Changes in arterial structure and function under trandolapril-verapamil combination in hypertension.
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BACKGROUND AND PURPOSE: Converting enzyme inhibition and calcium blockade alter large arteries in hypertension. However, the heterogeneity of the response according to the site of cardiovascular measurements has never been investigated. METHODS: In a double-blind study, we compared for 180 days 3 hypertensive patient groups treated with verapamil, trandolapril, or their combination. Using echo-Doppler technique and applanation tonometry, we independently measured mean pressure, local pulse pressure, arterial diameter, and distensibility at 3 arterial sites (brachial and common carotid arteries and abdominal aorta), as well as cardiac and carotid wall structure. RESULTS: Mean and pulse pressure decreased significantly to a greater extent with the drug combination. Regarding arterial and cardiac hemodynamics, significant and similar changes were noted in the 3 groups: decreases in abdominal aorta and carotid but not brachial diameter; increases in carotid artery, abdominal aorta, and brachial distensibility even after adjustment to mean blood pressure reduction; and more substantial regression of cardiac mass than carotid wall thickness. CONCLUSIONS: This study shows that both compounds and more significantly combination therapy decreased mean and pulse pressures measured independently and that the changes in diameter, thickness, and stiffness were influenced primarily by the site of cardiovascular measurements, resulting in a predominant increase in distensibility of muscular arteries, little change in carotid wall thickness, but a significant regression of cardiac hypertrophy. (+info)
Effects of moxonidine injected into rostral ventrolateral medulla on blood pressure, heart rate, and renal sympathetic nerve activity in rats.
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AIM: To examine the effects of moxonidine (Mox) injected into the rostral ventrolateral medulla (RVLM) on blood pressure (BP), heart rate (HR), and the renal sympathetic nerve activity (RSNA) in anesthetized normotensive rats. METHODS: BP, HR, and RSNA were simultaneously recorded after 1 microL Mox 1, 10, and 100 mumol.L-1 was injected into RVLM. RESULTS: Mox 1, 10, and 100 mumol.L-1 reduced BP from 13.9 +/- 1.0 kPa to 13.0 +/- 1.7 kPa (P < 0.05), 13.8 +/- 1.8 kPa to 11.4 +/- 1.5 kPa (P < 0.01), and 13.9 +/- 1.9 kPa to 9.4 +/- 1.7 kPa (P < 0.01), respectively. Mox did not influence HR. RSNA varied with the doses: Mox 1 mumol.L-1 increased RSNA by 50% (P < 0.05), 10 mumol.L-1 insignificantly influenced RSNA (P > 0.05), and 100 mumol.L-1 reduced RSNA by 23% (P < 0.05). In sinoaortic barodenervated rats, Mox 10 mumol.L-1 inhibited RSNA by 50% (P < 0.05), which substantially differed from that in buffer nerve intact rats (P < 0.01). CONCLUSION: Mox injected into RVLM decreased BP, but did not influence HR. The changes of RSNA did not parallel with the depressor effect of Mox. (+info)
Modulation of multidrug resistance by three bisbenzyl-isoquinolines in comparison with verapamil.
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AIM: To compare cycleanine (Cyc), insularine (Insr), insulanoline (Insn) and verapamil (Ver) in modulation of multidrug resistance (MDR) in vitro. METHODS: The cytotoxic effect was determined by 3-[4, 5-dimethylthiazol-2-yl], 5-diphenyl tetarzolium bromide (MTT) assay. The intracellular doxorubincin (Dox) accumulation was assayed by spectrofluorometer. RESULTS: Cyc, Insr, Insn, and Ver showed significant activities in modulating Dox and vincristine resistances in acquired resistant MCF-7/Adr and KBv200 cell lines in a dose-dependent manner. Cyc, Insr, Insn, and Ver increased intracellular Dox accumulation in MCF-7/Adr cells. Cyc and Insr had greater activities than Ver in modulating MDR, while Insn had similar activity to that of Ver. CONCLUSION: MDR was modulated by Cyc, Insr, and Insn, due to the increase of intracellular Dox accumulation. (+info)
Production of angiotensin II by homogeneous cultures of vascular smooth muscle cells from spontaneously hypertensive rats.
