Comparison of Endothelin-1 and Noradrenaline Stimulated Inositol Phosphate Formation in Cultured Aortic Smooth Muscle Cells from Spontaneously Hypertensive and Wistar Kyoto Rats

Total [³H]-inositol phosphate formation was measured in cultured aortic smooth muscle cells from 6 and 14 week spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) normotensive rats. Basal inositol phosphate formation was significantly increased in cells cultured from SHR compared to WKY at both 6 and 14 weeks as was basal phosphatidylinositol formation. This difference in basal values was apparent after 9 h or more incubation with [³H]-myoinositol. Both endothelin-1 and noradrenaline stimulated inositol phosphate formation was unchanged in cultured smooth muscle cells from 6-week SHR compared to WKY. In cultured smooth muscle cells from 14-week SHR a decrease was observed in endothelin-1 stimulated inositol phosphate formation compared to controls. Noradrenaline stimulated inositol phosphate formation was increased in cultured cells from 14 week SHR. Endothelin-1 and noradrenaline stimulated inositol phosphate formation does not appear to be involved in the development (at 6 weeks) of hypertension in this model. However, in established hypertension (14 weeks) cells from SHR have altered total [³H] inositol phosphate formation in response to stimulation with noradrenaline and endothelin-1 although these changes are in opposite directions. Therefore, in cultured smooth muscle cells from 14-week rats noradrenaline and endothelin-1 appear to be regulated independently with regard to their effects on the phosphatidylinositol cycle.     

Endothelin stimulates phosphatidylinositol hydrolysis in rat vascular smooth muscles

The ability of endothelin to stimulate phosphatidylinositol hydrolysis in rings of rat aorta was studied. Endothelin 10(-8)-10(-5) mol/l caused increases of 200-1000% in inositol phosphate levels. However, physiological responses to endothelin have been reported in the concentration range 10(-10)-10(-8) mol/l. Thus phosphatidylinositol hydrolysis as measured in the present study does not correlate directly with functional responses. Phosphatidylinositol hydrolysis in response to endothelin was attenuated but not abolished by removal of endothelium. Attenuation of inositol phosphate production was also observed with time, consistent with the hypothesis that continuous exposure to the agonist can cause desensitization of the endothelin receptor.     

Balloon-expandable stent treatment of experimental coarctation of the aorta: early hemodynamic and pathological evaluation

The present study was intended to evaluate the acute and short-term hemodynamic, angiographic, and pathological response to balloon-expandable stent treatment of experimental coarctation of the aorta. A discrete thoracic coarctation was surgically created in six mongrel dogs (two adults, four puppies). Two months postoperatively all six dogs (8.9-30 kg) underwent left heart catheterization and coarctation stenting performed through a femoral artery cutdown. A Palmaz PS-30 stent was advanced to the coarctation through a 10 French sheath, and expanded with an angioplasty balloon chosen to equal the diameter of the proximal aorta (9-12 mm). Stent implantation was successful in each dog. The systolic pressure gradient decreased from 26.3 +/- 9.1 mmHg (mean +/- SE) to 0.5 +/- 0.5 mmHg (P = 0.04), and the coarctation diameter improved from 50 +/- 6% to 82 +/- 6% of the diameter of the proximal descending aorta (P less than 0.01). Follow-up catheterization 4-7 weeks after stenting documented no stent migration, early restenosis, thrombosis, obstruction of arterial side branches, or aneurysm formation. Pathological evaluation of the explanted segments of stented aorta documented that by 6-7 weeks the stents are covered by a neointima composed of intimal proliferation and fibrosis with an endothelial cell surface. These data suggest that balloon-expandable stainless steel stents provide excellent acute and short-term relief of coarctation in this experimental model. Larger and longer-term studies are needed to better assess the incidence of restenosis or aneurysm formation following stenting of coarctation of the aorta.     

