Dissociation between the circulating renin-angiotensin system and angiotensin II receptors in central losartan-induced hypertension

Losartan, an AT1 angiotensin II (ANG II) receptor non-peptide antagonist, induces an increase in mean arterial pressure (MAP) when injected intracerebroventricularly (icv) into rats. The present study investigated possible effector mechanisms of the increase in MAP induced by icv losartan in unanesthetized rats. Male Holtzman rats (280-300 g, N = 6/group) with a cannula implanted into the anterior ventral third ventricle received an icv injection of losartan (90 µg/2 µl) that induced a typical peak pressor response within 5 min. In one group of animals, this response to icv losartan was completely reduced from 18 ± 1 to 4 ± 2 mmHg by intravenous (iv) injection of losartan (2.5-10 mg/kg), and in another group, it was partially reduced from 18 ± 3 to 11 ± 2 mmHg by iv prazosin (0.1-1.0 mg/kg), an alpha1-adrenergic antagonist (P<0.05). Captopril (10 mg/kg), a converting enzyme inhibitor, injected iv in a third group inhibited the pressor response to icv losartan from 24 ± 3 to 7 ± 2 mmHg (P<0.05). Propranolol (10 mg/kg), a ß-adrenoceptor antagonist, injected iv in a fourth group did not alter the pressor response to icv losartan. Plasma renin activity and serum angiotensin-converting enzyme activity were not altered by icv losartan in other animals. The results suggest that the pressor effect of icv losartan depends on angiotensinergic and alpha1-adrenoceptor activation, but not on increased circulating ANG II.

Vasopressin and angiotensin receptors of the medial septal area in the control of mean arterial pressure induced by vasopressin

Introduction. Brain arginine(8)-vasopressin (AVP), through the V-1a- and V-2-receptors, is essential for the maintenance of mean arterial pressure (MAP). Central AVP interacts with the components of the renin-angiotensin system, which participate in MAP regulation. This study all to determine the effects of V-1a-, V-2- and V-1a/V-2-AVP selective antagonists and AT(1)- and AT(2)-angiotensin II (Ang II) selective antagonists on the MAP induced by AVP injected into the medial septal area (MSA) of the brain.Materials and methods. Male Holtzman rats with stainless steel cannulae implanted into the MSA were used in experiments. Direct MAP was recorded in Conscious rats.Results. AVP administration into the MSA caused a prompt and potent pressor response in a dose-dependent fashion. Pretreatment with the V-1a- and V-2-antagonists reduced, whereas prior injection of the V-1a/V-2-antagonist induced a decrease in the MAP that remained below the baseline. Both AT(1)- and AT(2)-antagonists elicited a decrease, While simultaneous injections of two antagonists were more effective in decreasing the MAP induced AVP.Conclusion. These results indicate there is a synergism bell the V-1a- and V-2-AVP, and AT(1)- AT, and AT(2)-Ang II receptors in the MSA in the regulation of MAP.

Role of the medial septal area on pilocarpine-induced salivary secretion and water intake

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Chemosensory control by commissural nucleus of the solitary tract in rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Influence of arginine vasopressin receptors and angiotensin receptor subtypes on the water intake and arterial blood pressure induced by vasopressin injected into the lateral septal area of the rat

In this study we investigated the influence of d(CH2)(5)-Tyr(Me)-[Arg(8)]vasopressin (AAVP) and [adamanteanacetyl(1),0-ET-DTyr(2), Val(4), aminobutyryl(6), Arg(8,9)]-[Arg(8)]vasopressin (ATAVP), which are antagonists of vasopressin V-1 and V-2 receptors, and the effects of losartan, a selective angiotensin AT(1) receptor antagonist, and CGP42112A, a selective AT(2) receptor antagonist, injected into the lateral septal area (LSA) on thirst and hypertension induced by [Arg(8)]vasopressin (AVP). AAVP and ATAVP injected into the LSA reduced the drinking responses elicited by injecting AVP into the LSA. Both the AT(1) and AT(2) ligands administered into the LSA elicited a concentration-dependent decrease in the water intake induced by AVP injected into the LSA, but losartan was more effective than CGP42112A. The increase in MAP, due to injection of AVP into the LSA, was reduced by prior injection of AAVP from 18 +/- 1 to 6 +/- 1 mm Hg. Losartan injected into the LSA prior to AVP reduced the increase in MAP to 7 +/- 0.8 mm Hg. ATAVP and CGP42112A produced no changes in the pressor effect of AVP. These results suggest that the dipsogenic effects induced by injecting AVP into the LSA were mediated primarily by AT(1) receptors. However, doses of losartan were more effective when combined with CGP42112A than when given alone, suggesting that the thirst induced by AVP injections into LSA may involve activation of multiple AVP and angiotensin II receptor subtypes. The pressor response of AVP was reduced by losartan and by AAVP. CGP42112A and ATAVP did not change the AVP pressor response. These results suggest that facilitator effects of AVP on water intake are mediated through the activation of V-1 receptors and that the inhibitory effect requires V-2 receptors. The involvement of AT(1) and AT(2) receptors can be postulated. Based on the present findings, we suggest that the AVP in the LSA may play a role in the control of water and arterial blood pressure balance. (C) 2004 Elsevier B.V. All rights reserved.

