The functional ratio of chymase and angiotensin converting enzyme in angiotensin I-induced vascular contraction in monkeys, dogs and rats.
(49/324)
Recently, a chymase-dependent angiotensin (Ang) II-forming pathway was found in human cardiovascular tissues, and the significance of this pathway in the pathogenesis of some cardiovascular diseases was suggested. The present study examined the ratio of angiotensin converting enzyme (ACE) to chymase-dependent Ang II formation in various isolated vessels from monkeys, dogs and rats. In all of the examined vessels, the addition of KCl at a concentration of 50 mM could induce a maximal contraction. Except for monkey coronary artery and rat renal and femoral artery, the addition of Ang I could induce transitory contractions, whereas the force of contractions in these vessels was quite different. The sensitivity to Ang II in these vessels was similar to that for Ang I. In monkey gastroepiploic and mesenteric arteries, about 70% of the Ang I-induced contraction was suppressed by chymase inhibition, while it was suppressed about 50% in monkey renal, femoral and carotid arteries. In dog renal arteries, about 65% of the Ang I-induced contraction was suppressed by chymase inhibition, while it was suppressed by about 30% in other dog arteries. In contrast, in all rat arteries, Ang I-induced contractions were completely suppressed by treatment with ACE inhibitor alone. We concluded that regional differences in the response to Ang I exist in vascular tissues, and the ratio of ACE- to chymase-dependent Ang II formation is different in the various vessels. (+info)
Renin gene transfer restores angiogenesis and vascular endothelial growth factor expression in Dahl S rats.
(50/324)
In a previous study, we demonstrated that Dahl S rats (SS group) have low plasma renin activity, whereas transfer of a region of chromosome 13 containing the renin gene from Dahl R onto a congenic strain of Dahl SS/Jr/Hsd/MCW rats (S/ren(RR) group) restores renin secretory responses. In the present study, we compared the angiogenic responses to electrical stimulation in the SS and S/ren(RR) groups to explore the hypotheses that the renin-angiotensin system is involved in vascular endothelial growth factor (VEGF) expression and angiogenesis in skeletal muscle. Congenic SS and S/ren(RR) rats fed a 0.4% or 4% salt diet were surgically prepared by chronic implantation of an electrical stimulator. Another group of S/ren(RR) rats was treated with lisinopril 2 days before the surgery and throughout the stimulation protocol. The right tibialis anterior (TA) and extensor digitorum longus (EDL) were stimulated for 8 hours per day for 7 days. The contralateral muscles served as controls. Western blot analysis was performed to identify VEGF protein expression in these muscles. Electrical stimulation produced no change in vessel density of the SS group fed a 0.4% salt diet (change 5.50% and 8.14% for EDL and TA, respectively). Transfer of a region containing the renin gene restored the angiogenic response (change 16% and 30% for EDL and TA, respectively) despite a significantly higher blood pressure. Blockade of the renin-angiotensin system by lisinopril or high salt restored the responses observed in the SS group fed a low salt diet. In addition, increases in VEGF expression to electrical stimulation were observed only in the S/ren(RR) group fed a low salt diet. These results suggest that renin gene transfer restores angiogenesis and VEGF expression in the skeletal muscle of Dahl S rats. (+info)
Assembly and activation of HK-PK complex on endothelial cells results in bradykinin liberation and NO formation.
(51/324)
Prekallikrein (PK) activation on human umbilical endothelial cells (HUVEC) presumably leads to bradykinin liberation. On HUVEC, PK activation requires the presence of cell-bound high-molecular-weight kininogen (HK) and Zn(2+). We examined the Zn(2+) requirement for HK binding to and the consequences of PK activation on endothelial cells. Optimal HK binding (14 pmol/10(6) HUVEC) is seen with no added Zn(2+) in HEPES-Tyrode buffer containing gelatin versus 16--32 microM added Zn(2+) in the same buffer containing bovine serum albumin. The affinity and number of HK binding sites on HUVEC are a dissociation constant of 9.6 +/- 1.8 nM and a maximal binding of 1.08 +/- 0.26 x 10(7) sites/cell (means +/- SD). PK is activated to kallikrein by an antipain-sensitive mechanism in the presence of HK and Zn(2+) on HUVEC, human microvascular endothelial cells, umbilical artery smooth muscle cells, and bovine pulmonary artery endothelial cells. Simultaneous with kallikrein formation, bradykinin (5.0 or 10.3 pmol/10(6) HUVEC in the absence or presence of lisinopril, respectively) is liberated from cell-bound HK. Liberated bradykinin stimulates the endothelial cell bradykinin B2 receptor to form nitric oxide. Assembly and activation of PK on endothelial cells modulates their physiological activities. (+info)
Abnormalities of hemorheological, endothelial, and platelet function in patients with chronic heart failure in sinus rhythm: effects of angiotensin-converting enzyme inhibitor and beta-blocker therapy.
