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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The converting enzyme inhibitors (CEI) SA446 and Captopril (CAP) were given orally at a dose of 50 mg/kg per day to adult stroke-prone spontaneously hypertensive rats (SHRSP) over a period of four weeks. Both CEI lowered arterial blood pressure (BP) to a similar extent. CAP was more inhibitory on the plasma renin-angiotensin system (RAS) than SA446. Both CEI lowered urinary aldosterone excretion but had little (SA446) or no (CAP) natriuretic effect. CAP reduced the pressor responses to intravenous (i.v.) angiotensin I (ANG I) more (52%) than SA446 (18%) and potentiated the depressor responses to i.v. bradykinin more (fortyfold) than SA446 (tenfold). In contrast, SA446 treatment reduced the pressor responses to intracerebroventricular (i.c.v.) ANG I by 21% and led to a rise in the hypothalamic renin concentration. Oral CAP treatment for four weeks did not produce these signs of a brain converting enzyme inhibition. It is concluded that SA446 is equally as antihypertensive as CAP in SHRSP. SA446 appears to penetrate more readily into the brain and to exert its action partly through inhibition of the brain RAS which is known to be stimulated in SHRSP.
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PMID:SA446, a new orally active converting enzyme inhibitor: antihypertensive action and comparison with captopril in stroke-prone spontaneously hypersensitive rats. 628 Oct 36

Angiotensin II (ANG II)-sensitive septal neurons in the brain of stroke-prone spontaneously hypertensive rats (SHR-sp) and of normotensive Wistar-Kyoto rats (WKY) were investigated for possible differences at receptor sites. ANG II, the competitive ANG II-antagonist saralasin, and acetylcholine (ACh), were applied microiontophoretically onto neurons of the lateral septal area. ANG II-evoked neuronal firing which was specifically inhibited by saralasin occurred at a significant lower threshold in SHR-sp (23%) and showed an extended postactivity (340%) as compared to the age-matched WKY controls. In contrast, the activity due to ACh remained similar in both strains.
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PMID:Increased sensitivity of neurons to angiotensin II in SHR as compared to WKY rats. 629 59

Evidence has accumulated that systemic administration of converting enzyme inhibitors (CEI) such as captopril, MK 421 or SA 446 not only produces an inhibition of the plasma renin angiotensin system (RAS), but also of the RAS in various target organs which are relevant for blood pressure (BP) regulation. A potential target organ is the brain, where a local CE inhibition could contribute to the BP lowering action of CEI. CE in the brain can be inhibited by intracerebroventricular (i.c.v.) injection of CEI as evidenced by an inhibition of the pressor and drinking responses to i.c.v. angiotensin I (ANG I) or renin and by potentiation of the pressor responses to i.c.v. bradykinin. Site of the inhibition is not only the cerebrospinal fluid but also periventricular brain tissue such as the hypothalamus. I.c.v. injection of captopril at doses which inhibit brain CE but do not leak into the peripheral blood were shown to lower BP in conscious stroke-prone spontaneously hypertensive rats (SHRSP), but not in normotensive Wistar Kyoto (WKY) controls. Acute peripheral administration of CEI can produce an inhibition of brain CE. This was shown by an attenuation of the drinking responses to i.c.v. ANG I and renin and by direct measurements of CE activity in brain tissue. Chronic oral treatment with CEI produces changes of brain RAS parameters which suggest an inhibition of ANG II formation in the brain.
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PMID:Central effects of converting enzyme inhibitors. 631 70

