Effect of cystamine on blood pressure and vascular characteristics in spontaneously hypertensive rats.

BACKGROUND: Tissue transglutaminase (t-TG) has been implicated in small artery remodelling. The aim of this study was to determine if cystamine, an inhibitor of t-TG, could reduce blood pressure in spontaneously hypertensive rats (SHR) and if so to what extent this is mediated through small arteries. METHODS: In vitro inhibition of t-TG, with cystamine, was studied in organ culture and wire myograph setups in small mesenteric arteries obtained from SHR. In vivo treatment with cystamine (80 mg/kg/day) or amlodipine (10 mg/kg/day) was performed with osmotic pumps in adult SHR, and hemodynamic parameters determined with telemetry. Plasma concentrations of cystamine were determined with a liquid chromatography setup. Small arteries were harvested following administration of cystamine, and structural as well as functional characteristics were determined. RESULTS: SHR small arteries showed inward remodelling following in vitro activation. Administration of cystamine caused attenuation of the inward remodelling induced by activation. In vivo administration of cystamine caused a 9 ± 2 mm Hg reduction in blood pressure, but with no detectable alterations in small artery structure. CONCLUSION: t-TG is potentially involved in vascular remodelling of SHR small arteries and results support a possible role for t-TG in blood pressure control.

Orthostatic hypotensive effect of antipsychotic drugs in Wistar rats by in vivo and in vitro studies of alpha1-adrenoceptor function.

RATIONALE: Many antipsychotics cause orthostatic hypotension possibly due to antagonist action on resistance vessel alpha1A-adrenoceptors (alpha1A-AR). OBJECTIVE: We have tested this possibility by determining in Wistar rats how the orthostatic hypotensive effect of several antipsychotic drugs compares with their affinity for adrenoceptors in mesenteric small arteries (MSA with mainly alpha1A-AR) and aorta (mainly alpha1D-AR). MATERIALS AND METHODS: Using a tilt setup, orthostatic hypotension was measured in anaesthetized rats for prazosin and the antipsychotics haloperidol, sertindole, risperidone, clozapine, ziprasidone, domperidone, olanzapine, and aripiprazole. For in vitro studies, segments of MSA and aorta were mounted on a wire myograph for isometric tension recording. Cumulative concentration-response curves were constructed to phenylephrine (PE) in the absence and presence of the drugs. Apparent affinity (pA2) was calculated by Schild analysis. RESULTS: Prazosin antagonized tilt-induced and PE responses in both studies (threshold 4 ng/ml, pA2 9.52 MSA, 10.1 aorta). The rank order of the potency of the antipsychotics in the tilt experiments correlated (r2 = 0.69, P = 0.01) with the pA2-values in MSA: Risperidone and sertindole had the highest potency in the tilt test (threshold 159 and 97 ng/ml) and the highest apparent affinity in MSA (pA2 8.92 and 8.78), in contrast with aripiprazole and domperidone, which had the lowest in each case (threshold 4.1 and 3.0 microg/ml, pA2 7.17 and 6.99). In aorta, the pA2 values did not correlate with the in vivo potencies; in particular, sertindole had no functional affinity in aorta. CONCLUSION: We conclude that the orthostatic hypotensive effect in rats of the antipsychotic drugs investigated is mediated through alpha1A-ARs.

Combination of Ca2+ -activated K+ channel blockers inhibits acetylcholine-evoked nitric oxide release in rat superior mesenteric artery.

