Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure.

Angiotensin II (Ang II) is both a vasoactive and a potent growth-promoting factor for vascular smooth muscle cells. Little is known about the in vivo contribution of AT1 and AT2 receptor activation to the biological action of Ang II. Therefore, we investigated the effect of AT1 or AT2 subtype receptor chronic blockade by losartan or PD123319 on the vascular hypertrophy in rats with Ang II-induced hypertension. Normotensive rats received for 3 wk subcutaneous infusions of Ang II (120 ng/kg per min), or Ang II + PD 123319 (30 mg/kg per d), or Ang II + losartan (10 mg/kg per d) or PD 123319 alone, and were compared with control animals. In normotensive animals, chronic blockade of AT2 receptors did not affect the plasma level of angiotensin II and the vascular reactivity to angiotensin II mediated by the AT1 receptor. Chronic blockade of AT1I in rats receiving Ang II resulted in normal arterial pressure, but it induced significant aortic hypertrophy and fibrosis. Chronic blockade of AT2 receptors in Ang II-induced hypertensive rats had no effect on arterial pressure, but antagonized the effect of Ang II on arterial hypertrophy and fibrosis, suggesting that in vivo vasotrophic effects of Ang II are at least partially mediated via AT2 subtype receptors.

Impaired flow-induced dilation in mesenteric resistance arteries from mice lacking vimentin.

The intermediate filament vimentin might play a key role in vascular resistance to mechanical stress. We investigated the responses to pressure (tensile stress) and flow (shear stress) of mesenteric resistance arteries perfused in vitro from vimentin knockout mice. Arteries were isolated from homozygous (Vim-/-, n = 14) or heterozygous vimentin-null mice (Vim+/-, n = 5) and from wild-type littermates (Vim+/+, n = 9). Passive arterial diameter (175+/-15 micron in Vim+/+ at 100 mmHg) and myogenic tone were not affected by the absence of vimentin. Flow-induced (0-150 microl/min) dilation (e. g., 19+/-3 micron dilation at 150 mmHg in Vim+/+) was significantly attenuated in Vim-/- mice (13+/-2 micron dilation, P < 0.01). Acute blockade of nitric oxide synthesis (NG-nitro- L-arginine, 10 microM) significantly decreased flow-induced dilation in both groups, whereas acute blockade of prostaglandin synthesis (indomethacin, 10 microM) had no significant effect. Mean blood pressure, in vivo mesenteric blood flow and diameter, and mesenteric artery media thickness or media to lumen ratio were not affected by the absence of vimentin. Thus, the absence of vimentin decreased selectively the response of resistance arteries to flow, suggesting a role for vimentin in the mechanotransduction of shear stress.

Aminoguanidine treatment increases elasticity and decreases fluid filtration of large arteries from diabetic rats.

The accumulation of advanced glycosylation end-products (AGEs) on collagen and the subsequent stiffening of this matrix protein in diabetes has been described many years ago. Structural modification of collagen in the arterial wall might have important effects on arterial elasticity. Aminoguanidine is known to decrease the formation of AGEs. In this study we evaluated the effects of aminoguanidine treatment on different parameters reflecting arterial wall elasticity in diabetic rats. We demonstrated that treatment of diabetic rats with aminoguanidine resulted in a significant increase in carotid static compliance (+39%, P < 0.01 under control conditions, and +27%, P < 0.01 after abolition of vascular tone by KCN), and a decrease in characteristic aortic input impedance (-40%, P < 0.01). The arterial pulse pressure in aminoguanidine-treated rats was decreased (-15%, P < 0.05) and the pulsatile component of left ventricular power output was relatively diminished (-35%, P < 0.05). In addition, we observed a lower fluid filtration across the carotid wall. These results indicate an increased vascular elasticity, an improved left ventricular-arterial coupling, and a decreased vascular permeability in diabetic rats after aminoguanidine treatment, suggesting that AGE-accumulation on collagen negatively affects arterial wall properties in experimental diabetes.