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Production of angiotensin II (Ang II) in spontaneously hypertensive rats (SHR)-derived vascular smooth muscle cells (VSMC) has now been investigated. A nonpeptide antagonist (CV-11974) of Ang II type 1 receptors inhibited basal DNA synthesis in VSMC from SHR, but it had no effect on cells from Wistar-Kyoto (WKY) rats. Ang II-like immunoreactivity, determined by radioimmunoassay after HPLC, was readily detected in conditioned medium and extracts of SHR-derived VSMC, whereas it was virtually undetectable in VSMC from WKY rats. Isoproterenol increased the amount of Ang II-like immunoreactivity in conditioned medium and extracts of SHR-derived VSMC, whereas the angiotensin-converting enzyme inhibitor delapril significantly reduced the amount of Ang II-like immunoreactivity in conditioned medium and extracts of these cells. Reverse transcription-polymerase chain reaction analysis revealed that the abundance of mRNAs encoding angiotensinogen, cathepsin D, and angiotensin-converting enzyme was greater in VSMC from SHR than in cells from WKY rats. The abundance of cathepsin D protein by Western blotting was greater in VSMC from SHR than in cells from WKY rats. Ang I-generating and acid protease activities were detected in VSMC from SHR, but not in cells from WKY rats. These results suggest that SHR-derived VSMC generate Ang II with increases in angiotensinogen, cathepsin D, and angiotensin-converting enzyme, which contribute to the basal growth. Production of Ang II by homogeneous cultures of VSMC is considered as a new mechanism of hypertensive vascular disease. (+info)
Effects of long-term angiotensin II AT1 receptor blockade on survival, hemodynamics and cardiac remodeling in chronic heart failure in rats.
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OBJECTIVE: The beneficial effect of chronic angiotensin I converting enzyme (ACE) inhibition on survival has for long been established in the rat post-infarction model of chronic heart failure (CHF) and has subsequently been confirmed in humans. This study investigates in rats whether chronic angiotensin II AT1 receptor blockade shares with ACE inhibition the same beneficial effect. METHODS: Rats we subjected to coronary artery ligation and, from 7 days later, orally treated for 7.5 months with placebo or irbesartan (5 or 50 mg/kg/day). RESULTS: Irbesartan dose-dependently increased survival (placebo: 27%, low dose: 52%, high dose: 82%, sham-ligated: 100%; high dose vs placebo: P < 0.001 and vs low dose: P < 0.05; low dose vs placebo: P = 0.11). Irbesartan also dose-dependently decreased urinary cyclic GMP excretion throughout the study. At 7.5 months, it dose-dependently decreased left ventricular (LV) end diastolic pressure. normalized LV pressure maximal rate of rise (dP/dt) and cardiac index values and improved LV and right ventricular regional blood flows (radioactive microspheres) and resistances. At 7.5 months, irbesartan markedly decreased myocardial hypertrophy but had almost no effect on LV dilatation and subendocardial fibrosis. CONCLUSIONS: Long-term angiotensin II AT1 receptor blockade with irbesartan strongly and dose-dependently increases survival in the rat model of coronary ligation-induced CHF. This effect is due to the combination of the beneficial effects that the drug exerts on systemic and coronary hemodynamics, on cardiac pump function and vs cardiac hypertrophy development. Long-term AT1 receptor blockade might thus prove useful and prolong survival in human CHF. (+info)
Modulation of constitutive nitric oxide synthase, bcl-2 and Fas expression in cultured human coronary endothelial cells exposed to anoxia-reoxygenation and angiotensin II: role of AT1 receptor activation.
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BACKGROUND: Angiotensin II (Ang II) plays a critical role in the pathophysiology of myocardial ischemia-reperfusion injury. We have recently shown that reoxygenation following a period of anoxia causes apoptosis of cultured human coronary artery endothelial cells (HCAECs). Ang II further enhances apoptosis of HCAECs via Ang II type 1 receptor (AT1R) activation. Recent studies suggest an important role of constitutive nitric oxide synthase (cNOS), Fas and bcl-2 proteins in apoptosis. This study was designed to examine the modulation of cNOS, and Fas and bcl-2 expression in HCAECs during exposure to anoxia-reoxygenation and Ang II. METHODS AND RESULTS: HCAECs were exposed to anoxia-reoxygenation and Ang II. Anoxia-reoxygenation significantly decreased cNOS mRNA, protein and activity in cultured HCAECs (P < 0.05 vs. control). Anoxia-reoxygenation also caused an increase in Fas and a decrease in bcl-2 protein expression in cultured HCAECs (both P < 0.05 vs. control). The presence of Ang II (0.3 microM) further enhanced these effects of anoxia-reoxygenation on cNOS, Fas and bcl-2 expression. The effects of Ang II were significantly attenuated by the AT1R inhibitor losartan (10 microM). CONCLUSION: During exposure of HCAECs to anoxia-reoxygenation and Ang II, AT1R activation induces important changes in cNOS mRNA, protein expression and activity, as well as bcl-2 and Fas protein expression which may have a bearing on the development of apoptosis. (+info)
Functional reduction and associated cellular rearrangement in SHRSP rat basilar arteries are affected by salt load and calcium antagonist treatment.
