Chronic intravenous infusion of noradrenaline produces labile hypertension in conscious rats

Kleinjans, Jos; Kasbergen, C. M.; Vervoort-Peters, L. H. T. M.; Smits, J. F. M.; Boudier, H. A. J. Struyker

doi:10.1016/0024-3205(81)90218-6

Cited by 14 publications

(10 citation statements)

References 22 publications

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“…The overall mean systolic BP during the PE infusion was only 140 to 145 mm Hg. However, there was a dramatic increase in BP variability, an observation that has been noted previously, 3,10 resulting in frequent BP elevations of Ն170 mm Hg (Figure 1). The finding of mildly elevated mean systolic BP with episodic fluctuations is often used to define the syndrome of borderline hypertension, which is also linked with an elevated SNS, 1 and is also reminiscent of pheochromocytoma, another elevated catecholamine state.…”

Section: Discussionsupporting

confidence: 73%

“…11,12 However, continuous infusions of catecholamines markedly increase BP lability (defined as the amplitude of BP fluctuations). 3,10 In this article we report that chronic infusion (8 weeks) of phenylephrine (PE) in rats results in microvascular injury and tubulointerstitial fibrosis. Although BP returns to normal after the PE infusion is stopped, persistent hypertension redevelops on a high salt diet.…”

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confidence: 99%

“…9 One way to examine the effects of chronic adrenergic stimulation is by administering catecholamines chronically to animals. Interestingly, chronic infusions of catecholamines in rats only cause a modest increase (10 to 20 mm Hg) in mean systolic BP, 3,10 which is at a level that is usually not associated with renal damage. 11,12 However, continuous infusions of catecholamines markedly increase BP lability (defined as the amplitude of BP fluctuations).…”

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confidence: 99%

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Renal Injury and Salt-Sensitive Hypertension After Exposure to Catecholamines

et al. 1999

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Abstract-We investigated whether chronic infusion of phenylephrine could induce structural and functional changes in the kidney of rats with the subsequent development of salt-sensitive hypertension. Rats were infused with phenylephrine (0.15 mmol/kg per day) by minipump, resulting in a moderate increase in systolic blood pressure (BP) (17 to 25 mm Hg) and a marked increase in BP variability as measured by an internal telemetry device. After 8 weeks, the phenylephrine infusion was stopped with the return of BP to normal, and a nephrectomy was performed for histological studies. Glomeruli were largely spared, but focal tubulointerstitial fibrosis was present, with the de novo expression of osteopontin by injured tubules, macrophage and "myofibroblast" accumulation, and focal increases in mRNA for transforming growth factor ␤ by in situ hybridization. Peritubular capillaries at sites of injury had distorted morphology with shrinkage, rounding, and focal rarefaction, and endothelial cell proliferation was also identified. Rats were randomized to a high (8% NaCl or 1.36 mol/kg) or low (0.1% NaCl or 17 mmol/kg) salt diet. After 4 to 8 weeks, phenylephrine-treated rats on a high salt diet developed marked hypertension, which was in contrast with phenylephrine-treated rats placed on a low salt diet or vehicle-treated rats given a high salt diet. Hypertension after phenylephrine exposure correlated with the initial mean systolic BP (r 2 ϭ0.99) and the degree of BP lability (r 2 ϭ0.99) during the phenylephrine infusion, the amount of osteopontin expressed in the initial biopsy/nephrectomy (r 2 ϭ0.74), and the final glomerular filtration rate (r 2 ϭ0.58). These studies provide a mechanism by which a markedly elevated sympathetic nervous system can induce salt-dependent hypertension even when the hyperactive sympathetic state is no longer engaged. (Hypertension. 1999;34:151-159.) Key Words: phenylephrine Ⅲ renal circulation Ⅲ hypertension, episodic Ⅲ sympathetic nervous system T here is ample evidence that a hyperactive sympathetic nervous system (SNS) is present in some forms of human hypertension, especially in early, borderline essential hypertension. 1 In addition to the acute effects of SNS activation to raise blood pressure (BP), adrenergic stimulation may induce target organ damage by both hemodynamic and nonhemodynamic mechanisms. 2 Adrenergic stimulation can be associated with left ventricular hypertrophy as well as hypertrophy and stiffening of large arteries. Adrenergic agents have also been shown to stimulate vascular smooth muscle cell proliferation and hypertrophy both in vivo and in vitro. 3,4 We have been interested in the potential role of the SNS as a mediator of renal injury. It is known that catecholamine infusions can induce acute elevations in glomerular hydrostatic pressure in association with intense renal vasoconstriction and a fall in renal blood flow (RBF). 5,6 Infusions of norepinephrine can also induce microalbuminuria in both normal and diabetic individuals. 7 A combination of intrarenal and i...

