Arterial properties in relation to genetic variation in alpha-adducin and the renin-angiotensin system in a White population.

Earlier studies have demonstrated the interaction between ADD1 and ACE in relation to arterial properties. We investigated whether arterial characteristics might also be related to interactions of ADD1 with other renin-angiotensin system genes. Using a family-based sampling frame, we randomly recruited 1064 Flemish subjects (mean age, 43.6 years; 50.4% women). By means of a wall-tracking ultrasound system, we measured the properties of the carotid, femoral and brachial arteries. In multivariate-adjusted analyses, we assessed the multiple gene effects of ADD1 (Gly460Trp), AGT (C-532T and G-6A) and AT1R (A1166C). In ADD1 Trp allele carriers, but not in ADD1 GlyGly homozygotes (P-value for interaction < or =0.014), femoral cross-sectional compliance was significantly higher (0.74 vs 0.65 mm(2) kPa(-1); P=0.020) in carriers of the AT1R C allele than in AT1R AA homozygotes, with a similar trend for femoral distensibility (11.3 vs 10.2 x 10(-3) kPa(-1); P=0.055). These associations were independent of potential confounding factors, including age. Family-based analyses confirmed these results. Brachial diameter (4.35 vs 4.18 mm) and plasma renin activity (PRA) (0.23 vs 0.14 ng ml(-1) h(-1)) were increased (P< or =0.005) in AGT CG haplotype homozygotes compared with non-carriers, whereas the opposite was true for brachial distensibility (12.4 vs 14.4 x 10(-3) kPa(-1); P=0.011). There was no interaction between AGT and any other gene in relation to the measured phenotypes. ADD1 and AT1R interactively determine the elastic properties of the femoral artery. There is a single-gene effect of the AGT promoter haplotypes on brachial properties and PRA.

High dietary potassium chloride intake augments rat renal mineralocorticoid receptor selectivity via 11beta-hydroxysteroid dehydrogenase.

Glucocorticoid access to renal corticosteroid receptors is regulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs), converting 11beta-hydroxyglucocorticoids into inactive 11-ketones. This mechanism plays a key role in maintaining normal salt-water homeostasis and blood pressure. To study whether renal cortical proximal and distal tubular 11beta-HSDs are modulated, upon shifting the electrolyte status (and may thereby contribute to adjusting the salt-water homeostasis), rats were treated for 14 days with diets with low (0.058 w/w%), normal (0.58%, which is the KCl content of standard European laboratory rat food) or high (5.8%) potassium chloride content. In proximal tubules, dietary KCl had no effect regarding corticosterone 11beta-oxidation in intact cells as well as 11beta-HSD1 and 11beta-HSD2 protein (Western blotting) and mRNA levels (semi-quantitative RT-PCR). In distal tubules, the low KCl diet also had no effect. However, distal tubules of rats fed the high KCl diet showed increased corticosterone 11beta-oxidation rates (1.6-fold, P<0.01) and 11beta-HSD2 protein (4-fold, P<0.01), whereas 11beta-HSD1 protein was decreased (no longer detected, P<0.05). Distal tubular 11beta-HSD mRNA levels were not changed upon dietary treatment. Our results suggest that upon dietary KCl loading distal tubular mineralocorticoid receptor selectivity for aldosterone is increased because of enhanced corticosterone 11beta-oxidation. This may contribute to the fine-tuning of salt-water homeostasis by the kidney.

Arteriolar reactivity in conscious diabetic rats: influence of aminoguanidine treatment.

