Constriction In Rats Research Articles

Time-course changes in gastric mucosal blood perfusion following portal vein constriction in rats

Background/Aims: Gastric mucosal blood flow is increased in all experimental models of chronic portal hypertension, when portosystemic shunting and the hyperdynamic circulation are fuly developed. However, some controversy exists concerning the time course of this event. This study was undertaken to investigate the chronological changes in gastric mucosal blood perfusion during the first 7 days after partial portal vein constriction.Methods: Portal hypertensive and sham operated animals were studied. Gastric mucosal blood flow was measured by hydrogen-gas clearance and gastric oxygen and hemoglobin content by reflectance spectrophotometry prior to and immediately after partial portal vein constriction, and 1, 2, 7 and 15 days after induction of portal hypertension.Results: Immediately after partial portal vein constriction, gastric mucosal blood flow and gastric oxygen were significantly decreased by 27% and 32% respectively, and gastric hemoglobin significantly incrased by 19%. On day 1, gastric mucosal blood flow was increased in both portal hypertensive and sham operated rats. However, while this parameter returned to normal in sham operated rats, it remained high on days 2, 7 and 15 in portal hypertensive rats. In portal hypertensive rats, gastric oxygen values were not significantly different from those in sham operated animals, but hemoglobin tended to increase with development of portal hypertension, being significantly higher than in sham operated rats at days 2 and 7. Similar results were obtained when analyzing gastric mucosal blood perfusion 2 and 7 days after two-staged total portal vein constriction.Conclusion: Increased gastric mucosal blood perfusion is present in portal hypertensive rats from the first day after partial portal vein constriction. The lack of significant differences in all parameters on day 1 between portal hypertensive and sham operated rats is probably related to an increased mucosal blood perfusion related to surgery.

The effect of aortic coarctation on expression of endothelin-1 and endothelin receptors in heart and lungs.

Expression of prepro-endothelin-1 (ppET-1), and endothelin (ET) receptor subtype (ETA, ETB) mRNAs was studied in atria, ventricles, and lungs of aortic coarctated rats. During 8 weeks following aortic banding, rats developed ventricular hypertrophy. The levels of expression of ppET-1, ETA- and ETB-receptors were significantly lower in the ventricles of coarctated rats than in sham-operated animals. In atria, the level of expression of ppET-1, ETA and ETB-receptors was not significantly changed. These results indicate that production of ET-1 is decreased and ETA and ETB-receptors are down-regulated in hypertrophied ventricles 8 weeks after aortic coarctation. This may be a compensatory response to pressure overload.

In vivo pharmacology of a novel AT 1 selective angiotensin II receptor antagonist, MK-996

MK-996, N-(4'-(5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl- methyl)1,1'-biphenyl-2-yl)-sulfonylbenzamide, is a potent, orally active, highly selective, nonpeptide angiotensin II (AII) receptor antagonist. MK-996 prevents the pressor response to intravenous AII in the conscious rat, dog, and rhesus monkey (ED50, mg/kg; oral/intravenous = 0.067/0.014, 0.035/0.017, and 0.1/0.036, respectively). In the anesthetized chimpanzee, MK-996 (1 mg/kg, iv) produces 100% (peak) inhibition of the AII pressor response and is still active (52%) at 24 h. To our knowledge this pharmacologic profile in the rat, dog, rhesus monkey, and chimpanzee presents the least species variability of any AII receptor antagonist yet described. Responses to methoxamine and arginine vasopressin are not affected by MK-996. In aortic coarcted (high renin) rats, MK-996 (3 mg/kg, by mouth) reduces blood pressure to normotensive (< 120 mm Hg) levels without reflex tachycardia. This dose of MK-996 reduces blood pressure to approximately the same level as both losartan (3 mg/kg, by mouth) and enalapril (3 mg/kg, by mouth) in this model. The duration of antihypertensive activity of MK-996 is similar to enalapril and shorter than losartan at the doses tested. Additionally, in the rat MK-996 does not potentiate the vasodepressor response to bradykinin and completely prevents the ability of AII to stimulate an increase in plasma levels of aldosterone. Therefore, MK-996 is a potent, orally active, nonpeptide AII receptor antagonist with a long duration of action, little species variability, and anti-hypertensive activity.

Hypertension increases insulin-like growth factor binding protein-4 mRNA levels in rat aorta.

