Resistance Artery Structure Research Articles

Pulse pressure and resistance artery structure in the elderly.

There has been recent interest in the possibility that resistance vessel structural adaptation in hypertension may be more closely related to pulse pressure than to other blood pressure parameters. We investigated the relation between blood pressure and resistance vessel structure in a group of subjects from an age group (older than 60 years) in which a widening of pulse pressure is a typical finding and characterized blood pressure parameters using 24-hour ambulatory blood pressure monitoring. We studied resistance vessels retrieved from biopsies of skin and subcutaneous fat taken from the gluteal region of 32 subjects under local anesthesia (age, 70 +/- 1 years [mean +/- SEM], 21 of whom were hypertensive and 11 normotensive. Media-lumen ratio was higher in the hypertensive than the normotensive subjects (18.6 +/- 1.6% versus 12.8 +/- 1.2%, P < .01) and correlated with age (r = .44, P < .05), clinic systolic pressure (r = .35, P < .05), 24-hour systolic pressure (r = .40, P < .05), and 24-hour pulse pressure (r = .56, P < .001). Stepwise multivariate regression analysis identified clinic and 24-hour pulse pressure as the only significant predictors of media-lumen ratio independent of age, other parameters of clinic blood pressure, and blood pressure variability (R2 = 41%, P < .05). These findings confirm those from animal models of hypertension in demonstrating the importance of pulse pressure in relation to cardiovascular structural adaptation and have important implications for the goals of treatment of hypertension in the elderly.

Regulation of PDGF-A: a possible mechanism for angiotensin II-induced vascular growth.

This study was designed to determine the effects of angiotensin II infusion on structure of conduit and resistance arteries and to see if the effects correlate with changes in platelet-derived growth factor A chain (PDGF-A) gene and protein expression. Wistar rats were subcutaneously infused by osmotic minipump with either angiotensin II (ANG II) at 200 ng.kg-1.min-1 or physiological saline (control) for 14 days. Tail-cuff systolic blood pressure was significantly higher in ANG II compared with control rats beginning the second day of infusion and continuing to the end of 2 wk. Both aorta and external spermatic artery (first-order arteriole of the cremaster muscle) developed increased wall-to-lumen ratios in the ANG II rats, but this occurred by hypertrophy of the wall in the aorta and reduction of the lumen in the arteriole. Digoxigenin-labeled cRNA probes were used for in situ hybridization of vascular sections to identify PDGF-A mRNA. Gene expression of PDGF-A in ANG II rats was upregulated in the hypertrophied aorta and the nonhypertrophied arteriole. With the use of immunocytochemistry techniques, PDGF-A and proliferating cell nuclear antigen were increased in the aorta but not in the arterioles of ANG II rats compared with control rats. These results suggest that the difference in growth response between the aorta and the arteriole induced by ANG II may lie in posttranscriptional modification of PDGF-A mRNA, differential control of transition, or turnover of PDGF-A protein.

Progressive improvement in the structure of resistance arteries of hypertensive patients after 2 years of treatment with an angiotensin i-converting enzyme inhibitor comparison with effects of a β-locker

To investigate the effects of antihypertensive drugs on resistance artery structure, 17 essential hypertensive patients were randomly assigned to be treated with an angiotensin I-converting enzyme inhibitor, cilazapril, or a beta-blocker, atenolol, for 2 years. Blood pressure was well controlled throughout the 2 years. Before starting treatment, at the end of the first year and at the end of the second year, patients were subjected to gluteal subcutaneous fat biopsies, from which resistance-size arteries were dissected to be studied. The media width to lumen diameter ratio of arteries from patients in the cilazapril group was 7.5 +/- 0.3% before starting treatment, and decreased significantly (P < .05) to 6.3 +/- 0.2% at the end of the first year, and to 5.8 +/- 0.2% at the end of the second year, at which time it was not different from that of arteries from normotensive subjects (5.2 +/- 0.2%). In patients treated with atenolol, resistance arteries exhibited a media-to-lumen ratio of 8.0 +/- 0.6% before treatment, 8.1 +/- 0.5% after 1 year of treatment, and 7.9 +/- 0.3% at the end of the second year of treatment, all significantly higher (P < .01) than that of arteries from normotensive subjects. Thus, treatment for 2 years with the angiotensin I-converting enzyme inhibitor cilazapril resulted in progressive normalization of the structure (media-to-lumen ratio) of gluteal subcutaneous fat resistance arteries of essential hypertensive patients, whereas there was no change in patients treated with the beta-blocker atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Resistance artery structure and neuroeffector mechanisms in hypertension induced by inhibition of nitric oxide synthase.