The effect of 6 weeks' streptozotocin (STZ)-induced (70 mg/kg) diabetes and aminoguanidine (AG) treatment (50 mg/kg s.c. or 250-750 mg/l given in drinking water) on arteriolar reactivity to vasoactive substances was investigated in conscious rats. Studies were performed in untreated control rats (n = 13), STZ-induced diabetic rats (n = 11), AG-treated control rats (n = 12), and AG-treated diabetic rats (n = 12). Rats were provided with a dorsal microcirculatory chamber that allowed intravital microscopy of striated muscle arterioles of varying diameter (A1, large; A2, intermediate; and A3, small arterioles) in conscious animals. The mean arterial pressure (MAP) and arteriolar diameter responses to intravenous infusion of the following drugs were examined: the endothelium-dependent vasodilator acetylcholine (ACh; 3, 10, and 30 microg x kg(-1) x min(-1)), the potassium-channel opener levcromakalim (LC; 30 microg/kg), and the vasoconstrictor agents ANG II (0.1 and 0.3 microg x kg(-1) x min(-1)) and norepinephrine (NE; 0.2, 0.6, and 2.0 microg x kg(-1) x min(-1)). Baseline MAP was lower in both diabetic groups versus the nondiabetic groups (P < 0.05). AG treatment had no influence on baseline MAP. The absolute change in MAP after drug infusion tended to be lower in the diabetic rats than in their nondiabetic littermates. Arteriolar vasodilatory responses to ACh and LC were attenuated in the diabetic animals (1 +/- 7 vs. 19 +/- 7% [P < 0.05] and 7 +/- 3 vs. 34 +/- 8% [P < 0.01] in A2, respectively). AG treatment of diabetic animals did not prevent the development of this disturbance. Vasoconstrictor responses were not influenced by the diabetic state. In the intermediate arterioles of AG-treated control rats, a hyperresponse was observed after ANG II infusion (-10 +/- 2 vs. -2 +/- 2%; P < 0.05) and a hyporesponse was observed after ACh and LC infusion (2 +/- 3 and 15 +/- 6%, respectively; P < 0.05 vs. untreated control rats). These data indicate that 6 weeks of experimental diabetes is associated with a decreased endothelium-dependent and -independent vasodilatation. AG treatment had no beneficial effect on this disturbance.

Short- and long-term effects of smoking on arterial wall properties in habitual smokers.

OBJECTIVES: This study investigated the short-term effects of smoking on hemodynamic function and distensibility and compliance of large arteries in habitual smokers. In addition, the effect of smoking was not measured in nonsmokers, but vessel wall properties were compared between smokers and nonsmokers (basal state). BACKGROUND: Smoking is a well known risk factor for atherosclerosis. Loss of distensibility and compliance of large arteries may play a role in the onset of atherosclerosis. METHODS: The distensibility and compliance coefficients of the common carotid and brachial arteries were determined from the arterial wall displacement during systole and the end-diastolic diameter by using a vessel wall movement detector and from the pulse pressure as assessed in the upper arm. Cardiac function (cardiac output, stroke volume) was measured with Doppler echocardiography. Systemic vascular resistance was calculated as mean arterial pressure divided by cardiac output. RESULTS: In habitual smokers, smoking one cigarette caused a sharp increase in blood pressure (6%) and heart rate (14%). Cardiac index increased (16%), mainly because of the marked increase in heart rate. Stroke and systemic vascular resistance indexes did not change significantly. Smoking enhanced forearm blood flow after wrist occlusion (17%), but total forearm blood flow was unchanged, suggesting an increase in muscle blood flow and a decrease in skin flow. Because of higher blood pressure, the diameter of the elastic common carotid artery increased by 3% (passive phenomenon). Distensibility of the carotid artery decreased (7%), and as a result, carotid compliance was preserved. In contrast, despite higher blood pressure, the diameter of the muscular brachial artery did not change, suggesting an increased vascular tone. Brachial distensibility and compliance decreased (18% and 19%, respectively). Habitual smokers were comparable to nonsmokers with regard to blood pressure, cardiac function, vascular resistance and vessel wall properties of large arteries. Heart rate was higher in habitual smokers (14%). CONCLUSIONS: These data indicate that in habitual smokers, smoking one cigarette causes short-term increases in arterial wall stiffness that might be harmful to the artery and increase the risk for plaque rupture. Except for a higher heart rate, no obvious long-term effect of smoking was observed on hemodynamic variables and arterial stiffness. Because acute cardiovascular events are mainly due to plaque rupture, the short-term effects of smoking might be a more important risk than long-term effects for these acute ischemic events.

Vessel wall properties of large arteries in uncomplicated IDDM.