Insulin-like growth factor-I (IGF-I) is an endocrine and autocrine/paracrine growth factor. Recently, we have demonstrated that interrenal aortic coarctation in the rat increases IGF-I mRNA levels in the thoracic aorta, consistent with a role for this mitogen in hypertensive vascular remodeling. The effects of IGF-I are modulated by several IGF binding proteins including IGFBP-3, the main circulating carrier of IGF-I, and IGFBP-4, the main IGF binding protein produced by vascular smooth muscle cells in vitro. To obtain insights into the regulation of IGF-I and more specifically to study potential changes in IGF binding proteins in high-renin hypertension, we studied male Sprague-Dawley rats that had undergone abdominal aortic coarctation. Compared with sham-operated rats, the study rats showed a rapid increase in IGFBP-4 mRNA levels in the hypertensive (thoracic) aorta, reaching a plateau at 3 days (2.5-fold increase) and persisting for at least 14 days. In striking contrast, IGFBP-4 mRNA decreased slightly in the normotensive (abdominal) aorta at 14 days. IGFBP-3 mRNA levels did not change in either vascular bed after coarctation. Study of hepatic tissue indicated that in coarcted rats IGFBP-4 and IGFBP-3 mRNA levels decreased transiently (approximately 50% at 7 days compared with sham). Circulating IGF-I in coarcted animals decreased slightly (P = .08), and Western ligand analysis indicated that circulating levels of IGF binding proteins were not altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary artery constriction in rats affects the activation of alpha 1 adrenergic receptors in cardiac myocytes.

To determine whether alpha 1 adrenergic receptor mediated myocyte contractility and growth are depressed acutely after non-occlusive coronary artery narrowing, the left coronary artery was constricted in rats and mechanical behaviour, cytosolic calcium, and regulation of alpha 1 adrenergic receptors were examined in myocytes seven days later. Coronary artery stenosis was surgically induced in rats and following the estimation of global cardiac performance myocytes were enzymatically dissociated and radioligand binding studies were performed. In addition, the isotonic contractile performance, cytosolic calcium transients and noradrenaline stimulated inositol phosphate generation in myocytes were measured in the presence of WB 4101 or after chlorethylclonidine treatment. Estimations of cell mechanics in vitro established that peak shortening was decreased by 36% and 18% in left and right ventricular myocytes of coronary stenosed rats. Time to peak shortening was prolonged by 29% in left and 20% in right myocytes, whereas velocity of shortening was decreased by 27% in left myocytes. These alterations were associated with increases in cell length and width, indicative of myocyte hypertrophy. In addition, coronary stenosis was accompanied by reductions in the expression of alpha 1a and alpha 1b receptor subtypes in myocytes. alpha 1 Adrenergic receptor density and noradrenaline stimulated phosphoinositol turnover were decreased by 30% and 34% in left myocytes. alpha 1a Adrenergic receptor subtype mediated cytosolic calcium concentration and myocyte mechanical performance were also impaired in left myocytes only. The alpha 1a adrenergic receptor subtype antagonist WB 4101 abolished noradrenaline stimulated inositol phosphate generation in myocytes, whereas chlorethylclonidine at large doses only partially inhibited this response. In conclusion, coronary narrowing leads to defects in the regulation of alpha 1 adrenergic receptors on myocytes which are coupled with attenuation in the transmission of signals, possibly affecting myocyte cell function and ongoing reactive cellular hypertrophy.

In situ morphology of fetal aortic isthmus following ductal constriction in rats.

To clarify the effect of experimentally increased blood flow to the aortic isthmus, in situ cross-sectional morphology of the aortic isthmus and the juxta-ductal descending aorta was studied in fetal rats. Indomethacin (10 mg/kg) was administered to 10 near-term pregnant rats, and fetuses were studied 4 and 24 h later with cesarean section, rapid whole-body freezing, sectioning on a freezing microtome in a plane perpendicular to the aortic isthmus, and photographing cross-sections. Fetuses without treatment served as controls. The ductus was constricted and its cross-sectional area was 12 +/- 3% (mean +/- SEM, % of control; p < 0.05 vs. control) at 4 and 24 h. The aortic isthmus was enlarged and the cross-sectional area was 146 +/- 5% at 24 h in response to the increased flow. These results support the concept that the size of the fetal aortic isthmus can change rapidly depending on the flow in late gestation.

