Plasma angiotensins and blood pressure during converting enzyme inhibition.

Abstract

The relationship between plasma angiotensin and the reduction of blood pressure with the angiotensin converting enzyme inhibitor enalapril was studied in rats. Blood pressure was measured in conscious rats with indwelling arterial catheters. To measure angiotensin II, plasma was analyzed by physical separation of angiotensins using high performance liquid chromatography followed by radioimmunoassay. The effects of both single (acute) and long-term (chronic) dosages of enalapril were measured. After a single oral dose of enalapril (10 mg/kg), mean arterial pressure fell from 111 ± 3 to 86 ± 3 nun Hg (p<0.005). Despite the blood pressure reduction, plasma angiotensin II was unaffected (control, 9.9 ± 1.8 vs 9.7 ±1.1 pg/ml). After a higher single oral dose of enalapril (30 mg/kg), there was a reduction in both mean arterial pressure (81 ± 5 mm Hg, p<0.005) and plasma angiotensin II concentration (2.3 ± 0.6 pg/ml, p<0.01). The chronic effects of converting enzyme inhibition were evaluated in rats given enalapril in their drinking water (30 mg/kg/24 hr) for 1 week or 2 months. Mean arterial pressure remained equally low after chronic administration (for 1 week or 2 months), but plasma angiotensin II increased above normal (after 1 week, 28.9 ±8.7, p<0.01 vs control; after 2 months, 43.1 ± 16.2 pg/ml, p< 0.05 vs control). Although plasma angiotensin converting enzyme activity was undetectable at any time after enalapril administration, there was a partial return of the angiotensin I pressor response with chronic administration. The data are most compatible with actions of converting enzyme inhibitors independent of the blockade of plasma angiotensin II formation. (Hypertension 9 [Suppl III]: III-42- III-48, 1987) KEY WORDS • angiotensin II • converting enzyme inhibition • high performance liquid chromatography • radioimmunoassay • enalapril A NGIOTENSIN converting enzyme (ACE) in-/ \ hibitors were designed to lower blood pres-A. V . sure by blocking the formation of the potent vasopressor, angiotensin II (ANG II). 1 -2 Evidence from many studies seems to confirm this mechanism of ACE inhibitor action. The acute administration of ACE inhibitors lowers blood pressure, decreases levels of immunoreactive ANG II in plasma, 3 " 5 and prevents blood pressure rise in the two-kidney, one clip Goldblatt model. 6 Several recent observations suggest that the mechanism of action of ACE inhibitors is more complex than

Chymase-dependent angiotensin II formation in human blood vessels

“…14 Another enzyme present in mast cells is the metalloprotease, carboxypeptidase A enzyme. This enzyme cleaves the His 9 -Leu 10 bond in angiotensin I and as a result generates the fragment angiotensin [1][2][3][4][5][6][7][8][9] , which although capable of inhibiting ACE, has no known intrinsic contractile activity. 26 The human heart has been shown to possess carboxypeptidase A activity, generation of angiotensin [1][2][3][4][5][6][7][8][9] by this enzyme is sufficient to block cardiac ACE.…”

“…This enzyme cleaves the His 9 -Leu 10 bond in angiotensin I and as a result generates the fragment angiotensin [1][2][3][4][5][6][7][8][9] , which although capable of inhibiting ACE, has no known intrinsic contractile activity. 26 The human heart has been shown to possess carboxypeptidase A activity, generation of angiotensin [1][2][3][4][5][6][7][8][9] by this enzyme is sufficient to block cardiac ACE. 27 It is undetermined if human blood vessels also exhibit cardoxypeptidase A activity, or if endogenous local ACE activity in the vessel wall is regulated by the synthesis of angiotensin [1][2][3][4][5][6][7][8][9] .…”

“…26 The human heart has been shown to possess carboxypeptidase A activity, generation of angiotensin [1][2][3][4][5][6][7][8][9] by this enzyme is sufficient to block cardiac ACE. 27 It is undetermined if human blood vessels also exhibit cardoxypeptidase A activity, or if endogenous local ACE activity in the vessel wall is regulated by the synthesis of angiotensin [1][2][3][4][5][6][7][8][9] . Other angiotensin fragments may be generated by the action of neutral endopeptidase 24.11 and propyl-endopeptidase 24.26.…”

“…28 Both of these enzymes are capable of forming angiotensin 1-7 from angiotensin I. It has been shown that angiotensin [1][2][3][4][5][6][7] possesses the ability to stimulate the release of vasodilator prostanoids and nitric oxide, as well as inhibiting proliferation of vascular smooth muscle cells in balloon injured carotid arteries and rat aorta. [29][30][31] Angiotensin II may also be generated via the action of tonin.…”

“…However, angiotensin II levels have been shown to return to pre-treatment levels following chronic ACE inhibitor therapy, and reductions in blood pressure greater than those observed with ACE inhibitors alone can be obtained by co-administration of angiotensin receptor antagonists with an ACE inhibitor. 5,6 In addition, increases in plasma angiotensin II following exercise or during ischaemic conditions could not be prevented by an ACE inhibitor. 7,8 The concept of alternative pathways for angiotensin II formation is supported by a number of in vivo and in vitro experiments.…”