Myogenic properties of brain and cardiac vessels and their relation to disease.

Intrinsic arterial myogenic function comprises the degree of constriction (myogenic tone), the arterial constriction to an increase in intraluminal pressure and vice versa (myogenic response), and forced dilation at high intraluminal pressure. Although the development of myogenic tone at 40-60 mmHg involves the influx of calcium (Ca(2+)) through voltage- dependent Ca(2+) channels and an elevation in arterial intracellular Ca(2+) (Ca(2+) i), myogenic responses between 60-140 mmHg involves predominantly Rho kinase (ROK)-mediated changes in Ca(2+) sensitivity. In the cerebral circulation an impaired myogenic response results in impaired cerebral autoregulation and susceptibility hypertension-induced cerebral haemorrhage. An impaired cerebral artery myogenic response, due to blunted ROK mediated changes in Ca(2+) sensitivity, may be a consequence of defective mechanotransduction of the intraluminal pressure stimulus; this may be a result of abnormalities in the extracellular matrix. In the coronary circulation distinctions between the mechanisms involved in the development of myogenic tone and the myogenic response have not been clearly defined. However, coronary artery myogenic tone is dependent on both Ca(2+) entry through voltage -dependent Ca(2+) channels and protein kinase C (PKC) activity. Impaired coronary myogenic tone has been observed in animal models of disease but the implications of these findings are currently uncertain.

Impaired myogenic properties of cerebral arteries from the Brown Norway rat.

OBJECTIVES: The Brown Norway rat is highly susceptible to cerebral haemorrhage when hypertension is induced experimentally, compared with the Long Evans. The aims of the study were to compare the myogenic properties and also the collagen-staining profile of the middle cerebral artery (MCA) and a small systemic artery (cremaster) from Brown Norway and Long Evans rats. METHODS: In-vitro pressure myography was used to compare the myogenic properties and the distensibility of MCA and cremaster arteries from Brown Norway rat, with those of the Long Evans rat. Histologically prepared arterial sections were stained with picrosirius red to compare the collagen-staining profile of MCA and cremaster from these strains of rat. RESULTS: In the presence of myogenic tone, the active pressure-diameter relationship (20-200  mmHg) was significantly different in MCA from the Brown Norway, but not cremaster arteries, compared with the Long Evans, characterized by in the lack of a myogenic range in the Brown Norway. Midwall collagen staining was significantly increased in MCA from the Brown Norway rat, compared with the Long Evans rat; this difference between rat strains was not observed in the cremaster arteries. However, the stress-strain relationship of MCA and cremaster arteries from the Brown Norway rat was shifted to the right, indicating an increased distensibilty of arteries from both vascular beds, compared with the Long Evans. CONCLUSION: These data demonstrate impaired myogenic properties and differences in the collagen-staining profile of MCA but not cremaster arteries from the Brown Norway rat, compared with the Long Evans. The impaired myogenic properties of MCA from the Brown Norway rat compared with the Long Evans may explain their increased susceptibility to cerebral haemorrhage when hypertension is induced experimentally.

Effects of diabetes and hypertension on structure and distensibilty of human small coronary arteries.

OBJECTIVES: Previous studies have demonstrated that hypertension and diabetes induce significant structural remodelling of resistance arteries from various vascular beds. The hypothesis of this study is that structural alterations of small coronary arteries may occur during hypertension and diabetes. This study is the first to compare human coronary small resistance artery structure from normotensive and hypertensive patients, with and without diabetes undergoing coronary arterial bypass graft surgery. METHODS: Small arteries were dissected from the atrial appendage removed from nondiabetic normotensive patients, nondiabetic hypertension and diabetic normotensive patients and hypertensive diabetic patients. Arteries were mounted in a pressure myograph and lumen diameter and wall thickness were measured across the pressure range of 3-100 mmHg to assess vessel structure and distensibility. RESULTS: There were no significant differences in the lumen diameter, wall thickness, wall-to-lumen ratio and cross-sectional area of arteries in all groups. Arteries from nondiabetic patients with hypertension demonstrated decreased distensibility compared with nondiabetic normotensive patients. There is no difference in distensibility between vessels from diabetic hypertensive patients and either diabetic or nondiabetic normotensive patients. CONCLUSION: Neither diabetes nor hypertension appears to have influenced arterial structure which may indicate that successful treatment of hypertension is associated with normal vascular structure in coronary small arteries.

Small artery structure and function in hypertension.

It has been known for some considerable time that sustained hypertension changes the circulatory architecture both in the heart and blood vessels. The histopathological alterations are of considerable interest because once they have developed they appear to carry an adverse prognostic risk. In the heart it is apparent that there is hypertrophy. This extends also to the large- and medium-sized blood vessels but at the level of the smaller arteries that contribute to vascular resistance, this is not the case: it is clear that the physiological response to higher pressures is a change in the positional conformation of the pre-existing tissue constituents and as a result of this the lumen is narrowed. This brief review looks at our knowledge in this area and attempts to clarify our understanding of how hypertension brings these about and what happens when these homeostatic mechanisms break down. From a therapeutic perspective it appears imperative to control blood pressure in an attempt to reverse or prevent such alterations to cardiovascular structure. Our knowledge is fast expanding in this field and it is only to be anticipated that as detection methodology improves everyday practice will alter as we profile our patients in terms of structural alterations in the ventricle and blood vessels.