Effects of alpha 1-blockade on arterial compliance in normotensive and hypertensive rats.

The effects of blockade of alpha 1-adrenergic receptors on the mechanical properties of the arterial wall were studied in 10 spontaneously hypertensive rats (SHR) as compared with 10 matched normotensive Wistar-Kyoto (WKY) rats. Ascending aortic pressure and flow were recorded in open-chest anesthetized rats, and the systemic arterial compliance was calculated. Intravenous injection (1 mg/kg) of Urapidil, a selective alpha 1-adrenergic antagonist, induced a significant decrease in arterial pressure (-26%, p less than 0.01 and -37%, p less than 0.001 in WKY rats and SHR, respectively) without significant changes in cardiac output. In control conditions, systemic arterial compliance was lower in SHR (3.29 +/- 1.52 microliters/mm Hg) than in WKY rats (4.35 +/- 1.35 microliters/mm Hg, p less than 0.01). Urapidil injection induced significant increases in systemic arterial compliance values in both strains (p less than 0.001). In another set of experiments (15 WKY rats and 15 SHR), the carotid compliance (microliters/mm Hg) was determined from the arterial volume-pressure relation under control conditions, after local incubation with Urapidil, and after total abolition of the vascular smooth muscle by KCN. In WKY rats, the carotid compliance increased markedly after incubation with Urapidil at doses corresponding to 1 mg/kg (+31%, p less than 0.01). A further increase in the carotid compliance was observed after KCN poisoning (+11%, p less than 0.05). In SHR, incubation with Urapidil at doses corresponding to 2 mg/kg were necessary to induce a significant increase in compliance (+38%). At this dosage, there was no further increase in compliance after KCN poisoning.(ABSTRACT TRUNCATED AT 250 WORDS)

Biaxial mechanical properties of carotid arteries from normotensive and hypertensive rats.

Hypertension is known to decrease arterial distensibility and volumetric compliance, as reported from pressure-volume experiments and ring and strip studies of human and animal large arteries. However, recent data using noninvasive in vivo recording of vessel diameter suggest that the cross-sectional compliance of large arteries can be unchanged or even increased in hypertensive subjects. The present study was performed to test the hypothesis that differences between volumetric and cross-sectional compliance could be related to differences in biaxial mechanical properties in normotensive and hypertensive rats. In normotensive (Wistar-Kyoto [WKY]) rats and spontaneously hypertensive rats (SHR) we measured the simultaneous changes in length and diameter of in situ isolated carotid arteries submitted to static pressures (50 to 200 mm Hg by steps of 25 mm Hg each). Carotid artery diameters and lengths were determined by video microscopy and computer-assisted image analysis. At low transmural pressure (50 mm Hg), carotid artery diameter was 710 +/- 41 microns in WKY rats and 980 +/- 31 microns in SHR (P < .01). In response to pressure increases, the carotid diameter increased by 91 +/- 6% in WKY rats and by 41 +/- 4% in SHR (P < .01). In parallel, the percent increase in carotid length was much larger in WKY rats than in SHR (31 +/- 2% versus 7 +/- 1%, respectively; P < .01). In WKY rats, longitudinal distensibility causes significantly larger volumetric values than cross-sectional compliance values; in contrast, because of the very small longitudinal distensibility, volumetric and cross-sectional compliances are almost identical in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Static and dynamic mechanical properties of the carotid artery from normotensive and hypertensive rats.

