Changes In Resistance Vessels Research Articles

Effect of bempedoic acid on angiotensin-II induced hypertension and vascular tissue remodelling in renal hypertensive rats through AMPK multiple signalling pathways modulation.

Angiotensin II (Ang II), the effector of the renin-angiotensin system (RAS), is a key player in the pathogenesis of chronic hypertension, accompanied by vascular tissue resistance, remodelling, and damage. Chronic activation of Ang II receptor 1 (AT-1R) impairs multiple cellular targets implicated in cellular protection and survival, including adenosine Monophosphate-activated protein kinase (AMPK) signalling. In addition, it induces oxidative damage, endoplasmic reticulum (ER) stress, and fibrotic changes in resistance vessels. Our study investigated the antihypertensive and antifibrotic effects of bempedoic acid, a first-in-class antihyperlipidemic drug that targets adenosine triphosphate-citrate lyase enzyme to inhibit cholesterol synthesis. We also studied the modulation of multiple AMPK signalling pathways by bempedoic acid in a chronic hypertension model in rats. Sixty male Sprague-Dawley rats were divided into four groups: sham group, hypertensive group, standard captopril group, and bempedoic treated group. All groups underwent left renal artery ligation except the sham group. Fourteen days post-surgery, captopril and bempedoic acid were administered with a dose of 30mg/kg/day orally to captopril-standard and bempedoic acid-treated groups for two weeks, respectively. In mesenteric resistance arteries, bempedoic acid activated AMPK energy independently and augmented AMPK multiple cellular targets to adapt to Ang II-induced cellular stress. It exerted antioxidant activity, increased endothelial nitric oxide synthase, and reversed the ER stress. Bempedoic acid maintained vascular integrity and prevented vascular remodelling by inhibiting extracellular signal-regulated kinase (ERK)/transforming growth factor-β fibrotic pathway. These effects were reflected in the improved hemodynamic measurements.

P4993Tissue sodium concentration emerged as a determinant of hypertrophic vascular remodeling in type 2 diabetes

Abstract Background Studies describe a linkage between greater sodium intake and higher incidence of organ damage and cardiovascular end points. Sodium intake is usually assessed by measuring 24-hour urinary sodium excretion, which is prone to high fluctuation. For the assessment of tissue sodium a new technique (23Na-MRI) has been developed. We analyzed whether tissue sodium is linked to vascular remodeling of small resistance vessels in patients with type-2 diabetes. Methods In patients with type 2 diabetes we assessed tissue sodium content and vascular structural parameters of the retinal arterioles, since structural changes of resistance vessels (150–300 μm) can be non-invasively and reliably assessed in the retinal circulation by Scanning Laser Doppler Flowmetry (SLDF). Patients with antidiabetic medication were off the therapy (antihypertensives were kept constant) for 4 weeks. The structural parameters of retinal arterioles assessed were outer- and inner diameter (OD & ID), wall thickness (WT), wall-to-lumen ratio (WLR) and wall cross sectional area (WCSA). Tissue sodium content was assessed non-invasively with a 3.0 T clinical MRI system in each patient. Subject placed their lower legs in the center of a 23Na knee coil and sodium content in skin and muscle (musculus triceps surae) were measured. Results In patients with type 2 diabetes (N=52) we observed a significant correlation between tissue sodium content (muscle and skin) and OD, WT and WCSA and a trend has been noticed between muscle sodium content and ID and WLR. Multiple linear regression analysis demonstrated that tissue sodium content is a significant determinant of hypertrophic vascular remodeling as indicated by increased WT and WCSA, independent of age, gender and 24-hour ambulatory diastolic blood pressure. Correlation coefficients Muscle sodium content (mmol/l) Skin sodium content (mmol/l) OD (μmol) r=0.402, p=0.003 r=0.299, p=0.033 ID (μmol) r=0.265, p=0.058 r=0.202, p=0.154 WT (μm) r=0.402, p=0.003 r=0.313, p=0.026 WLR r=0.247, p=0.078 r=0.171, p=0.230 WCSA (μm2) r=0.417, p=0.002 r=0.322, p=0.021 Conclusion With the novel 23Na-MRI technology, we could demonstrate that high tissue sodium concentration is linked to with hypertrophic vascular remodeling of retinal arterioles. Thus, the reduction of tissue sodium content may emerge as a therapeutic target.

