ACE inhibitors and myocardial infarction.
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Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
H Gavras
Publications and source records attributed to H Gavras.
Contribution of vasopressin to orthostatic blood pressure maintenance in essential hypertension.
Arginine vasopressin (AVP) has been found to participate in blood pressure maintenance especially when other pressor systems are endogenously or pharmacologically impaired. The purpose of this study was to assess the pressor contribution of AVP to orthostatic blood pressure maintenance in otherwise healthy patients with essential hypertension. Twenty-seven patients were grouped according to age (young n = 13, elderly n = 14) and race (white n = 13, black n = 14). Integrity of autonomic nervous system (ANS) was assessed by Valsalva's maneuver, cold pressor test and head-up tilt. AVP contribution to blood pressure was estimated by the fall in mean arterial pressure in response to IV injection of 0.5 mg of a V1 AVP inhibitor (AVPi). Elderly subjects were found to have a mild (subclinical) ANS impairment as indicated by absence of bradycardia in phase 4 of Valsalva's maneuver and hypotension without concurrent tachycardia during head up tilt. Depressor responses to AVPi while subjects were in the upright position, were greater in elderly and blacks (-15 +/- 11 mm Hg and -15 +/- 12 mm Hg, respectively, P < .05) than young and whites (-8 +/- 6 and -7 +/- 6 mm Hg, respectively, ns). The greater importance of the AVP component in the elderly may be at least partially explained by a mild ANS impairement, whereas hormonal characteristics of hypertension in blacks may explain greater AVPi induced fall in mean arterial pressure. Our data show that both age and race influence the response to AVPi.
Adult↗
Diverse tissue expression of rat alpha 2-adrenergic receptor genes.
Previously, we have reported two major alpha 2-adrenergic receptor transcripts in rat brain of 3.8 and 3.0 kb and the cloning and characterization of the rat brain complementary DNA (cDNA) (RB alpha 2C) specific for the 3.0-kb messenger RNA. In this report, we used rat brain cDNAs specific for the 3.0 and 3.8 kb transcripts, which encode the alpha 2C- and alpha 2A-adrenergic receptors, respectively, and the RNG alpha 2 cDNA, which encodes for the nonglycosylated alpha 2B-adrenergic receptor in rat, to study tissue-specific expression of the three alpha 2-adrenergic receptor genes in rat. To eliminate cross-hybridization of probes with transcripts from other alpha 2 genes, we subcloned fragments that encode for the highly divergent third cytoplasmic loop of each rat alpha 2-adrenergic receptor cDNA and used RNase protection analysis to detect specific transcripts. We show that the three rat alpha 2-adrenergic receptor genes have diverse patterns of tissue expression, and although transcripts specific for each alpha 2-adrenergic receptor gene are found in brain and kidney, the levels of expression of each subtype differ in these tissues. We speculate on the significance of tissue-specific expression of the alpha 2-adrenergic receptor genes.
Animals↗
Pressor hormone profile during stress in hypertension: does vasopressin interfere with left ventricular hypertrophy?
Neurohormonal factors may account for the fact that patients with similar severity and duration of hypertension develop different degrees of left ventricular hypertrophy (LVH). The purpose of this work was to compare the pressor hormone profiles of hypertensive subjects off medication during exercise testing. Nineteen patients, stratified according to echocardiographically diagnosed absence (Group I n = 6) or presence (Group II n = 13) of LVH, underwent testing on the treadmill according to the Bruce protocol. Both groups were comparable in age, severity and duration of hypertension and reached similar double product at peak exercise. Measurements of plasma renin activity (PRA), plasma catecholamines and vasopressin (AVP) at baseline, peak exercise and post exercise revealed significant differences between groups: Group I had suppressed PRA levels throughout and had significantly higher baseline AVP levels, which increased further at peak effort. Group II had significantly higher baseline PRA levels, which tended to increase further at peak effort, and had suppressed AVP levels throughout. There was a significant negative correlation between percent increments in AVP and increments in double product. Norepinephrine increased significantly with effort in both groups, but the levels attained were higher in Group I. In view of the known negative inotropic action of AVP and the trophic effect of angiotensin, we speculate that lower baseline AVP and higher PRA, together with inability of AVP to increase with effort, may be causally related to development of LVH.
Adult↗
Long-range safety and protective benefits of angiotensin-converting enzyme inhibitors for hypertension. Do we need more clinical trials?