Comparative study of mechanical interdependence: effect of lung volume on Raw during induced constriction

The mechanical load imposed by the parenchyma can decrease the magnitude of agonist-induced airway constriction. To examine whether variability in mechanical interdependence could account for differences in airway narrowing among different species, we compared the effects of changing lung volume on airway resistance (Raw) under baseline conditions and during methacholine (MCh)-induced constriction in rats and guinea pigs. Direct measurements of Raw were made under baseline conditions at different levels of end-expiratory transpulmonary pressure (PL = 3-11 cmH2O). Then aerosolized MCh was delivered (128 mg/ml in rats, 8 mg/ml in guinea pigs), and measurements were obtained at different levels of PL (3-11 cmH2O). We measured tracheal flow and tracheal and alveolar pressure (using alveolar capsules) in open-chest animals during mechanical ventilation (tidal volume 6 ml/kg, frequency 1 Hz) and calculated Raw by subtracting tissue from total lung resistance. For interspecies comparisons, data were standardized using percent change in Raw (delta % Raw) at PL of 3 cmH2O during baseline and, after MCh, log-scaled delta % Raw at PL of 3 cmH2O. We found that increasing lung volume decreased Raw both at baseline and after MCh in both species. However, changes were far smaller in guinea pigs. During baseline, the slope of the delta % Raw/delta PL was -3.37 and -12.48 %/cmH2O for guinea pigs and rats, respectively (P < 0.001). After MCh, the slope of delta log %Raw/delta PL was -0.065 and -0.154 cmH2O-1 for guinea pigs and rats, respectively (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Maintenance of endothelin-induced renal arteriolar constriction in rats is cyclooxygenase dependent.

Influence of arachidonate cyclooxygenase (COX) products on endothelin (ET)-evoked renal vasoconstriction was assessed. In microperfused rat afferent (AA) and efferent arterioles (EA), indomethacin had no effects on the maximal contraction of both AA and EA by ET, but reduced the duration of ET-induced constriction in both arterioles. ET infusion to rats in vivo resulted in a selective increase in efferent but not afferent arteriolar resistance, leading to a dramatic increase in transcapillary hydraulic pressure difference. Glomerular filtration rate (GFR), which fell progressively during infusion of ET alone, was markedly preserved by COX inhibition, but not during selective thromboxane A2 antagonism. In isolated glomeruli, release of prostaglandin (PG) F2 alpha in response to 10(-6) mol/l ET exceeded that the PGE2 by a ratio of 3.2. Collectively, these data provide strong evidence that locally released COX products, possibly PGF2 alpha, play a key role in sustaining ET-induced renal arteriolar constriction. COX inhibition leads to acute vasorelaxation of AA despite continued ET administration, without affecting EA constriction in vivo, thereby resulting in a dramatic reversal of the effects of ET on GFR.

Hemodynamic and Metabolic Activities of Propionyl-L-Carnitine in Rats with Pressure-Overload Cardiac Hypertrophy

Evidence has been put forth that a number of human and experimental cardiomyopathies are associated with a lower myocardial carnitine content. This study was performed to test the hypothesis that the correction of carnitine derivative, propionyl-L-carnitine (PLC), may improve cardiac function. Repeated administration of PLC was compared to saline with respect to cardiac function in rats with pressure-overload cardiac hypertrophy and low myocardial carnitine levels. Cardiac hypertrophy was induced by abdominal aorta constriction in rats. Separate groups of rats were used for (a) determination of myocardial carnitine content, (b) evaluation of in vivo hemodynamics, and (c) evaluation of performance and metabolic state of Langendorff perfused hearts. Results showed the following: (i) The myocardial carnitine content was inversely correlated to cardiac hypertrophy (r = 0.68, p less than 0.05) and PLC treatment (50 mg/kg i.a. for 4 days) restored it to normal values (ii) The PLC effect on cardiac function was significantly and directly related to cardiac hypertrophy [correlations between heart weight and percent changes in cardiovascular parameters: cardiac output (CO), p less than 0.001; cardiac work (CW), p less than 0.01, stroke volume (SV) and stroke work (SW), p less than 0.02]. In animals with heart weight greater than 1,400 mg, the effect of PLC on CO, CW, SV, SW, and total peripheral resistance (TPR) was significantly different from that of saline (CO, CW, SV, and SW, p less than 0.005 each; TPR, p less than 0.05). The effect was observed 24 h after the first PLC administration and significantly diminished following a 4 day suspension of the treatment. (iii) Perfused hearts from PLC-treated rats displayed a significantly lower left ventricular end-diastolic pressure (p less than 0.01) and greater relaxation rate (p less than 0.05) than those from control rats. Moreover, in PLC-treated hearts, the content of creatine phosphate, ATP, and total adenine nucleotides (ATP+ADP+AMP; TAN) was significantly increased (CP, p less than 0.05; ATP and TAN, p less than 0.01 vs. control). These data show that PLC exerts a stimulatory activity on hearts with hypertrophy and low carnitine content, implying that carnitine deficiency may contribute to the depression of cardiac function in this model.

