To elucidate mechanisms of angiotensin II (Ang II)-related hypertension, we infused angiotensin (76 ng/min s.c.) into rats with minipumps for 10-14 days. Control rats received sham pumps. We measured blood pressure by tail-cuff, and the excretion of aldosterone and prostaglandins (PG) (PGE 2 , prostacyclin derivative 6kPGF, a , and thromboxane [Tx] derivative TxB 2 ). Angiotensin II increased blood pressure by 20 mm Hg by day 2 and by 90 mm Hg by day 10. Aldosterone excretion increased from 10 to 70 ng/day in Ang II rats by day 7. Urine PGE 2 did not increase in angiotensin rats; however, both 6kPGF, a and TxB 2 excretion increased with angiotensin. Control rats had no changes in any of these parameters. A sympathetic component was tested in a separate group of angiotensin rats that received phenoxybenzamine (300 Mg/kg/day) during angiotensin infusion; their increase in blood pressure of 40 mm Hg at 10 days was less than in those rats with angiotensin alone but more than in control rats. Phenoxybenzamine did not influence the angiotensin-induced increases in excretion of 6kPGF la or TxB 2 . Additional groups of conscious angiotensin and control rats were equipped with splanchnic nerve electrodes on day 14 for recording of sympathetic nerve activity. Angiotensin rats had greater basal sympathetic nerve activity than the control rats. Incremental methoxamine injections demonstrated altered baroreceptor reflex function in rats receiving angiotensin. We conclude that increased blood pressure with chronic angiotensin infusion is accompanied by increased production of aldosterone and increased sympathetic tone. The latter may be modulated by PG. {Hypertension 1989;14:396-403) A ngiotensin II (Ang II) is intimately involved in / \ the homeostatic regulation of blood pres-.Z \ . sure and body fluids, although the details of its mechanisms of action remain quite controversial. 1In addition to a well-characterized vasoconstrictor action, Ang II has also been proposed to increase peripheral vascular resistance indirectly through peripheral and central mechanisms that lead to an increased activity of the sympathetic nervous system.2 -4 Further, Ang II causes sodium retention both by a direct action on the renal tubule, 5 and through the stimulation of aldosterone release. 5Finally, Ang II administration influences the plasma concentration, renal excretion, and tissue generation of prostaglandins (PGs) that modulate the vasoconstriction.6 However, the relevance of some of these studies to the pathophysiological role of Ang II in hypertension is not clear, as many were conducted during short-term Ang II infusion in animals under anesthesia.To further define mechanisms in the production of Ang II-related hypertension, we infused Ang II into conscious rats over a 14-day period. We measured sympathetic nervous system activity directly with bipolar electrodes implanted on their splanchnic nerves. We determined the excretion of aldosterone and PG (PGE2, 6kPGFi a , and thromboxane [Tx]B 2 ). To further investigate the role of the s...
The centrally induced effects of angiotensin II and substance P on the cardiovascular system and on neuronal efferent activity of the splanchnic, renal, and adrenal nerves were investigated in chronically instrumented conscious rats. The pressor responses to substance P injected into the lateral brain ventricle were accompanied by marked and short latency increases in heart rate, cardiac output, splanchnic, renal, and adrenal nerve activity, and a rise in plasma noradrenaline and adrenaline. Behaviorally, an arousal-type reaction was observed. In contrast, the pressor responses to intracerebroventricular angiotensin II were associated with initial decreases in heart rate, cardiac output, splanchnic, renal, and adrenal nerve activity, and a fall in plasma noradrenaline at the time of the maximal blood pressure increase. In some but not all animals, a second blood pressure peak associated with increases in heart rate and splanchnic nerve activity was observed after several minutes. Incomplete chronic sinoaortic baroreceptor deafferentiation prevented the angiotensin II-induced fall in heart rate but not the initial fall in splanchnic nerve activity. The decreases in splanchnic nerve activity also occurred in diabetes insipidus rats and persisted in Long Evans rats after vascular vasopressin receptor blockade with d(CH2)5AVP, despite marked reductions of the pressor responses in both groups. Peripheral alpha-adrenoceptor blockade with prazosin or ganglion blockade with hexamethonium inhibited the central angiotensin II pressor responses only in combination with vasopressin receptor blockade. On the other hand, either sympatholytic drug, alone, abolished the pressor responses in the diabetes insipidus rats. This indicates that in intact conscious rats the central pressor effects of angiotensin II are initiated by vasopressin release but become dependent on the sympathetic nervous system when vasopressin is absent or not effective. When rats were allowed to drink in response to angiotensin II, a further sharp rise in blood pressure occurred, together with increases in heart rate and splanchnic nerve activity. The results demonstrate fundamental differences in the mechanisms by which central pressor peptides can influence cardiovascular and autonomic function. It is conceivable that the distinct sympathetic response patterns to central angiotensin II and substance P receptor stimulation form part of a specific cardiovascular adjustment to the individual behavioral reactions, such as drinking, as in the case of angiotensin II, or arousal within the central processing of pain, as in the case of substance P.
In this study in conscious rats, we tested the hypothesis that substance P, a central pressor peptide and a potential transmitter substance of pain pathways, could be involved in the cardiovascular defense reaction that is typically associated with unpleasant sensory stimuli. The hemodynamic responses to centrally administered substance P were pharmacologically characterized. The increases in blood pressure and heart rate after intracerebroventricular injections of substance P were accompanied by mesenteric and renal vasoconstriction and hind limb vasodilation (pulsed-Doppler flow probes). The pressor and vasoconstrictor responses were attenuated by peripheral alpha 1-adrenoceptor blockade with prazosin but were not influenced by blockade of vascular vasopressin receptors with d(CH2)5Tyr(Me) arginine vasopressin (AVP). Cardiac beta 1-adrenoceptor blockade with metoprolol abolished the tachycardic and reduced the pressor responses. Substance P-induced hind limb vasodilation was not sensitive to intravenous atropine but was largely prevented by peripheral beta 2-adrenoceptor blockade with ICI 118,551. Thus, the substance P-induced pressor effects are mediated by alpha 1-adrenergic sympathetic vasoconstriction and beta 1-adrenergic cardiac stimulation, whereas the hind limb vasodilation is mainly due to beta 2-adrenergic stimulation. Substance P dose-dependently (0.01-10 micrograms i.c.v.) released oxytocin but not vasopressin or adrenocorticotropic hormone (ACTH) from the pituitary gland. High doses reduced basal ACTH levels. Together with the hemodynamic responses, a behavioral arousal reaction was observed, which included increased locomotion, grooming, scratching, and skin biting. Our results demonstrate that a neuropeptide can induce classic cardiovascular defense reaction.(ABSTRACT TRUNCATED AT 250 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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