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The stroke-prone spontaneously hypertensive rat (SHRSP) is a strain with high incidence of cerebrovascular accidents increased by salt-rich diet and decreased by calcium-antagonist treatment. In the SHRSP rat basilar artery the authors have previously shown reduced contractility and altered structure including regions of smooth muscle cell (SMC) disorganization. The aims of this study have been to analyze (1) the morphology of these abnormal regions, (2) the structural modifications responsible for the reduced function, and (3) the effect of salt and calcium-antagonist treatment on vascular structure and function. Wistar Kyoto and SHRSP rats, untreated or treated from week 8 through 14 with 1% NaCl or 1% NaCl + 1 mg x kg(-1) x d(-1) lacidipine, were used. Function was studied with wire myography. Structure was analyzed in fixed intact arteries with confocal microscopy. Basilar arteries from SHRSP rat showed (1) reduced contractility, (2) discrete foci of SMC disarray with altered proportion of adventitia to SMC, and (3) decreased SMC and increased adventitial cell number. Arteries from salt-loaded SHRSP rats showed a higher degree of SMC disarray and further reduction in contractility. Lacidipine treatment of salt-loaded rats significantly improved structure and function. These data suggest that vascular remodeling can provide an explanation for the observed reduction in vascular contractility of SHRSP rat basilar arteries and might show light on the effects of salt load and calcium-channel blockers in life span and the incidence of cerebrovascular accidents in SHRSP rats. (+info)
Prevention of cold ischaemia-reperfusion injury by an endothelin receptor antagonist in experimental renal transplantation.
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BACKGROUND: Endothelin (ET) is known to play a role in the pathogenesis of warm ischaemic renal damage, however, little is known about its involvement in renal cold ischaemia. This study was designed to investigate the response of ET after kidney cold ischaemia, and to assess the potential protective effect of bosentan, a dual, non-selective ET(A)/ET(B) receptor antagonist, against cold ischaemia reperfusion injury in a rat model of syngeneic renal transplantation. METHODS: Kidneys from Lewis rats were transplanted, either immediately or after 5 h of cold preservation. After 48 h, contralateral nephrectomy was performed. Rats were organized into three groups: Tr-NoISC, no cold ischaemia; Tr-ISC, 5 h cold ischaemia; and Tr-BOS, 5 h cold ischaemia plus bosentan (100 mg/kg/day, from the day before transplantation until the seventh day post-transplantation). On day 7, plasma and tissue immunoreactive ET (irET), as well as ET mRNA tissue expression, were evaluated. Renal function was measured by means of serum creatinine on days 3, 4, 5 and 7, and by creatinine clearance on day 7. Conventional histology was performed. RESULTS: The ischaemic group had significantly higher plasma irET levels than the non-ischaemic group and significantly lower levels than the bosentan group. Tissue irET levels and ET mRNA expression were similar in the ischaemic and bosentan groups and were higher than in the non-ischaemic group. Throughout the follow-up, serum creatinine was significantly higher in the ischaemic group than in the bosentan group. Moreover, creatinine decreased rapidly in the bosentan group after nephrectomy, whereas it continued to increase for 48 h in the ischaemic group. Kidneys from the ischaemic group showed a higher degree of tubular-cell necrosis and epithelial-cell detachment than kidneys from the bosentan group. CONCLUSIONS: We conclude that cold ischaemia and preservation damage induces an increase in renal ET mRNA and irET expression in the reperfusion phase, contributing both to the deterioration of renal function and to tubular necrosis. Bosentan is effective in protecting kidneys from this cold ischaemia reperfusion damage. Non-selective ET(A)/ET(B) receptor antagonists might be potentially useful in clinical renal transplantation. (+info)