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Section: Discussionsupporting

confidence: 73%

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confidence: 99%

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confidence: 99%

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Renal Injury and Salt-Sensitive Hypertension After Exposure to Catecholamines

et al. 1999

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“…) that raises plasma NE approximately fivefold and that is just subthreshold for producing a detectable increase in mean arterial pressure in conscious rats (24,32). Because NE was suffused extravascularly rather than intravenously, the plasma concentration was at least 150-fold times below (compare data in Refs.…”

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confidence: 96%

“…It is possible that the different responses reflect differences in the in vitro and in vivo models or to duration of exposure and concentration of NE. Vascular wall hypertrophy is commonly observed with chronic systemic infusion of NE, although past studies have only examined doses that raise arterial pressure (7,20,21,24,32). However, physiological sympathoexcitation simultaneously increases both wall NE and arterial pressure.…”

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α₁-Adrenoceptor stimulation directly induces growth of vascular wall in vivo

Erami

Zhang

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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Previous studies suggesting that norepinephrine is directly trophic for the vascular wall have been confounded by concomitant hemodynamic disturbances. Herein, a microcatheter connected to an osmotic minipump was implanted adjacent to the rat carotid for 2-wk perivascular suffusion of agents at systemic levels ϳ1,000 times below the threshold for altering arterial pressure. Norepinephrine decreased lumen and adventitial areas and circumference by 10, 14, and 5%, respectively (all P Ͻ 0.05); a nonsubtype-specific ␣ 1-adrenoceptor (AR) antagonist had no effect. When begun at the time of balloon injury, 2-wk norepinephrine increased lumen loss by 45%, increased neointimal area by 64% and collagen content by 33%, and reduced vessel circumference by 5% (all P Ͻ 0.05). ␣ 1-AR antagonists decreased neointimal area by 33% (all P Ͻ 0.05). ␣ 1A-AR antagonist reduced lumen loss by 70%, neointimal area by 54%, circumference decline by 84%, and adventitial thickening by 87% (all P Ͻ 0.05), whereas ␣ 1B-, ␣1D-, ␣2-and ␤-AR antagonists were without effect. These are the first in vivo studies demonstrating that norepinephrine is directly trophic for the vascular wall and augments injury-induced intimal lesion growth. artery; smooth muscle; adventitia; injury; adrenergic VASCULAR HYPERTROPHY and remodeling are adaptive structural changes in response to sustained increases in arterial pressure or altered shear stress that favor restoration of normal physiological regulation. On the other hand, excessive wall growth, fibrosis, and inward or inadequate outward remodeling cause failure of surgical procedures (e.g., restenosis after angioplasty/ stent, atherectomy, and bypass grafting) and underlie diseases such as atherosclerosis, pulmonary hypertension, and accelerated arteriosclerosis (31,35). Thus the mechanisms regulating growth of vascular wall cells are under intense investigation. Besides the vasoactive actions of norepinephrine (NE), there is growing evidence that NE may be a trophic mediator for vascular smooth muscle cells (SMCs) and adventitial fibroblasts (AFBs). In vivo studies using surgical or systemic sympathetic denervation (16), systemic infusion of catecholamines (7, 21), or ␣-adrenoceptor (AR) antagonists (20), as well as positive correlation of plasma catecholamines with wall hypertrophy and stiffness (8) and severity of atherosclerosis (22) in humans, suggest that NE may have direct trophic effects on the normal and diseased vascular wall. Moreover, in the ballooninjured rat and rabbit carotid, chronic systemic ␣ 1 -AR antagonists reduced cell proliferation, neointimal growth, and restenosis by at least 50% (14,18,30,34). ␣ 1 -AR antagonists also attenuated angiotensin II-induced DNA synthesis (33) and atherogenesis (26,29). However, interpretation of these past in vivo studies is complicated by concomitant hemodynamic disturbances that, themselves, have trophic effects. For example, chemical or immunological systemic denervation and systemic ␣-AR antagonists cause significant hypotension and humoral changes. A...

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