Early depression of the baroreceptor sensitivity during onset of hypertension.

We studied the correlation of changes in gain sensitivity of the baroreceptors and the development of resetting of the baroreceptors 2 and 6 days after the onset of hypertension produced by subdiaphragmatic aortic constriction in rats. Mean arterial pressure of anesthetized rats was maintained at approximately the same level as that of conscious rats, and baroreceptor function curves were studied on a beat-to-beat basis by computer. After 2 days of hypertension, the difference between the systolic pressure threshold and the control diastolic pressure was -13 +/- 2 mm Hg (125 +/- 3 versus 138 +/- 4 mm Hg). Individual values showed that in seven of nine hypertensive rats, the difference was less than 15 mm Hg, indicating complete resetting. After 6 days of hypertension, all rats exhibited complete resetting, when the systolic pressure threshold was similar to control diastolic pressure (143 +/- 4 versus 141 +/- 2 mm Hg), indicating that more than 2 days of hypertension is necessary for full displacement of the pressure thresholds when all hypertensive rats are considered. Slopes of the baroreceptor curves after 2 and 6 days of hypertension showed that baroreceptor gain was depressed by 25% and 34%, respectively. The difference was not statistically significant (1.07 +/- 0.054% versus 0.94 +/- 0.049% and 1.43 +/- 0.075% in controls). When changes in pressure were circumscribed to a more physiological range, a depression of 25% in response to +10 mm Hg and 37% in response to -10 mm Hg was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic nonocclusive coronary artery constriction in rats. Beta-adrenoceptor signal transduction and ventricular failure.

To determine the effects of chronic coronary artery constriction on the relationship between cardiac function and regulation of beta-adrenoceptor signal transduction, the left main coronary artery was narrowed in rats and the animals were killed 5 mo later. An average reduction in coronary luminal diameter of 44% was obtained and this change resulted in an increase in left ventricular end-diastolic pressure and a decrease in positive and negative dP/dt. Significant increases in left and right ventricular weights indicative of global cardiac hypertrophy were observed. Radioligand binding studies of beta-adrenoreceptors, agonist-stimulated adenylate cyclase activity, and ADP ribosylation of 45-kD substrate by cholera toxin were all depressed in the failing left ventricle. In contrast, in the hypertrophic non-failing right ventricle, beta-adrenoreceptor density was preserved and receptor antagonist affinity was increased. In spite of these findings at the receptor level, agonist stimulated cyclic AMP generation was reduced in the right ventricular myocardium. The quantity of the 45-kD substrate was also decreased. In conclusion, longterm nonocclusive coronary artery stenosis of moderate degree has profound detrimental effects on the contractile performance of the heart in association with marked attenuation of adrenergic support mechanisms.

Noradrenaline turnover and metabolism in myocardium following aortic constriction in rats