CARDIOVASCULAR EFFECTS OF CENTRAL CLONIDINE IN CONSCIOUS RATS AFTER HYPOTHALAMIC-LESIONS

The central injection of clonidine (an alpha-2-adrenoceptor agonist) in conscious normotensive rats produces hypertensive responses and bradycardia. The present study was performed to investigate the effect of electrolytic lesions in the anteroventral third ventricle (AV3V) region or in the lateral hypothalamus (LH) on the pressor and bradycardic responses induced by central clonidine in rats. Mean arterial pressure and heart rate were recorded in sham or AV3V-lesioned rats with cerebral stainless steel cannulae implanted into the lateral cerebral ventricle (ICV) or LH. and in sham or bilateral LH-lesioned rats with cannulae-implanted ICV. The injection of clonidine (40 nmol) ICV or into the LH of sham rats produced a pressor response (37 +/- 2-48 +/- 3 mmHg) and bradycardia (-45 +/- 10--93 +/- 6 bpm). After AV3V-lesion (3 and 12 days) or LH-lesion (3 days) the pressor response was abolished and a small hypotensive response was induced by the injection of clonidine (-1 +/- 3--16 +/- 3 mmHg). The bradycardia (-27 +/- 6--57 +/- 11 bpm) was reduced, but not abolished by the lesions. These results show that the AV3V region and LH are important cerebral structures that participate in the excitatory pathways involved in the pressor response to central clonidine in rats. They also suggest that, in the absence of these pressor pathways, the hypotensive responses to central clonidine may appear in conscious rats.

CHANGES IN VASCULAR-RESISTANCE DURING CAROTID OCCLUSION IN NORMAL AND BARORECEPTOR-DENERVATED RATS

In the present study, we investigated changes in mesenteric, renal, and hindquarter vascular resistance during the pressor response produced by bilateral carotid occlusion (BCO) in conscious, freely moving normal and denervated (aortic, carotid, or both) rats. BCO was performed using special previously implanted cuffs. In control normal rats, the increase in mean arterial pressure (MAP) during early and late responses (37 +/- 4 and 21 +/- 2 mm Hg, respectively) was related to increased renal (125 +/- 12% and 45 +/- 10%) and mesenteric (38 +/- 13% and 41 +/- 5%) but not hindquarter (14 +/- 4% and 8 +/- 7%) vascular resistance. In aortic-denervated rats, the greater MAP increase in early and late responses (57 +/- 4 and 44 +/- 4 mm Hg, respectively) compared with normal rats was related to a marked increase in hindquarter (137 +/- 26% and 106 +/- 26%) and mesenteric (104 +/- 14% and 66 +/- 9%) vascular resistance. In carotid-denervated rats, MAP increase and change in vascular resistance were similar to those values observed in control rats. Sinoaortic-denervated rats showed a greater MAP increase (34 +/- 4 mm Hg) during late response and a reduced increase in renal vascular resistance (46 +/- 6%) during early response. The present results show that 1) the pressor response to BCO in normal rats is associated with an increase in renal and mesenteric vascular resistance, 2) the aortic baroreceptors buffer the increase in mesenteric and especially hindquarter vascular resistance during BCO, and 3) the reduced pressor response in late response is probably related to a reduced increase in renal vascular resistance during this component compared with the early response.