Oral administration of NW-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, results in blood pressure elevation. In this study we investigated resistance artery structure and neuroeffector mechanisms in rats treated with L-NAME. After 5 days of treatment the morphology of resistance arteries was unchanged, whereas after 2 or 4 weeks, when rats were hypertensive, the media was thicker and the media-to-lumen ratio was enhanced. When L-NAME administration was stopped for 2 weeks, the media-to-lumen ratio remained increased. At all time periods under L-NAME and 2 weeks after stopping treatment, the dose-response to norepinephrine was significantly more sensitive than in controls, with a concomitant slight increase in efficacy. Cocaine (3 mumol/L) or L-NAME (100 mumol/L) applied in vitro produced a leftward displacement of the dose-response of arteries from controls to norepinephrine, and abolished the difference with vessels from L-NAME-treated rats. Responses evoked by electrical field stimulation were also displaced to the left in L-NAME-treated rats and by L-NAME in vitro, and exhibited a slight increase in maximal response. Dose-response curves to methoxamine, which is not subject to neuronal reuptake, were displaced to the left by L-NAME in vivo and in vitro, similarly to those of norepinephrine, but were not displaced by cocaine in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

29 Prospective trial of effects of an angiotensin I-converting enzyme inhibitor and a beta-blocker on structure and function of resistance arteries in mild essential hypertension

Methods: Seventeen male untreated mild essential hypertensive patients with a mean age of 41 years agreed to participate in a double-blind randomized trial to test the effects of treatment with cilazapril, an inhibitor of angiotensin I converting enzyme, in comparison with treatment with atenolol, a beta-blocker, on the structure and function of subcutaneous resistance arteries. Patients were randomized to receive either 2.5–5 mg cilazapril or 25–100 mg atenolol per day. Results: Systolic/diastolk blood pressure was 147/99 and 148/99 mmHg before treatment and 132/86 and 131/85 mmHg at 1 year of treatment in the two groups, respectively. Cilazapril treatment for 1 year resulted in a reduction in the media: lumen ratio of resistance arteries (150–400 μm lumen diameter) dissected from subcutaneous gluteal biopsies from 7.5±0.3% before treatment to 6.3±0.2% 1 year later (P<0.05), still slightly but significantly larger (P<0.05) than the media: lumen ratio of resistance arteries of normotensive controls (5.1 ±0.3%). In arteries from patients treated with atenolol there was no significant change with treatment (8.0±0.6% before and 8.1 ±0.5% after 1 year of treatment). Active wall tension responses to endothelin-1 were blunted in hypertensive patients and normalized in the cilazapril-treated patients, but unchanged in those taking atenolo). Relaxation in response to acetylcholine of norepinephrine pre-contracted arteries was stiD significantly reduced after 1 year (P<0.05) in normotensive participants treated with atenolol, but not in those who had received cilazapril. Conclusion: Treatment for 1 year with the converting enzyme inhibitor cilazapril thus corrects some structural and functional abnormalities of resistance arteries from mild essential hypertensive patients.

Intracellular signal transduction for vasoactive peptides in hypertension.

Increased peripheral resistance is the hallmark of hypertension. It may result in part from exaggerated vascular reactivity of resistance arteries. Some changes in density of surface receptors for different vasoconstrictors and vasorelaxants have been described that could play a role in physiological findings in hypertension. Smooth muscle cells of resistance arteries have increased cytosolic free calcium concentration in some models of experimental hypertension, which may contribute to enhance vascular responses. Exaggerated response of the inositol phosphate-calcium pathway has been demonstrated after stimulation with some vasoconstrictor agents such as norepinephrine, angiotension II, and vasopressin. In contrast, responses to the potent vasoconstrictor peptide endothelin-1 are either normal (in spontaneously hypertensive rats) or blunted (in deoxycorticosterone-salt hypertension). In the latter case, endothelin receptor density, inositol phosphate and diacylglycerol generation, and cytosolic calcium responses agree with blunted response of blood vessels. Increased basal cytosolic calcium and exaggerated sensitivity of myosin light chain to calcium may be mechanisms underlying increases in sensitivity of signal transduction in smooth muscle in some models of hypertension. However, in general, signal transduction of receptors for vasoconstrictors appears to be blunted rather than exaggerated, except for responses to angiotensin II. Altered structure of resistance arteries (remodeling) may be a mechanism that, even in presence of blunted intracellular signal transduction, may result in enhanced pressor responsiveness of blood vessels in hypertension.