Endothelial Cell Tetrahydrobiopterin Modulates Sensitivity to Ang (Angiotensin) II-Induced Vascular Remodeling, Blood Pressure, and Abdominal Aortic Aneurysm.

GTPCH (GTP cyclohydrolase 1, encoded by Gch1) is required for the synthesis of tetrahydrobiopterin; a critical regulator of endothelial NO synthase function. We have previously shown that mice with selective loss of Gch1 in endothelial cells have mild vascular dysfunction, but the consequences of endothelial cell tetrahydrobiopterin deficiency in vascular disease pathogenesis are unknown. We investigated the pathological consequence of Ang (angiotensin) II infusion in endothelial cell Gch1 deficient (Gch1fl/fl Tie2cre) mice. Ang II (0.4 mg/kg per day, delivered by osmotic minipump) caused a significant decrease in circulating tetrahydrobiopterin levels in Gch1fl/fl Tie2cre mice and a significant increase in the Nω-nitro-L-arginine methyl ester inhabitable production of H2O2 in the aorta. Chronic treatment with this subpressor dose of Ang II resulted in a significant increase in blood pressure only in Gch1fl/fl Tie2cre mice. This finding was mirrored with acute administration of Ang II, where increased sensitivity to Ang II was observed at both pressor and subpressor doses. Chronic Ang II infusion in Gch1fl/fl Tie2ce mice resulted in vascular dysfunction in resistance mesenteric arteries with an enhanced constrictor and decreased dilator response and medial hypertrophy. Altered vascular remodeling was also observed in the aorta with an increase in the incidence of abdominal aortic aneurysm formation in Gch1fl/fl Tie2ce mice. These findings indicate a specific requirement for endothelial cell tetrahydrobiopterin in modulating the hemodynamic and structural changes induced by Ang II, through modulation of blood pressure, structural changes in resistance vessels, and aneurysm formation in the aorta.

Association Between Graded Exercise Test Indicators of Cardiovascular Disease Risks and Peripheral Vascular Stiffness

Exaggerated systolic blood pressure (SBP) responses to graded exercise testing in normotensive adults have been associated with risk of future hypertension. Venous occlusion plethysmography (VOP) non-invasively characterizes endotheliumdependent vasodilatory capacity in peripheral arteries (reactive hyperemia: RH). Endothelial dysfunction has been hypothesized to lead to functional and structural changes in resistance vessels and also contribute to increased risk for future hypertension. Limited research has been done to assess the relationship between exaggerated SBP in exercise testing and vascular status by the VOP/RH test in young normotensive adults. PURPOSE: To determine if an association exists between exaggerated SBP responses to graded exercise and peripheral vascular vasodilatory capacity. METHODS: Subjects were 50 young males (Mean ± SD: age = 22.4 ± 2.6 yr; body fat = 24.3 ± 6.1 %; BMI = 27.7 ± 5.7). Post-occlusive RH was assessed after a 5-min brachial artery occlusion using VOP and standard procedures recommended by the manufacturer (Hokanson EC-6, Bellevue, WA). Each subject performed maximal cycle ergometer exercise tests with a 15 watts/min ramping protocol. Blood pressures (BP) were measured at rest, every 2 min during, and at 15 sec intervals after exercise. Subjects recovered in the seated position, with minimal-load pedaling. Exaggerated BP was defined as any one of the following: SBP at METpk >195 mm Hg; Δ SBP >60 mm Hg at 35% METpk; Δ SBP >70 mm Hg at 65% METpk and (4) Δ diastolic BP >10 mm Hg at METpk. RESULTS: Resting SBP showed modest (r ∼ 0.33) but statistically significant (p<0.02) associations with RH scores from 30–60 sec post-occlusion. However, during exercise no relationship was found between any of the exaggerated SBP indices and the measures of peripheral artery status by VOP. DBP at 4 min post-exercise was significantly associated with RH immediately post-occlusion (r = 0.28, p = 0.04). Furthermore, when individual SBP responses from peak exercise at the highest (200–246 mmHg) vs. lowest tertiles (138–176 mmHg) were contrasted, no differences in the VOP measures of vascular status were found. CONCLUSION: Regulations of blood pressure at rest and during exercise are complex and the mechanisms by which vascular status may contribute to risk of hypertension remain poorly understood, especially with respect to younger vs. older adults. Within the limitations of this study, exaggerated SBP response to graded exercise in young adult males seems to be regulated largely by factors other than peripheral vascular status, as assessed by VOP/RH. Supported by a grant from ResMed Sleep Disordered Breathing Foundation, Poway, CA.