The aim was to provide meaningful information on the function of the sympathetic system soon after an increased pressure overload on the heart. Noradrenaline storage, turnover, uptake, and synthesis were investigated at 3, 14, and 28 d after aortic banding in rats. Sham operated rats without aortic banding were used as control group. Left ventricle, spleen, and kidney from male Sprague-Dawley rats (175-200 g) were used in this study. Cardiac noradrenaline concentration was decreased at 3 d and 28 d after banding and increased at 14 d; left ventricular mass was increased from 14 d onwards. The rate of change in the specific activity of myocardial noradrenaline (noradrenaline turnover) as well as dopamine beta hydroxylase, an enzyme for noradrenaline synthesis, was unaltered at 3 d, increased at 14 d, and decreased at 28 d after aortic banding. Myocardial [3H]noradrenaline uptake, on the other hand, was decreased at all time points studied. The changes observed in the myocardium at day 14 were specific since noradrenaline turnover rate was unaltered in other peripheral organs such as spleen and kidney. Furthermore, after ganglionic blockade with pentolinium, both sham operated control and banded animals had identical, low noradrenaline turnover rate constants, and significant restoration of cardiac weight and noradrenaline stores was observed in the hearts from banded animals. Noradrenaline turnover and metabolism are altered soon after imposing increased workload on heart. Whether or not the changes in the sympathetic activity are a prerequisites for hypertrophy still remains to be seen.

Adaptational changes of MHC gene expression and isozyme transition in cardiac overloading

Distribution of cardiac myosin heavy-chain (MHC) isozymes is regulated during development by hemodynamic change and hormonal stimuli. To understand the evolution of cardiac hypertrophy and the underlying processes, the interaction between acute or chronic cardiac over-loading and serum thyroid hormone levels was studied. Biochemical, physiological, and pathological studies were performed using coarctated (Coa) rats with or without administration of thyroid hormone (Thy) and on sham-operated (Sham) rats and normal rats with or without administration of Thy. The results showed that 1) although serum Thy levels in Coa and Sham rats were nearly the same at all timing points, a significant induction of beta-MHC mRNA and isozyme occurred in Coa rats; 2) in Coa rats where Thy was administered, there was no increase in beta-MHC mRNA and isozyme as seen in Coa rats, and this level was nearly the same as in Sham rats, whereas serum Thy levels were significantly high, as in the normals with administration of Thy; and 3) 77 days after surgery, the hypertrophy was completed, judging from pathological findings at this time, and beta-MHC mRNA and isozyme reached similar levels in all groups, except for the normals with administration of Thy. These results demonstrate the following: 1) the MHC isoform transitions induced by pressure overload are not induced by decreases in serum Thy levels, and the regulation of MHC gene expression is responsive to other triggers in addition to Thy; and 2) the first adaptational process of the heart to hemodynamic overload is the MHC isoform transition, and the second adaptational process of that is the hypertrophy itself.

Spontaneous rhythmic contractile behaviour of aortic ring segments isolated from pressure loaded regions of the vasculature

The aim was to study contractile responses of segments of rat arteries taken from pressure loaded and pressure protected regions and to examine the role of endothelial derived factors on the spontaneous activity of pressure loaded ring segments. Rats were subjected to complete aortic coarctation between the origins of the renal arteries and allowed to recover for 8 d. After 8 d arterial pressures were measured in awake animals from the pressure loaded and pressure protected regions simultaneously. Ring segments (2-3 mm) were taken from the two regions and mounted in a tissue bath for isometric force measurements. Similar studies were conducted in sham animals and in animals in which the kidney distal to the coarctation had been removed. Female Sprague-Dawley rats, weight 200-250 g, were used. Eight days after coarctation mean aortic pressure proximal to the occlusion was 168(SEM 1.29) mm Hg (n = 104) while distally it was 38(2.42) (n = 40). Of the rings tested 96% showed spontaneous rhythmic activity, having a mean frequency of 3.94(0.17) cycles.min-1. Spontaneous activity was not present in the pressure protected segments taken from the same animals. Rats with the distal kidney removed (n = 25) failed to become hypertensive and similarly prepared ring segments failed to show spontaneous rhythmic activity. Prior removal of the endothelial layer had no effect on the spontaneous contractile responses in pressure loaded segments. Histological examination showed that the media to lumen ratio was increased in coarcted rats in both pressure loaded and pressure protected regions compared to similar regions in sham operated animals. Pressure loaded arterial segments show spontaneous contractile activity when compared to sham segments by mechanisms not dependent on endothelial derived factors. The increase in pressure proximal to the occlusion is dependent on the renin-angiotensin system, since pressure was not increased when the distal kidney was removed. We hypothesise that the chronic pressure load induces fundamental changes in membrane permeability which leads to spontaneous contractile activity.

Aortic hypertrophy and "waterlogging" in the development of coarctation hypertension.