Dose-dependent effects of perindopril on blood pressure and small-artery structure.

Long-term treatment of young spontaneously hypertensive rats (SHR) with angiotensin-converting enzyme (ACE) inhibitors has a persistent effect on blood pressure when treatment is withdrawn. The aim of the present study was to determine whether this effect could be mediated by the effect of treatment on resistance-artery structure. We determined the dose dependence of ACE-inhibitor therapy on blood pressure and small-artery structure during treatment and on the recovery of blood pressure when treatment was withdrawn. SHR (40 per group) were treated from age 4 to 24 weeks with one of three doses of perindopril (0.4, 0.8, or 1.5 mg/kg per day). Control groups were untreated SHR and Wistar-Kyoto rats. At 24 weeks, treatment was stopped and small arteries were taken from half of the rats from the mesenteric, femoral, cerebral, and coronary vascular beds for morphological and functional measurements. The blood pressure of the other half of the rats was followed until 36 weeks of age. During treatment, perindopril caused a dose-dependent reduction in blood pressure and in the media-lumen ratio and media area of the small arteries, whereas there was a dose-dependent increase in lumen diameter. The effect of treatment on the structure of arteries from the different vascular beds was homogeneous. Compared with values from Wistar-Kyoto rats, blood pressure normalization in SHR was not associated with full normalization of structure. After withdrawal of treatment, there was an inverse relation between perindopril dose and the persistent effect.(ABSTRACT TRUNCATED AT 250 WORDS)

REMODELLING OF RESISTANCE ARTERIES BY TREATMENT WITH ENALAPRIL IN THE NEW ZEALAND GENETICALLY HYPERTENSIVE RAT

1. New Zealand genetically hypertensive (GH) rats were treated with enalapril from the age of 4 to 10 weeks and the effects of treatment on the structure of mesenteric resistance arteries (MRA) was measured by use of stereological analysis of stained sections and by myograph techniques. 2. Tail-cuff blood pressure (BP) was measured weekly and intra-arterial BP recorded just before MRA were either fixed by perfusion or mounted on a myograph. 3. Stereological techniques (Cavalieri and optical dissector) were used to determine media and lumen volume, fraction of smooth muscle (SM) within the media and SM cell density. For MRA mounted on the myograph, lumen diameter, media thickness, active tension and active pressure were recorded. 4. BP was significantly (P < 0.0001) lowered by enalapril throughout the experiment. Intraarterial BP and left ventricular (LV) mass were also significantly lower in the enalapril treated GH rats (P < 0.0001). 5. Stereological measurements showed that enalapril treatment significantly (P < 0.0001) reduced media volume by 50%, doubled lumen volume (P < 0.0001), reduced the fraction of SM in the media (P < 0.04), and had no effect on the number of SM cell layers or on SM cell density. 6. Myograph measurements showed a decrease in the ratio media thickness/lumen diameter which was accompanied by a decrease in maximum active tension and pressure development. 7. In the GH rat early treatment with enalapril causes a true loss of medial tissue that is not simply due to rearrangement of existing media around an enlarged lumen.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Antihypertensive Treatment on Vascular Remodeling in Essential Hypertensive Patients

