Biomedical subjects

J de Champlain

Publications and source records attributed to J de Champlain.

At least 19 recordsLinked to original sources

PubMed1998

Overexpression of Gi-proteins precedes the development of DOCA-salt-induced hypertension: relationship with adenylyl cyclase.

OBJECTIVE: In the present studies, we have investigated if aorta, like heart from deoxycorticosterone acetate (DOCA)-salt hypertensive rats, (HR) also exhibit enhanced expression of G-protein levels and if these alterations occur before or after the development of blood pressure. METHODS: Sprague-Dawley rats treated with DOCA-salt or vehicle for 1, 2, 3 and 4 weeks were used for these studies. The levels of inhibitory guanine nucleotide regulatory proteins (Gi alpha-2, Gi alpha-3) and G beta proteins were determined by immunoblotting, whereas the levels of Gi alpha-2 and Gi alpha-3 and adenylyl cyclase type V enzyme mRNA were determined by Northern-blotting techniques. RESULTS: The blood pressure was significantly increased in DOCA-salt-treated rats as compared to sham-operated rats after 2 to 4 weeks of treatment; whereas no change in blood pressure was observed after 1 week of treatment (prehypertensive state). However, the levels of Gi alpha-2, Gi alpha-3 and G beta proteins and Gi alpha-2 and Gi alpha-3 mRNA were significantly enhanced in hearts and aorta from DOCA-salt treated rats after 1 week of treatment and remained elevated up to 4 weeks of treatment. In addition, the Gi-mediated inhibitions of adenylyl cyclase by Angiotensin II (Ang II) and C-ANF4-23 were also greater in DOCA-salt-treated rats as compared to sham-operated rats after 1 week and longer periods of treatments (2 to 4 weeks). On the other hand, the levels of Gs alpha were not altered up to 2 weeks of DOCA-salt treatment but significantly decreased in rats treated for 3 and 4 weeks. Furthermore, the stimulatory effects of guanine 5'-[gamma-thio]triphosphate (GTP gamma S), isoproterenol and forskolin on adenylyl cyclase were decreased in both hearts and aorta from DOCA-salt-treated rats after 1 to 4 weeks of treatment as compared to sham-operated rats. The mRNA levels of adenylyl cyclase, type V enzyme in hearts from DOCA-salt treated rats were significantly decreased after 3 and 4 weeks of DOCA-salt treatment but not in rats treated for 1 or 2 weeks. CONCLUSIONS: These results indicate that the enhanced expression of Gi alpha-2 and Gi alpha-3 precedes the development of blood pressure in DOCA-salt-induced hypertension. It can thus be suggested that the increased levels of Gi proteins and resulting decreased levels of cAMP may be one of the factors that contribute to the impaired cardiac contractility and increased vascular tone in DOCA-salt hypertension.

Adenylyl Cyclases↗

PubMed1998

Impaired basal sympathetic tone and alpha1-adrenergic responsiveness in association with the hypotensive effect of melatonin in spontaneously hypertensive rats.

Early investigations have suggested a relationship between hypertension and melatonin, a pineal hormone. The aims of this study were to evaluate the implication of the sympathetic nervous system in the acute effect of melatonin on blood pressure in conscious 12-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), and to determine whether the hypotensive effect of melatonin is associated with alterations in pre- or postsynaptic mechanisms. Melatonin, 10 mg/kg, produced a sustained time-dependent decrease of mean arterial pressure only in SHR without changes in heart rate in both groups. Until 20 min after melatonin administration, plasma epinephrine (EPI) levels were reduced by about 60% in both groups, but norepinephrine (NE) levels were decreased only in SHR by about 30%. The nitroprusside-induced hypotension responses and the associated increases in heart rate were similar in both groups before or after administration of melatonin. Unexpectedly, the sympathetic reactivity to nitroprusside, evaluated by the increases in NE and EPI, was markedly enhanced after melatonin treatment in both WKY and SHR. The stimulation induced [3H]-norepinephrine release from isolated atria was not altered by melatonin in SHR. In cultured aortic vascular smooth muscle cells, the basal and phenylephrine induced inositol phosphate formations were greater in SHR, and the melatonin pretreatment dose dependently attenuated the phenylephrine responses in cells from both WKY and SHR. Therefore the hypotensive action of melatonin appears to be associated with an inhibition of basal sympathoadrenal tone and could also be mediated partly by the blockade of postsynaptic alpha1-adrenergic receptor-induced inositol phosphate formation.

Animals↗

PubMed1998

A randomized, double-blind, placebo-controlled, parallel-group, multicenter trial of four doses of tasosartan in patients with essential hypertension. Tasosartan Investigator's Group.