Changes in resistance vessels during hemorrhagic shock and resuscitation in conscious hamster model.

The unanesthetized hamster dorsal skinfold preparation was used to monitor diameters and blood flow rates in resistance arteries (small arteries, A0: diameter, 156 +/- 23 micrometers) and capacitance vessels (small veins, V0: 365 +/- 64 micrometers), during 45 min of hemorrhagic shock at 40 mmHg mean arterial pressure (MAP) and resuscitation. A0 and V0 vessels constricted significantly to 52 and 70% of the basal values, respectively, whereas precapillary arterioles (A1-A4, 8-60 micrometers) and collecting venules (VC-VL, 26-80 micrometers) did not change or tended to dilate. Blood flow rates in the microvessels declined to <20% of the basal values. Resuscitation with shed autologous blood (SAB) showed incomplete recovery of A0 and V0 diameters even 2 h after resuscitation (71 +/- 14% and 81 +/- 18%, respectively, of basal value), whereas other vessels did not change significantly. The behavior of A0 diameter coincided with the incomplete recovery of blood flow rates in all the vessels (ca. 50%) according to Poiseuille's law, and the incomplete recovery of functional capillary density (ca. 75%). Resuscitation with 8% human serum albumin in saline (HSA) tended to show higher levels of A0 constriction and A4 dilation and lowered blood flow rates. Resuscitation with SAB restored tissue PO2 27 +/- 10 mmHg after 2 h, which was near control levels (28 +/- 5 mmHg), whereas resuscitation with HSA caused tissue PO2 to remain significantly depressed (6 +/- 2 mmHg), and flow rates were significantly lower than resuscitation with SAB. These results indicate that response of the A0 vessels is the crucial determinant of blood flow in the observed area. The constriction of A0 may help sustain MAP, and constriction of V0 may enhance blood redistribution from the skin to the vital organs under the hypotensive condition.

Racial differences in minimum lower leg vascular resistance in normotensive young adults with positive and negative parental histories of hypertension.

To determine whether peripheral hemodynamic differences exist in young adult normotensive African Americans and white Americans with a positive and negative parental history of hypertension. The participants were healthy men of whom 13 were African Americans and nine white Americans with a positive parental history and 19 were African Americans and 13 white Americans with a negative parental history. Lower leg blood flows were obtained at rest and during reactive hyperemia. Lower leg minimum vascular resistance (Rmin) was computed from reactive hyperemic blood flow measured by venous occlusion plethysmography, and mean arterial blood pressure was determined by auscultation of the brachial artery. Resting blood flow and mean arterial pressure were similar in all groups. A significant race x parental history interaction effect was observed for lower leg Rmin. In the white men the lower leg Rmin was significantly greater in the positive than the negative parental group (P < 0.05). Lower leg Rmin was significantly greater in African Americans than in white men without a parental histoy (P < 0.05). Mean arterial blood pressure and heart rate were similar among the groups. This study demonstrates that lower leg Rmin is greater in young white men with a positive parental history of hypertension than those with a negative parental history. In African Americans with either positive or negative parental histories, lower leg Rmin is not different. This finding suggests that heredity may have a greater influence in white populations than in African Americans on the structural changes in resistance vessels. The study also suggests that African Americans have an earlier structural change in the resistance vessels compared with white people, regardless of a parental history of hypertension. This suggests that factors other than heredity are of importance in changing the structure of the resistance vessels.

