Jack M. DeForrest

Angiotensin II is a necessary component for the development of hypertension in the two kidney, one clip rat

The current study was undertaken to define the role of the renin-angiotensin system in the development of hypertension in the two kidney, one clip Goldblatt rat. Captopril was administered orally (100 mg/kg/day) to two groups of rats (n = 8 each) 24 hours before and each day after unilateral renal artery clipping (0.2 mm internal diameter): the drug was given for either 16 weeks (group I) or 24 weeks (group II). Sham-operated (n = 5) and Goldblatt (n = 8) rats not receiving captopril were prepared for comparisons of plasma renin activity and systolic blood pressure. Indomethacin (20 mg/kg/day subcutaneously) was administered for 48 hours concomitantly with captopril to the rats in group I. In group II, systolic blood pressure was monitored for 7 weeks after cessation of captopril. Continual captopril administration to Goldblatt rats completely prevented the rise in systolic blood pressure, a rise that was observed in Goldblatt rats not receiving captopril. Whereas systolic blood pressure of captopril-treated rats approximated 100 mm Hg throughout the study, that of Goldblatt rats not receiving the drug increased to nearly 180 mm Hg within 6 weeks after clipping. Systolic blood pressure of sham-operated rats remained normal. Indomethacin did not change systolic blood pressure in the drug-treated rats in group I. On cessation of captopril therapy in group II, systolic blood pressure increased gradually in a manner that paralleled the development of the disease in the Goldblatt rats that did not receive captopril. Plasma renin activity was determined in Goldblatt and sham-operated rats at either 16 weeks (group I) or 24 weeks (group II) after clipping; the rats from either group with mild hypertension (systolic blood pressure less than 180 mm Hg) had normal plasma renin activity whereas those with severe hypertension (systolic blood pressure greater than 180 mm Hg) had greatly elevated plasma renin activity. In summary, captopril can completely prevent the increase in systolic blood pressure for up to 24 weeks in Goldblatt rats, and this hypotensive effect is not mediated by the prostaglandins. It is concluded that the renin-angiotensin system is a necessary component of the hypertensive process in this experimental model.

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

Summary: 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 moeity 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. Renal impairment has no effect on fosinoprils ACE inhibitory effect, a property that may be desirable during renal disease.

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

Summary: 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. Zofenoprils effects were longer lasting. A combination of zofenopril and hydrochlorothiazide lowered pressure more (34 mm Hg) than zofenopril alone (20 mm Hg) in SHR. In two-kidney, one-clip renal hypertensive rats, zofenopril was more effective than captopril as an antihypertensive and again zofenoprils effects lasted longer. In anesthetized dogs, zofenopril had no effect on catecholamine-induced pressor responses or reflex changes in blood pressure and heart rate during head-up tilting or bilateral carotid artery occlusion. It is concluded that zofenopril is an effective and long lasting inhibitor of ACE in rats, dogs, and monkeys and an effective antihypertensive agent in rats.

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

Summary: 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 μmol/kg) bolus plus 0.1 mg/kg/min (0.22 μmol/kg/min)], the active moiety of the prodrug fosinopril, increased PAH clearance and GFR by 25 and 16%, respectively (p < 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 μmol/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 < 0.05, each). When given orally to SHR at 10 and 30 mg/kg (5.9 and 17.6 μmol/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 μmol/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 μmol/kg), and from 205 ± 7 to 145 ± 7 mm Hg after 30 mg/kg (17.6 μmol/kg). In DOCA/Salt hypertensive rats, AP fell by only 11 mm Hg after 30 mg/kg (17.6 μmol/kg), a fall that was not statistically different from vehicle-treated DOCA/Salt rats (−9 mm Hg). Finally, in a high renin model of primate hypertension (bilateral perinephritis), fosinopril [15 μmol/kg (8.8 mg/kg) p.o.] lowered AP from 148 ± 3 to 117 ± 5 mm Hg (p < 0.05). It is concluded that fosinopril is an effective blood pressure lowering agent in hypertensive and sodium-depleted monkeys and several experimental murine models of hypertension. Fosinopril also increased renal hemodynamic function in normotensive, conscious, sodium-replete dogs.

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

Summary: 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 μmol/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 μmol/kg) administration. In rats, the duration of ceranaprils inhibition of an AI pressor response was longer than an equimolar dose of captopril. Similarly, in SHR, ceranaprils blood pressure lowering effect had a longer duration than that of captopril. Ceranaprils 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 μmol/kg resulted in significant blood pressure lowering that lasted 24 h. Oral doses of 2.3, 6.8, 23, and 68 μmol/kg in two-kidney, one-clip hypertensive rats resulted in significant and dose-related falls in arterial pressure, which again persisted for 24 h. Finally, in two-kidney perinephritic hypertensive monkeys, 15 μmol/kg of p.o. ceranapril lowered arterial pressure from 152 ± 15 to 80 ± 12 mm Hg. It is concluded that ceranapril is an effective inhibitor of ACE, although its in vivo potency is species dependent.

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.

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.

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.

Pharmacology of novel imidazole alcohol inhibitors of primate renin.

SQ 30774 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 or 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 1.0μmol/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 10μmol/kg or when the compounds were administered by infusion. In sodium-replete monkeys, SQ 30774 inhibited the rise in arterial pressure and PRA following administration of exogenous monkey renin. When the compounds were administered orally at 50μmol/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.

Chapter 6. Antihypertensive Agents

Publisher Summary Cardiovascular disease accounts for more expenditures on health care than any other diagnostic category and hypertension is the most prevalent cardiovascular condition. While unit costs for hypertension treatment are low, aggregate costs are enormous because of the large and growing population of patients who are treated. Pharmacologic therapy of hypertension decreases the overall cardiovascular morbidity and mortality but fails to show a clear reduction in the risk of coronary heart disease (CHD). Although many explanations have been offered for the lack of demonstrated benefit for CHD, the hypothesis that has been under continued focus involves the unfavorable metabolic and biochemical changes caused by diuretics or β-adrenoceptor antagonists devoid of intrinsic sympathomimetic activity. These drugs are used in majority of the hypertensive clinical trials and adversely affect many of the known risk factors for CHD, including hyperlipidemia, hyperglycemia, and elevated plasma catecholamine levels. These potentially deleterious changes might have offset expected benefits of blood pressure reduction. As CHD is still the primary cause of death, long-acting calcium entry blockers, angiotens in converting enzyme (ACE) inhibitors, α 1 -adrenoceptor antagonists and centrally acting α 2 -adrenoceptor agonists, which have less negative impact on the risk factors, continue to gain support as alternate choices for first-line therapy. Proponents of the traditional drugs argue that diuretics and beta-blockers have been shown to reduce the cardiovascular morbidity and mortality in long-term clinical trials and that the lower doses of diuretics now used may not have persistent adverse effects on serum lipids.