OBJECTIVE: Patients with insulin-dependent diabetes mellitus (IDDM) are at high risk for cardiovascular disease. Arterial distensibility and compliance are vessel wall properties of large arteries. Altered large artery wall properties can be an early feature of vascular dysfunction. This study investigates vessel wall properties in 30 patients with uncomplicated IDDM and 30 matched healthy control subjects. RESEARCH DESIGN AND METHODS: Vessel wall properties of the elastic common carotid (CCA) and the muscular femoral (FA) and brachial arteries (BA) were measured with a vessel wall movement detector system. Blood pressure and heart rate were recorded simultaneously with a semiautomated device. Aortic pulse wave velocity was estimated from the carotido-femoral transit time. RESULTS: Blood pressure (IDDM patients: 118 +/- 10/69 +/- 5 mmHg), pulse pressure (IDDM patients: 49 +/- 8 mmHg), and heart rate (IDDM patients: 65 +/- 9 beats/min) were similar in IDDM patients and control subjects. No statistically significant changes between IDDM patients and control subjects were found for diameter, distensibility, and compliance of the elastic CCA and the muscular BA. Distensibility (IDDM patients: 16.9 +/- 6.4 10(-3)/kPa; control subjects: 22.4 +/- 11.8 10(-3)/kPa) of the muscular FA was decreased in IDDM (P < 0.05). However, FA compliance (IDDM patients: 0.80 +/- 0.23 mm2/kPa; control subjects: 0.94 +/- 0.41 mm2/kPa) and FA diameter (IDDM patients: 7.87 +/- 1.10 mm; control subjects: 7.57 +/- 1.11 mm) did not differ statistically between IDDM patients and control subjects. Aortic pulse wave velocity was the same in IDDM patients and control subjects (IDDM patients: 5.1 +/- 0.6 m/s). No relation was found between vessel wall properties and duration of disease, actual glucose level, and HbA1c for all three arteries (CCA, BA, and FA). But the groups might have been too small to draw conclusions. CONCLUSIONS: The results of the present study show that in this group of patients with uncomplicated IDDM, vessel wall properties of elastic and muscular large arteries were not obviously reduced when compared with healthy control subjects. However, distensibility of the FA was lower in IDDM patients. Early atherosclerotic changes in IDDM frequently occur at this site. A difference related to the duration of diabetes could not be excluded.

Disproportional arterial hypertrophy in hypertensive mRen-2 transgenic rats.

In the present study, we investigated the role of enhanced vascular renin-angiotensin activity in vascular hypertrophy. We used transgenic (mRen-2)27 (renin TGR) rats, spontaneously hypertensive rats (SHR), and their respective normotensive control rats to study in situ pressure-diameter relationships in second-generation mesenteric arterial branches (in vivo diameter, 400 to 500 microns) over a pressure range of 0 to 200 mm Hg. We studied pressure-diameter curves under both control (Tyrode's solution) and fully relaxed (Tyrode's solution containing 100 mg/L potassium cyanide) conditions. From these curves, we determined mechanical properties at operating blood pressure. In both hypertensive strains, mesenteric arterial media cross-sectional area was increased, with a significantly (P < .05) stronger degree of hypertrophy in renin TGR rats. Arterial distensibility of relaxed vessels was decreased to an equal degree in both hypertensive strains. Under control conditions, distensibility was higher in SHR than in renin TGR rats but still significantly reduced compared with distensibility in normotensive rats. Wall tension was increased to an equal degree in both hypertensive strains, whereas circumferential wall stress was normal in SHR but significantly (P < .05) reduced in renin TGR rats. These results indicate that whereas vascular hypertrophy in SHR causes adaptive normalization of arterial wall stress, enhanced vascular renin-angiotensin activity causes vascular hypertrophy in excess of the hypertrophy associated with pressure elevation alone.

Effects of antihypertensive agents on local arterial distensibility and compliance.

Distensibility and compliance are important vessel wall properties. Distensibility is related to elastic properties of the arterial wall, and compliance reflects the buffering function of the artery. Distensibility is a determinant of stress on the vessel wall. A decreased distensibility might increase the risk of arterial wall damage. Therefore, a preserved local distensibility might be important in protecting the arterial wall of each particular artery and especially of those arteries that are more susceptible to vascular disease. Local distensibility and compliance of various large arteries can be measured noninvasively with echo tracking techniques. Studies on local distensibility and compliance revealed that with the calcium antagonist verapamil and the angiotensin-converting enzyme inhibitor perindopril arterial compliance increased mainly because of an increase in distensibility, with only a minor effect on arterial diameter. In contrast, the nitrate compound isosorbide dinitrate increased compliance mainly by increasing arterial diameter, without an increase in distensibility. This indicates that an increase in arterial compliance does not automatically imply an increase in arterial distensibility. The effect of antihypertensive drugs may also depend on the vascular territory. The diuretic amiloride/hydrochlorothiazide increased brachial artery compliance but not common carotid artery compliance. During angiotensin-converting enzyme inhibition the effect on arterial compliance was smaller at the carotid than the femoral artery. However, the opposite held for the nitrate compound. These distinctive effects of antihypertensive drugs on arterial distensibility and compliance and on vascular territories may be relevant to pharmacological prevention and management of arterial disease.