Influence of Isradipine and Spirapril on Left Ventricular Hypertrophy and Resistance Arteries

Left ventricular hypertrophy is a common clinical feature in hypertensive patients and may be associated with structural changes in vessel morphology. In an open prospective trial, we evaluated 14 patients with previously untreated hypertension (163 +/- 2/104 +/- 2 mm Hg) and an echocardiographically determined left ventricular mass index of 141.6 +/- 5.2 g/m2, indicating left ventricular hypertrophy. We obtained a gluteal skin biopsy sample before starting treatment to investigate subcutaneous small-artery (approximately 200 to 400 microns diameter) morphology and function. Patients then received antihypertensive treatment with a combination of spirapril (3 or 6 mg) and isradipine (2.5 or 5 mg). Echocardiographic recordings were made after 6 months and 1 year, and a final biopsy was taken after 1 year. After 1 year, blood pressure was significantly reduced to 142 +/- 3/ 90 +/- 1 mm Hg (P < .001), and left ventricular mass index decreased significantly to 105.3 +/- 5.8 g/m2 (P < .001). Baseline media-lumen ratio (7.64 +/- 0.48%) was not markedly reduced (7.21 +/- 0.55%), although a decrease occurred in 7 of 12 evaluable patients. Norepinephrine-induced vasoconstriction was markedly reduced after 1 year. In conclusion, a significant regression of left ventricular hypertrophy was obtained after 1 year of treatment with spirapril and isradipine, whereas a similar reduction in medial thickness relative to lumen diameter of subcutaneous small arteries could not be observed in all patients. Reversal of structural changes in resistance vessels may require a longer treatment period in patients with proven left ventricular hypertrophy.

Vascular reactivity and flow-pressure curve in isolated kidneys from rats with N-nitro-L-arginine methyl ester-induced hypertension.

The purpose of this study was to determine the contribution of the functional changes in resistance vessels to the hypertension induced by chronic nitric oxide synthase inhibition in rats. Another goal of this study was to evaluate whether this model of hypertension is accompanied by changes in the activity of endothelium-derived hyperpolarizing factor (EDHF). Hypertension was induced by long-term (6 weeks) oral administration of N-nitro-L-arginine methyl ester (L-NAME; 75 mg/100 ml in the drinking fluid). Vascular reactivity to vasoconstrictors (phenylephrine and barium chloride) and vasodilators (acetylcholine and nitroprusside) and the flow-pressure curve were examined in isolated perfused kidneys preparations. Vascular reactivity to vasoconstrictors and the flow-pressure curve were studied under basal conditions or after the infusion of L-arginine (100 mumol/l). The activity of EDHF was evaluated by comparing the dose-response curves for acetylcholine obtained in potassium chloride- and phenylephrine-preconstricted preparations. Kidneys from L-NAME-induced hypertensive rats showed increased sensitivity to vasoconstrictors with a greater duration of the pressor responses at high doses and markedly up-shifted flow-pressure curve in comparison with that obtained in control kidneys. These differences disappeared when the kidneys from control and L-NAME-treated rats were infused with L-arginine. The kidneys from L-NAME-treated rats also showed a decreased responsiveness to acetylcholine with an augmented reactivity to nitroprusside. The acetylcholine dose-response curve was reduced in control preparations and greatly attenuated in L-NAME-treated preparations when the renal vasculature was preconstricted with potassium chloride. The changes in vascular reactivity observed in L-NAME-induced hypertensive rats may play an important role in the pathogenesis of this type of hypertension. Moreover, it is also suggested that long-term nitric oxide inhibition may be associated with increased activity of EDHF.

Biology of Blood Vessels in Hypertension

Increased peripheral vascular resistance is the hemodynamic characteristic of essential hypertension and is associated with structural and functional changes in resistance vessels. The major structural alterations constitute reduced vessel lumen diameter with thickening of the vascular wall. Only a 10% narrowing of the vessel lumen and a slight thickening of the vessel wall, which includes the medial and intimal layers, are sufficient to significantly increase peripheral resistance. At the cellular level, there is a significant increase in cell mass and collagen and elastin deposition with vascular smooth muscle hypertrophy and hyperplasia. Direct hemodynamic forces, as well as circulating and local growth regulators, stimulate cell growth in hypertensive vessels. Functional alterations that increase peripheral resistance include enhanced vascular reactivity to vasoconstrictor agents or impaired relaxation and reflect changes in excitation-contraction coupling and/or electrical properties of cells. Excess systemic or local production of vasoconstrictors or growth factors, abnormal agonist-receptor interactions, increased cell membrane permeability, defective transmembrane ion transport, intracellular calcium overload, exaggerated responses of the phosphoinositide signaling system, and altered endothelial function result in increased vascular smooth muscle growth and contractility. Whether these changes are a primary cause or secondary consequence of hypertension remains unclear but is a major focus of investigation. (Cardiol Rev 1993;1:2, 87-96)