BACKGROUND AND PURPOSE: The present study investigated whether calcium-activated K+ channels are involved in acetylcholine-evoked nitric oxide (NO) release and relaxation. EXPERIMENTAL APPROACH: Simultaneous measurements of NO concentration and relaxation were performed in rat superior mesenteric artery and endothelial cell membrane potential and intracellular calcium ([Ca2+]i) were measured. KEY RESULTS: A combination of apamin plus charybotoxin, which are, respectively, blockers of small-conductance and of intermediate- and large-conductance Ca2+ -activated K channels abolished acetylcholine (10 microM)-evoked hyperpolarization of endothelial cell membrane potential. Acetylcholine-evoked NO release was reduced by 68% in high K+ (80 mM) and by 85% in the presence of apamin plus charybdotoxin. In noradrenaline-contracted arteries, asymmetric dimethylarginine (ADMA), an inhibitor of NO synthase inhibited acetylcholine-evoked NO release and relaxation. However, only further addition of oxyhaemoglobin or apamin plus charybdotoxin eliminated the residual acetylcholine-evoked NO release and relaxation. Removal of extracellular calcium or an inhibitor of calcium influx channels, SKF96365, abolished acetylcholine-evoked increase in NO concentration and [Ca2+]i. Cyclopiazonic acid (CPA, 30 microM), an inhibitor of sarcoplasmic Ca2+ -ATPase, caused a sustained NO release in the presence, but only a transient increase in the absence, of extracellular calcium. Incubation with apamin and charybdotoxin did not change acetylcholine or CPA-induced increases in [Ca2+]i, but inhibited the sustained NO release induced by CPA. CONCLUSIONS AND IMPLICATIONS: Acetylcholine increases endothelial cell [Ca2+]i by release of stored calcium and calcium influx resulting in activation of apamin and charybdotoxin-sensitive K channels, hyperpolarization and release of NO in the rat superior mesenteric artery.

Smooth muscle cell changes during flow-related remodeling of rat mesenteric resistance arteries.

To obtain information on the molecular and cellular mechanisms of flow-induced arterial remodeling, we analyzed the morphology and smooth muscle cell (SMC) characteristics in rat mesenteric resistance arteries after interventions that decreased and increased flow. Juvenile male Wistar Kyoto rats were subjected to surgery that, compared with control arteries, provided arteries with chronic low flow and chronic high flow. Low flow resulted in a decreased passive lumen diameter, hypotrophy of the artery wall, and both loss and decreased size of SMCs. Time course studies, with intervention length ranging from 2 to 32 days of altered blood flow, showed that the narrowing of the lumen diameter in low-flow arteries appeared within 2 days and that an early dedifferentiation of SMC phenotype was indicated by markedly reduced levels of desmin mRNA. High flow resulted in an increased passive lumen diameter and in hypertrophy of the artery wall. The hypertrophy resulted from SMC proliferation because SMC number, measured by the 3D-dissector technique, was increased and immunohistochemical assessment of proliferating cell nuclear antigen also showed an increase. The widening of high-flow arteries required 16 days to become established, at which time desmin mRNA was reduced. This time was also required to establish changed wall mass in both low-flow and high-flow arteries. Apoptotic cells detected by TdT-mediated dUTP-biotin nick end labeling staining were mainly located in the medial layer, and evaluation of DNA fragmentation indicated that increased apoptosis occurred in both low flow and high flow. This study shows for the first time direct evidence that reduced and elevated blood flow in resistance arteries produce, respectively, decrease and increase in SMC number, with dedifferentiation of the SMCs in both cases.

Positive effects of aggressive vasodilator treatment of well-treated essential hypertensive patients.

Increased systemic vascular resistance and coronary microvascular dysfunction are well-documented in essential hypertension (EH). We investigated the effect of additional vasodilating treatment on coronary and peripheral resistance circulation in EH patients with high systemic vascular resistance index (SVRI) despite well-treated blood pressure (BP). We enroled patients on stable antihypertensive treatment that were given intensified vasodilating therapy (ACE inhibitor, angiotensin II receptor blocker or calcium channel blocker). Before and following 6 months of intensified therapy, coronary resting and maximal artery flow were measured by transthoracic Doppler echocardiography to calculate coronary flow reserve (CFR) and minimum vascular resistance (C-Rmin). Cardiac output was estimated by inert gas rebreathing to calculate SVRI. Maximal forearm blood flow was determined by venous occlusion plethysmography to calculate minimum vascular resistance (F-Rmin). Patients were assigned into two groups: high-SVRI and low-SVRI subgroups, based on a median split at baseline. Following additional treatment SVRI decreased more in the high-SVRI group than in the low-SVRI group (14.4 vs -2.2%: P=0.003), despite similar baseline ambulatory BP (132/81 mm Hg) and BP reduction (6.5 and 4.6%: P=0.19). F-Rmin remained unchanged (6.5 vs -2.0%: P=0.30), while C-Rmin decreased by 22 and 24% (P=0.80) and CFR increased by 23 and 17% (P=0.16). Thus, intensified vasodilating therapy improved SVRI more in patients with high SVRI than in those with low SVRI. Regardless of SVRI status, the treatment improved cardiac but not forearm dilatation capacity. The substantial improvement of the hypertensive cardiac microvascular dysfunction was not related to the reduction in SVRI.