Aortic wall properties in normotensive and hypertensive rats of various ages in vivo.

The distensibility of the arterial system, which is partly determined by arterial wall structure, smooth muscle tone, and actual pressure level, decreases with aging and hypertension. Our aim was to compare aortic wall properties in 3- and 6-month-old normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) at comparable blood pressures in vivo. During ketamine/xylazine anesthesia in rats we performed ultrasound arterial wall tracking and invasive pressure measurements to determine, at the level of the thoracic aorta, diastolic pressure, diastolic lumen area, changes in pressure and lumen area during the cardiac cycle, and indexes of compliance and distensibility. These observations were combined with histological measurements for determination of media cross-sectional area and thickness and the incremental elastic modulus under conditions as expected in situ. Anesthesia abolished the difference in diastolic pressure between SHR and WKY. Between 3 and 6 months of age in WKY, diastolic area and incremental elastic modulus increased significantly, distensibility decreased, and all other recorded variables were not modified. Between 3 and 6 months of age in SHR, diastolic area and incremental elastic modulus increased, distensibility of the aortic wall decreased, and all other mechanical and structural properties did not change significantly. At both ages, diastolic area and compliance were significantly smaller in SHR than WKY. The other mechanical and structural properties measured or calculated at comparable pressure did not differ between strains. Differences between the aorta of 3- and 6-month-old rats and between strains observed in vivo at comparable pressures can largely be attributed to differences in lumen caliber.(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular effects of 5-HT1B/1D-receptor agonists in patients with migraine headaches.

OBJECTIVES: Second-generation triptans are believed to have fewer cardiovascular effects than sumatriptan. This was investigated in vivo by comparing the vascular effects of equipotent therapeutic dosages of selective 5-HT1B/1D-receptor agonists. METHODS: Sixteen patients with migraine headaches completed a double-blind, placebo-controlled, four-way crossover study. With ultrasonography and applanation tonometry used 1.5 hours after the oral intake of sumatriptan (50 mg), rizatriptan (10 mg), zolmitriptan (2.5 mg), or placebo arterial vessel wall properties, blood flow and pressure waveforms were measured in common carotid, brachial, and temporal arteries. At the brachial artery, flow-induced vasodilation (an endothelium-dependent process) was evaluated, and blood pressures were recorded. RESULTS: Mean arterial pressure, 91 +/- 2 mm Hg after placebo, increased (P < .05) by 4% to 6% after administration of each triptan. Each active treatment decreased (P < .001) both brachial and carotid artery diameter. Isobaric compliance of the brachial artery, 0.077 +/- 0.010 mm2/kPa after placebo, decreased (P < .01) by 11% +/- 8%, 11% +/- 11%, and 23% +/- 7% after administration of sumatriptan, rizatriptan, and zolmitriptan, respectively. Isobaric compliance of the carotid artery was 1.31 +/- 0.10 mm2/kPa after placebo (no change). Zolmitriptan was the only triptan that decreased temporal artery diameter significantly (by 12% +/- 3%, P < .001). The resistance of the temporal artery vascular bed increased after administration of sumatriptan (by 26% +/- 11%, P < .05) and zolmitriptan (by 40% +/- 9%, P = .001). Flow-induced vasodilation was unaffected. CONCLUSIONS: Selective 5-HT1B/1D-receptor agonists induce vasoconstriction and decrease compliance of conduit arteries. These effects are more pronounced at muscular (temporal, brachial) compared with elastic (carotid) arteries. Resistance is only increased at the temporal artery vascular bed, suggesting cranioselectivity for resistance vessels. Endothelial function is not differently affected by any of the triptans tested.

Validation of a continuous baroreceptor reflex sensitivity index calculated from spontaneous fluctuations of blood pressure and pulse interval in rats.