Functional and Structural Effects of ACE Inhibitors on the Cardiovascular System

There is considerable interest in the ability of angiotensin-converting enzyme (ACE) inhibitors not only to lower blood pressure, but also to reverse hypertension-induced remodelling of the circulation. Recently published data would suggest that treatment of spontaneously hypertensive rats from an early age with ACE inhibitors will prevent the development of the expected changes in the resistance vessels as the animals age and that withdrawal of treatment is followed by a lag period before the blood pressure rises. Such findings appear to be contrary to those obtained with other hypertensive drugs where morphological changes are not as effectively attenuated and blood pressure rises rapidly after withdrawal of treatment. There is some evidence for a relationship between the efficacy of ACE inhibitors in this area and lipid solubility. This raises the possibility that the mechanism at work is related to the inhibition of tissue-located renin-angiotensin systems both in vascular smooth muscle and elsewhere, possibly in the central nervous system. An overall review of the literature indicates that treatment of spontaneously hypertensive rats with ACE inhibitors can result in prolonged reduction of blood pressure, even after treatment is withdrawn. Comparisons with other treatments suggest that it is easier to reduce blood pressure than to reverse vascular structure. However, achieving a reversal in morphological changes in resistance vessels as well as controlling blood pressure may be important for reducing the mortality from ischaemic heart disease. ACE inhibitors may have a direct effect on reversal of vascular structure, but other sites of action may also be important in this aspect of their action.

Angiotensin II

The consequence of a sustained rise in blood pressure is an adaptive change in the structure of the heart and the vasculature. In humans, the left ventricle, aorta, and medium-sized arteries undergo hypertrophy whereas the changes in resistance vessels are unclear at present. Recent studies suggest that left ventricular hypertrophy is a better predictor of stroke or cardiac risk than age or blood pressure. Therefore, the cellular mechanisms that bring about these structural alterations to the circulation in hypertension are the subject of intense research at this time. The main factor was assumed to be the pressure load imposed on the wall of the left ventricle and the arteries. However, recent work has suggested that pressor hormones can act as growth factors in vascular tissues by pressure-independent actions. This article examines the cellular mechanisms activated by angiotensin II that could be involved in producing growth and the evidence available that this nonpressor role is important in vitro and in vivo.

Histometric assessment of renal arterioles during DOCA and post-DOCA hypertension and hydralazine treatment in rats

It is now well established that structural changes in resistance vessels contribute to the long-term maintenance of many forms of hypertension. This study measured the time course of structural change in smaller resistance vessels during the development of deoxycorticosterone acetates (DOCA) hypertension and after cessation of DOCA in Wistar rats by histometric assessment of cross-sections of renal arterioles. The relationship of structural change to blood pressure was assessed by preventing hypertension during DOCA treatment with hydralazine. Blood pressure rose progressively during DOCA treatment reaching 192 +/- 3 mmHg compared with 132 +/- 2 mmHg in controls after 10 weeks. Five and 10 weeks after cessation of DOCA, following 10 weeks of DOCA treatment, post-DOCA reversal of hypertension was only partial. Medial area to internal elastic lamina (IEL) radius ratio, wall to lumen ratio and intimal area to IEL radius ratio of renal arterioles increased progressively during 10 weeks of DOCA treatment with partial reversal of the increased medial area and wall to lumen ratio 5 weeks post-DOCA. Hydralazine completely prevented hypertension in DOCA rats and also largely prevented structural change.

Does cytosolic free calcium concentration in platelets reflect tone and structural changes of resistance vessels?