Combined neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) inhibition produces greater acute hemodynamic effects than either treatment alone. We investigated whether BMS-182657 (BMS), which bears inhibitory activities against both NEP and ACE, elicited similar enhanced effects. BMS inhibited NEP and ACE, in vitro (IC50 = 6 and 12 nM, respectively) and the pressor response to Ang I in rats. In deoxycorticosterone acetate (DOCA)-salt hypertensive rats sensitive to NEP inhibition but not to ACE inhibition, BMS at 100 mumol/kg i.v. lowered mean arterial pressure (MAP) from 180 +/- 6 to 151 +/- 5 mm Hg. In sodium-depleted, spontaneously hypertensive rats (SHR) sensitive to ACE inhibition but not to NEP inhibition, BMS at 100 mumol/kg p.o. lowered MAP from 151 +/- 4 to 123 +/- 5 mm Hg. Cardiomyopathic hamsters with heart failure were administered vehicle or one of the following (30 mumol/kg i.v.): the ACE inhibitor enalaprilat; the NEP inhibitor SQ-28603; or BMS. Enalaprilat and SQ-28603 had minimal hemodynamic effects. BMS decreased left ventricular end-diastolic pressure by 12 +/- 2 and 10 +/- 1 mm Hg and left ventricular systolic pressure by 27 +/- 2 and 23 +/- 3 mm Hg at 30 and 60 min, respectively (P < .05 vs. each other group). These changes were associated with a 40% increase in cardiac output, a 47% decrease in peripheral vascular resistance and a lowering of MAP by 21 +/- 3 mm Hg at 60 min (P < .05 vs. each other group). There were no significant differences in the changes in heart rate or left ventricular stroke work index among the four groups. Hence, BMS-182657 is a dual inhibitor of NEP and ACE, is antihypertensive irrespective of the activity of the renin-angiotensin system and has acute hemodynamic effects in hamsters with heart failure greater than those produced by selective inhibition of NEP or ACE. The NEP and ACE inhibitory activities of BMS-182657 act synergistically and mimic the interaction resulting from combining selective inhibitors of these enzymes.
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PMID:Cardiovascular effects of the novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme BMS-182657 in experimental hypertension and heart failure. 747 62

Angiotensin II (Ang II) is the primary mediator of the renin-angiotensin system (RAS). Inappropriate control of the RAS is critically involved in the development and maintenance of hypertension and congestive heart failure. The actions of Ang II are thought to be mediated by specific surface receptors on the various target organs. At present, two receptors for Ang II have been firmly established in mammals, including man. According to current nomenclature, losartan represents the prototype antagonist of the Ang II type 1 (AT1) receptor and does not possess significant affinity for the so-called AT2 receptor. Losartan is the first of a new class of orally active, nonpeptide Ang II receptor antagonists able to very specifically and selectively inhibit the RAS while lacking the agonistic effects of the peptide receptor antagonists, e.g. sarlasin, or the bradykinin potentiating effects of the angiotensin converting enzyme (ACE) inhibitors. Virtually all of the known actions of Ang II, e.g. those defined by Ang II itself, saralasin, ACE or renin-inhibitors are blocked by losartan, emphasizing the major role of this distinct Ang II receptor subtype in mediating the responses of Ang II. The functional correlate of the AT2 receptor remains poorly understood. In several models of experimental and genetic hypertension, AT1 receptor antagonists are effective antihypertensive agents with similar efficacy to that of ACE and renin-inhibitors. In animal models of renal disease, AT1 receptor antagonists significantly decrease proteinuria, protect against diabetic glomerulopathy and increase survival in stroke-prone spontaneously hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A new class of therapeutic agents: the angiotensin II receptor antagonists. 763 3