Influence of nitric oxide synthase and adrenergic inhibition on adenosine-induced myocardial hyperemia.

BACKGROUND: Myocardial perfusion during adenosine-induced hyperemia is used both in clinical diagnosis of coronary heart disease and for scientific investigations of the myocardial microcirculation. The objective of this study was to clarify whether adenosine-induced hyperemia is dependent on endothelial NO production or is influenced by adrenergic mechanisms. METHODS AND RESULTS: In 12 healthy men, myocardial perfusion was measured with PET in 2 protocols performed in random order, each including 3 perfusion measurements. First, perfusion was measured at rest. Second, either saline or the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 4 mg/kg) was infused, and perfusion during adenosine-induced hyperemia was determined. Last, in both protocols, the alpha-receptor blocker phentolamine was infused, and perfusion during adenosine-induced hyperemia was determined again. Resting perfusion was similar in the 2 protocols (0.69+/-0.14 and 0.66+/-0.18 mL. min(-1). g(-1)). L-NAME increased mean arterial blood pressure by 12+/-7 mm Hg (P<0.01) and reduced heart rate by 16+/-7 bpm (P<0.01). Adenosine-induced hyperemia (1.90+/-0.33 mL. min(-1). g(-1)) was attenuated by L-NAME (1.50+/-0.55 mL. min(-1). g(-1), P<0.01). The addition of phentolamine had no effect on the adenosine-induced hyperemia (2.10+/-0.34 mL. min(-1). g(-1), P=NS). In the presence of L-NAME, however, when the adenosine response was attenuated, phentolamine was able to increase hyperemic perfusion (2.05+/-0.44 mL. min(-1). g(-1), P<0.05). CONCLUSIONS: Inhibition of endogenous NO synthesis attenuates myocardial perfusion during adenosine-induced hyperemia, indicating that coronary vasodilation by adenosine is partly endothelium dependent. alpha-Adrenergic blockade has no effect on adenosine-induced hyperemia unless NO synthesis is inhibited.

The active tension-length curve of vascular smooth muscle related to its cellular components.

The active and passive isometric tension-length (internal circumference) relation of vascular smooth muscle has been investigated using a 100-200-micron lumen diameter artery from the rat mesenteric bed. Conditions were established under which maximal activation was obtained at all lengths. Below L0 (the length at which maximum tension, delta T0, was developed) the active tension fell with decreasing length along a line which extrapolated to 0.38 L0; below 1.1 L0 the relation was reversible regardless of the protocol used. Above L0 the active tension fell linearly with increasing length along a line which extrapolated to zero tension at 1.82 L0. At the longer lengths investigated (up to 1.6 L0) the passive tension upon which the active responses were superimposed was as high as 4.4 delta T0. However, measurements of the dynamic characteristics of the preparation (with a time resolution of 2 ms) suggest that the active tension measured is nevertheless a measure of the active properties of the contractile apparatus. Direct light microscopic observation of the effect of length change on the cells within the walls of the preparation showed that changes in vessel length produced, on average, the same percentage change in cell length. Histological examination showed no signs of cell destruction following large extensions. The results suggest that the decrease in tension with extension above L0 is due to changes in the properties of the contractile apparatus, rather than to cellular damage.

Lack of effect of anti-hypertensive treatment with felodipine on cardiovascular structure of young spontaneously hypertensive rats.