OBJECTIVE: To develop and validate a technique for the continuous computerized calculation of the baroreceptor reflex sensitivity (BRS) of the heart rate in rats. DESIGN: The BRS was calculated from spontaneous changes in blood pressure and pulse interval using spectral analysis as well as time-series techniques. The BRS values obtained with these techniques were compared with those obtained by standard pharmacological methods. METHODS: The blood pressure and pulse interval in adult Wistar-Kyoto (WKY) rats were recorded on a beat-to-beat basis for two consecutive 30 min periods. During one of these periods the BRS was determined pharmacologically by injections of nitroprusside and phenylephrine. Measurements were performed after administration of saline as vehicle or during manipulation of the autonomic nervous system by infusion of metoprolol, methyl-atropine and hexamethonium. Sequential time-series methods for continuous BRS calculation were tested for 24 h periods in intact WKY rats as well as in WKY rats that had been subjected to sino-aortic denervation or to electrical lesioning of the nucleus tractus solitarius. RESULTS: The correlation coefficient between BRS values in intact WKY rats derived from the pharmacological method and those from spectral analysis techniques was low (R2 = 0.16). The correlation coefficient between BRS values from the pharmacological method and those from the developed time-series method was higher (R2 = 0.64). The BRS measured using the latter method was found to vary over 24 h with the highest values during the sleeping period. After surgical elimination of the baroreflex, the algorithm returned BRS values close to zero throughout the 24 h period. The BRS estimate was found to be a measure of the parasympathetic rather than of the sympathetic component of the baroreceptor reflex. CONCLUSION: The developed time-series method calculates an index of the gain of the cardiac baroreflex in rats faithfully. This method can be implemented in data acquisition software, allowing continuous on-line monitoring of the cardiac baroreflex gain.

Autonomic control of ultradian and circadian rhythms of blood pressure, heart rate, and baroreflex sensitivity in spontaneously hypertensive rats.

OBJECTIVE: To examine the influence of the autonomic nervous system on ultradian and circadian rhythms of blood pressure, heart rate and baroreflex sensitivity of heart rate (BRS) in spontaneously hypertensive rats (SHR). METHODS: Spontaneous fluctuations in blood pressure, heart rate and BRS in SHR were recorded continuously for 24 h using a computerized system and compared with those in Wistar-Kyoto (WKY) rats. Furthermore, 24 h recordings were performed in SHR during cardiac autonomic blockade by metoprolol and methyl-atropine, vascular autonomic blockade by prazosin, ganglionic blockade by hexamethonium and vagal stimulation by a low dose of scopolamine. The magnitudes of the ultradian fluctuations in blood pressure, heart rate and BRS were assessed by wide-band spectral analysis techniques. RESULTS: The BRS was lower in SHR than it was in WKY rats throughout the 24 h cycle. In both strains high values were found during the light, resting period, whereas low values were found during the first hours of the dark, active period. The circadian rhythmicity of the blood pressure in SHR was abolished completely during the infusions of prazosin and hexamethonium. In contrast, the circadian rhythmicities of the blood pressure and heart rate were not altered by infusions of metoprolol, methyl-atropine and the low dose of scopolamine. Power spectra of the blood pressure and heart rate lacked predominant peaks at ultradian frequencies and showed 1/f characteristics. In the absence of autonomic tone, the ultradian fluctuations in heart rate, but not in blood pressure, were decreased. The ultradian BRS spectra had no 1/f shape, but showed a major peak at approximately equal to 20 min for 71% of the WKY rats and 42% of the SHR. CONCLUSIONS: The influence of the autonomic nervous system on the blood pressure and heart rats in SHR is frequency-dependent. The circadian, but not ultradian, blood pressure rhythmicity is controlled by vascular autonomic activity. Conversely, the circadian, but not ultradian, heart rate rhythmicity is independent of autonomic tone. In rats, just as in humans, the trough in baroreflex sensitivity occurred after the sleeping period, when locomotor activity is resumed.

The effect of weight loss with or without exercise training on large artery compliance in healthy obese men.