Resistance arteries may play a critical role in hypertension, and correcting their structural abnormalities may improve the clinical outcome of hypertensive patients. There have been several studies of the effects of antihypertensive treatment on the structure of resistance vessels in hypertension. These studies have yielded inconclusive results regarding the ability of individual drugs to induce regression of the changes occurring in blood vessels in hypertension, both in experimental models and in humans. This article reviews the results of studies of antihypertensive treatment on resistance vessel structure and function, and in particular those of a recent study in which the effects of treatment with the angiotensin-converting enzyme inhibitor cilazapril and the beta-blocker atenolol on the structure and function of subcutaneous resistance arteries were evaluated in a double-blind randomized trial in patients with mild essential hypertension. In this study, patients were randomly assigned to receive either cilazapril or atenolol, and blood pressure was effectively controlled for 1 year. Treatment for 1 year with cilazapril resulted in a significant reduction in the media-to-lumen ratio of resistance arteries dissected from subcutaneous gluteal fat biopsy samples, although the ratio was still slightly but significantly larger than that of resistance arteries of normotensive controls. In arteries from patients treated with atenolol there was no significant change in media-to-lumen ratio with treatment. Contractile responses to several vasoconstrictors, particularly endothelin-1, which were blunted in hypertensive patients, were normalized in the cilazapril-treated patients, but were unchanged in those taking atenolol. These results suggest that in humans it is possible to correct in part the vascular remodeling present in hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Persistent hypertension following inhibition of nitric oxide formation in the young Wistar rat: role of renin and vascular hypertrophy.

To determine whether induction of arterial hypertension in young normotensive Wistar rats by chronic inhibition of nitric oxide production with NG-nitro-L-arginine methyl ester (L-NAME) produced a form of self-sustained hypertension, and to investigate the role of the renin-angiotensin system and vascular hypertrophy in the hypertensive process. Three-week-old Wistar rats were given 100 or 40 mg/kg per day L-NAME or 40 mg/kg per day L-NAME plus 100 mg/kg per day captopril in their drinking water for between 4 and 7 weeks. Systolic blood pressure was measured by tail-cuff plethysmography both during treatment and after the treatment had been stopped. The effect of treatment on plasma renin was measured and the effect of treatment on mesenteric resistance artery structure was determined using a small-vessel myograph. L-NAME produced a progressive and marked increase in blood pressure during the period of treatment. Hypertension was sustained for 14 weeks after stopping treatment. L-NAME resulted in a fourfold increase in plasma renin which remained elevated after treatment was stopped. Blood pressure was correlated with plasma renin levels. Treatment with L-NAME plus captopril markedly attenuated the rise in blood pressure and captopril also produced a marked fall in blood pressure in rats that developed persistent hypertension. Rats with self-sustained hypertension exhibited both cardiac and mesenteric resistance vessel hypertrophy. The induction of vascular hypertrophy with low-dose L-NAME did not result in the development of self-sustained hypertension. Chronic L-NAME treatment in young rats can produce a form of persistent hypertension which is renin-dependent and which does not seem to involve a vascular amplifier mechanism.

Effect of hypertension induced by nitric oxide synthase inhibition on structure and function of resistance arteries in the rat.

To determine whether inhibition of generation of endothelium-derived relaxing factor or nitric oxide (NO) resulted in elevated blood pressure and its effect on resistance arteries, rats were offered NG-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NO synthase, in their drinking water. Blood pressure (BP) rose slightly from 100 +/- 2 mmHg in controls to 130 +/- 5 mmHg with 25 mg/Kg L-NAME per day and to 173 +/- 9 mmHg with 100 mg/Kg per day for 2 1/2 to 4 weeks. Rats were studied after 1-2 weeks of hypertension (BP > 150 mmHg). The concentration of cyclic guanosine monophosphate, the intracellular second messenger of NO, was significantly depressed in aorta and in the mesenteric vascular bed in L-NAME-treated rats. Mesenteric resistance arteries studied on a wire-myograph exhibited similar external and lumen diameters, whereas media width and media/lumen ratio were greater (p < 0.01). Cross-sectional area of the media was similar. Active wall tension in response to norepinephrine tended to be greater in blood vessels from L-NAME-treated rats, while responses to vasopressin and endothelin-1 were unaltered. Sensitivity to norepinephrine was significantly enhanced in L-NAME-treated rats (p < 0.001), while that to endothelin-1 and arginine8 vasopressin was similar. In conclusion, administration of an NO synthase inhibitor produces hypertension, with exaggerated media/lumen ratio in resistance arteries and enhancement of response to norepinephrine, which together with decreased NO generation may contribute to elevation of blood pressure.