Reduction of aortic wall motion inhibits hypertension-mediated experimental atherosclerosis

Hypertension is a well-known risk factor for coronary artery disease and carotid and lower extremity occlusive disease. Surgically induced hypertension in hypercholesterolemic animals results in increased aortic wall motion and increased plaque formation. We tested the hypothesis that reduction in aortic wall motion, despite continued hypertension, could reduce plaque formation. New Zealand White rabbits (n=26) underwent thoracic aortic banding to induce hypertension and were fed an atherogenic diet for 3 weeks. In 13 rabbits, a segment of aorta proximal to an aortic band was externally wrapped to reduce wall motion. All animals were fed an atherogenic diet for 3 weeks. Four groups were studied: 1, coarctation control (no wrap, n=7); 2, coarctation with loose wrap (n=6); 3, coarctation with firm wrap (n=7); and 4, control (noncoarcted, n=6). Wall motion, blood pressure, and pulse pressure were measured at standard reference sites proximal and distal to the coarctation by use of intravascular ultrasound. Quantitative morphometry was used to measure intimal plaque. Mean arterial pressure and cyclic aortic wall motion were equally increased proximal to the aortic coarctation in all 3 coarcted rabbit groups compared with the control group (P:<0.001). Wall motion in the segment of aorta under the loose and firm wraps was no different from the control value. The external wrap significantly reduced intimal thickening in the 4 groups by the following amounts: group 1, 0.30+/-0.03 mm(2); group 2, 0.06+/-0.02 mm(2); group 3, 0. 04+/-0.02 mm(2); and group 4, 0.01+/-0.01 mm(2) (P:<0.001). Localized inhibition of aortic wall motion in the lesion-prone hypertensive aorta resulted in significant reduction in intimal plaque formation. These data suggest that arterial wall cyclic motion may stimulate cellular proliferation and lipid uptake in experimental atherosclerosis.     

Time course of arteriogenesis following femoral artery occlusion in the rabbit

OBJECTIVE: We examined the time course of arteriogenesis (collateral artery growth) after femoral artery ligation and the effect of monocyte chemoattractant protein-1 (MCP-1). METHODS: New Zealand White rabbits received MCP-1 or phosphate buffered saline (PBS) for a 1-week period, either directly or 3 weeks after femoral artery ligation (non-ischemic model). A control group was studied with intact femoral arteries and another 1 min after acute femoral artery ligation. RESULTS: Collateral conductance index significantly increased when MCP-1 treatment started directly after femoral artery ligation (acute occlusion: 0.94+/-0.19; without occlusion: 168.56+/-15.99; PBS: 4.10+/-0.48; MCP-1: 33.96+/-1.76 ml/min/100 mmHg). However, delayed onset of treatment 3 weeks after ligation and final study of conductance at 4 weeks showed no significant difference against a 4-week control (PBS: 79.08+/-7.24; MCP-1: 90.03+/-8.73 ml/min/100 mmHg). In these groups increased conductance indices were accompanied by a decrease in the number of visible collateral vessels (from 18 to 36 identifiable vessels at day 7 to about four at 21 days). CONCLUSION: We conclude that the chemokine MCP-1 markedly accelerated collateral artery growth but did not alter its final extent above that reached spontaneously as a function of time. We show thus for the first time that a narrow time window exists for the responsiveness to the arteriogenic actions of MCP-1, a feature that MCP-1 may share with other growth factors. We show furthermore that the spontaneous adaptation by arteriogenesis stops when only about 50% of the vasodilatory reserve of the arterial bed before occlusion are reached. The superiority of few large arterial collaterals in their ability to conduct large amounts of blood flow per unit of pressure as compared to the angiogenic response where large numbers of small vessels are produced with minimal ability to allow mass transport of bulk flow is stressed.     

