oxprenolol, acebutolol, alprenolol and pindolol) and agents with local anesthetic activity (propranolol, oxprenolol, acebutolol, alprenolol and labetalol). All 12 beta adrenoceptor antagonists, administered once daily for 4 days (30 mg/kg p.o.), significantly decreased MBP of SHR. This reduction in MBP was dissociable from both reductions in HR as well as peripheral beta adrenoceptor blockade. In addition, the onset of MBP reduction was slower than the onset of beta adrenoceptor blockade and became greater with duration of treatment. PRA activity was significantly and markedly reduced by both bunolol and metoprolol shortly after dosing at a time when HR was significantly reduced but MBP was not. Conversely, at a time when MBP was significantly reduced by both bunolol and metoprolol, PRA and HR were found to be normal. The changes in HR and PRA were correlated with peripheral beta adrenoceptor blockade but changes in MBP were not. Bunolol, metoprolol and propranolol had no consistent inhibitory effect on pressor responses to nerve stimulation in pithed SHR, although positive chronotropic responses to norepinephrine, tyramine, dimethylphenylpiperazinium and angiotensin I and II were significantly and markedly reduced. It is concluded that beta adrenoceptor antagonists, as a class, reduce MBP of conscious SHR, provided that sufficient time is allowed for this observation to occur. Furthermore, the reduction in MBP caused by beta adrenoceptor antagonists is unrelated to acute beta adrenoceptor blockade, changes in HR, reductions in PRA or inhibition of sympathetic nerve function. Finally, cardioselectivity, intrinsic sympathomimetric activity and local anesthetic activity are not required for the antihypertensive activity of these agents.

Hypertension after ending captopril administration: pathogenesis in 2-kidney, 1-clip rat.

We have previously shown that continuous captopril administration prevents hypertension from developing in the two-kidney, one-clip (2K, 1C) rat. The present investigation was designed to determine the mechanism(s) producing the hypertension. In one series of experiments captopril prevented pressure from increasing during an 8-wk treatment period. Relative to the last day of treatment, mean arterial pressure and total peripheral resistance (TPR) were increased and cardiac output was unchanged at 3, 7, and 28 days after captopril cessation. Plasma renin activity (PRA) was unchanged 3, 7, and 14 days after captopril cessation but was elevated at 28, 49, and 56 days after captopril cessation only in 2K, 1C rats with severe hypertension (systolic blood pressure greater than 180 mmHg). Guanethidine (45 mg/kg po, bid) did not prevent the development of 2K, 1C hypertension but did prevent the hypertension from developing after cessation of captopril. Blockade of the prostaglandin system with indomethacin (5 mg/kg + 50 micrograms X kg-1 X min-1) and of the kallikrein-kinin system with aprotinin (25,000 KIU + 150 KIU X kg-1 X min-1) for 2 h had no effect on captopril's antihypertensive effect. Additionally, no change in sodium or water balance was observed after captopril cessation. Taken together these data demonstrate that hypertension after captopril cessation is due to an increase in TPR. Additionally, the rise in TPR is due to both the sympathetic nervous and the renin-angiotensin systems since both systems must be functional before pressure rises.

Renal response to captopril in conscious dogs pretreated with indomethacin.

This study was designed to determine whether the prostaglandins mediate the renal effects of captopril in the conscious sodium-replete dog. In a group of control animals (n = 9), effective renal plasma flow (ERPF) increased from 185 +/- 15 to 230 +/- 12 ml/min and plasma renin activity (PRA) increased from 0.64 +/- 0.15 to 12.9 +/- 1.1 ng ANG I . ml-1 . h-1 after captopril (10 mg/kg bolus plus 10 micrograms . kg-1 . min-1 i.v.) administration. Glomerular filtration rate (GRF) and sodium excretion (UnaV) were also increased significantly following captopril treatment, whereas urine volume (V), potassium excretion (UkV), mean arterial pressure (MAP), and heart rate (HR) remained unchanged throughout the experiment. When the same dose of captopril was given to indomethacin-pretreated dogs (5 mg/kg bolus plus 2 micrograms . kg-1 . min-1 i.v.), ERPF increased from 170 +/- 8 to 265 +/- 18 ml/min and PRA increased from 1.2 +/- 0.4 to 14.6 +/- 3.0 ng ANG I . ml-1 . h-1 after the captopril, while UnaV, UkV, and V remained unchanged. These data demonstrate that the prostaglandins do not mediate the ability of captopril to increase PRA or effective renal plasma flow in this experimental model.