We examined the mechanisms mediating hypertension in conscious rats during acute and chronic infusion of angiotensin II (ANG II) at pressor doses (50, 100, and 200 ng.kg-1.min-1). Trimethaphan-induced blood pressure reduction was inversely related to the acute dose of ANG II, consistent with a constrictor action of ANG II on vascular smooth muscle and withdrawal of sympathetic tone. During chronic ANG II infusion, the entire increase in mean arterial pressure (MAP) was inhibited by trimethaphan, consistent with neural mediation. During acute ANG II hypertension, the AT1-specific receptor blocker losartan induced a large fall in MAP (64 +/- 4 mmHg) in ganglion-blocked (chlorisondamine) rats, whereas, during chronic ANG II hypertension, losartan had only a small hypotensive effect (11 +/- 3 mmHg). To determine the time course of the change from vascular smooth muscle action to neural action, we measured MAP in response to trimethaphan during the first 24 h of ANG II infusion. After 5 h, the minimal MAP in response to trimethaphan was significantly higher than that before ANG II. After 10 h of infusion, trimethaphan decreased MAP to pre-ANG II levels. That is, the neural component was fully active after only 10 h of infusion in rats. Finally, chronic administration of ANG II resulted in a dose-related increase in MAP that, at all doses, was completely inhibited by trimethaphan. These findings are consistent with ANG II acting primarily on vascular smooth muscle during acute infusion and via neural pathways during chronic treatment. The transition from direct smooth muscle to indirect neural action is rapid in rats (< 10 h), and the MAP and neural responses to ANG II are dose related during chronic hypertension.
Membranes from rabbit aorta and from rabbit and rat kidney cortex possess high-affinity (Kd = 10-10 M) specific binding sites for atrial natriuretic factor (ANF). Similar high-affinity sites are present in an established cell line from pig kidney, LLC-PK,. Results of fractionation studies indicate that the receptors are localized in the plasma membrane of these tissues. The binding is time-dependent and saturable. An excellent quantitative correlation was found between the affinity of synthetic ANF and analogs of intermediate activity to aorta membranes and the half-maximal concentration needed for relaxation of rabbit aorta rings contracted by addition of serotonin. Furthermore, the binding affinity of the receptor in kidney membranes is consistent with the concentration required for in vivo natriuresis in the rat. Biologically inactive synthetic ANF fragments and other peptide hormones such as angiotensin II and vasopressin do not significantly inhibit binding. These data suggest that the receptors for ANF in vascular and renal tissues are responsible for mediating the physiological actions of this peptide in these target tissues.A possible role for the cardiac atria in the regulation of extracellular fluid volume and electrolyte concentration has been shown by the induction of sodium and water excretion in response to changes in intraatrial pressure and stretch of the atrial wall (1). The cardiac atria possess granules that have the appearance of secretory granules (2-4) and whose number can be altered by manipulation of the water-electrolyte balance in experimental animals (5). Crude extracts of atria from several species have been shown to possess potent diuretic and natriuretic activity when given intravenously to rats (6). Subcellular fractionation (7) and immunocytochemistry (8) indicated that these granules are storage sites for an atrial natriuretic factor (ANF). Furthermore, in vitro, atrial extracts were shown to be potent vasorelaxants (9-14). As little as 0.0006 atrial equivalent per milliliter gave 50% relaxation of precontracted aorta tissues (12). In vivo, ANF caused lowering of mean arterial blood pressure in normal and hypertensive animals (6,15,16). Recently, a family of peptides has been isolated from acidic extracts of rat (10,11,(19)(20)(21)(22) and human (23) atria and sequenced independently by several laboratories. From rat atria, the longest peptide that has been reported contains 33 amino acids, 1, and was isolated as the free COOH-terminal tyrosine acid (20,21). Shorter rat ANF peptides are truncated at either the NH2 or COOH terminus.5 10 H-Leu -Ala-Gly-Pro -Arg-Ser -Leu-Arg-Arg-Ser-Ser-15 20Cys-Phe-Gly-Gly-Arg-Ile -Asp-Arg-Ile -Gly-Ala--30Gln -Ser-Gly-Leu-Gly-Cys -Asn-Ser-Phe-Arg-Tyr-OH 1 A peptide consisting of residues 8-33, designated sANF, has been synthesized (21, 24) and shown to possess full biological activity (12,16,21,24). The IC50 of sANF for relaxation of precontracted rabbit aorta rings is 550 pM (12). The amount of sANF required for half-maximal natriuresis wh...
The proteolytic enzyme renin (EC3.4.99.19) cleaves the protein substrate angiotensinogen to yield angiotensin I, the decapeptide substrate transformed by converting enzyme into the pressor substance angiotensin II. Although the contribution of this pathway to the maintenance of normal blood pressure is unclear, it seems to be a major factor in various hypertensive states. Important progress in the control of hypertension has been achieved by development of the potent inhibitors SQ-14,225 (captopril) and MK-421 (enalapril maleate), which block the generation of angiotensin II by the inhibition of angiotensin converting enzyme. An attractive alternative to the inhibition of converting enzyme would be the blockade of the preceding step in the cascade, the renin reaction. We report here new highly potent (IC50 = 10(-9)-10(-8) M) competitive inhibitors of renin in which statine, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, is incorporated into analogues of the pig renin substrate (Fig. 1).
To investigate the mechanism by which angiotensin-converting enzyme (ACE) inhibition attenuates atherogenesis, we have studied the effects of a nonsulfhydryl ACE inhibitor, enalapril, and an angiotensin receptor antagonist, SC-51316, in cholesterol-fed rabbits. After 3 mo of enalapril treatment (10 mg/kg per d, p.o.) the percent plaque areas in the thoracic aortas of treated animals were significantly reduced (controls: 86.8±3.5%; treated: 31.1±8%, P < 0.001). Aortic cholesterol content was also reduced (controls: 31.4±3.2 mg/g tissue; treated: 7.4±1.8 mg/g, P < 0.001). Enalapril had no significant effect on plasma lipid levels or conscious blood pressure. In a second study, the angiotensin II receptor antagonist SC-51316 was administered at a dose equivalent to enalapril at blocking angiotensin pressor effects in vivo (30 mg/kg per d, p.o.). Evaluation after 3 mo indicated no significant attenuation of aortic atherosclerosis. These results demonstrate that: (a) enalapril attenuates atherogenesis without affecting either blood pressure or plasma lipid levels; (b) antioxidant activity, found with sulfhydryl-containing ACE inhibitors, is not necessary for reducing plaque formation; and (c) the attenuation of atherogenesis by ACE inhibition may not be due to blockade of the renin-angiotensin system. Alternatively, one must consider the multiple effects of ACE inhibition on other hormone systems, such as bradykinin, or the possibility that alternate angiotensin II receptors may be involved in atherosclerosis. (J. Clin.
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