SUMMARY Spike potentials in abdominal sympatheticDenes were recorded together with aortic blood pressure before and during electrical stimulation of the posterior hypothalamus in urethane-anesthetized rats. Both the initial rate of sympathetic nerve firing and the subsequent acceleration produced by hypothalamic stimulation were higher in deoxycorticosterone acetate (DOCA) hypertensive than in normotensive rats. Pressor responsiveness was generally augmented, but responses to hypothalamic stimulation were increased far more than those to injected noreplnephrine. Vasodepression produced by blocking autonomlc ganglia pharmacologically with pentolinium was also more pronounced in DOCA hypertensive rats than in normotensive controls. These results support the conclusion that a centrally induced sympathetic hyperactivity is important for maintaining the blood pressure elevation in rats with established DOCA hypertension. conflicting but almost equally popular views now exist on whether sympathetic hyperactivity participates in causing deoxycorticosterone acetate (DOCA) hypertension. Supporting the belief that sympathetic hyperactivity is essential, the hypotension induced by combining adrenalectomy with chemical sympathectomy has been shown to result in identical blood pressure levels in adult normotensive and DOCA hypertensive rats. 1 Also, to restore blood pressure levels following splanchnicotomy during pentobarbital anesthesia, the splanchnic nerves had to be stimulated at much higher frequencies in DOCA hypertensive than in other rats. s Furthermore, destruction of central catecholaminergic neurons through intracerebroventricular injection of 6-hydroxydopamine prevents not only the elevation in tail-cuff systolic pressure 3 but also the attendant increase in plasma norepinephrine* in unanesthetized DOCA hypertensive rats. On the contrary, however, others have found DOCA hypertension either unaffected in adult rats Received January 22,1979; revision accepted September 17,1979. worse in neonates 79 after chemical sympathectomy. Observations that seem contradictory have also been made in our laboratory: DOCA hypertensive rats have an enhanced pressor responsiveness to hypothalamic stimulation, 10 yet their pressures fell only to the same levels as those of normotensive rats when the hypothalamus was destroyed. 11 In an attempt to find a logical explanation for this, we recorded sympathetic nerve activity directly before and during hypothalamic stimulation. To determine if the sympathetic overactivity thereby revealed would account for the elevation in blood pressure, we also measured vasodepression occurring after pentoliniuminduced ganglion blockade. MethodsFemale Sprague-Dawley rats, 3 weeks old, were purchased from Charles River Breeding Laboratories (Wilmington, MA). Soon after arrival, all were anesthetized with sodium amobarbital (8 mg/100 g i.p.) and their left kidneys removed. Silicon rubber molds containing DOCA (200 mg/kg) were implanted subcutaneously in eight rats, according to the method of Ormsbee ...

SUMMARY. To determine whether or not salt loading restricted to the brain would elevate blood pressure, chronically implanted osmotic minipumps were used to infuse hypertonic sodium chloride solutions made in artificial cerebrospinal fluid into a jugular vein intravenously or the third cerebral ventricle, intracerebroventricularly, for 11 days in awake rats. During intracerebroventricular infusion of hypertonic sodium chloride, tail-cuff systolic pressures began to rise on day 4 and were significantly elevated by day 9. In contrast, infusions of either artificial cerebrospinal fluid alone, intracerebroventricularly, or hypertonic sodium chloride, intravenously, were ineffective. Confirming the blood pressure elevation thereby detected, systolic and mean pressures recorded directly from indwelling aortic catheters after the same rats had been anesthetized with urethane on day 11, were also significantly higher following intracerebroventricular infusion of hypertonic sodium chloride than after infusion of artificial cerebrospinal fluid alone. Magnitude of depressor and sympatho-inhibitory responses elicited by graded electrical stimulation of the anterior hypothalamus invariably increased with the current strength used for stimulation. At all current strengths used for hypothalmic stimulation, depressor responses as well as attendant decreases in sympathetic neural firing, were smaller in rats that had been infused intracerebroventricularly with hypertonic sodium chloride than in any of the controls. Inhibition seemed specific for the anterior hypothalamus because pressor responses to stimulation of the ventromedial hypothalamus were the same whether or not the intracerebroventricular infusion contained hypertonic sodium chloride. An explanation based on diminished cardiovascular sensitivity also appeared unlikely, since depressor responses to intravenously injected histamine were almost equal in both groups. Our results are compatible with the interpretation that hypertonic sodium chloride infused chronically into the 3rd ventricle acts by reducing anterior hypothalamic inhibition of sympathetic vasomotor tone, and that this, in turn, then elevates blood pressure. (Circ Res 54:566-575, 1984) ALTHOUGH the hypertensive effects of excessive salt intake in rats have often been attributed to peripheral sympathetic or renal pressor mechanisms, recent evidence suggests that a centrally induced sympathetic overactivity may also be involved. Together with the blood pressure elevation produced by deoxycorticosterone acetate (DOCA)-salt pretreatment, norepinephrine turnover decreases in the hypothalamus and brainstem (Nakamura et al., 1971; van Ameringen et al., 1977). In Dahl salt-sensitive rats, dietary salt loading enhances pressor responsiveness to intracerebroventricular (icv) injections of hypertonic saline solution (Ikeda et al., 1978) and to electrical stimulation of the ventromedial hypothalamus (Bunag et al., 1983). Furthermore, the resulting hypertension is greatly attenuated after either chemical destructio...