Felodipine (4(2,3-dichlorophenyl)-1,4-dihydro-2, 6-dimethyl-3-ethoxycarbonyl-5-methoxycarbonyl pyridine)), a selective vasodilating anti-hypertensive drug, was used in the treatment of spontaneously hypertensive rats (SHRs) and age-matched Wistar-Kyoto rats (WKYs) from age 6 to 14 weeks, ie during the time of high blood pressure development in SHRs. The effect of treatment on heart weight and on mesenteric resistance vessels (i.d. ca 170 microns) characteristics was investigated. In a first study, two oral doses of felodipine were added to the diet of SHRs, in concentrations of either 0.5 or 1.5 mg X g-1 rat food. Both treatments lowered mean arterial pressure by about 19% (p less than 0.001). In a second study, the lower dose of felodipine (0.5 mg . g-1 rat food) was therefore used to treat both SHRs and WKYs. Treatment did not interfere with weight or food intake of either SHRs or WKYs but increased average weekly water intake significantly. In neither strain was the pulse rate or, surprisingly, heart/body weight ratio affected by treatment. Furthermore, mesenteric resistance vessel morphology and mechanics were not affected by the blood pressure reduction. The noradrenaline and calcium sensitivity of mesenteric resistance vessels from treated rats was greater (p less than 0.001) than those from control rats. These findings indicate that blood pressure reduction with felodipine does not affect cardiovascular structure in young SHRs.

Reduced medication and normalization of vascular structure, but continued hypertension in renovascular patients after revascularization.

OBJECTIVE: The effect of invasive treatment of renal artery stenosis on the use of antihypertensive medication, blood pressure, and morphology and function of resistance arteries was investigated in 14 renovascular hypertensive patients before and after treatment compared to normotensive controls. METHODS: Use of antihypertensive medication was calculated as defined daily doses (DDD). Resistance arteries were taken from gluteal subcutaneous biopsies and analyzed in a myograph. RESULTS: Prior to invasive treatment, blood pressure of the patients was elevated compared to normotensive controls. Six months after technically successful invasive treatment, patients were still hypertensive compared to time-matched controls. The use of antihypertensive medication was reduced from 4.4+/-0.7 DDD before invasive treatment to 3.0+/-0.6 DDD 6 months after treatment. Vascular structure of resistance arteries, expressed as media/lumen ratio (media thickness to diameter), was greater in patients before invasive treatment (10.7+/-1.0%) compared to normotensive controls (7.9+/-0.8%). Media/lumen ratio of resistance arteries was reduced to that of the controls 6 months after invasive treatment despite the remaining hypertension. The functional studies showed no difference in response to acetylcholine, adenosine, noradrenaline or angiotensin II between patients and controls before or after treatment. CONCLUSIONS: This study shows that hypertension and increased media/lumen ratio of resistance arteries prevail in renovascular hypertensive patients despite antihypertensive medication and that invasive treatment is of benefit as regards use of antihypertensive medication. The study provides the novel information that the remaining hypertension is not due to uncorrected media/lumen ratio of the resistance arteries.

Determinants of vascular hemodynamic characteristics.

This discussion concerns some of the parameters affecting the hemodynamic characteristics of a blood vessel: impedance, flow resistance, and vascular wall stiffness. The parameters of greatest importance are the vessel internal radius (ri) and the elastic modulus of the vascular wall. When the smooth muscle cells in the vascular wall are inactive, the elastic modulus is determined by the combined elastic modulus of the structural components of the connective tissue, primarily elastin and collagen fibers. This combined elastic modulus is found to be proportional to the wall stress. From the proportionality factor and from knowledge of the vessel dimensions in the unpressurized vessel, one can predict the relation of ri to transmural pressure. When a vessel is activated under isometric conditions, the wall force and elastic modulus are increased by the force and elastic modulus of the smooth muscle cells. Under isobaric conditions, however, the effect of activation is to reduce both the ri and the elastic modulus. Pathologic changes resulting either in a stiffening of the connective tissue components, in an increased wall cross-sectional area, which encroaches on the lumen, or in an increased smooth muscle quantity will all cause increases in vascular characteristic impedance, vascular flow resistance, and vascular wall stiffness.

Are vascular abnormalities a primary cause or secondary consequence of hypertension?