Effect of hypertension and risk factors on diameters of abdominal aorta and common iliac and femoral arteries in middle-aged hypertensive and control subjects: a cross-sectional systematic study with duplex ultrasound

There is a general tendency towards atherosclerosis and arterial dilatation in older age, and high blood pressure also tends to increase arterial diameters. The purpose of this study was to examine the effect of hypertension and other cardiovascular risk factors on aortic, common iliac and common femoral artery diameters. The diameters of the abdominal aorta and the iliac and femoral arteries and the extent of echogenic plaques in the aorta and the iliac arteries down to groin level were evaluated with ultrasound in 1007 middle-aged (40-60 years) men (505) and women (502), 496 with arterial hypertension and 511 controls. Twenty-eight subjects were excluded because of poor visualization. Men had significantly larger diameters of the abdominal aorta (mean 21.3+/-2.8 vs. 17.8+/-1.3 mm) and the common iliac (13.4+/-2.0 vs. 12.2+/-1.2) and common femoral arteries (11.0+/-1.4 vs. 9.7+/-0.9) than women (P for all <0.001), but arterial diameter was also related to the subject's size. Atherosclerotic plaques, age and height were associated with the diameter of the abdominal aorta in men, while high body mass index (BMI) had less significance. The diameter of the aorta was larger in hypertensive men aged 56-60 than in controls of the same age. In women, height, BMI and diastolic blood pressure (DBP) were associated with the diameter of the aorta, while systolic blood pressure (SBP) had less and age no effect. Age, plaques, height, BMI, DBP and SBP were associated with the diameters of the common iliac arteries in both genders, while smoking had an inverse correlation. The results on lipid values were inconsistent and an abnormal glucose tolerance test proved nonsignificant. In conclusion, arterial size measured as a diameter related to the subject's size was larger in men. Age, arterial plaques and blood pressure increased arterial diameter significantly. However, the hypertensive disease itself had only a minimal effect. The changes were smaller in women than in men.     

Increased inositol monophosphate production in cardiovascular tissues of DOCA-salt hypertensive rats

The purpose of the present study was to investigate alpha 1-adrenergic receptors in the heart as well as the activity and the sensitivity of the phosphoinositide pathway on tissue slices of atria, ventricles, and femoral artery of hypertensive rats treated for 4 weeks with deoxycorticosterone acetate (DOCA) and 1% saline. DOCA-salt hypertensive rats were characterized by an increased sympathoadrenal tone, as suggested by increased norepinephrine and epinephrine plasma levels. The basal activity of the phosphoinositide pathway, estimated by measuring the accumulation of inositol monophosphate in the presence of an excess of lithium, was found to be greater in atria than in ventricles and femoral artery in both normotensive and DOCA-salt hypertensive rats, but it was twofold greater in atria and ventricles of DOCA-salt hypertensive rats compared with normotensive rats. Following stimulation by norepinephrine, the production of inositol monophosphate was greater in atria and femoral artery than in ventricles in both groups. However, in DOCA-salt hypertensive rats, the production of inositol monophosphate was markedly enhanced, being about twofold greater in atria and femoral artery and about three times greater in ventricles than in tissues of normotensive rats. These differences between DOCA-salt hypertensive and normotensive animals do not appear to be associated with a difference in alpha 1-adrenergic receptor number or affinity since cardiac alpha 1-adrenergic receptor number was unchanged in hypertensive rats and the binding affinity to the receptor was significantly decreased in hypertensive rats compared with normotensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of captopril and nicardipine on baroreflex control of sympathetic nerve activity and heart rate in renal hypertension.

OBJECTIVE: To test the hypothesis that an angiotensin I converting enzyme inhibitor and a calcium channel blocker have different effects on the arterial baroreflex in renal hypertension. DESIGN AND METHODS: We examined the baroreflex control of renal sympathetic nerve activity and heart rate before and after blood pressure was reduced by a similar magnitude (11 +/- 1 mmHg) with intravenous captopril or nicardipine in two-kidney, one clip hypertensive (mean arterial pressure 92 +/- 2 mmHg, n = 12) and normotensive rabbits (mean arterial pressure 75 +/- 1 mmHg, n = 9) in the conscious state. Data obtained during activation and deactivation of baroreceptors were analysed with logistic function curves, and the maximum slope of the curve was taken as the sensitivity of the baroreflex. RESULTS: The maximum slopes of the curves relating mean arterial pressure to renal sympathetic nerve activity and to the heart rate in hypertensive rabbits were significantly smaller than the maximum slopes in normotensive rabbits. In renal hypertensive rabbits, the maximum slope of the mean arterial pressure-renal sympathetic nerve activity curve was increased with captopril compared with that with vehicle. In contrast, the maximum slope of the mean arterial pressure-heart rate curve was increased with nicardipine compared with that with vehicle. CONCLUSIONS: Our data indicating that the baroreflex control of renal sympathetic nerve activity was improved by captopril and that baroreflex control of the heart rate was potentiated by nicardipine suggest that these classes of antihypertensive agents had differential effects in conscious hypertensive rabbits.     