BACKGROUND: Obesity is an independent risk factor for cardiovascular morbidity and mortality. Large artery compliance is thought to be associated with cardiovascular risk. The effect of weight loss on large artery compliance is not yet clarified. OBJECTIVE: To investigate the effect of weight loss, with or without exercise, on vessel wall properties in healthy obese men. DESIGN: This was a pair-matched randomized intervention study. All subjects were on an energy-restricted diet. One subject from each pair was also on an exercise programme. Measurements were performed before and at the end of the study period. The study lasted for 3 months. METHODS: The vessel wall properties of the brachial and common carotid artery were assessed using a vessel wall movement detector system in combination with applanation tonometry. RESULTS: The mean body mass index was 32.3+/-0.4 kg/m2 and decreased (P < 0.001) to 27.6+/-0.4 kg/mm2 during the study. The mean blood pressure decreased (P < 0.001) by 6%. At operating pressures, carotid artery distensibility was 27.5+/-1.7 x 10(-3)/kPa at the start of the study and 31.1+/-1.8 x 10(-3)/kPa (P < 0.04) at the end of the study. Brachial and carotid artery compliances were 0.11+/-0.01 and 1.35+/-0.08 mm2/kPa at the start of the study and tended to increase to 0.12+/-0.001 (P = 0.06) and 1.48+/-0.08 mm2/kPa (P = 0.057), respectively, at the end of the study. Isobaric compliance did not change. The diet-and-exercise group did not differ statistically from the only-diet group in the effects on weight loss, blood pressure and arterial compliance. CONCLUSION: This study shows that weight loss increased carotid artery distensibility at operating pressures, but not under isobaric conditions. This increase is probably due to the decrease in blood pressure. The addition of exercise did not result in an additional effect within 3 months.

Angiogenesis and hypertension.

BACKGROUND: The formation of new blood vessels is an important process in embryonic development and in physiological repair processes. Abnormalities in blood vessel growth have been associated with various pathologies. HYPERTENSION AND IMPAIRED VASCULAR GROWTH: The basic observation underlying the hypothesis that essential hypertension is based on an impaired capacity for vascular growth is the nature of the structural alterations of microvascular beds in essential hypertension. Recent advances in understanding the molecular and cellular mechanisms of vascular growth suggest that the remodeling of individual vessels and vascular networks in hypertension may be a pathological variant of the formation of mature networks. PATHOGENESIS OF IMPAIRED VASCULAR GROWTH: Genetic and fetal influences appear to have significant effects in determining impaired vascular development as an early cause of essential hypertension.

Is it possible to develop drugs that act more selectively on large arteries?

BACKGROUND: Patients with high pulse pressures have an increased risk for cardiovascular events. Drugs that selectively decrease high pulse pressure may be of interest for these patients. Such drugs have a more pronounced effect on large arteries than on resistance vessels. OBJECTIVE: To compare the selectivity to large arteries of the new nitric oxide donor sinitrodil with the classic nitrate isosorbide dinitrate in healthy young men in order to investigate whether it is possible to develop drugs that act more selectively on large arteries. DESIGN: The study had a double-blind, 5-way cross-over design. In randomized order, subjects received a single oral dose of 10 mg sinitrodil, 20 mg sinitrodil, 40 mg sinitrodil, isosorbide dinitrate and placebo. Measurements were performed before and 45 min after administration of the drugs. Between each drug administration, at least 3 days of wash-out was allowed. METHODS: The effects of the drugs on large arteries and resistance vessels were assessed by their effects on brachial artery compliance and total peripheral resistance, respectively. RESULTS: Brachial artery compliance increased gradually with increasing doses of sinitrodil (by 10, 20 and 27% with 10, 20 and 40 mg sinitrodil, respectively). Total peripheral resistance index decreased with isosorbide dinitrate (by 11%) and 40 mg sinitrodil (by 7%), while it remained unchanged with 10 mg and 20 mg sinitrodil. CONCLUSIONS: The results of this study show that it may be possible to develop drugs with a higher selectivity for large arteries. Such drugs may be good candidates to decrease high pulse pressure without substantially decreasing mean and diastolic blood pressures.

DNA synthesis in isolated arteries of normotensive and hypertensive rats: effects of the endothelium.