This paper reviews the evidence that the resistance vasculature is altered in hypertension and the role that the vasculature may play in the pathogenesis of the disease. Although functional changes (i.e., increased vascular smooth muscle sensitivity) have been found to be associated with some models of hypertension (e.g., spontaneously hypertensive rat), in human essential hypertension it appears that the abnormalities that predominate in the resistance vasculature are structural in nature. These changes result in an increased media/lumen ratio of the more proximal resistance vessels (i.d. 100-300 microns), and the changes are such that they could account for many of the altered hemodynamic characteristics seen in patients with essential hypertension (e.g., increased minimum vascular resistance, increased pressor response). However, evidence that the abnormal structure of the peripheral vasculature is a prime determinant of blood pressure is still lacking, and much of the available evidence suggests that the altered structure is a secondary adaptation. Nevertheless, the abnormal vascular structure may play an important pathological role concerning the morbid consequences of the hypertensive disease, suggesting that normalization of vascular structure is a desirable aim for antihypertensive treatment. At present it seems that treatment must be continued for long periods, maybe many years, before vascular structure is normalized.

Cellular hypertrophy in mesenteric resistance vessels from renal hypertensive rats.

To determine whether the increased thickness seen in media of mesenteric resistance vessels of Wistar-Kyoto rats made hypertensive by a Goldblatt procedure (one-kidney, one clip model) was due to hypertrophy or hyperplasia of smooth muscle cells, the cellular dimensions of these vessels were estimated using a new, unbiased stereological method (the disector). Furthermore, to investigate whether the changes seen could be secondary to the increased blood pressure, morphometric measurements were also made in renal arcuate arteries, which, due to the constricting silver clip, probably had not been exposed to the increased pressure load. Vessels were mounted on a myograph, and their media thickness, lumen diameter, and maximum active wall tension response were measured. In the mesenteric vessels media thickness had increased by 58%, whereas no changes were seen in the renal vessels. Vessels were then fixed, and serial sections were made in the mesenteric vessels. The disector was used to calculate the numerical cell density in each vessel. By combining the myograph measurements and the estimated numerical cell density, the number of cells per segment unit length was calculated (renal hypertensive rats, 6.8 micron-1; sham-operated Wistar-Kyoto rats, 6.3 micron-1; p greater than 0.40) and mean cell volume was determined (renal hypertensive rats, 1541 micron 3; sham-operated Wistar-Kyoto rats, 1256 micron 3; p less than 0.02). No morphometrical changes were found in single sections of the renal arteries. We conclude that the increased media thickness observed in mesenteric resistance vessels of one-kidney, one clip Goldblatt hypertensive rats mainly was caused by smooth muscle cell hypertrophy.

Perindopril changes the mesenteric pressure profile of conscious hypertensive and normotensive rats.

Information about how antihypertensive therapy affects the arterial blood pressure profile in conscious animals is at present not available. Here we report measurements of part of the pressure profile in conscious spontaneously hypertensive rats (SHR, n = 7) and Wistar-Kyoto (WKY, n = 7) rats before and after treatment with the angiotensin-converting enzyme inhibitor perindopril. The previously developed technique that we used, provided simultaneous measurements of the undisturbed arterial blood pressure at the base of mesenteric arcades (P(arc); diameter, approximately 100 microns) and systemic mean blood pressure (MBP). The ratio P(arc)/MBP was 63 +/- 2% (mean +/- SEM) in SHR and 64 +/- 3% in WKY rats. When a bolus of perindopril (0.8 mg/kg) was injected into the aorta, P(arc)/MBP fell within 2 minutes to 51 +/- 2% (P < .05) for SHR and 56 +/- 2% (P < .05) for WKY rats, and these levels were maintained for the next hour. In contrast, MBP did not change for approximately 5 minutes in either strain, whereas after 1 hour MBP still had not changed significantly in WKY rats, but MBP had fallen by 16 +/- 2% (P < .05) in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged exposure to ouabain eliminates the greater norepinephrine-dependent calcium sensitivity of resistance vessels in spontaneously hypertensive rats.