Changes in the aortic wall oxygen tensions of hypertensive rabbits. Hypertension and aortic wall oxygen.

Hypertension is a known risk factor for atherosclerosis. We hypothesize that hypertension causes artery wall hypoxia that contributes to the formation of atherosclerotic lesions. Therefore, we examined the effect of hypertension on the transarterial wall oxygen gradient of the rabbit aorta. Hypertensive rabbits were created by unilateral nephrectomy and contralateral renal artery narrowing. Transarterial wall oxygen gradients of the infrarenal aorta were measured using an oxygen microelectrode 14-16 weeks (short-term hypertension) and 56-58 weeks (long-term hypertension) after the rabbits were made hypertensive. The transarterial wall oxygen gradients showed significant differences among the groups. Short-term hypertension caused significantly higher oxygen tensions in the outer 30% of the artery wall and significant thinning of the artery wall when compared with long-term hypertension and control groups. Long-term hypertension caused significantly lower oxygen tensions in the inner 40% of the artery wall and significant thickening of the artery wall when compared with short-term hypertension and control groups. These changes were noted despite no difference in the partial pressure of oxygen in arterial blood or visual evidence of atherosclerotic lesion formation in the three groups. These findings suggest that hypertension alters the transarterial wall oxygen gradient. This altered transarterial wall oxygen gradient may contribute to the formation of atherosclerotic lesions.     

Paradoxical structural effects in the unilaterally denervated spontaneously hypertensive rat kidney

OBJECTIVE: To determine the effects of chronic denervation on renal vascular structure and function in young adult spontaneously hypertensive rats (SHRs). DESIGN: Unilateral renal denervation (SHRUDx) or sham-operation (SHRS) was performed in SHRs at 6 weeks of age. At 10 weeks, rats were allocated to one of three procedures designed to examine renal vascular structure and function. A further group underwent bilateral renal denervation. METHODS: In SHRUDx or SHRS groups, either the kidneys were perfusion-fixed for stereological estimates of artery wall and lumen dimensions or for vascular casting to determine arteriole lumen diameters, or the rats were anaesthetized for estimation of glomerular capillary pressure. RESULTS: Chronic unilateral renal denervation had no significant effect on the development of hypertension between 6 and 10 weeks of age, as previously reported, but resulted in luminal narrowing of the interlobular artery (denervated group 52 +/- 2 mum, sham-operated group 64 +/- 1 mum; P < 0.01 for interaction between strain and treatment), without alterations in interlobular or arcuate artery wall dimensions. There were no significant effects on either afferent or efferent arteriole lumen diameters. Estimated glomerular capillary pressure was significantly lower in the denervated kidneys of SHRUDx (47 +/- 1 mmHg) compared with kidneys of the SHRS (50 +/- 1 mmHg; P < 0.04). Mean arterial pressure was approximately 12 mmHg lower in the bilaterally denervated SHRs than in the sham-operated SHRs. CONCLUSIONS: Although bilateral denervation attenuated the development of hypertension in SHRs, unilateral denervation did not, indicating that one neurally intact kidney was sufficient to drive the normal development of SHR hypertension, but only with apparent prohypertensive compensatory changes in the denervated kidney.     

Central infusion of L-arginine or superoxide dismutase does not alter arterial pressure in SHR.