To investigate tone and vascular changes of resistance vessels as related to cytosolic free calcium concentration [( Ca2+]i) in platelets, we measured forearm vascular resistance and free calcium concentration in platelets from 10 essential hypertensives and 15 normotensives. The [Ca2+]i in platelets was significantly higher in essential hypertensives than in normotensives (184 +/- 43 versus 146 +/- 23 nmol/l, P less than 0.01). The [Ca2+]i levels in platelets were significantly correlated with both systolic (r = 0.50, P less than 0.05) and diastolic blood pressures (r = 0.57, P less than 0.01). Resting vascular resistance and minimal vascular resistance were significantly higher in essential hypertensives than in normotensives (30.6 +/- 12.6 and 2.57 +/- 1.30 versus 16.3 +/- 8.0 and 1.47 +/- 0.63 mmHg/ml per min per 100 ml, P less than 0.05 and P less than 0.01, respectively). Both resting and minimal vascular resistance were significantly correlated with [Ca2+]i in platelets (r = 0.40 and P less than 0.05, r = 0.55 and P less than 0.01, respectively). These results suggest that [Ca2+]i in platelets reflects [Ca2+]i in vascular smooth muscle cells and may be a significant determinant of not only tone but also structural changes of resistance vessels.

Vasoconstrictor and vasodilator effects in normal and atherosclerotic conscious rabbits.

1. Rabbits were fed a cholesterol-rich diet for 5 two-week intervals. Polyvinyl catheters were then implanted into the femoral artery and vein. Dose-response curves to acetylcholine (ACh), noradrenaline (NA), phenylephrine (Phen) and angiotensin II (AII), were obtained in 6 cholesterol-fed and 6 control rabbits before and after isradipine (code name PN200-110) 100 micrograms kg-1. After these experiments the animals were killed and aortic rings were suspended in an organ bath. ACh but not nitroprusside-induced relaxation was impaired in atherosclerotic but not in control preparations. 2. ACh decreased blood pressure dose-dependently in both groups of rabbits even though ACh did not relax the aortae of the same rabbits in vitro. 3. Blood pressure effects reflect mostly changes in resistance vessels. The pressor effects of NA, Phen and AII were enhanced in atherosclerotic compared with normal rabbits. 4. After a dose of 100 micrograms kg-1 isradipine the dose-response curves of all agents were shifted to the right. The differences between atherosclerotic and control rabbits disappeared, except for the AII-induced pressor response, which remained enhanced in atherosclerotic animals. The calcium antagonist thus only partly corrected the atherosclerosis-associated hyperresponsiveness to vasoconstrictor agents.

Functional versus structural changes of forearm vascular resistance in hypertension.

Structural changes in resistance vessels have been considered an important factor in triggering and maintaining chronic hypertension in humans and in experimental animals. To determine whether the increased forearm vascular resistance observed following vasodilator maneuvers in hypertensive patients is predominantly due to structural or to functional changes, we examined the influence of different vasodilator stimuli on forearm blood flow and blood pressure in 22 male patients with established essential hypertension and in 22 age-matched normotensive men (age range, 28-52 years). Blood pressure was measured directly, and blood flow was measured by venous occlusion plethysmography. The maneuvers applied were 1) arterial occlusion combined with handgrip exercise and local heating, 2) intra-arterial infusion of the calcium entry blocker nifedipine, 3) intra-arterial infusion of the nonspecific vasodilator sodium nitroprusside, 4) arterial occlusion initiated after intra-arterial infusion of nifedipine. Vascular resistance during vasodilation induced by arterial occlusion or infusion of nifedipine or sodium nitroprusside remained significantly higher in the hypertensive than in the normotensive subjects. However, the maximal vasodilation achieved by the combination of arterial occlusion and nifedipine resulted in a similar resistance in both groups (1.6 +/- 0.2 in the hypertensive vs 1.4 +/- 0.2 mm Hg/ml/min/100 ml tissue in the normotensive subjects. These data suggest that there is an important functional component of the elevated resistance in patients with essential hypertension.