To study the mechanisms and roles of vascular structural changes during the development of hypertension, we coarcted or sham-coarcted the abdominal aorta of rats. At intervals of 3 to 56 days later, we obtained standardized segments of thoracic and abdominal aortas for measurement of dry weight, water content, and amino acid content. Carotid arterial pressure was elevated by day 5 in coarcted rats and remained elevated. Femoral and tail arterial pressures remained normal. Cardiac ventricular weight and dry weight of the thoracic aorta, normalized for body weight, rose rapidly over 3-10 days in coarcted rats, remaining constant at 50-60% above levels in sham-coarcted rats thereafter. In contrast, water content of thoracic aorta in coarcted rats peaked at 123% of control values on day 7 (p less than 0.001), falling rapidly thereafter to levels about half of peak. Increments in dry weight and water content of the normotensive abdominal aortic segments were of far lesser magnitude and occurred 1 to 2 weeks later, probably reflecting the effects of initial hypotension of the hindquarters. Percent hydroxyproline of intima-media segments of the thoracic aorta remained normal during the 8-week period, indicating that increases in aortic dry weight did not represent disproportional fibrosis and thus are attributable to muscular hypertrophy. These results provide support for the hypothesis that arterial wall "waterlogging" is primarily an early manifestation of the hypertensive process. The greatest magnitude of waterlogging coincides with the rapid early increase in aortic dry weight, representing hypertrophy, which suggests common mechanisms, such as activation of Na+-H+ antiport.

Direct correlation between calcium content and blood pressure: a study of aortic coarctation in rats.

The calcium content of aorta was measured by atomic absorption after coarctation in the rat. At 7 and 14 days, the calcium content was elevated on the proximal side of the coarctation, where pressure was increased significantly. On the distal, low pressure side of the aortic coarctation, calcium was reduced significantly. There is a direct correlation between the blood pressure and the content of calcium (r = 0.69, P less than 0.001). The width of the aortic media on the high pressure side was increased significantly at 7 and 14 days after coarctation, whereas no significant changes in width were present on the low pressure side of the constriction. We conclude that pressure regulates the aortic calcium content, likely acting through a local effect.

Arteriolar wall thickening in hypertensive rats unrelated to pressure or sympathoadrenergic influences.

We have previously reported that experimental aortic coarctation in rats is accompanied by non-pressure-related increases in the wall-to-lumen ratio (W/L) of cremaster arterioles. To investigate the role of the sympathoadrenergic system in this arteriolar wall thickening, we partially constricted or sham-constricted the abdominal aorta in adrenal-demedullated, 6-week-old rats that had had guanethidine injections to produce peripheral sympathectomy (S rats, n = 17 coarcted, 16 sham-coarcted) and in sham-demedullated, sham-sympathectomized control rats (SS rats, n = 13 coarcted, 15 sham-coarcted). In both SS and S rats with coarctation, tail and femoral arterial and conscious abdominal aortic pressures were not increased but carotid pressures rose by greater than 30% (p less than 0.01), accompanied by 46-75% increases in cardiac ventricular weight/body weight. In coarcted rats, 4-6 weeks after aortic constriction, compared with sham-coarcted rats, whether S or SS, observation of the cremaster microcirculation revealed increased wall area, wall thickness, and W/L of third- to fifth-order arterioles, both in the resting state and after maximal relaxation with topical nitroprusside. For example, in coarcted S rats wall area after nitroprusside was elevated by 24%, 39%, and 37% in third-, fourth-, and fifth-order arterioles (p less than 0.01). These findings indicate that arteriolar wall thickening in hypertension may occur independently of intra-arterial pressure or sympathoadrenergic influences. Humoral growth factors may be involved.

Morphometric evidence for non-pressure-related arterial wall thickening in hypertension.