Morphological and functional alterations of mesenteric small resistance arteries in early renal hypertension in rats

We investigated the structure and reactivity of small resistance arteries of two-kidney, one-clip (2K,1C) and one-kidney, one-clip (1K,1C) Goldblatt hypertensive rats within 4-6 wk of development of hypertension. Blood vessels from the mesenteric vascular bed with lumen diameter less than 300 microns were mounted on a wire myograph. The media of the vessel wall was significantly increased and lumen diameter was decreased in 2K,1C and 1K,1C rats. External diameter of blood vessels was reduced in both 2K,1C and 1K,1C rats, whereas cross-sectional area of the wall was increased significantly in 1K,1C rats. Wall tension in response to KCl was significantly lower in 2K,1C and 1K,1C hypertensive rats, whereas tension in response to norepinephrine (NE) was reduced in 1K,1C hypertensive rats but was similar in 2K,1C rats and controls. Active tension in response to arginine vasopressin (AVP) was similar in all groups. As a consequence of the reduced lumen circumference of small arteries, effective pressure in response to NE was similar in hypertensive and control rats, whereas effective pressure in response to AVP was exaggerated in the hypertensive rats. The sensitivity to NE and AVP was similar in all groups. These results show the rapid development of functional and structural changes in small resistance arteries in renal hypertensive rats within 4-6 wk of hypertension, with significant reduction in external and lumen diameters, increased media width, and increased media-to-lumen ratio, which enhance vascular reactivity to vasoconstrictors, in particular NE and AVP.

Effects of protection from pressure on resistance artery morphology and reactivity in spontaneously hypertensive and Wistar-Kyoto rats.

The effects of regional hypotension on femoral resistance artery reactivity and morphology were investigated in spontaneously hypertensive rats (SHR) and control Wistar-Kyoto (WKY) rats. A partially constricting ligature (0.4 mm i.d.) was placed around the left external iliac artery at 5 weeks, which resulted in significantly reduced femoral mean arterial pressures distal to the ligature at 12 and 24 weeks. The femoral mean arterial pressure distal to the ligature in SHR was similar to that in WKY unprotected hind limbs. Resistance arteries (approximately 200 microns i.d.) were taken from unligatured and protected hind limbs and mounted in a myograph for reactivity and morphological measurements. Each experiment therefore utilized one artery distal to a ligature and one from the control hind limb. Histological examination revealed that nuclear density differed neither between strains nor between arteries from protected and unprotected femoral beds. Media thickness, media cross-sectional area, and media/lumen ratios were reduced in arteries from the hypotensive hind limb in SHR and WKY rats at 12 and 24 weeks. Arteries from the protected hind limbs of SHR were structurally indistinguishable from those from the normally perfused WKY vasculature. It is concluded that the medial content and maximal contractile responses of femoral resistance arteries from SHR and WKY rats are mainly determined by the local perfusion pressure and that normalization of perfusion pressure in SHR normalizes resistance artery structure.

Changes to the Vascular System Resulting from Hypertension and Their Effects on Response to Therapy

This review is concerned with the structure and function of resistance arteries in hypertension. By use of a variety of techniques, results indicate that raised blood pressure, in patients with essential hypertension and in animal models of hypertension, is associated with abnormalities in the structure of small arteries, expressed as an increased media: lumen ratio and reduced lumen. Functional changes, expressed as an increased sensitivity of resistance arteries to various agonists, have been seen in the spontaneously hypertensive rat, but there is no evidence for such increased sensitivity of resistance arteries in patients with essential hypertension. The role of resistance artery structural abnormalities in the long term control of peripheral resistance is not clear. On the one hand, resistance artery structure appears to be determined by the factors which produce the hypertension, both directly through neurohumoral influences and indirectly through the resulting raised intravascular pressure. On the other hand, the limited experimental evidence available suggests that small artery structure does not have a dominating effect on blood pressure and thus on the control of peripheral resistance. Furthermore, once produced, it is difficult to obtain regression of an abnormal structure. These results suggest that small artery structure is determined primarily by the prevailing intravascular pressure and the mechanisms which produce it. It is still not clear if small artery structure in itself is a major controller of peripheral resistance, but it appears that the effects of altered small artery structure may be overridden by extravascular factors.

Changes in noradrenaline sensitivity and morphology of arterial resistance vessels during development of high blood pressure in spontaneously hypertensive rats.

Changes in noradrenaline sensitivity and morphology of arterial resistance vessels during development of high blood pressure in spontaneously hypertensive rats.

Mechanical properties of arteries

Mechanical properties of arteries