The components of the renin-angiotensin system have been implicated in the development of primary hypertension in humans and genetically hypertensive rats. In humans a mutation in the angiotensinogen gene and elevated plasma angiotensinogen levels have been linked to primary hypertension. Although we had previously excluded a linkage of blood pressure to the angiotensinogen gene in the stroke-prone spontaneously hypertensive rat (SHRSP), elevated angiotensin II (Ang II) levels in this strain compared with the normotensive reference, the Wistar-Kyoto rat (WKY), prompted us to investigate further into the origins and effects of altered Ang II regulation using a range of physiological, biochemical, molecular, and genetic approaches. Ang II plasma levels determined by radioimmunoassay were confirmed to be significantly elevated in SHRSP compared with WKY. Sequence comparison among the two rat strains revealed a mutation in the coding region of the angiotensinogen gene that results in an isoleucine-to-valine substitution in SHRSP at amino acid position 154 (I154V). We performed a cosegregation analysis in an F2 intercross cohort bred from SHRSP and WKY from the University of Heidelberg (SHRSPHD and WKYHD) to address the following questions: (1) whether this or another mutation of the angiotensinogen gene may be casually related to the observed differential Ang II plasma levels, (2) whether Ang II plasma levels may be correlated with blood pressure or organ hypertrophy, and (3) whether genetic linkage to the renin or angiotensin-converting enzyme (ACE) gene loci (the two classic regulatory enzymes of the renin-angiotensin system) may provide an explanation for elevated Ang II plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered angiotensinogen amino acid sequence and plasma angiotensin II levels in genetically hypertensive rats. A study on cause and effect. 763 35

To investigate the effects of renal transplantation on the plasma and local kidney renin-angiotensin systems of the recipients the left kidneys of 13 adult male Wistar-Kyoto rats (WKY) and 13 stroke-prone spontaneously hypertensive rats (SHRSP) were transplanted to bilaterally nephrectomized (WKYxSHRSP)-F1 hybrids. Nine unilaterally nephrectomized WKY and nine SHRSP served as controls. Four weeks after surgery recipients of an SHRSP kidney but not recipients of a WKY kidney had significant post-transplantation hypertension. Plasma renin activity (PRA) was higher in SHRSP than in WKY. Transplanted rats had lower PRAs than nontransplanted controls. Plasma ACE activity was lowest in SHRSP, intermediate in transplanted F1 hybrids and highest in WKY. Plasma Ang I and Ang II concentrations closely paralleled each other. They were not significantly different between WKY and SHRSP and lower in transplanted than in nontransplanted rats. ACE and renin mRNA were lower in transplanted than in nontransplanted kidneys. Glomerular angiotensin II receptor density was higher in transplanted than in nontransplanted kidneys with no significant differences between strains. We conclude that renal transplantation has profound long-term effects on the recipients' plasma and local kidney renin-angiotensin systems. These do not appear to be involved in the pathogenesis of post-transplantation hypertension in recipients of an SHRSP kidney, but may reflect a role for the intrarenal renin-angiotensin system in long-term renal adaptation and repair processes after transplantation.
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PMID:Effects of kidney transplantation on the renin-angiotensin systems of the recipients. 769 99

To investigate the role of autonomic reflexes in stroke-work optimization, we studied ventriculoarterial coupling in unanesthetized dogs with the autonomic system intact and blocked. Ventricular contractility was quantified by the slope of the end-systolic pressure-volume relation, ventricular elastance (Ees). Arterial system properties were quantified by the ratio of end-systolic pressure to stroke volume, arterial elastance (Ea). The coupling between left ventricle and arterial system was expressed by the Ea-to-Ees ratio. Changes in arterial blood pressure during nitroprusside or angiotensin II infusion were used to elicit reflex-mediated influences on ventriculoarterial coupling. With the autonomic system intact, Ees doubled during nitroprusside infusion while Ea remained unchanged due to reactive vasoconstrictor forces and tachycardia. Consequently, the Ea-to-Ees ratio fell 50% from baseline. Angiotensin II infusion increased Ea 46% but did not significantly change Ees, resulting in a 26% increase in the Ea-to-Ees ratio. In contrast to ventriculoarterial coupling, stroke work was insensitive to changes in afterload, remaining close to its theoretical maximum. After autonomic blockade, Ees tended to decrease during nitroprusside and increased during angiotensin II infusion in parallel with changes in Ea, so that the Ea-to-Ees ratio did not change from baseline as much as it did with the autonomic system intact. Again, the left ventricle maintained nearly 90% of its maximal stroke work. Thus, over a wide range of afterload, stroke work was kept near its theoretical maximum, independent of autonomic neural regulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neural modulation of ventriculoarterial coupling in conscious dogs. 814 75