Several recent results obtained in hypertensive animals and subjects under in vivo isobaric conditions do not confirm the classic view of stiffer arteries in hypertensive subjects. We compared the mechanical behavior of in situ isolated common carotid arteries from normotensive Wistar-Kyoto rats (WKY) and age-matched spontaneously hypertensive rats (SHR) under both static and dynamic conditions for transmural pressure ranging from 50 to 200 mm Hg. The static pressure (P)-diameter (D) relationship was shifted to higher values of diameters in the SHR mainly because of a larger unstressed carotid diameter (Do) in hypertensive rats. The carotid mechanical strain, calculated as (D-Do)/Do, was significantly reduced in SHR at pressure levels between 100 and 200 mm Hg. The static carotid compliance and distensibility were markedly smaller in SHR than in WKY carotid arteries, indicating a stiffer wall in hypertensive animals. In contrast, carotid compliance and distensibility were similar under dynamic conditions close to the in vivo pulse pressure (frequency, 300 bpm; peak amplitude of the oscillatory pressure, 20 to 25 mm Hg). However, marked differences in dynamic compliance- and distensibility-strain relationships in SHR and WKY are evidence of clearly different arterial wall material properties in both strains. We therefore conclude that larger lumen carotid arteries in hypertensive rats could compensate for a stiffer arterial wall, resulting in similar dynamic compliance and distensibility in normotensive and hypertensive rats.

Microvasculature in angiotensin II-dependent cardiac hypertrophy in the rat.

The long-lasting effect of angiotensin II (Ang II) on the microvasculature in the rat left ventricle was studied. Immunolabeling of ventricular cryosections combined with morphometric analysis allowed us to (1) distinguish between capillaries and arterioles and (2) precisely evaluate their respective densities in the endomyocardium. Ang II-induced hypertensive cardiac hypertrophy was associated with an 18% decrease in capillary density (P<0.05) and an increase in arteriole density (+54%, P<0.001). Treatments with losartan or PD123319, the respective antagonists of the angiotensin subtype 1 and subtype 2 receptors, prevented the increase in arteriolar density, whereas only losartan, which restored normal arterial pressure, prevented changes in capillary density. Taken together, these results indicate that Ang II-induced cardiac hypertrophy was associated with capillary rarefaction and arteriolar growth, the 2 processes being independently regulated.

Chronic infusion of low-dose angiotensin II potentiates the adrenergic response in vivo.

OBJECTIVE: The aim of this study was to investigate the role of angiotensin II-induced potentiation of the alpha 1-adrenergic contractile response in the aetiology of low-dose angiotensin II-induced hypertension. METHODS: Wistar rats (250g) received angiotensin II (120 ng/kg per min) from subcutaneous minipumps for 21 days. The responses of vaso-active properties of second-order mesenteric arteries (200 micron) to potassium, phenylephrine, angiotensin II and acetylcholine were assessed. The acute amplification effects of angiotensin II on the response to phenylephrine were examined. RESULTS: Angiotensin II induced a progressive hypertension, which reached a plateau after approximately 5 days. The responses to potassium, angiotensin II and acetylcholine were not significantly modified in rats treated chronically with angiotensin II. The major finding of this study is that the response to phenylephrine (1-3 mumol/l) was potentiated (sevenfold at 1.75 mumol/l) after chronic treatment with angiotensin II. In control vessels acute addition of angiotensin II (10(-10) mol/l) produced no contraction but induced potentiation of the phenylephrine response (1-3 mumol/l). No further potentiation of the phenylephrine response was observed in the rats treated chronically with angiotensin II. CONCLUSIONS: Thus, although the direct contractile responses to potassium and angiotensin II remain unaffected following chronic angiotensin II treatment, the alpha 1-adrenergic contractile response to phenylephrine is significantly potentiated by angiotensin II in this model of hypertension. We suggest that this potentiation contributes to the hypertension observed in response to infusion of low-dose angiotensin II.

Different effects of calcium antagonists on fluid filtration of large arteries and albumin permeability in spontaneously hypertensive rats.