The effects of 30 minutes of exposure to ouabain on calcium sensitivity have been investigated in two types of resistance vessels from 12 pairs of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Branches of the superior mesenteric and femoral arteries, with internal diameters of about 200 micrometer, were mounted as ring preparations in a myograph capable of measuring their isometric wall tension. Dose-response curves for calcium upon norepinephrine stimulation were determined under conditions where neuronal uptake was eliminated. Initially, when stimulated with norepinephrine, the SHR vessels from both locations were more sensitive to calcium and had stronger contractions than their controls. The addition of ouabain (1 mM) to the relaxed vessels immediately elicited a moderate, transient contraction in the branches of the femoral artery, whereas no response was observed in the mesenteric vessels. Although the addition of ouabain to activated vessels produced an immediate potentiation of the response, prolonged (30-minute) exposure to ouabain reduced active tension development upon norepinephrine stimulation in all vessels. The reduction was greatest in the SHR vessels, so that, under these conditions, the norepinephrine-activated calcium sensitivity of corresponding SHR and WKY vessels was similar. By contrast, responses to norepinephrine in high potassium solution were unaffected. The results suggest that under normal conditions, SHR vessels may have a specific increase in the permeability of the norepinephrine-activated calcium channels. Prolonged exposure to ouabain appears to reduce the permeability of these channels, providing an explanation for why this treatment eliminates the difference in calcium sensitivity of the SHR and WKY vessels.

Morphology of renal afferent arterioles in spontaneously hypertensive rats.

We present a new perfusion technique that allows arteries down to the level of capillaries to be fixed while relaxed and under a known intravascular pressure. Through a catheter inserted into the right renal artery of 12-week-old male spontaneously hypertensive rats (n = 9) and control Wistar-Kyoto rats (n = 11), the kidney vessels were rinsed with human plasma, relaxed by papaverine, and perfused with a casting resin containing microspheres. The microspheres (12 microns) became trapped in the glomeruli of the kidney and, together with a closing of the venous outflow, they caused the flow through the kidney to stop, so that the intravascular pressure was raised to the level of the input perfusion pressure (100 mm Hg). The resin material was allowed to harden, and the kidney was immersion-fixed and prepared for histomorphometrical investigations. This technique made it possible to measure both the structurally determined lumen diameter and the corresponding media thickness under clearly defined conditions. The lumen diameter of afferent arterioles close to the glomeruli showed a 17% reduction in spontaneously hypertensive rats (15.4 +/- 0.6 microns; mean +/- SEM) compared with Wistar-Kyoto rat arterioles (18.5 +/- 0.3 microns, p < 0.001). However, this was not due to media hypertrophy, because media cross-sectional area was smaller (p < 0.001) in spontaneously hypertensive rats (210 +/- 6 microns 2) compared with Wistar-Kyoto rats (274 +/- 16 microns 2). We conclude that the lumen reduction in renal afferent arterioles in spontaneously hypertensive rats is not the result of an encroachment on the lumen by a hypertrophic media.

Effects of an angiotensin-converting enzyme inhibitor, a calcium antagonist, and an endothelin receptor antagonist on renal afferent arteriolar structure.

Narrowed afferent arteriolar diameter in young, spontaneously hypertensive rats (SHR) may be a contributor to later development of high blood pressure. Thus, treatment that causes dilation of the afferent arterioles in SHR may inhibit the redevelopment of high blood pressure when treatment is withdrawn. We treated SHR with an ACE inhibitor (cilazapril, 5 to 10 mg/kg per day, high; 1 mg/kg per day, low), a calcium antagonist (mibefradil, 20 to 30 mg/kg per day), and an endothelin receptor antagonist (bosentan, 100 mg/kg per day) from age 4 to 20 weeks. Untreated SHR and Wistar-Kyoto rats were also investigated. At 20 weeks, the rats were killed, and morphology of the afferent arterioles was studied. Other SHR (untreated, high cilazapril, low cilazapril, mibefradil) were treated in exactly the same way and then followed to 32 weeks without treatment. The morphometric studies showed that cilazapril increased the lumen diameter in the afferent arterioles and decreased the media-lumen ratio in a dose-dependent manner. On withdrawal of cilazapril treatment, the reduction in blood pressure persisted. Mibefradil tended to increase afferent arteriolar diameter, whereas it did not alter media-lumen ratio. The persistent effect on blood pressure was only moderate after withdrawal of mibefradil. Bosentan had no effect on renal afferent arteriolar structure or blood pressure. In conclusion, cilazapril was more effective than mibefradil in altering afferent arteriolar structure and caused the most persistent effect on blood pressure after treatment withdrawal. The association of increased afferent arteriolar diameter and lower blood pressure level after withdrawal of treatment may suggest a pathogenic role for afferent arteriolar diameter in the development of high blood pressure in SHR.