Inhibition of the renin-angiotensin system is being applied with considerable success to the treatment of hypertension and heart failure. Angiotensin-converting enzyme (ACE) inhibitors are the only currently available agents that can achieve this objective. In general, the major therapeutic effects of these agents in the treatment of mild to moderate hypertension or of heart failure are exerted on the vascular tissue through inhibition of the renin-angiotensin system and, secondarily, of the sympathetic nervous system. When cardiovascular functional reserve is diminished and autoregulation of regional and systemic blood flow is strained, however, ACE inhibitors may affect other organ functions (heart, kidneys, and possibly brain), hormones other than the renin system, and local tissue humoral systems. The interrelations between the renin-angiotensin system and several other vasoactive systems--including circulating and locally generated tissue hormones and centrally acting neurohormonal factors--are complex and unclear. A better understanding of these mechanisms and interrelations would allow for a more rational therapeutic use of these agents. Unknown also are the clinical effects of prolonged ACE inhibition. Whether the use of ACE inhibitors can provide primary cardiorenal protection requires proof through definitive clinical trials.
Angiotensin-Converting Enzyme Inhibitors↗
Promoter region of the human alpha 2A adrenergic receptor gene.
In order to locate the promoter region of the human alpha 2A adrenergic receptor gene we used RNase protection analysis and antisense RNA probes to map the cap site of the alpha 2 transcripts. Prior sequence analysis has shown two potential TATA box motifs in the human alpha 2A adrenergic receptor gene, TATATAT and TATAAAA, located 427 and 1037 base pairs (bp), respectively, upstream of the protein coding region. RNase protection experiments and primer extension show that transcription starts downstream of the distal TATAAAA, indicating that the 5'-untranslated region is approximately 1 kilobase in length. We have used the chloramphenicol acetyltransferase reporter gene and transient transfection into HT29, a human adenocarcinoma cell line that expresses the alpha 2A receptor, to show that as little as 150 bp upstream of the cap site can direct transcription. Sequence analysis shows that although this region contains the TATA box motif it lacks a CCAAT box motif. DNase I footprint analysis of a fragment from -17 to -193 (where +1 is the transcription initiation site), using nuclear extracts from HT29, showed hypersensitive sites (-68/-69) and two protected regions: -70 to -87, which includes a 10-bp palindrome, and -92 to -105, which includes a GC box, a common motif for Sp1 nuclear factor binding. Gel mobility shift assays indicate that Sp1 or a related factor may bind to this GC box. Deletion of the GC box and the palindrome from chloramphenicol acetyltransferase constructs abolishes transcription. We propose that these cis sequences may function in lieu of a CCAAT box to regulate transcription of the human alpha 2A adrenergic receptor gene.
Adenocarcinoma↗
Oral milrinone in severe chronic heart failure.
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Angiotensin-Converting Enzyme Inhibitors↗
Inhibition of nitric oxide, bradykinin, and prostaglandins in normal rats.
We assessed the vasodilator effect of endothelium-derived nitric oxide by inhibiting its formation with NG-monomethyl L-arginine (LNMMA) on systemic and regional hemodynamics in conscious, normotensive rats, using the radioactive microsphere technique. In rats injected with 10 mg/kg LNMMA (n = 8), mean blood pressure increased by 16.2 +/- 2.6 mm Hg, and heart rate decreased by 54.3 +/- 16.7 beats per minute. In comparison with rats injected with 5% dextrose (n = 14), cardiac index was lower by 35.6% (p less than 0.01), and total peripheral vascular resistance was higher by 51.6% (p less than 0.01); regional blood flows were lower and vascular resistance higher in most organs. Changes were significant in the heart, kidney, stomach, large intestine, skin, and adrenals (p less than 0.05). Preinjection of 100 mg/kg L-arginine prevented the pressor response but only partially attenuated the other hemodynamic effects of LNMMA. Combination of LNMMA with the bradykinin antagonist (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg)trifluoroacetic acid (50 micrograms/min for 5 minutes) did not produce systemic or regional effects different from those obtained with LNMMA alone. Combination of LNMMA with indomethacin (10 mg/kg) resulted in additional changes in the cerebral circulation, blood flow decreasing by an additional 44.2% (p less than 0.01) and vascular resistance increasing by 75.3% (p less than 0.01) compared with changes produced by LNMMA alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Comparison of systemic and regional hemodynamic effects of a diuretic, an angiotensin II receptor antagonist, and an angiotensin-converting enzyme inhibitor in conscious renovascular hypertensive rats.
