1.Angiotensin is produced by the intrinsic isorenin-angiotensin system.2. Angiotensin is secreted into the cerebrospinal fluid of nephrectomized rats. 3. Angiotensin in cerebrospinal fluid elevates systemic blood pressure. 4. Rats with hereditary diabetes insipidus are virtually non-responsive to intraventricular angiotensin. 5. Angiotensin I1 is devated in the cerebrospinal fluid of spontaneously hypertensive rats.6. An intraventricular perfusion of the angiotensin I1 receptor-blocking agent P 113 decreases blood pressure in spontaneously hypertensive rats.Key words : angiotensin analogue, blood-brain barrier, central blood pressure regulation, cerebrospinal fluid, diabetes insipidus rats, intrinsic brain iso-renin-angiotensin system, spontaneously hypertensive rats.

We studied neuroeffector defects in hypertrophied myocardium of hypertensive transgenic rats harboring the mouse Ren-2' 1 gene. In transgenic rats, epinephrine and neuropeptide Y concentrations were reduced. A heterologous desensitization of adenylyl cyclase was observed, which was accompanied by a downregulation of 0,-adrenergic receptors, an increase of inhibitory G protein a-subunits, and a mildly depressed catalyst activity of adenylyl cyclase, whereas the bioactivity of stimulatory G protein a-subunits and /3 2 -adrenergic receptors was unchanged. Desensitization of adenylyl H ypertension is well known to produce cardiac hypertrophy as an adaptive mechanism to reduce wall stress, when an increased pressure load is imposed on the myocardium. 1 The cardiac hypertrophy process has been regarded as a precursor of heart failure, 2 and in the Framingham study the prevalence of hypertension was highest in those individuals who developed heart failure. 3 However, it is still unresolved which factors predispose or accelerate the progression from cardiac hypertrophy to cardiac failure. In heart failure, several neurohormonal mechanisms are activated, among which are the circulating and tissue renin-angiotensin systems (RAS) 4 and the sympathetic nervous system. 5 The functional consequence is an increase in peripheral vascular resistance. In addition, several alterations of neuroeffector mechanisms have been observed. Besides an activation of the RAS, the activation of cardiac sympathetic nerves in patients with heart failure is followed by an increased release of norepinephrine from the heart, 6 leading to reduced myocardial norepinephrine and neuropeptide Y concentrations. 7 This neurohumoral stimulation resulting from activation of cardiac sympathetic nerves leads to a desensitization of the adenylyl cyclase caused by a downregulation of j3-adrenergic receptors 8 -10 and an increase of the inhibitory guanine nucleotide binding proteins (G i(V ) in the heart."-' 3 However, the unanswered questions are which signals trigger the sympathetic activation and whether these neuroeffector effects are specific for cardiac failure Received April 8, 1994; accepted in revised form August 10, 1994.From the Klinik III fiir Innere Medizin der Universitat zu Koln (Germany) (M.B., MM, B.S., E.E.); Max Delbruck Zentrum fur Molekulare Medizin Berlin (Germany) (M.P., D.G.); and Cattedra di Medicina Interna, University of Brescia (Italy) (M.C.).Correspondence to PD Dr Michael Bohm, Klinik III fiir Innere Medizin der Universitat zu Koln, Joseph-Stelzmann-Str 9, 50924 Koln, FRG.© 1994 American Heart Association, Inc.cyclase was accompanied by a reduced positive inotropic response to isoproterenol, whereas the effect of Ca 2+ was unchanged. We conclude that sympathetic neuroeffector defects occur in transgenic rats similar to those observed in human failing myocardium. These alterations occur in the stage of hypertrophy and could contribute to contractile dysfunction in later stages. (Hypertension. 1994;24:653-662.) Key Words • ...

Plasma vasopressin sensitizes the baroreceptor reflex, whereas vasopressin given into the cerebral ventricle overrides the baroreceptor reflex by means of sympathetic stimulation. To test the hypothesis that arginine vasopressin stimulates two different receptor subtypes (V, and V 2 ) in the central nervous system, we measured the baroreceptor reflex (change in pulse interval vs change in blood pressure) after administering methoxamine (10-300 fj-glkg i.v.) in conscious rats. Animals were pretreated either with a V, vasopressin receptor antagonist administered intravenously or intracerebroventricularly, or with a V 2 receptor antagonist administered intravenously. The central V, antagonist caused sensitization of the baroreceptor reflex, whereas the intravenous V 2 antagonist attenuated it. The intravenous V! vasopressin antagonist had no effect on baroreceptor reflex sensitivity. When the experiments were repeated in rats with hereditary diabetes insipidus, neither antagonist influenced the baroreceptor reflex. Volume expansion lowered circulating vasopressin levels and also attenuated the baroreceptor reflex -effects similar to those observed with the intravenous V 2 antagonist. We conclude that vasopressin sensitizes the baroreceptor reflex through V 2 receptors accessible from the blood and inhibits the reflex through V, receptors in the brain that cannot be reached from the blood. These observations suggest a direct interaction between hormonal and neuronal vasopressin in cardiovascular control. (Hypertension 8 [Suppl II]: 11-157-11-162, 1986) KEY WORDS V| receptors vasopressin V 2 receptors baroreceptor reflex • central cardiovascular controlA RGININE vasopressin (AVP) is one of the most / \ potent circulating vasoconstrictor agents A. jk. known. 1 Plasma AVP induces vasoconstriction through specific receptors of the V, (vascular) subtype. However, unlike other circulating pressor hormones, such as angiotensin II, AVP increases blood pressure only at plasma concentrations well above those sufficient to produce an antidiuretic action through receptors of the V 2 (renal) subtype. 1 -2 This unique feature of AVP is due to the fact that circulating AVP sensitizes the baroreceptor reflex (BRR) and thereby counteracts its own vasoconstrictor action. 1

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When given systemically, isoproterenol will induce water intake in various species. The drug also causes hypotension and renin release from the kidney. Angiotensin II and arterial baroreceptors have been hypothesized to be involved in the mediation of beta-adrenoceptor agonist-induced thirst, but their relative importance has been disputed. In the present series of experiments, isoproterenol was infused intravenously at different rates into nephrectomized and ureteric-ligated rats. Thus, different levels of hypotension could be achieved and maintained while water intake was measured. Also, plasma levels of angiotensin II were determined in ureteric-ligated rats following the intravenous infusion of a dipsogenic dose of isoproterenol. The results indicate that for moderate blood pressure changes a renal-related factor, probably angiotensin II, plays a major role in the mediation of isoproterenol-induced thirst. Under extreme conditions involving a very dramatic drop of arterial blood pressure, extrarenal mechanisms (e.g., arterial baroreceptors) are implicated.