(52/324)
BACKGROUND: To investigate the hypothesis that abnormalities of hemorheological (fibrinogen, plasma viscosity), endothelial (von Willebrand factor [vWF]), and platelet (soluble P-selectin) function would exist in patients with chronic heart failure (CHF) who are in sinus rhythm, we conducted a cross-sectional study of 120 patients with stable CHF (median ejection fraction 30%). We also hypothesized that ACE inhibitors and beta-blockers would beneficially affect the measured indices. METHODS AND RESULTS: In the cross-sectional analysis, plasma viscosity (P=0.001), fibrinogen (P=0.02), vWF (P<0.0001), and soluble P-selectin (P<0.001) levels were elevated in patients with CHF compared with healthy controls. Women demonstrated greater abnormalities of hemorheological indices and vWF than males (all P<0.05). Plasma viscosity (P=0.009) and fibrinogen (P=0.0014) levels were higher in patients with more severe symptoms (New York Heart Association [NYHA] class III-IV), but there was no relationship with left ventricular ejection fraction. When ACE inhibitors were introduced, there was a reduction in fibrinogen (repeated-measures ANOVA, P=0.016) and vWF (P=0.006) levels compared with baseline. There were no significant changes in hemorheological, endothelial, or platelet markers after the introduction of beta-blocker therapy, apart from a rise in mean platelet count (P<0.001). CONCLUSIONS: Abnormal levels of soluble P-selectin, vWF, and hemorheological indices may contribute to a hypercoagulable state in CHF, especially in female patients and in those with more severe NYHA class. Treatment with ACE inhibitors improved the prothrombotic state in CHF, whereas the addition of beta-blockers did not. These positive effects of ACE inhibitors may offer an explanation for the observed reduction in ischemic events in clinical trials. (+info)
Neurohormonal activation, the renal dopaminergic system and sodium handling in patients with severe heart failure under vasodilator therapy.
(53/324)
The benefits of tailoring therapy with vasodilators in patients with severe heart failure are well documented, but this may lead to neurohormonal activation and sodium retention. Renal dopamine has local natriuretic actions and interacts with other hormones involved in renal sodium handling. The aim of the present work was to determine the effects of arterial underfilling induced by vasodilator therapy on renal sodium handling, neurohormonal activation and the activity of the renal dopaminergic system in patients with severe heart failure. For this purpose we monitored haemodynamic parameters, plasma levels of type B natriuretic peptide (BNP), catecholamines, aldosterone, renin activity (PRA), sodium and creatinine, and urinary excretion of sodium, creatinine, L-DOPA, dopamine and its metabolites, before initiation of sodium nitroprusside therapy and every 6 h thereafter (for 42 h), and again after 5 days of angiotensin-converting enzyme (ACE) inhibition, in 10 male patients with severe heart failure. The results of nitroprusside therapy were a marked increase in cardiac index and a substantial decrease in systemic vascular resistance index. Plasma levels of BNP decreased significantly, while PRA, noradrenaline and aldosterone showed marked increases, resulting in a substantial reduction in urinary sodium excretion. Creatinine clearance was not affected. Urinary dopamine and dopamine metabolites increased in response to nitroprusside therapy. After 5 days of ACE inhibition, urinary sodium returned to baseline values, while urinary dopamine was markedly reduced. These results suggest that the renal dopaminergic system is activated in patients with severe heart failure by stimuli leading to sodium renal reabsorption. (+info)
RXP 407, a selective inhibitor of the N-domain of angiotensin I-converting enzyme, blocks in vivo the degradation of hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro with no effect on angiotensin I hydrolysis.