The present experiments were designed to compare the antihypertensive action and the systemic and regional hemodynamic effects of a diuretic (furosemide), an angiotensin II (AngII) receptor blocker (Dup 753), and an angiotensin converting enzyme (ACE) inhibitor (enalapril) in conscious, two-kidney, one-clip renovascular hypertensive rats by the radioactive microsphere technique. Measurements were done 3 hours after a single dose treatment. Furosemide (20 mg/kg) produced a marked diuresis and tachycardia with no change in blood pressure; in comparison with control rats, furosemide-treated rats had total peripheral vascular resistance increased by 46.55% (p less than 0.01) and local vascular resistance increased in most organs, to a significant degree in the spleen, muscle, stomach, intestine, and skin (p less than 0.05 to 0.01). Dup 753 (20 mg/kg) and enalapril (10 mg/kg) decreased mean blood pressure by 41.89 +/- 7.17 mm Hg and 47.13 +/- 8.67 mm Hg, respectively (p less than 0.01), with tachycardia only in the Dup 753 group. Total peripheral and local vascular resistances in several tissues were significantly lower in both the Dup 753 and enalapril groups than in the furosemide group. In particular, both antiangiotensin agents, in contrast to furosemide, produced significant decrease in renal vascular resistance by 42.28% and 38.81%, respectively (p less than 0.01), with a tendency to increase the renal blood flow (of the intact kidney). No detectable differences were found in systemic and regional hemodynamic changes between the Dup 753 and enalapril group.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cloning and expression of a rat brain alpha 2B-adrenergic receptor.
We have isolated a cDNA clone (RB alpha 2B) and its homologous gene (GR alpha 2B) encoding an alpha 2B-adrenergic receptor subtype by screening a rat brain cDNA and a rat genomic library. Nucleotide sequence analysis showed that both clones code for a protein of 458 amino acids, which is 87% homologous to the human kidney glycosylated adrenergic receptor (alpha 2-C4) and divergent from the rat kidney nonglycosylated alpha 2B subtype (RNG alpha 2). Transient expression of RB alpha 2B in COS-7 cells resulted in high-affinity saturable binding (Kd = 0.25 nM) for [3H]rauwolscine and a high receptor number (Bmax = 7.7 pmol/mg of protein) in the membranes of transfected COS-7 cells. Pharmacological analysis demonstrated that the expressed receptor bound adrenergic ligands with the following order of potency: rauwolscine greater than yohimbine greater than prazosin greater than oxymetazoline, with a prazosin-to-oxymetazoline Ki ratio of 0.34. This profile is characteristic of the alpha 2B-adrenergic receptor subtype. Blotting analysis of rat brain mRNA gave one major (3.0-kilobase) and two minor (4.6- and 2.3-kilobase) mRNA species, and hybridization with strand-specific probes showed that both DNA strands of GR alpha 2B may be transcriptionally active. These findings show that rat brain expresses an alpha 2B-adrenergic receptor subtype that is structurally different from the rat kidney nonglycosylated alpha 2B subtype. Thus the rat expresses at least two divergent alpha 2B-adrenergic receptors.
Amino Acid Sequence↗
Cardioprotective potential of angiotensin converting enzyme inhibitors.
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Angiotensin-Converting Enzyme Inhibitors↗
Effects of bradykinin and prostaglandin inhibition on systemic and regional hemodynamics in conscious normotensive rats.
These experiments were designed to study the effects of inhibition of endogenous bradykinin and/or prostaglandins on systemic and regional hemodynamics in conscious normotensive rats, using the radioactive microsphere technique. Administration of either a bradykinin antagonist (50 micrograms/min for 5 min) or indomethacin (10 mg/kg) alone, decreased the cardiac output by an average of 17.58 and 25.94%, respectively (P less than 0.05), without significant change in total peripheral resistance. Regional blood flow decreased and local vascular resistance increased in most organs. Coronary and renal blood flow decreased by an average of 16.45 and 17.26% with bradykinin antagonist and 23.85 and 19.80% with indomethacin, respectively (P less than 0.05). Indomethacin but not bradykinin antagonist also decreased cerebral blood flow by an average of 47.57% (P less than 0.01). Infusion of the bradykinin antagonist following prior prostaglandin inhibition with indomethacin did not induce further changes in either systemic or regional hemodynamics, except in the liver where a significant additional increment in vascular resistance was observed. Our data suggest that most organs have similar patterns of regional vascular sensitivity to bradykinin and prostaglandins (including the heart, kidney, testis, stomach, skin and adrenal). The major differences were in the cerebral vasculature, which was much more sensitive to prostaglandins, and in the liver, spleen and small intestine, which were more sensitive to bradykinin. We conclude that both hormonal systems participate to a varying extent in the maintenance of resting vascular tone in most organs; however, in some cases, their effects may be additive and in others they may work in opposite directions.