Ouabain binding and Na+ content in resistance vessels and skeletal muscles of spontaneously hypertensive rats and K+-depleted rats.

The possible role of Na+ in the development of hypertension in rats was explored in measurements of intracellular Na+, 22Na efflux, and 3H-ouabain binding sites in resistance vessels and skeletal muscles. In resistance vessels obtained from 13-week-old spontaneously hypertensive rats (SHR) or age-matched Wistar-Kyoto rats (WKY), (Na)i, total or ouabain-resistant 22Na efflux, and the concentration of 3H-ouabain binding sites showed no significant differences. Soleus muscles obtained from 6-week-old and 13-week-old SHR contained 5 to 11% more 3H-ouabain binding sites than those of WKY. The small difference in ouabain binding probably was related more to variations in growth rate and strain than to the hypertension. In SHR and WKY the Na+ and K+ contents of gastrocnemius muscles were almost identical at 6 and 13 weeks of age. By contrast, in Wistar rats in which the (Na)i of skeletal muscle was increased sixfold by K+ depletion, the systolic blood pressure was decreased by 10%. The K+ depletion was associated with a 35 to 55% decrease in the concentration of 3H-ouabain binding sites in both resistance vessels and skeletal muscles. The results provide no support for any simple cause-effect relationships between either elevated (Na)i or altered concentration of 3H-ouabain binding sites and hypertension in SHR.

Studies of isolated resistance vessels from offspring of essential hypertensive patients.

In order to investigate whether functional and morphological changes are present in the resistance vasculature before hypertension is established, isolated subcutaneous resistance vessels were studied from 21 young normotensive subjects with a family history of hypertension and 22 controls matched for age, sex, and weight. The vessels from the offspring of hypertensive patients displayed no morphological changes or differences in reactivity or sensitivity to the vasoconstrictor agonists norepinephrine, angiotensin II, serotonin, and vasopressin. In the presence of cocaine, however, vessels from offspring showed a significantly greater shift in sensitivity to norepinephrine, a phenomenon also observed in previous studies of vessels from hypertensive patients. The results suggest that in essential hypertension, while morphological and functional abnormalities of the resistance vasculature may develop as the blood pressure rises, a defect in neuroeffector activity is present before hypertension is established and may be a manifestation of abnormal sympathetic nervous system activity underlying the disease.

Cardiac mass and peripheral vascular structure in hydralazine-treated spontaneously hypertensive rats.

We have examined the effect of antihypertensive treatment on heart weight and on structural and functional characteristics of isolated mesenteric resistance vessels (internal diameter 170-220 micron) in spontaneously hypertensive rats (SHR) and in Wistar-Kyoto rats (WKY). The SHR and WKY were treated with hydralazine from the age of 4 weeks and were examined at ages 12 to 14 weeks and 23 to 27 weeks. Treated SHR had a mean blood pressure as much as 29% below that of control WKY, which in turn was 25 to 40% less than that of control SHR. In 12- to 14-week-old rats the heart to body weight ratio (which in control SHR was 13% greater than of WKY) was unaffected by treatment. Thereafter, the heart to body weight ratio of treated SHR did not increase as much as usual. At both ages, the media thickness and contractile response of the resistance vessels of the SHR (which were, respectively, 37% and 30% greater than those of vessels of WKY) were unaffected by treatment. However, because treatment caused a small (8%) increase in the lumen diameter of the vessels of the SHR, treatment did cause small, but possibly physiologically important, decreases both in the media to lumen ratio (11%) and in the pressure against which these vessels would have been able to contract (10%). Treatment had little effect on the pharmacological characteristics of vessels of either SHR or WKY. The results suggest that the increased heart weight, media thickness, and contractile response in mesenteric resistance vessels of SHR up to ages 23 to 27 weeks are due primarily to factors other than increased pressure.

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)