SEX-RELATED DIFFERENCES IN CARDIOVASCULAR-RESPONSES TO COMMON CAROTID OCCLUSION IN CONSCIOUS RATS

Mean arterial pressure and heart rate were determined in conscious, unrestrained groups of 10 male, female and androgenized female Wistar rats 20 s (early pressor response) and 1 min (late sustained response) after bilateral carotid artery occlusion. The early pressor response, which is of carotid reflex origin, was 40% greater in female than in male rats (45 +/- 2 vs 63 +/- 3 mmHg, respectively). The late sustained response, which is of central origin (probably ischemic), did not differ between male and female rats (32 +/- 2 vs 37 +/- 4 mmHg, respectively). The magnitude of the early pressor response of androgenized female tats (50 +/- 2 mmHg) was similar to that of male rats (45 +/- 2 mmHg) but the late sustained response was 19% smaller (26 +/- 2 mmHg). Common carotid occlusion caused increases in heart rate which were greater in female (51 +/- 9 and 34 +/- 9 beats/min in the early pressor response and late sustained response, respectively) than in male rats (31 +/- 5 and 8 +/- 4 beats/min, respectively). In androgenized female rats, heart rate decreased during common carotid occlusion (34 +/- 7 and 35 +/- 8 beats/min after 20 s and 1 min, respectively). These data provide evidence that there are substantial sex-related differences in the cardiovascular responses to common carotid occlusion in conscious rats and indicate that administration of androgens to newborn female rats affects the baroreceptor reflex control of their arterial pressure.

Sedative and cardiorespiratory effects of acepromazine or atropine given before dexmedetomidine in dogs

To test the hypothesis that acepromazine could potentiate the sedative actions and attenuate the pressor response induced by dexmedetomidine, the effects of acepromazine or atropine were compared in six healthy adult dogs treated with this alpha(2)-agonist. In a randomised block design, the dogs received intravenous doses of either physiological saline, 0.05 mg/kg acepromazine or 0.04 mg/kg atropine, 15 minutes before an intravenous dose of 5 mu g/kg dexmedetomidine. The dogs' heart rate was reduced by 50 to 63 per cent from baseline and their mean arterial blood pressure was increased transiently from baseline for 20 minutes after the dexmedetomidine. Atropine prevented the alpha(2)-agonist-induced bradycardia and increased the severity and duration of the hypertension, but acepromazine did not substantially modify the cardiovascular effects of the a2-agonist, except for a slight reduction in the magnitude and duration of its pressor effects. The dexmedetomidine induced moderate to intense sedation in all the treatments, but the dogs' sedation scores did not differ among treatments. The combination of acepromazine with dexmedetomidine had no obvious advantages in comparison with dexmedetomidine alone, but the administration of atropine before dexmedetomidine is contraindicated because of a severe hypertensive response.

Effect of AV3V lesion on the cardiovascular, fluid, and electrolytic changes induced by activation of the lateral preoptic area

In this study we investigated the effect of the anteroventral third ventricle (AV3V) lesion on the pressor, bradycardic, natriuretic, kaliuretic, and dipsogenic responses induced by the injection of the cholinergic agonist carbachol into the lateral preoptic area (LPOA) in rats. Male Holtzman rats with sham or electrolytic AV3V lesion were implanted with stainless steel cannula directly into the LPOA. Injection of carbachol (7.5 nmol) into the LPOA of sham rats induced natriuresis (405 ± 66 μEq/120 min), kaliuresis (234 ± 44 μEq/120 min), water intake (9.5 ± 1.7 ml/60 min), bradycardia (-47 ± 11 bpm), and increase in mean arterial pressure (28 ± 3 mmHg). Acute AV3V lesion (1-5 days) reduced the natriuresis (12 ± 4 μEq/120 min), kaliuresis (128 ± 27 μEq/120 min), water intake (1.7 ± 0.9 ml/60 min), and pressor responses (14 ± 4 mmHg) produced by carbachol into the LPOA. Tachycardia instead of bradycardia was also observed. Chronic (14-18 days) AV3V lesion reduced only the pressor response (10 ± 2 mmHg) induced by carbachol. These results showed that acute, but not chronic, AV3V lesion reduced the natriuretic, kaliuretic, and dipsogenic responses to carbachol injection into the LPOA. The pressor response was reduced in acute or chronic AV3V-lesioned rats. The results suggest that the lateral areas may control the fluid and electrolyte balance independently from the AV3V region in chronic AV3V-lesioned rats. © 1992.