OBJECTIVES: To compare DNA synthesis in isolated arteries of normotensive and hypertensive rats and to evaluate whether removal of the endothelium affects this process. DESIGN: Carotid and renal artery segments were isolated from normotensive Wistar, Wistar-Kyoto (WKY) and Sprague-Dawley rats, and from spontaneously hypertensive rats (SHR), transgenic Sprague-Dawley rats harbouring the mouse Ren-2 gene and from WKY rats rendered hypertensive by aortic coarctation. METHODS: Artery segments were exposed in vitro to serum with or without previous gentle removal of the endothelium. Nuclear incorporation of the thymidine analogue 5-bromo-2'-deoxyuridine was visualized by immunocytochemistry and the percentage of labelled medial nuclei was determined. RESULTS: In both types of artery, obtained from 6-week-old WKY rats and from 6-week-old SHR, removal of endothelium increased the percentage of 5-bromo-2'-deoxyuridine-labelled medial nuclei (L%). Also, in the arteries of 20-week-old Wistar rats, WKY rats and WKY rats rendered hypertensive by aortic coarctation and in vessels of 11-week-old Sprague-Dawley rats and Sprague-Dawley rats harbouring the mouse Ren-2 gene, removal of endothelium increased L%. Conversely, in the arteries of 20-week-old SHR removal of the endothelium did not alter L%. Furthermore, maximally stimulated DNA synthesis was considerably smaller in de-endothelialized arteries of adult SHR than in denuded vessels from the other strains and models. CONCLUSION: These findings confirm that the endothelium can reduce DNA synthesis in the intact rat arterial smooth muscle. This effect is not modified by hypertension, but is selectively reduced in the arteries of adult SHR.

Non-invasive assessment of local arterial pulse pressure: comparison of applanation tonometry and echo-tracking.

OBJECTIVES: Pulse pressure is not constant throughout the arterial tree. Use of pulse pressure at one arterial site as surrogate for pulse pressure at another arterial site may be erroneous. The present study compares three non-invasive techniques to measure local pulse pressure: (i) internally calibrated readings from applanation tonometry, (ii) alternative calibration of pressure waves obtained with applanation tonometry and (iii) alternative calibration of arterial distension waves obtained with echo-tracking. Alternative calibration assumes mean and diastolic blood pressure constant throughout the large artery tree. DESIGN AND METHODS: Study 1 used invasive measurements in the ascending aorta as a reference method and internally calibrated tonometer readings and alternatively calibrated pressure waves at the common carotid artery as test methods. Study 2 used alternatively calibrated pressure waves as a reference method and alternatively calibrated distension waves and internally calibrated applanation tonometer readings as test methods. RESULTS: In study 1, pulse pressure from internally calibrated tonometer readings was 10.2+/-14.3 mmHg lower and pulse pressure from alternatively calibrated pressure waves was 1.8+/-5.2 mmHg higher than invasive pulse pressure. Pulse pressure from calibrated distension waves was 3.4+/-6.9 mmHg lower than pulse pressure from alternatively calibrated pressure waves. According to British Hypertension Society criteria, pulse pressure from the internally calibrated tonometer achieved grade D and pulse pressure from alternatively calibrated pressure waves achieved grade A. Pulse pressure from calibrated distension waves achieved grade B when alternatively calibrated pressure waves were used as a reference method. CONCLUSIONS: Pulse pressure obtained from alternatively calibrated tonometer-derived pressure waves and echo-tracking-derived distension waves demonstrates good accuracy. Accuracy of pulse pressure from internally calibrated applanation tonometer readings at the carotid artery is poor.

Regional haemodynamic effects of dopamine and its prodrugs L-dopa and gludopa in the rat and in the glycerol-treated rat as a model for acute renal failure.

1. In this study the renal selectivity of dopamine and its prodrugs L-dopa and gludopa, with respect to their effects on regional blood flow, vascular resistance and central haemodynamics was investigated in normal rats and in rats with glycerol-induced acute renal failure (ARF). 2. In normal, anaesthetized rats, dopamine as well as its prodrugs caused a dose-dependent reduction of vascular resistance in the kidney (RR), mesentery (MR) and hindquarters (HQR) (dose range: dopamine: 0.1-5 mumol kg-1 h-1; L-dopa and gludopa: 1-200 mumol kg-1 h-1). Blood pressure and heart rate were affected at the highest dose only. 3. Administration of glycerol induced a preferential renal vasoconstriction; renal blood flow (-60%) and vascular resistance (+190%) were significantly more affected than MR (+40%) and HQR (+60%). This was only ameliorated by a low rate (10 mumol kg-1 h-1) infusion of gludopa: the glycerol-induced reduction of renal flow and increase in RR were significantly attenuated. A high dose of gludopa (100 mumol kg-1 h-1) or any dose of L-dopa or dopamine did not induce this beneficial effect. The glycerol-induced increase in MR and HQR was not attenuated by any of the treatments used. 4. The results indicate that gludopa is not renally selective at a pharmacodynamic level in normal, anaesthetized rats. Contrary to this, a low dose of gludopa does cause a renal selective vasodilatation and reduction of RR in rats with glycerol-induced ARF. This difference could be explained by a difference in renal vascular tone between normal rats and glycerol-induced ARF rats. A high dose ofgludopa does not cause these renal-selective effects: renal resistance and renal flow are at the same level as following glycerol and saline. This is probably due to the systemic effects of the released dopamine.