The cardiovascular phenotype of a mouse model of acromegaly.

BACKGROUND: Although, it is accepted that there is an excess of cardiovascular mortality in acromegaly, it is uncertain whether this is due to the direct effects of growth hormone-induced-cardiomyopathy or is a consequence of atherosclerosis secondary to the metabolic syndrome often observed in this condition. Direct comparison of a mouse model of acromegaly to a mouse model of Laron's syndrome allowed us to carry out detailed phenotyping and better understand the role GH plays in the circulatory system. METHODS AND RESULTS: Transgenic mice that overexpress the growth hormone gene (GH) developed gigantism, including insulin resistance and higher blood pressures commensurate with increased body mass. In these giant mice, the hearts were hypertrophied but haemodynamic studies suggested contractile function was normal. Segments of small arteries mounted in a pressure myograph showed vascular wall hypertrophy but a preserved lumen diameter. Vascular contractile function was normal. Mice in which the GH receptor gene was disrupted or 'knocked out' were dwarf and had low blood pressure, small hearts and blood vessels but a normally functioning circulation. Correlations of body mass with cardiovascular parameters suggested that blood pressure and structural characteristics develop in line with body size. CONCLUSION: In this transgenic mouse model of acromegaly, there is cardiac and vascular hypertrophy commensurate with GH excess but normal function. Our findings support the contention that the excess mortality in this condition may be due to the development of hypertrophic cardiomyopathy rather than increased rates of atherosclerotic coronary artery disease.

Small vessel remodeling and impaired endothelial-dependent dilatation in subcutaneous resistance arteries from patients with acromegaly.

CONTEXT: Patients with acromegaly have increased morbidity and mortality, predominantly from cardiovascular disease. Hypertension and diabetes are more prevalent, and both cause small vessel remodeling and endothelial dysfunction. OBJECTIVE: To understand the structure and function of small arteries in acromegaly, sc blood vessels from gluteal fat biopsies were harvested from 18 patients with active disease (AD; age, 56 +/- 15 yr; 14 males), 23 patients in remission (CD; age, 55 +/- 12 yr; 15 males), and 20 healthy controls (age, 55 +/- 11 yr; 10 males) and examined in vitro using pressure myography. DESIGN: Contractile responses to cumulative noradrenaline concentrations were recorded and followed by dose-dependent dilator responses to acetylcholine. The acetylcholine protocol was repeated after incubation with a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester) and cyclooxygenase inhibitor (indomethacin). After perfusion with Ca(2+)-free physiological saline solution, structural measurements were recorded at varying intraluminal pressures (3-180 mm Hg). RESULTS: Wall thickness and wall:lumen ratio were increased in AD, reduced with treatment but remained greater in CD than controls. Wall cross-sectional area was increased in AD vs. controls (P < 0.001), decreased with treatment (AD vs. CD, P < 0.001), but remained higher than controls (CD vs. controls, P = 0.015). Growth index was increased in AD (20%) compared to controls (CD, 9%). Contractility was similar in all groups. Endothelial-dependent dysfunction was evident in AD compared with CD (P < 0.001) and controls (P < 0.01). Dilation did not change after N-nitro-L-arginine methyl ester but was impaired after indomethacin incubation. CONCLUSION: Active acromegaly is associated with hypertrophic remodeling of the vascular wall and embarrassed endothelial function due to reduced nitric oxide and endothelium-derived hyperpolarizing factor bioavailability, both of which may contribute to the early mortality from cardiovascular disease.

Middle cerebral artery structure and distensibility during developing and established phases of hypertension in the spontaneously hypertensive rat.

OBJECTIVE: The aims of the current study were to examine the structural properties of middle cerebral arteries (MCA) from young (5-7 weeks) and adult (20-24 weeks) spontaneously hypertensive rats (SHR), compared with age-matched Wistar-Kyoto (WKY) control rats. DESIGN: MCA segments (8-10 per group) were secured onto glass pipettes in a small vessel chamber and studied using a pressure arteriograph system. Vessels were perfused in Ca2+-free physiological salt solution to ensure the absence of tone. The wall thickness and lumen diameter were recorded at intraluminal pressures ranging from 3 to 180 mmHg using a video dimension analyser. RESULTS: There was a borderline increase in systolic pressure of the young SHR, compared with WKY controls, but the systolic pressure of the older SHR was significantly raised. The MCA lumen diameter from young SHR was reduced across the entire pressure range and arterial distensibility was not reduced, compared with WKY vessels. The MCA lumen diameter from adult SHR was reduced at high pressure, but converged with the lumen diameter of the WKY vessels at 3 mmHg, and the stress-strain relation was shifted to the left, compared with the WKY vessels; nevertheless, the slope of the tangential elastic modulus-stress relation was not significantly increased. The pressure-wall cross-sectional area relationship did not differ between strains at either time point. CONCLUSIONS: These data demonstrate eutrophic inward remodelling of the MCA from young SHR, compared with WKY controls. In the adult SHR the structural changes are probably a consequence of a reduced arterial distensibility.

