SUMMARYThe effect of surgical ablation of the area postrema on acute (5-10 minutes) and chronic (5-10 days) increases in mean arterial pressure produced by intravenous infusion of angiotensin II hi conscious, instrumented rats was studied. In agreement with previous studies, pressor responses of area postrema-ablated rats (a = 11) to acute angiotensin II infusion were identical to those of control sham-lesioned rats (n = 13). In these same rats, however, a 5-day infusion of angiotensin II produced a sustained hypertension hi the sham-lesioned group whereas mean arterial pressure was increased only transiently (1-3 days) hi the area postrema-ablated rats. No differences before infusion of arterial pressure, heart rate, water intake, urinary sodium excretion, and urinary potassium excretion were observed between sham-lesioned and area postrema-ablated rats; only arterial pressure was changed significantly during angiotensin II infusion hi either group. Twenty-four hours after terminating angiotensin II infusion, mean arterial pressure was within the normotensive range hi both shamlesioned and area postrema-ablated rats. In a separate group of sham-lesioned (n = 13) and area postrema-ablated (n = 12) rats, angiotensin n was infused intravenously for a 10-day period; mean arterial pressure was increased significantly over the entire 10-day infusion hi sham-lesioned rats, but for only 1 day hi area postrema-ablated rats. An intact area postrema appears necessary for the development of chronic, but not acute, hypertension during intravenous infusion of angiotensin II hi the rat. Supported by National Heart, Lung, and Blood Institute Grants HL24111 andHL32981.Address for reprints: Dr. Gregory D. Fink, Dept. of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824.Received January 27, 1986; accepted October 20, 1986. perimental hypertension. A detailed analysis 1 of many of these studies led to the conclusion that ANG II does not cause chronic hypertension by direct vascular constriction, but rather by an ability to stimulate a more slowly developing (hours to days) pressor mechanism: a mechanism whose sensitivity to ANG II increases with prolonged exposure to the hormone. Actions of ANG II on aldosterone secretion, 2 renal handling of salt and water,

A central pressor effect of angiotensin II (ANG II) has been implicated in the pathogenesis of several forms of experimental hypertension. Therefore, the present studies were designed to investigate mechanisms that contribute to hypertension resulting from selective stimulation of brain ANG II receptors by chronic intracerebroventricular (ICV) infusion of ANG II. Specifically, the role of the sympathetic nervous system, the pressor actions of vasopressin, and the direct vasoconstrictor effect of blood-borne ANG II were investigated in rats made hypertensive by 5- to 7-day ICV ANG II infusions (6 micrograms/h). Rats were chronically instrumented with indwelling arterial and venous catheters and a lateral cerebral ventricular cannula. Acute intravenous infusion of the competitive ANG II receptor antagonist [Sar1-Ala8]ANG II during the period of ICV ANG II infusion resulted in a moderate decrease in arterial pressure, indicating that an increase in blood-borne ANG II may account for a small component of the hypertensive response to ICV ANG II. Activation of the sympathetic nervous system appeared to be the major contributor to the elevated arterial pressure, since acute ganglionic blockade and combined alpha- and beta-adrenergic blockade produced greater depressor responses in rats made hypertensive with chronic ICV ANG II infusion than in normotensive rats. Furthermore, peripheral sympathectomy delayed hypertension development. Intravenous administration of a specific antagonist of the vascular vasopressin receptor did not cause a depressor response in rats made hypertensive with chronic ICV ANG II infusions. These studies demonstrate that a major mechanism involved in the pressor response to acute ICV ANG II injections, namely vasopressin release, does not appear to contribute to hypertension produced by chronic ICV infusions of ANG II. Rather, this form of hypertension is characterized predominantly by an increase in sympathetic vasoconstrictor tone and possibly by a mechanism activated by a small increase in circulating levels of ANG II.

Experiments were performed to characterize the hypertension produced by chronic intracerebroventricular (ICV) infusion of angiotensin II (ANG II) in conscious rats. Infusion of ANG II into a lateral cerebral ventricle for 5 days (1 or 6 micrograms/h) produced dose-dependent increases in mean arterial pressure associated with increased water intake. No consistent changes in heart rate, urinary electrolyte excretion, or water balance were observed. Similarly, no alterations in plasma sodium and potassium concentration, plasma osmolality, or plasma ANG II levels were seen during ICV ANG II infusion. Controlling fluid intake at 40 ml/day did not alter the development of hypertension in this model. Hypertension was found to be sodium dependent, with high sodium intake augmenting the increase in arterial pressure in response to chronic ICV ANG II. Although plasma aldosterone concentrations were increased in some situations during ICV ANG II infusion, adrenalectomy failed to alter the course of hypertension. This study demonstrates that chronic selective stimulation of brain ANG II receptors by means of continuous ICV infusion of ANG II produces sodium-sensitive increases in arterial pressure associated with, but not dependent on, increased fluid intake. This form of hypertension cannot be attributed to sodium and water retention, elevations in plasma aldosterone, or leak of significant amounts of ANG II from cerebrospinal fluid into the peripheral circulation.