Mild hypertension with reduced chronotropic baroreflex sensitivity to phenylephrine occurred in Sprague-Dawley rats fed a high-salt diet for 5 wk. Progressive elevation of systolic and mean pressures, detected initially by indirect tail-cuff measurement, was later verified by direct recording of phasic pressures from indwelling aortic catheters in the same rats. Reflex bradycardia during pressor responses to phenylephrine was consistently less pronounced in salt-loaded than in control rats, whether tested while rats were awake or anesthetized. However, attendant decreases in renal nerve activity were not appreciably altered. Neither central nor carotid baroreceptor mechanisms were considered likely but aortic baroreceptors must have somehow been depressed because increases in afferent aortic nerve activity elicited during intravenous infusion of phenylephrine were invariably smaller in salt-loaded than in control rats. Whatever the underlying mechanisms may be, our results show that when hypertension develops during dietary salt loading, baroreflex chronotropic responses are selectively inhibited while attendant decreases in renal nerve activity are preserved.

SUMMARY To determine whether diabetes predisposes rats to hypertension, tail-cuff systolic pressures were measured in male rats made diabetic by pretreatment with streptozotocin. From Weeks 2 through 7, diabetic rats weighed less but had higher systolic pressures than nondiabetic ones. Further comparisons made while the rats were anesthetized with urethane showed that pressor and sympathetic nerve responses to ventromedial hypothalamic stimulation, as well as pressor responses to injected vasopressin, were significantly reduced in the diabetic group. A generalized reduction of cardiovascular reactivity was considered unlikely because systemic pressor responses to norepinephrine and tyramine were unimpaired. Yet reflex bradycardia elicited by norepinephrine was enhanced indicating that baroreceptor resetting had not occurred. Thus, diabetic rats were characterized by hypertension, narrowed pulse pressure, bradycardia with increased reflex responses to norepinephrine, and reduced pressor responses to hypothalamic stimulation and to vasopressin. The successful induction of diabetes was confirmed not only by the presence of hyperglycemia, hypoinsulinemia, glycosuria, and abnormal glucose tolerance, but also by reductions in pancreatic weight, insulin, and /3-cell content. Although our results suggest that diabetic rats are predisposed to become hypertensive, other mechanisms such as hypothalamic depression may be activated to restrict further elevations in blood pressure. H YPERTENSION is generally believed to be more prevalent among diabetics than nondiabetics, 1 -2 but why this might be so is uncertain. Previous attempts to record blood pressure in rats with experimental diabetes have yielded equivocal results. Although blood pressure in normotensive rats is usually elevated by either alloxan 2 " 1 or streptozotocin, 5 -6 it has also been found unaffected 7 or even slightly decreased by streptozotocin. 8 In spontaneously hypertensive rats (SHR), blood pressure falls during the first few weeks after alloxan diabetes is induced, 4 6 9 but several months later becomes even higher than before. 3 From the Department of Pharmacology, College of Health Sciences and Hospital, University of Kansas Medical Center, Kansas City, Kansas.Supported by Research Grant AM 27660 from the National Institute of Arthritis, Metabolism, and Digestive Diseases.An abstract of this paper was published in Federation Proceedings 40: 391, 1981. Dr. Susumu Sasaku is a postdoctoral research fellow from the Second Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.Address for reprints: Dr. Ruben D. Bunag, Department of Pharmacology, University of Kansas Medical Center, 39th and Rainbow Boulevard, Kansas City, Kansas 66103.Received May 27, 1981; revision accepted December 7, 1981. While trying to characterize the cardiovascular changes occurring in normotensive rats that had been pretreated with streptozotocin, we found the ensuing diabetes accompanied by mild hypertension. Both blood pressure 10 and blood sugar" a...

Cardiovascular responses to centrally administered thyrotropin-releasing hormone (TRH) were studied in urethan-anesthetized rats to allow continuous recording of attendant changes in sympathetic nerve activity. Intracerebroventricular infusions of TRH (0.05-5.0 micrograms) consistently increased not only blood pressure and heart rate, but also spike frequency in splanchnic, renal, or cervical sympathetic nerves. Parasympathetic inhibition seemed unlikely because TRH responses were unaltered by cholinergic blockade with atropine, and efferent vagal nerve firing, instead of being reduced, was actually increased by TRH. An increased secretion of endogenous vasopressin also appeared unlikely, since TRH responses were essentially unaffected by either hypophysectomy or pretreatment with a vasopressin antagonist. Inasmuch as pharmacological ganglion blockade with pentolinium eliminated increases in splanchnic nerve firing but reduced the attendant tachycardia by only 50%, residual tachycardia after ganglion blockade was considered partly due to persistent sympathetic cardioaccelerator tone. On the other hand, because pressor responses to TRH were always accompanied by increased sympathetic nerve firing and were completely abolished after pentolinium-induced ganglioplegia, they were attributed solely to sympathetic hyperactivity.