The effects of the endogenous pressor agents noradrenaline (NA), and angiotensin II (Ang II), and of the hypotensive agents acetylcholine (ACh) and adenosine (ADS), on blood pressure and heart rate in conscious and unrestrained stroke-prone spontaneously hypertensive rats (SHR-SP) and normotensive Wistar Kyoto rats (WKY) of different ages (4-9 weeks old) were investigated. Pressor responses to NA were enhanced in 7- and 9- week-old SHR-SP compared with those in WKY, but pressor responses to Ang II in SHR-SP were not different from those in WKY at all ages. The bradycardias following pressor responses to NA and Ang II were markedly attenuated in SHR-SP, especially older ones. Hypotensive responses to ACH were enhanced in SHR-SP, particularly at 9 weeks of age. However, hypotensive responses to ADS were attenuated in SHR-SP, especially at 7 weeks of age. Transient fall of heart rate due to ADS was also attenuated in 7- and 9- week-old SHR-SP. These alterations of hemodynamic or cardiovascular responses in SHR-SP became more evident in the established stages of hypertension. These results suggest intimate relationships of the enhanced pressor responses to NA, attenuated bradycardias following pressor effects with NA or Ang II, and the attenuated hypotensive responses to ADS with the development or the maintenance of hypertension in SHR-SP.
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PMID:Studies of cardiovascular responses to some endogenous pressor and hypotensive agents in conscious stroke-prone spontaneously hypertensive rats of different ages. 824 50

Through the multiple actions of angiotensin II (AII), the renin-angiotensin system (RAS) participates in cardiovascular homeostasis. Angiotensin II acts by binding to specific membrane-bound receptors, which are coupled to one of several signal transduction pathways. These AII receptors exhibit heterogeneity, represented by AT1 and AT2 receptor subtypes. The AT1 receptor mediates the major cardiovascular action of the RAS. This receptor has been cloned from multiple species, disclosing features consistent with a transmembrane, G-protein-linked receptor. Further AII receptor heterogeneity is evident by the cloning of isotypes of the AT1 receptor. Blocking the interaction of AII with its receptor is the most direct site to inhibit the actions of the RAS. Many AII receptor antagonists, including peptide analogs of AII and antibodies directed against AII, possess unfavorable properties that have limited their clinical utility. The discovery and further development of imidazole compounds with AII antagonist properties and favorable characteristics, however, has promise for clinical utility. The leader in this field is a selective AT1 receptor antagonist losartan (previously known as DuP 753 or MK-954). Losartan was demonstrated to be an effective antagonist of many AII-induced actions and an effective antihypertensive agent in many animal models of hypertension (HTN). Losartan also demonstrated secondary benefits in preventing stroke, treating congestive heart failure (CHF), and delaying the progression of renal disease in animal models. Clinical studies confirm the AII antagonist action of losartan and suggest that losartan will be effective in the treatment of essential HTN. AII antagonism is likely to provide useful treatment in essential HTN and CHF, conditions in which the RAS is known to play a major role. The utility of AII antagonism may extend beyond that of HTN and CHF, as suggested by the potential usefulness of angiotensin-converting enzyme (ACE) inhibition in the treatment or prevention of many other diseases. The key advantage AII antagonists provide over ACE inhibitors is that they may avoid unwanted side effects, related to bradykinin potentiation with the latter drugs. The AII antagonists will help determine the role of the RAS in physiologic regulation and in the pathophysiology of various disease states.
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PMID:Angiotensin II receptor blockade: an innovative approach to cardiovascular pharmacotherapy. 830 Aug 85


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