Cardiovascular responses to L-arginine and nitric oxide (NO) are augmented in the rostral ventrolateral medulla (RVLM) of spontaneously hypertensive rats (SHR), and the intravenous injection of superoxide dismutase (SOD) mimetic decreases the arterial pressure in these rats. In the present study, we examined whether the chronic central infusion of L-arginine or an SOD mimetic would reduce the blood pressure of SHR and alter responses to an NOS inhibitor or an NO donor in the RVLM. For this purpose, we administered L-arginine (SHR-Arg: 13.2 micromol/day, n=6), a stable membrane-permeable SOD mimetic, 4-hydroxy-2, 2,6,6-tetramethyl piperidine-1-oxyl (tempol) (SHR-Temp: 13.2 micromol/day, n=6), or vehicle (SHR-C: n=6) into the lateral ventricle of 12-week-old SHR for 2 weeks. When the rats reached 14 weeks of age, N(G)-nitro-L-arginine methyl ester (L-NAME: 10 nmol/50 nl) or NOC 18 (NO donor: 10 nmol/50 nl) was microinjected into the unilateral RVLM. Blood pressure did not decrease in any of the treatment groups (SHR-Arg: 209+/-4 mmHg, SHR-Temp: 210+/-6 mmHg, SHR-C: 197+/-6 mmHg). The microinjection of L-NAME into the RVLM induced a significant increase in the mean arterial pressure (MAP) (SHR-Arg: 10-4 mmHg, SHR-Temp: 12+/-4 mmHg, SHR-C: 11+/-3 mmHg), and the increases in MAP did not differ among the groups. The micro-injection of NOC 18 reduced MAP (SHR-Arg: -12+/-2 mmHg, SHR-Temp: -15+/-3 mmHg, SHR-C: -13+/-3 mmHg), and the depressor responses were comparable among groups. These results do not support the hypothesis that chronic L-arginine deficiency or the enhanced degeneration of NO by superoxide radicals in the central nervous system contributes to the maintenance of arterial pressure in SHR.     

Left internal mammary artery flap aortoplasty

In 14 consecutive 9- to 18-year-old patients with preductal aortic coarctation and isthmic hypoplasia, we resected the coarctation ridge through a longitudinal aortotomy and widened the aorta with an in situ left internal mammary artery flap. This technique resulted in no surgical complications. At 6-month follow-up examination, the average decrease in systolic pressure across the repair was 8.8 mmHg; all patients showed a clear reduction in arterial hypertension at rest and during exercise. Femoral pulses were easily palpable in all cases. Angiography and magnetic resonance imaging showed no aneurysm formation. The narrowest internal diameter of repair was 88% +/- 12% (mean +/- SD) of the diameter of the aortic arch. The internal mammary artery flap technique, which reflects the basic principle of autogenous arterial grafting in situ, allows appropriate circumferential widening of the aorta in many patients with coarctation and hypoplasia of the aortic isthmus involving delayed repair. This procedure should be considered when the internal mammary artery is of good caliber and quality and the anatomic conditions are not ideal for classic end-to-end anastomotic repair.     

Two-kidney, one clip renal hypertension in the marmoset

The purpose of this study was to assess whether two-kidney, one clip (2K1C) renal hypertension can be induced in the marmoset. During the first 3-5 weeks after renal arterial clipping, blood pressure (BP) and plasma renin activity (PRA) increased in approximately one-third of the operated marmosets. However, within 10 weeks after clipping, BP and PRA had returned to control values. There was a significant positive correlation between BP and log PRA 3 and 5 weeks after the operation, but no correlation was observed at 10 weeks. In a selected group of marmosets with the highest values of BP (greater than 140 mmHg; n = 4), the converting enzyme inhibitor, enalapril (2 mg/kg s.c.) lowered BP by 58 +/- 7 (s.e.m.) mmHg when given 3 weeks after clipping. At 18 weeks the response to enalapril was only -17 +/- 6 mmHg. These results demonstrate that unilateral renal arterial clipping in marmosets results in a transient renin-dependent hypertension. Marmosets in this initial hypertensive phase could be useful for investigating the antihypertensive effects of inhibitors of human renin.     