(54/324)
The phosphinic peptide RXP 407 has recently been identified as the first potent selective inhibitor of the N-active site (domain) of angiotensin-converting enzyme (ACE) in vitro. The aim of this study was to probe the in vivo efficacy of this new ACE inhibitor and to assess its effect on the metabolism of AcSDKP and angiotensin I. In mice infused with increasing doses of RXP 407 (0.1--30 mg/kg/30 min), plasma concentrations of AcSDKP, a physiological substrate of the N-domain, increased significantly and dose dependently toward a plateau 4 to 6 times the basal levels. RXP 407 significantly and dose dependently inhibited ex vivo plasma ACE N-domain activity, whereas it had no inhibitory activity toward the ACE C-domain. RXP 407 (10 mg/kg) did not inhibit the pressor response to an i.v. angiotensin I bolus injection in mice. In contrast, lisinopril infusion (5 and 10 mg/kg/30 min) affected the metabolism of both AcSDKP and angiotensin I. Thus, RXP 407 is the first ACE inhibitor that might be used to control selectively AcSDKP metabolism with no effect on blood pressure regulation. (+info)
Blocking angiotensin II synthesis/activity preserves glomerular nephrin in rats with severe nephrosis.
(55/324)
Angiotensin-converting enzyme inhibitors restore size-selective dysfunction of the glomerular barrier in experimental animals and humans with proteinuric nephropathies, although the structural and molecular determinants of such an effect are not completely understood. This study used an accelerated model of experimental nephrosis to assess nephrin gene and protein expression in the kidney and the possible modulating effect of drugs that block angiotensin II (AII) synthesis/activity. Passive Heymann nephritis (PHN) and control animals were studied at day 7, month 4, and month 8. Additional PHN rats were treated with lisinopril or AII receptor blocker L-158,809 and studied at 8 mo. Lisinopril and L-158,809 controlled BP, prevented proteinuria, and protected PHN animals from renal injury. An intense signal of nephrin mRNA was detected in glomeruli of control animals mainly restricted to podocytes. In PHN rats, nephrin staining progressively and remarkably decreased with time. Lisinopril and L-158,809 fully prevented the decrease in nephrin transcripts to levels comparable to those of control rats. Consistent with nephrin mRNA expression, immunostaining of the protein showed a progressive decrease in kidneys from PHN rats that was completely abolished by lisinopril and L-158,809. In summary, progressive renal injury was associated with downregulation of nephrin gene that was totally prevented by angiotensin-converting enzyme inhibitor and AII receptor blocker, suggesting that renoprotection afforded by drugs that interfere with AII synthesis/activity was related to an effect on nephrin assembly. (+info)
Effect of Lisinopril on the progression of renal insufficiency in mild proteinuric non-diabetic nephropathies.
(56/324)
BACKGROUND: The aim of the study was to determine whether Lisinopril, an ACE-inhibitor (ACEi), was more effective than other antihypertensive agents in slowing the progression of non-diabetic chronic renal diseases in patients with baseline proteinuria < or =1.0 g/day. METHODS: In an open, multicentre study all eligible patients entered a 3 months run-in phase during which antihypertensive therapy (with exclusion of ACEi) was adjusted in order to obtain a supine diastolic blood pressure < or =90 mmHg and urinary protein excretion and renal function stability were verified. One hundred and thirty-one patients with chronic renal insufficiency (Clcr between 20-50 ml/min) because of primary renoparenchymal diseases and proteinuria < or =1.0 g/day, were randomized to Lisinopril (L=66) or alternative antihypertensive therapy (C=65). Changes in renal function were assessed by inulin (Clin) clearance. RESULTS: During the follow-up period of 22.5+/-5.6 months, Clin did not change significantly in group L (-1.31+/-0.6 ml/min/1.73 m(2)) differing significantly from group C in which it declined markedly (-6.71+/-3.6 ml/min/1.73 m(2)) (P<0.04). Seven patients experienced adverse events that prompted discontinuation of treatment: four in group L and three in group C; in addition seven patients showed severe deterioration in renal function requiring dialysis: two in group L and five in group C. The overall risk of the combined end-points: need for dialysis or halving of GFR was significantly higher in group C versus group L. During the study the mean value for systolic blood pressure was 137.8+/-14.6 SD mmHg in group L and 140.8+/-14.1 SD mmHg in group C; the mean difference between groups, during and at the end of the study, was 2 mmHg (NS). The mean diastolic blood pressure during the study was 83.8+/-8.6 SD mmHg in group L and 84.3+/-7.56 SD mmHg in group C; during and at the end of the study the mean diastolic difference between groups was 1 mmHG: CONCLUSION: This study, employing a sensitive measurement of renal function and with similar blood pressure in both groups, provides support to the hypothesis that ACEi have a specific renoprotective effect, in addition to blood pressure control, also in patients with mild proteinuria. (+info)