Animals↗
Angiotensin converting enzyme inhibitors.
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Angiotensin-Converting Enzyme Inhibitors↗
A novel bradykinin antagonist with improved properties.
Acylation of the N-terminus of [D-Arg0, Hyp3, Thi5,8, D-Phe7] bradykinin with 1-adamantanecarboxylic acid results in an analogue with enhanced potency of at least 33-fold. The new antagonist has potential as a pharmacological tool in the investigation of the role of endogenous bradykinin in cardiovascular regulation.
Adamantane↗
Two highly effective V1/V2 antagonists of vasopressin containing novel thioacids at position 1.
In an attempt to develop more effective and selective V1/V2 antagonists of arginine vasopressin (AVP), two analogues have been designed and synthesized. In position 1 they contain thioacids that include a heteroatom in the cyclohexane ring. The 4-thio-4-tetrahydrothiopyraneacetic acid modification of position 1 used in one of them had advantages over the 1-mercaptocyclohexaneacetic acid substituted compound used as reference. The new compound was weaker at lower doses, but elicited a greater response at higher doses, whereas the reference compound reached its plateau earlier. Although the 4-thio-4-tetrahydropyraneacetic acid substitution used in the second compound resulted in a less potent analogue on a weight basis, this substitution also confers enhanced overall efficacy in terms of magnitude of effect.
Animals↗
Gene expression of catecholaminergic receptors in the central nervous system of hypertensive rats.
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Animals↗
Effects of chronic administration of a vasopressin antagonist with combined antivasopressor and antiantidiuretic activities in rats with left ventricular dysfunction.
The present experiments were designed to study the long-term aquaretic effect of [d(CH2)5-D-Tyr(Et)VAVP], an antagonist to arginine vasopressin (AVP) with combined vascular (V1) and renal (V2) receptor inhibiting properties, in rats with left ventricular dysfunction resulting from myocardial infarction (MI). The continuous intravenous infusion of the AVP antagonist (36 micrograms/12 microliters/day) via osmotic minipumps over 11 days resulted in an increase in urine volume and a decrease in urinary osmolality by approximately 10-fold on the first day, but in subsequent days this response decreased in both the post-MI (n = 7) and normal (n = 6) rats. Nevertheless, the daily urine volume remained significantly higher and the urinary osmolality lower in the post-MI rats than in the normal ones throughout the study (p less than 0.05). In two other groups of post-MI (n = 5) and normal (n = 6) rats, intermittent intraperitoneal injections of the AVP antagonist (100 micrograms/kg) every third day resulted in a profound diuresis that was reproducible by each injection and was again significantly greater in the post-MI rats than in the normal rats (p less than 0.05). The cumulative urinary output over the first 10-day period of each treatment was greater with intermittent injections than with continuous infusion in both the post-MI and normal rats, but the difference was significant only in the post-MI rats (398.82 +/- 12.87 ml vs 309.07 +/- 32.44 ml, intermittent vs continuous, respectively, p less than 0.05), even though the cumulative dose of AVP antagonist given intermittently was only about one third of that given continuously.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cardioprotective potential of angiotensin-converting enzyme inhibitors.
Antihypertensive drugs have various effects, both positive and negative, on metabolic and hemodynamic risk factors for coronary artery disease. Cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors have recently been described. The benefits of ACE inhibition include not only a reduction in blood pressure but also improved insulin responsiveness, prevention of potassium loss, diminished myocardial oxygen demand, suppression of catecholamines, and interaction with bradykinin and prostaglandins. These benefits result in improved perfusion of vital organs, diminished cardiac work, and protection of coronary vessels, evident in improved left ventricular systolic and diastolic function, elevation of the anginal threshold in ischemic heart disease, and decreased morbidity and mortality in congestive heart failure.
Angiotensin-Converting Enzyme Inhibitors↗