Adenosine- and hypoxia-induced dilation of human coronary resistance arteries: evidence against the involvement of K(ATP) channels.

1. The ATP-sensitive potassium (K(ATP)) channel may be an important mediator of metabolic dilation in the human coronary circulation. As adenosine and hypoxia are considered to be major mediators of metabolic dilation in the coronary circulation, we investigated the effect of glibenclamide (a K(ATP) channel blocker) on adenosine and hypoxic dilation of human coronary resistance arteries, with myogenic tone, in vitro. 2. Vessels were dissected from the atrial appendage from consenting patients and studied in vitro using a pressure arteriograph system. Segments of coronary resistance artery were pressurized to 60 mmHg and the vessels studied developed spontaneous myogenic tone. 3. The K(ATP) opener pinacidil (final conc. 5 x 10(-6) M) resulted in dilation, which was completely reversed by 5 x 10(-6) glibenclamide (84+/-14 vs -10+/-9%, pinacidil and pinacidil plus glibenclamide, respectively, P=0.009, n=5). 4. Adenosine (final conc. 10(-5) M) resulted in dilation, glibenclamide (5 x 10(-6) and 10(-5) M) was without effect (118+/-12 vs 104+/-16% adenosine and adenosine plus 10(-5) glibenclamide, respectively, n.s., n=4). 5. Hypoxia (8+/-3 mmHg O2) resulted in a dilation that reversed when normoxic conditions were restored (60+/-9 vs 3+/-11% hypoxia and post-hypoxia, respectively, P=0.014, n=3). The hypoxic dilation was not affected by glibenclamide (63+/-14 vs 55+/-6% hypoxia and hypoxia plus glibenclamide, respectively, n.s., n=4). In a further series of experiments, vessels were incubated with glibenclamide (5 x 10(-6)) prior to a hypoxic challenge; again, glibenclamide was without effect on the hypoxic dilation (-0.008+/-2 vs 95+/-3% glibenclamide and glibenclamide plus hypoxia, respectively, P=0.0005, n=3). 6. These data demonstrate that glibenclamide is without effect on both adenosine and hypoxic dilation of human coronary resistance arteries with myogenic tone, from the right atrial appendage in vitro. Our findings suggest that the K(ATP) channel is unlikely to be a major mediator of metabolic dilation in these arteries.

Small artery structure and hypertension: adaptive changes and target organ damage.

Hypertension is known to be associated with an increase in the wall/lumen ratio (W/L) of the resistance arteries. Growth, eutrophic remodelling and changes in arterial distensibility can all contribute to an increase W/L. Wall stress may stimulate growth, whereas remodelling and/or reduced distensibility may be the result of prolonged contraction. Impaired or overwhelmed pressure-induced myogenic constriction, causing increased wall stress, may explain the small artery growth seen in diabetes and secondary hypertension, respectively. We find that small artery growth is a greater predictor of cardiovascular events than an increased W/L.

Myogenic and structural properties of cerebral arteries from the stroke-prone spontaneously hypertensive rat.

The aims of the study were to compare the myogenic and structural properties of middle cerebral arteries (MCAs) from the stroke-prone spontaneously hypertensive rat (SHRSP) with MCAs from the spontaneously hypertensive rat (SHR) before stroke development in SHRSP. Rats were fed a "Japanese" diet (low-protein rat chow and 1% NaCl in drinking water) for 8 wk, and cerebral arteries were studied in vitro at 12 wk using a pressure arteriograph. Systolic pressure was significantly increased in SHRSP compared with SHR at 12 wk. Between 60 and 180 mmHg, MCAs from SHR maintained an essentially constant diameter, i.e., displayed a "myogenic range," whereas the diameter of MCAs from SHRSP progressively increased as a function of pressure. Passive lumen diameter of MCAs from SHRSP was reduced at high pressure, and wall thickness and wall/lumen were increased, compared with SHR. Wall cross-sectional area was also increased in MCAs from SHRSP compared with the SHR, indicating growth. The stress-strain relationship was shifted to the left in MCAs from SHRSP, indicating decreased MCA distensibility compared with SHR. However, collagen staining with picrosirius red revealed a redistribution of collagen to the outer half of the MCA wall in SHRSP compared with SHR. These data demonstrate impaired myogenic properties in prestroke SHRSP compared with SHR, which may explain stroke development. The structural differences in MCAs from SHRSP compared with SHR were a consequence of both growth and a reduced distensibility.