Impaired arterial reactivity following cytomegalovirus infection in the immunosuppressed rat.

1. Cytomegalovirus (CMV) is a major pathogen in immunocompromised individuals and may participate in the pathogenesis of atherosclerosis in the general population. We evaluated whether CMV-infection alters the function of arterial smooth muscle. 2. Blood pressure (BP) and arterial reactivity were recorded in immunosuppressed rats that had been infected with CMV (10(5) plaque forming units i.p.). Furthermore, the reactivity of isolated arteries was compared between CMV-infected rats and rats injected with bacterial endotoxin (LPS). 3. Initially resting BP and heart rate (HR) were not modified in CMV-infected rats, but baroreflex control of HR was impaired. By the eighth day post-CMV, BP dropped precipitously and could no longer be raised by phenylephrine (PHE). 4. In mesenteric resistance arteries, isolated at this stage from CMV-infected rats, contractile responses to nerve stimulation, noradrenaline, PHE and 5-hydroxytryptamine (5-HT) were virtually absent while those to high potassium and vasopressin (AVP) were not modified. In aortae of CMV-infected rats, responses to 5-HT and AVP were impaired while those to PHE or potassium were hardly affected. Reduced contractile responses could not be restored by NG-nitro-L-arginine methyl ester (L-NAME). 5. Continuous treatment of CMV-infected rats with prazosin (0.1 mg kg-1 day-1) prevented blood pressure lowering and resistance artery changes. 6. Observations in arteries of LPS-treated rats (5-10 mg kg-1, i.p.) differed markedly from those in vessels of CMV-infected animals. The contractile reactivity of their mesenteric resistance arteries was not altered while in their aortae, responses to PHE, 5-HT and AVP were reduced. With the exception of the AVP responses, this was more pronounced in the presence of 1-arginine and reversed by L-NAME. 7. These findings indicate that CMV-infection results in a reduction of resistance artery reactivity and hypotonia. This seems not to involve cytokine-mediated induction of NO synthase in the vascular wall but may be due to alterations of excitation-contraction coupling in arterial smooth muscle in response to increased sympathetic nervous input.

Arteriolar and capillary remodelling in hypertension.

The major haemodynamic abnormality underlying elevated blood pressure in hypertension is an increase in vascular resistance. The microcirculation is a key site of increased vascular resistance in hypertension. A reduced density of arterioles and capillaries is an important common characteristic of various microvascular beds in many forms of hypertension. This microvascular rarefaction has been observed even in very early stages of the development of hypertension. A hypothesis is discussed for early microvascular rarefaction being the result of genetic and fetal mechanisms of decreased small blood vessel growth.

Timed inhibition of the renin-angiotensin system suppresses the rise in blood pressure upon awakening in spontaneously hypertensive rats.

In this study we investigated whether timed administration of drugs that inhibit the renin-angiotensin system can be used to blunt the rise in blood pressure that occurs during the transition from the resting to the active period of the day. For this purpose we compared in spontaneously hypertensive rats (SHR) the antihypertensive efficacy of the angiotensin converting enzyme (ACE) inhibitors captopril (doses: 3, 10, and 30 mg/ kg/6 h) and enalaprilat (0.3 mg/kg/6 h), and the AT1-receptor antagonist losartan (10 mg/kg/6 h) at two different treatment regimens. The antihypertensive drugs were given as a continuous 6-h infusion either during the transition from the dark to light period (DL) or that from the light to dark period (LD) for 5 consecutive days. For all agents, the average 24-h reduction of blood pressure was comparable for the LD or DL treatment regimen. However, the dynamics of the antihypertensive response were markedly different. The increase in blood pressure at awakening could be blunted much more effectively by the LD than DL treatment regimen. Furthermore, as indicated by the trough:peak ratios, blood pressure profiles were flatter with the LD than with the DL regimen. Thus, in SHR, 24-h rhythms of blood pressure can be modulated by timed administration of ACE inhibitors and losartan, such that the early morning rise in blood pressure is suppressed.