OBJECTIVE: To compare the effects of chronic administration of two dihydropyridines, nifedipine and amlodipine, and the non-dihydropyridine Ca2+ antagonist mibefradil on fluid filtration of large arteries and extravasation of albumin in spontaneously hypertensive rats. METHODS: Spontaneously hypertensive rats aged 2 months were randomly allocated to oral treatment once a day with 30 mg/kg mibefradil (n=12), 100 mg/kg nifedipine (n=12), 20 mg/kg amlodipine (n=12) or placebo (n=12) for 1 month. Instantaneous blood pressure of rats under pentobarbital anaesthesia was recorded at the end of the treatment Fluid filtration across the carotid arterial wall was determined in situ in the isolated carotid artery. Extravasation of 25 mg/kg Evans Blue dye that had been injected intravenously was used to assess whole vascular permeability to albumin after chronic treatment with mibefradil. RESULTS: Similar reductions in mean arterial pressure were obtained in all Ca2+ antagonist-treated rats. Heart rate was similar in rats in control, nifedipine and amlodipine groups but was significantly lower in mibefradil-treated rats (by 19%, P< 0.001). Fluid filtration across the carotid wall was greater in all Ca2+ antagonist-treated animals. However, fluid filtration was significantly less in mibefradil-treated rats than it was in nifedipine-treated, and amlodipine-treated rats. Furthermore, administration of mibefradil did not significantly modify extravasation of albumin in all tested tissues (pancreas, testis, spleen, lung, kidney, intestine, liver, skeletal muscle) except for cardiac and brain tissues, in which the permeability of albumin was increased by 24 and 33%, respectively, compared with values for the control group (P < 0.05). CONCLUSION: These results indicate that Ca2+ antagonists increase fluid filtration through large arteries from spontaneously hypertensive rats. That the lower fluid filtration in mibefradil-treated rats was associated with no change in extravasation of albumin in most tissues and especially in skeletal muscle suggests that vascular permeability in hypertensive rats was impaired less by mibefradil treatment than it was by dihydropyridine Ca2+ antagonist treatments.

Sodium, survival, and the mechanical properties of the carotid artery in stroke-prone hypertensive rats.

BACKGROUND: Reduction in sodium intake improves the survival of stroke-prone spontaneously hypertensive rats (SHR-SP) without causing any change in their blood pressure. OBJECTIVE: To investigate whether the diuretic indapamide improves survival of SHR-SP and whether changes in the structure and the function of large arteries are associated with survival. EXPERIMENTAL DESIGN: Forty-eight hypertensive rats aged 6 weeks were divided into three groups: a control SHR-SP group (n = 24) and a control spontaneously hypertensive rat (SHR) group (n = 12), with 1% saline drinking water; and an indapamide-treated SHR-SP group (n = 12) with 1% saline drinking water administered 1 mg/kg per day indapamide via their food. At the end of a 12-week follow-up period, pulsatile changes in blood pressure and common carotid artery diameter (measured by high-resolution echo-tracking techniques) were determined and aortic histomorphometry was performed. RESULTS: By the end of the study 58% of the SHR-SP control group rats had died. There were no deaths in the other two groups. In these two groups the mean blood pressure (217+/-10 and 212+/-7 mmHg), carotid diameter and distensibility (0.48+/-0.09 and 0.61+/-0.22 mmHg[-1]), arterial thickness (116+/-4 and 116+/-3 microm), and collagen content of the arterial wall were identical. In the SHR-SP control group the mean blood pressure was significantly lower (168+/-9 mmHg), the carotid distensibility was higher (1.47+/-0.35 mmHg[-1]), and the arterial thickness (138+/-5 microm) and collagen content were substantially higher than those in the other two groups. In the study population as a whole, for a given mean arterial pressure the carotid distensibility was identical in the three groups, although the arterial thickness was substantially greater in the SHR-SP control group rats. CONCLUSIONS: The study provides evidence that the diuretic compound indapamide improved the survival of SRH-SP even though their blood pressure was higher than that of untreated animals, and that genetic sensitivity to sodium, rather than blood pressure, influences the changes in arterial structure.