Wistar-Furth rats have been shown to be resistant to mineralocortlcoid-salt hypertension, but the mechanism for this resistance is unknown. In the current experiments, adult male Wistar and Wistar-Furth rats were given a subcutaneous aldosterone infusion (0.15 /ig/hr) for 4 weeks, and changes in blood pressure and vascular reactivity were studied. Rats received a 1% NaCI, 0.2% KC1 solution to drink. After 4 weeks of aldosterone infusion, systolic blood pressure measured using a tail-cuff technique had increased by 60 mm Hg in Wistar rats but was unchanged in Wistar-Furth rats. Hypokalemia occurred in both strains in response to the aldosterone infusion. Isolated, helically cut strips of common carotid artery and aorta were prepared for isometric force recording. Cumulative concentration-response curves to norepinephrine, serotonin, KCI, calcium, nitroprusside, and acetylcholine were performed in carotid artery strips, and concentration-response curves to ouabain were performed in aortic strips. Increased vascular contractile sensitivity to KCI, ouabain, norepinephrine, and serotonin was observed in vessels from Wistar rats treated with aldosterone and salt The same treatment in Wistar-Furth rats produced only increased vascular sensitivity to ouabain and serotonin, and these changes were of smaller magnitude than those seen in Wistar rats. Aldosterone-salt treatment produced decreased vascular sensitivity to acetylcholine and nitroprusside in both Wistar and Wistar-Furth rats. These results support the hypothesis that resistance of Wistar-Furth rats to aldosterone-salt hypertension is due to resistance to the effects of aldosterone-salt treatment that normally result in increased vasoconstrictor sensitivity. espite long-standing recognition that hypertension can be produced by mineralocorticoid excess, the physiological mechanisms that contribute to the genesis and maintenance of such hypertension are still a matter of debate. One factor that has been suggested to contribute to mineralocorticoid-salt hypertension in experimental animals is changes in the sensitivity of vascular smooth muscle to vasoactive stimuli. An increase in sensitivity to vasoconstrictors such as norepinephrine and serotonin has been demonstrated in vascular preparations from mineralocorticoid-salt-treated rats, 1 " 4 and in some cases these vascular changes have been shown to precede the development of elevated blood pressure.5 - 6 The changes in vascular reactivity do not seem to be secondary to hypertension per se because protection of vascular beds from high pressure by proximal arterial ligation or antihypertensive therapy does not prevent the appearance of such changes. It recently has been reported that hypertension does not develop in response to the administration of excess deoxycorticosterone (DOC) and salt in the WistarFurth (WF) rat strain. 9 The current experiments were designed to test the hypothesis that a lack of development of changes in vascular reactivity is a mechanism involved in the resistance of WF rats to this form o...

Numerous studies have focused on functional vascular changes that characterize the hypertensive state. Recent evidence that suggests that increased vascular reactivity in hypertension is due to changes in the delivery of activator Ca++ through channels in the cell membrane will be reviewed. The primary evidence supporting this hypothesis comes from studies that characterize the effects of Ca++-free solution and calcium channel blockers on contractile properties of isolated vascular smooth muscle. In the present study, experiments were performed to investigate the role of Ca++ influx in vascular contractions produced by interventions that cause membrane depolarization. Isometric tension development in helical strips of carotid arteries from stroke-prone spontaneously hypertensive rats in response to elevated K+ and tetraethylammonium chloride was greater than that in carotid arteries from Wistar-Kyoto normotensive rats. The rate of tension development to K+-free solution in carotid arteries from stroke-prone spontaneously hypertensive rats was faster than in Wistar-Kyoto normotensive rat arteries. Contractile responses to all 3 depolarizing interventions were reduced in arterial strips incubated in Ca++-free solution containing the chelator ethylene glycol bis-(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid and in arterial strips treated with the Ca++ channel blocker verapamil. These results are consistent with the hypothesis that constrictor stimuli that produce membrane depolarization cause an opening of Ca++ channels in the plasma membrane that are sensitive to the organic channel blockers. Further, a change in Ca++ permeability or membrane depolarizing mechanisms contributes to increased contractile responsiveness in carotid arteries of stroke-prone spontaneously hypertensive rats.