Summary1. In newborn rats treated with 6-hydroxydopamine hydrobromide (6-OHDA) (50-150 mg/kg on 5-7 days) a widespread and long-lasting dose related sympathectomy was demonstrated. 2. When rats given 6-hydroxydopamine (100 mg/kg, seven treatments) in the neonatal period were killed at 10 weeks the concentration of noradrenaline (NA) in the heart, mesentery and vas deferens was significantly reduced. There was no alteration in the catecholamine content of the adrenal glands. 3. The amplitude of the responses of perfused mesenteric arteries from 6-hydroxydopamine treated rats to intra-arterial noradrenaline was not increased, compared with controls, but the duration of responses was increased. 4. 6-Hydroxydopamine given to newborn rats caused a long-lasting depletion of noradrenaline in three of the five regions of the central nervous system (cortex, cerebellum and spinal cord) studied. The concentration of noradrenaline in the pons-medulla was increased, but in the thalamic region was unchanged. The treated rats showed significantly lower exploratory activity. 5. Treatment of newborn rats with 6-hydroxydopamine thus has striking and long-lasting effects on peripheral and central adrenergic systems.
1. The cardiovascular effects of prazosin, a new antihypertensive drug, were studied in normotensive and genetically hypertensive rats. 2. Prazosin, infused intra-arterially, lowered vascular resistance in the blood-perfused rat hind limb. This effect was dependent on the presence of intact sympathetic innervation to the limb; no direct vasodilatation was demonstrated. In this preparation prazosin infusion reduced vasoconstrictor responses to noradrenaline. 3. In the saline-perfused rat mesenteric artery preparation prazosin reduced responses to noradrenaline and sympathetic nerve stimulation but not those to serotonin and vasopressin. Prazosin was more potent than phentolamine, on a molar basis, in reducing the vasoconstrictor effects of noradrenaline. 4. A comparison of the effects of prazosin injected intravenously and into a lateral cerebral ventricle failed to show any central action of the drug on blood pressure. Experiments using the donor blood-perfused, vascularly isolated rat hind limb preparation confirmed that the sympatholytic effect of prazosin occurred within the limb itself.
S U M M A R Y1. The New Zealand strain of rats with genetic hypertension (GH rats), the Japanese strain with spontaneous hypertension and the salt-sensitive strain of Dahl are now well established as three genetically pure lines for use in hypertensive research. Other pure lines not consciously selected for high blood pressure have also recently been shown to exhibit hypertension.2. In the GH rats the inheritance of the blood pressure appears to be polygenic; thus a simple causation of the hypertension appears unlikely. The inheritance is also complex in the other pure lines of hypertensive rats.3. In the GH rats variation in intake of sodium from 0.050/, to 1 0/, of the solid diet does not affect the development of the hypertension.4. The renin-angiotensin-aldosterone system does not appear to play a primary role in the initiation of the hypertension in the GH rats. Compared with normotensive rats of the parent colony, plasma and renal renin aredecreased, total exchangeableand carcass sodium are decreased, as are also the plasma volume and total extracellular fluid volume. Plasma sodium is normal and plasma potassium increased.5. There is no evidence of a primary abnormality of catecholamine storage or turnover. Prevention of the development of the sympathetic nervous system from birth does not entirely abolish the difference in blood pressure between GH rats and comparably treated normotensive rats.6. The increased peripheral resistance in blood-perfused hind limbs and tails of GH rats is due both to increased neurogenic and myogenic components and to a structural element. Increased vascular reactivity to a variety of constrictor agents is readily demonstrated in saline-perfused preparations.7. The different strains of hypertensive rats may in their diversity mirror the differences between the various forms of human essential hypertension. 15s 16sF. 0. Simpson et a/.
The relative efficacy of three antihypertensive drugs in the prevention of further elevation of blood pressure (BP) and cardiovascular structural remodeling in 4-week-old genetically hypertensive (GH) rats was studied by means of two complementary methods, stereology and myography. Four to 10-week-old GH rats were treated with valsartan (10 mg/kg/day), enalapril (10 mg/kg/day) or felodipine (30 mg/kg/day). Untreated GH and normotensive control rats of Wistar origin served as controls. Tail-cuff systolic SBP was measured weekly and left ventricular (LV) mass determined at the end of the experiment. Mesenteric resistance arteries (MRA) were either fixed by perfusion, embedded in Technovit and sections stained for stereological analysis, or mounted on a wire myograph for structural and functional measurements. BP and LV mass were significantly reduced by all drugs; decreases in BP and LV mass were smaller after felodipine treatment. Valsartan and enalapril caused a decrease in BP to normotensive control values. Felodipine kept BP at the 4-week level and prevented further rise with age. Valsartan caused hypotrophic outward remodeling of MRA, enalapril eutrophic outward remodeling and felodipine hypotrophic remodeling. Myograph measurements showed remodeling of the same order. While all drugs lowered the media/lumen ratio in GH to normal, the outward remodeling after valsartan and enalapril indicates that valsartan and enalapril might be more effective in reversing the inward remodeling of resistance arteries found in essential hypertension.
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