Prostaglandin I2 does not contribute to the hypotensive effect of the superoxide dismutase mimetic Tempo in rats with aortic coarctation-induced hypertension

This study was designed to investigate the contribution of prostaglandins to the vasodepressor effect of the superoxide dismutase mimetic Tempo in rats made hypertensive by ligation of the abdominal aorta at a point between the left and right renal arteries. Rings of thoracic aorta taken from rats with aortic coarctation released more 6-keto-PGF1alpha (a non-enzymatic product of PGI2 degradation) in the presence than in the absence of Tempo (1 mmol/L; 35.3 +/- 10.1 versus 13.6 +/- 2.6 pg/mg tissue). However, Tempo administered intravenously (2 mg/kg bolus injection plus infusion at 3 mg/kg/h) to rats with aortic coarctation did not increase significantly the concentration of 6-keto-PGF1alpha in vena cava blood. Treatment with Tempo did not affect the arterial pressure of un-operated normotensive rats but promptly decreased the arterial pressure of rats with aortic coarctation-induced hypertension (from 178 +/- 2 to 125 +/- 6 mmHg). The vasodepressor effect of Tempo in hypertensive animals was not affected by pretreatment with indomethacin to inhibit prostaglandin synthesis. These data argue against the hypothesis that PGI2 contributes to the acute hypotensive effect of Tempo in rats with aortic coarctation.     

Impaired cardiopulmonary baroreflex control of renal nerves in renal hypertension

We recently reported that arterial baroreflex control of renal nerve traffic is impaired in renal hypertensive rabbits. The purpose of this study was to determine if vagal cardiopulmonary baroreflex control of renal nerve traffic is also impaired. Experiments were performed in 10 hypertensive (mean arterial pressure +/- SE in conscious state, 110 +/- 3 mm Hg) and 10 normotensive (79 +/- 1 mm Hg) chloralose-anesthetized rabbits. Responses to graded blood volume expansion (+5, +10, +15 ml/kg) with dextran in saline were recorded with all baroreflexes intact, after sinoaortic baroreceptor denervation, and after vagotomy. With arterial and cardiopulmonary baroreflexes intact, volume expansion resulted in decreases in renal nerve traffic of -12 +/- 2%/mm Hg increase in left atrial pressure in normotensive rabbits, but of only -5 +/- 2%/mm Hg in the hypertensive rabbits (P less than 0.05). This difference is particularly striking in view of the larger maximum increases in arterial (25 +/- 7 vs. 12 +/- 3 mm Hg) and left atrial pressure (9 +/- 1 vs. 6 +/- 1 mm Hg) during volume expansion in hypertensive vs. normotensive rabbits. After sinoaortic baroreceptor denervation, the responses of normotensive rabbits were preserved (-11 +/- 3%/mm Hg), while those of hypertensive rabbits were impaired further (-2 +/- 1%/mm Hg). Vagotomy abolished responses of renal nerves to volume expansion in both groups. These data demonstrate striking impairment of vagal cardiopulmonary baroreflex control of renal nerve traffic in renal hypertension. Even though arterial baroreflexes have been shown to be abnormal in renal hypertension, they still may partially compensate for markedly impaired cardiopulmonary baroreflex control of the renal nerves.     

Beneficial effect of trandolapril on the lifespan of a severe hypertensive model.

It remains to be clarified whether ACE Inhibitors extend the lifespan in cases of severe hypertension. In the present study, we examined whether inhibition of angiotensin-converting enzyme (ACE) would affect mortality in a very severe hypertensive model. Twelve-week-old stroke-prone spontaneously hypertensive rats (SHR-SP) and Wistar-Kyoto rats (WKY) were used, and measurements at this age were taken as the basal values. At this age, the systolic blood pressure of SHR-SP was 219+/-4 mmHg, while that of WKY was 102+/-3 mmHg. After 12 weeks of sodium loading, the systolic blood pressure in the placebo-treated SHR-SP reached to 251+/-4 mmHg. At 4 weeks of sodium loading, 85% of the placebo-treated SHR-SP had died, and the systolic blood pressure of the surviving rats was 249+/-26 mmHg. In the trandolapril-treated SHR-SP, the systolic blood pressure was gradually increased to 293+/-5 mmHg at 16 weeks, and none of the mice had died at this time point (0% mortality). The ACE activities of the aorta, brain, heart and kidney were increased in the surviving placebo-treated SHR-SP at 4 weeks compared with the basal levels, while they were significantly decreased in the trandolapril-treated SHR-SP at 16 weeks. These data demonstrate that trandolapril extends the lifespan of this severe hypertensive model, even in cases in which the blood pressure cannot be lowered.     