Different effects on rat arterial pressure and heart rate when losartan is injected into the third or fourth ventricle

Cardiovascular responses to central losartan (LOS), a non-peptide angiotensin II (ANG II) receptor antagonist, were investigated by comparing the effects of LOS injection into the 3rd and 4th cerebral ventricles (3rdV, 4thV) on mean arterial pressure (MAP) and heart rate (HR). Adult male Holtzman rats were used (N=6 animals per group). Average basal MAP and HR were 114±3 mmHg and 343±9 bpm (N=23), respectively. LOS (50, 100 or 200 nmol/2 μl) injected into the 3rdV induced pressor (peak of 25±3 mmHg) and tachycardic (peak of 60±25 bpm) responses. LOS injected into the 4thV had no effect on MAP, but it induced bradycardia (peak of -35±15 bpm). KCl (200 nmol/2 μl) injected into the 3rdV or into the 4thV had no effect on either MAP or HR compared to 0.9% saline injection. The results indicate that LOS injected into the third ventricle acts on forebrain structures to induce its pressor and tachycardic effects and that bradycardia, likely dependent on hindbrain structures, is obtained when LOS is injected into the fourth ventricle.

Effects of intracerebroventricular injections of losartan or PD123319 on arterial pressure and heart rate of sodium replete and sodium deplete rats

Angiotensin II (Ang II) non-peptide antagonists were injected i.c.v. (6.25-200 nmol, n = 5-8 rats/group): In sodium replete rats, losartan (AT1 receptor antagonist) induced an increase in mean arterial pressure (MAP) and in heart rate (HR) by 3rd ventricular (3rdV) injection, and a weaker pressor response and bradycardia by 4th ventricular (4thV) injection. PD123319 (AT2 receptor antagonist) induced an increase in MAP and in HR by 3rdV injection, and an increase in MAP and no alteration in HR by 4thV injection. In sodium deplete (furosemide plus removal of ambient sodium for 24 h) rats, losartan induced an increase in MAP and no alteration in HR by 3rdV injection, and no alteration in MAP and bradycardia by 4thV injection. PD123319 induced an increase in MAP and in HR by 3rdV injection, and an increase in MAP and bradycardia by 4thV injection. Thus, there was no fall in MAP by central injections of Ang II antagonists. Intravenous injection of losartan, but not of PD123319, induced a fall in MAP in both sodium replete and sodium deplete animals. Therefore, losartan and PD123319 can have similar effects on MAP and HR when injected intracerebroventricularly, although some differences are also present. The bradycardia is consistent with an withdrawal of Ang II inhibitory action on baroreflex.

Commissural NTS lesions and cardiovascular responses in aortic baroreceptor-denervated rats

Both acute (1 day) lesions of the commissural nucleus of the solitary tract (commNTS) and aortic baroreceptor denervation increase pressor responses to bilateral common carotid occlusion (BCO) during a 60-second period in conscious rats. In this study, we investigated the following: (1) the effects of commNTS lesions on basal mean arterial pressure (MAP) and heart rate (HR) of aortic denervated (ADNx) rats; (2) the effects of acute commNTS lesions on pressor responses to BCO in ADNx rats; and (3) the effects of chronic (10 days) commNTS lesions on the pressor response to BCO. ADNx increased basal MAP and HR in sham-lesioned rats. Acute commNTS lesions abolished the MAP and HR increases observed in ADNx rats. Acute commNTS lesions increased the pressor responses to BCO in rats with intact- baroreceptor innervation but produced no additional change in the pressor response to BCO in ADNx rats. Chronic commNTS lesions did not change the pressor responses to BCO in rats with intact-baroreceptor innervation. The data show that acute commNTS lesions abolish the MAP increase produced by aortic baroreceptor denervation. They also suggest that acute commNTS lesions enhance the pressor response to BCO by partial withdrawal of aortic baroreceptor inputs into the NTS. Chronically, reorganization in the remaining aortic baroreceptor or in the baroreflex function as a whole might produce normalization of the cardiovascular responses to BCO.