Maximal hand blood flow in hypertensive and normal subjects

The present study examined whether patients with systemic hypertension have evidence of structural vascular changes, whether such changes can be detected in early stages of hypertension and whether they are reversible with treatment. Hypertensive and normal subjects were studied under conditions of maximal vasodilation in which flow at a given driving pressure was considered to give an index of structural changes in resistance vessels. Thirty-two subjects were separated into 4 groups: 8 with sustained hypertension, 8 with intermittent hypertension, 8 treated hypertensive subjects maintained at systolic pressures of less than 125 mm Hg with drugs for 5 years, and 8 normal subjects. Flow was measured by venous occlusion plethysmography after 10 minutes of ischemia, using a water-filled plethysmograph at 43 °C. Arterial blood pressure was measured by the arm cuff method. Transmural pressure, calculated as mean arterial minus external pressure, was varied by imposing varying external hydrostatic pressures. Flow at a transmural pressure of 85 mm Hg was calculated for each subject from the least-mean-square plot of transmural pressure vs flow. Mean flow for normal subjects was 41 ml/100 ml/min and differed significantly from that for sustained hypertensive patients (30 ml/100 ml/min), treated hypertensive patients (33 ml/100 ml/min), and intermittent hypertensive patients (32 ml/100 ml/min) (p < 0.05). There was no overlap between sustained hypertensives and normal subjects, but half of the treated hypertensive patients were normal. Intermittent hypertensive patients usually showed evidence of pronounced arterial changes. Prolonged therapy appeared to reverse changes in some sustained hypertensives. This noninvasive method permits comparisons of hypertensive and normotensive subjects at equivalent transmural pressures.

Prevention of structural arteriolar changes in DOCA hypertension with hydrallazine.

Structural changes in resistance vessels were studied by (a) hindquarter perfusion; and (b) planimetry of cross-sections of renal arterioles in uninephrectomized rats treated for 10 weeks with saline and either DOCA (deoxycorticosterone acetate), DOCA plus hydrallazine, vehicle plus hydrallazine or vehicle only. DOCA-treated rats developed hypertension and structural change. Addition of hydrallazine prevented both hypertension and the development of structural change. Structural arteriolar change in DOCA/salt hypertension is related to the high blood pressure or a closely associated factor rather than some other effect of DOCA.

Onset and offset of structural arteriolar changes in DOCA/salt hypertension in the rat.

1. Structural changes in resistance vessels were studied sequentially (a) by hindquarter perfusion and (b) by planimetry of renal arterioles less than or equal to 20 micrometers radius, for 10 weeks during development of DOCA (deoxycorticosterone acetate)/salt hypertension in uninephrectomized rats and 5 weeks after cessation of DOCA treatment. 2. Blood pressure and haemodynamically significant structural change increased progressively during DOCA treatment and both had partially reversed 5 weeks after cessation of DOCA. 3. Arteriolar structural changes contribute progressively to the hypertension during 10 weeks DOCA treatment. Partial reversal of structural changes contributes to the fall in blood pressure after cessation of DOCA. The persisting postDOCA hypertension can be attributed to relatively irreversible structural changes.

Cerebral vasomotor reactivity in normotensive and spontaneously hypertensive rats.

Intravenously injected metaraminol induced a larger blood pressure increase in spontaneously hypertensive rats (SHR) than in normotensive controls (NR) when the pressure was raised from the same starting level. Cerebral blood flow (CBF) response in NR was either perfect autoregulation, partial autoregulation or "break-through." When present, the autoregulatory response was very rapid, i.e. the flow returned to the initial value within 10-15 sec. All SHR showed an initial prompt vasoconstrictor response which was followed after 30-40 sec by a gradual flow increase. The blood pressure elevation was highest in SHR when hypertension was induced by compression of the aorta, which supports the hypothesis that the enhanced response is, at least in part, a consequence of an increased vessel wall to lumen ratio. The characteristic CBF pattern observed in SHR after a metaraminol-induced rise in blood pressure was not seen when the blood pressure was increased by aortic compression, which suggests an effect of the drug separate from its pressor effect. During maximum vasodilatation the cerebrovascular resistance (CVR) was considerably higher in SHR than in NR. Assuming an equivalent vessel density in the 2 groups, our results suggest that structural changes in resistance vessels in SHR encroach on the lumen.

Diastolic pressure and peripheral resistance during stellate ganglion stimulation.

The mechanism of the diastolic pressure elevation occurring during left stellate ganglion stimulation was investigated. The cardiac output rose considerably, the heart rate remained essentially unchanged, and the total peripheral resistance fell moderately. The diastolic rise appeared to be due to increased blood flow rather than to any active changes in resistance vessels.