Nitric oxide, peroxynitrite and cGMP in atherosclerosis-induced hypertension in rabbits: beneficial effects of cicletanine

We studied the effect of the furopyridine derivative antihypertensive drug, cicletanine, on blood pressure, vascular nitric oxide (NO) and cyclic guanosine 3':5'-monophosphate (cGMP) content in the aorta and the renal and carotid arteries, aortic superoxide production, and serum nitrotyrosine level in hypertensive/atherosclerotic rabbits. The effect of cicletanine was compared to that of furosemide. Rabbits were fed a normal or a cholesterol-enriched (1.5%) diet over 8 weeks. On the 8th week, the rabbits were treated per os with 2 x 50 mg/kg daily doses of cicletanine, furosemide, or vehicle for 5 days (n = 5-6 in each groups). The cholesterol diet increased mean arterial blood pressure (MABP) from 86 +/- 1 to 94 +/- 2 mm Hg (p < 0.05). Cicletanine decreased MABP in atherosclerotic rabbits to 85 +/- 1 mm Hg (p < 0.05), but it did not affect MABP in normal animals. Furosemide was without effect in both groups. In normal animals, NO content (assessed by electron spin resonance after in vivo spin trapping) in the aorta and the renal and carotid arteries was increased by cicletanine, and the drug increased cGMP in the renal artery as measured by radioimmunoassay. The cholesterol-enriched diet decreased both vascular NO and cGMP and increased aortic superoxide production assessed by lucigenin-enhanced chemiluminescence and serum nitrotyrosine determined by ELISA. In atherosclerotic animals, cicletanine increased NO and cGMP content in the aorta and the renal and carotid arteries and decreased aortic superoxide production and serum nitrotyrosine. Furosemide did not influence these parameters. We conclude that cicletanine lowers blood pressure in hypertensive/atherosclerotic rabbits. The antihypertensive effect of the drug in atherosclerosis may be based on its beneficial effects on the vascular NO-cGMP system and on the formation of reactive oxygen species.     

Effects of chronic aortic coarctation on atherosclerosis and arterial lipid accumulation in the Watanabe hereditary hyperlipidemic (WHHL) rabbit.

The effects of high blood pressure on atherosclerosis were examined in the Watanabe heritable hyperlipidemic (WHHL) rabbit. For this purpose, the subdiaphragmatic aorta of rabbits was partially ligated (coarctation) to increase blood pressure. Atherosclerosis was assessed 4 months later by morphometric analyses and quantitation of arterial lipids. Results were compared to control WHHL rabbits with matched plasma triglycerides and cholesterol levels. A marked increase in atherosclerotic lesions was observed in the thoracic aorta of the hypertensive rabbits without qualitative changes in its morphometric features. The cross sectional area of the atherosclerotic plaques of the ascending and descending aorta in the hypertensive rabbits was two- and six-times larger than in normotensive rabbits, respectively. Lesions represented 12.0% +/- 3.5% of the total medial cross sectional area of the descending aorta of normotensive rabbits, versus 45.0% +/- 5.7% in hypertensive rabbits. No lesions were observed downstream of the coarctation in hypertensive rabbits, nor in the normotensive rabbits. Accumulation of cholesterol and choline-containing phospholipids in the descending aorta of hypertensive rabbits was increased 3.2- and 1.5-fold, respectively, when compared to normotensive rabbits. Hypertension did not change the unesterified cholesterol/total cholesterol and sphingomyelin/lecithin + lysolecithin molar ratios. In conclusion, chronic coarctation enhances the atherosclerotic response in WHHL rabbits in the high blood pressure compartment, and reduces the variability of this response.     