To investigate the relation of pressure and vascular wall thickening in hypertension, we coarcted the abdominal aorta upstream to the renal arteries in 14 rats. Sham-coarcted (n = 16) and two-kidney, one-clip (Goldblatt) hypertensive rats (n = 13) served as controls. Tail, femoral, and carotid arterial pressures rose (p less than 0.01) in the two-kidney, one-clip hypertensives; only carotid pressure rose (p less than 0.01) in the coarcted rats, tail and femoral pressures remaining normal (p greater than 0.25). Thus, the hindquarters of the coarcted rats remained normotensive. Four to six weeks after surgery we perfusion-fixed vascular tissues of the hindquarters, including kidneys, with formalin at in vivo levels of pressure. Glycol methacrylate-embedded tissues were sectioned at 1 micron thickness and vessels quantitatively evaluated. The outer medial and lumen perimeters of abdominal aorta, femoral artery, and renal arterioles were measured; from these measurements, vessel outer and lumen diameters, medial thickness, medial area, and medial thickness-to-lumen radius ratios were calculated. Compared with sham-coarcted rats, abdominal aorta, femoral arteries, and renal arterioles less than 61 microns outer diameter in rats with coarctation and Goldblatt hypertension had significantly increased (up to +100%) medial area, medial thickness, and medial thickness-to-lumen radius ratios. In general, magnitudes of abnormalities were similar in Goldblatt and coarcted rats. Renal arterioles greater than 60 microns outside diameter in Goldblatt hypertensive, but not coarcted, rats also were thickened. These results indicate that vascular wall thickening occurs in conduit arteries and smaller renal arterioles in the normotensive hindquarters of coarcted rats, providing morphometric evidence for non-pressure-related mechanisms involved in vascular growth in this form of hypertension.

Mechanical catecholamine responsiveness and myosin isoenzyme pattern of pressure-overloaded rat ventricular myocardium.

Pressure-overloaded cardiac hypertrophy was induced by abdominal aortic constriction in 10-week-old male Wistar rats. 24-26 weeks after aortic constriction, the hearts were excised and a myocardial mechanical study was performed using isolated left ventricular papillary muscles. There was no significant difference in isometric developed tension (T) between sham-operated control and aortic constriction (AC) rats (control vs AC rats = 2.9 +/- 0.6 vs 2.7 +/- 0.7 g/mm2). dT/dtmax of AC rats, on the other hand, was significantly lower than that of controls (controls vs AC rats = 32.8 +/- 7.5 vs 26.3 +/- 6.1 g/mm2s, p less than 0.05). Myocardial mechanical responses to isoproterenol (10(-7) mol/l) were depressed in the group with aortic constriction compared with the control group (delta T: 18.5 +/- 6.7 vs 12.1 +/- 4.9%, p less than 0.05, delta dT/dt: 25.2 +/- 6.2 vs 17.5 +/- 5.8%, p less than 0.02). Responses of the parameters to dibutyryl cyclic AMP (10(-5) mol/l) were also smaller in the AC group than in the control group (delta T: 18.0 +/- 5.6 vs 13.3 +/- 4.0%, p less than 0.05, delta dT/dt: 20.4 +/- 6.9 vs 14.7 +/- 4.1%, p less than 0.05). Left ventricular myosin isoenzyme pattern, revealed by pyrophosphate gel electrophoresis, shifted towards VM-3 under pressure overload. The present study demonstrates that post-membrane processes may be mainly responsible for the decreased myocardial mechanical catecholamine responsiveness in pressure-overloaded cardiac hypertrophy.

Effects of plasma norepinephrine elevation on the heart's adaptation to chronic aortic constriction in rats.

Chronically elevated plasma norepinephrine has the potential for supporting function of diseased hearts, yet may also initiate harmful biochemical and (or) structural changes in the myocardium. The present study investigated the dosage-related effects of chronic norepinephrine infusion on markers of myocardial damage and then tested the influence of a relatively low norepinephrine infusion rate (0.05 microgram X kg-1 X min-1) on the heart's adaptation to pressure overload in aortic constricted rats. Norepinephrine infusion at 0.50 microgram X kg-1 X min-1 led to significantly increased myocardial hydroxyproline concentration and significant mortality. A rate of 0.25 microgram X kg-1 X min-1 increased myocardial hydroxyproline concentration and mortality in aortic constricted rats but had no such effects on sham-operated rats. The lowest rate tested (0.05 microgram X kg-1 X min-1) significantly increased mean arterial pressure and lung weight of aortic constricted rats, without affecting the degree of left ventricular hypertrophy. This infusion rate and aortic constriction each increased plasma norepinephrine and impaired cardiac performance during rapid preloading, although their combination did not cause further impairment. Thus, it appears that even modest plasma norepinephrine elevation has a negative effect on the heart's adaptation to sustained pressure overload.