Postural hypotension following N-type Ca2+ channel blockade is amplified in experimental hypertension

OBJECTIVE: To determine the relative importance of the cardiac and vascular sympathetic components of the orthostatic response to 90 degrees head-up tilt after N-type calcium-channel blockade in normotensive (sham renal cellophane wrap) and hypertensive (renal wrap) conscious rabbits. METHODS: The effects of N-type calcium-channel blockade with omega-conotoxin GVIA (omega-CTX, 10 microg/kg i.v. bolus) were assessed in the absence or presence of cardiac block by propranolol and methscopolamine. These were contrasted with the effects of alpha1-adrenoceptor antagonism (prazosin 0.5 mg/kg i.v. bolus, in the presence of cardiac block) or ganglion blockade (mecamylamine 4 mg/kg i.v. bolus). RESULTS: In vehicle (0.9% saline) treatment groups, the response to tilt consisted of a small pressor effect (4 +/- 2 and 7 +/- 1 mmHg) and tachycardia (29 +/- 6 and 17 +/- 6 beats/min) in sham (n = 6) and wrap (n = 5) rabbits, respectively. After prazosin administration (with cardiac block), there were significant falls in MAP of 3 +/- 1 and 7 +/- 2 mmHg in sham (n = 7) and wrap (n = 6) rabbits, respectively, in response to tilt omega-CTX caused postural hypotensive responses of 8 +/- 2 and 13 +/- 2 mmHg in sham (n = 6) and wrap (n = 7) rabbits, respectively, and 7 +/- 1 and 14 +/- 2 mmHg in sham (n = 7) and wrap (n = 7) rabbits with prior cardiac block. Similarly, mecamylamine caused falls in MAP of 8 +/- 1 and 10 +/- 2 mmHg in response to tilt in sham (n = 6) and wrap (n = 9) animals, respectively. CONCLUSION:Sympathetic vasoconstrictor effectors are primarily responsible for maintaining blood pressure during tilt in conscious rabbits. The postural hypotension caused by sympatholytic agents is about double in hypertensive rabbits, and N-type calcium-channel blockade is as effective as ganglion blockade at inducing this syndrome.     

Post-exercise elevations in sympathetic nerve activity and baroreflex function in normotensive rabbits

We tested the hypothesis that a single bout of dynamic exercise reduces post-exercise arterial pressure, heart rate, and renal sympathetic nerve activity and attenuates the arterial baroreflex control of heart rate and renal sympathetic nerve activity in normotensive New Zealand White rabbits. Animals were chronically instrumented with right jugular venous and left femoral arterial catheters, and electrodes around the renal sympathetic nerve. Arterial pressure, heart rate, and renal sympathetic nerve activity were recorded for two hours pre-exercise and two hours after a single bout of treadmill exercise (post-exercise). Post-exercise heart rate, arterial pressure, and renal sympathetic nerve activity were elevated above pre-exercise values (71+/-3 bpm, 13+/-1 mmHg, and 80+/-21%, respectively). These data demonstrate that normotensive rabbits do not exhibit post-exercise hypotension, due in part to elevations in sympathetic nerve activity. In addition, arterial baroreflex regulation of heart rate and renal sympathetic nerve activity were determined pre- and post-exercise. Exercise shifted the baroreflex function curve for heart rate and renal sympathetic nerve activity upward and to the right without a change in gain. These data suggest that post-exercise elevations in sympathetic nerve activity are due, in part, to an elevation of the operating point of the arterial baroreflex to a higher pressure. These responses in normotensive rabbits contrast sharply with the responses in hypertensive individuals and animals. Understanding the mechanisms contributing to the differences between hypertensive and normotensive subjects may lead to measures designed to lower arterial pressure in hypertensive individuals.