Tasosartan, a new, long-acting, nonpeptide angiotensin II receptor antagonist was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial at 21 sites in the United States and Canada. After a 2-week, placebo washout qualification period, 278 patients (187 men/91 women) with a mean age of 53.4+/-9.5 years (range, 30 to 70 years) and a baseline sitting diastolic blood pressure (DBP) of 95 to 114 mm Hg were randomly assigned to receive placebo (n = 56), or 10 mg (n = 57), 30 mg (n = 55), 100 mg (n = 55), or 300 mg (n = 55) tasosartan for 4 weeks. The treatment period was followed by a 2-week washout period. Ambulatory blood pressure (BP) monitoring was performed at the end of the placebo washout period and after at least 4 weeks of double-blind treatment. Clinically significant placebo-adjusted differences in baseline sitting systolic blood pressure (SBP)/DBP were observed in the 10 mg (5/3 mm Hg), 30 mg (5/4 mm Hg), 100 mg (10/7 mm Hg) and 300 mg (10/7 mm Hg) dose groups (P < .05). A dose-response relationship (P < .001) was observed within 1 to 2 weeks of treatment initiation and was maintained throughout the double-blind period. Discontinuation of tasosartan therapy was not associated with rebound hypertension. Moreover, significant (P < .05) placebo-adjusted differences in ambulatory SBP/DBP and a significant dose-response relationship (P < .001) were observed with all tasosartan dosages during the 24-h, daytime, and nighttime periods. Placebo-adjusted trough-to-peak ratios ranged from 87% to 100% for ambulatory SBP and 64% to 81% for DBP. In general, no significant differences were observed between the tasosartan treatment groups and the placebo group in the incidence of adverse events. Headache incidence was significantly lower in the 300 mg dose group than the placebo group. In conclusion, tasosartan at dosages of 10, 30, 100, or 300 mg given once daily produced a significant and dose-related reduction in both clinic and ambulatory BP that was maintained over the 24-h period. Tasosartan was generally well tolerated.

Adult↗

PubMed1998

Two-year time course and significance of neurohumoral activation in the Survival and Ventricular Enlargement (SAVE) Study.

AIMS: To describe the temporal evolution of neurohumoral activation in survivors of myocardial infarction with left ventricular dysfunction who are initially asymptomatic and to relate this to prognosis. METHODS AND RESULTS: Patients in the neurohumoral substudy (n = 534) of the Survival and Ventricular Enlargement (SAVE) study had their neurohormones measured at baseline, 3, 12 and 24 months post-infarction, were followed 38 +/- 7 months and had these values related to prognosis. All patients had a left ventricular ejection fraction < or = 40% early post-infarction. Atrial natriuretic peptide, aldosterone, norepinephrine and plasma renin activity decreased progressively over time. Patients with events had a persistent increase in these neurohormones with those dying within the first 24 months of follow-up having the greatest increase. Treatment with captopril affected only plasma renin activity (increase) and aldosterone (decrease). For patients who remained asymptomatic for the first 3 months post-infarction (n = 471), by multivariate analyses (all neurohormones together with non-neurohumoral risk factors), 3-month plasma atrial natriuretic peptide and aldosterone were the most closely related to the development of severe heart failure or to the combined end-points (cardiovascular death, myocardial infarction, or severe heart failure). No neurohormone was related to recurrent myocardial infarction or to cardiovascular mortality. When the last neurohormone measured prior to an event was considered along with non-neurohumoral risk factors (adjusted univariate), atrial natriuretic peptide, aldosterone, norepinephrine and epinephrine were associated with prognosis indicating that a time-dependent analysis identified a closer relationship between neurohormones and events than that identified by 3-month values. However, by multivariate analyses atrial natriuretic peptide was the only neurohormone associated with an event, being associated with the development of severe heart failure (P < 0.001) and the combined end-points (P = 0.022). However, when neurohormones were considered as binary variables, activated or non-activated (defined as > 1.96 SD above the mean of age-matched controls), an association between activation of norepinephrine prior to recurrent myocardial infarction (P < 0.001) and combined end-points (P < 0.01) and between activation of aldosterone and severe heart failure (P < 0.05) was identified. CONCLUSIONS: Neurohumoral activation decreases progressively post-infarction, but only in patients with a good prognosis. In patients with a left ventricular ejection fraction < or = 40% and asymptomatic post-infarction plasma atrial natriuretic peptide at 3 months, aldosterone levels appeared to be the neurohormones most closely associated with prognosis. Increased levels of atrial natriuretic peptide, aldosterone and norepinephrine appear to be temporally most closely associated with events.

Aldosterone↗

PubMed1998

Sympathetic functions in NG-nitro-L-arginine-methyl-ester-induced hypertension: modulation by the renin-angiotensin system.

BACKGROUND: Nitric oxide and angiotensin II have been shown to attenuate cardiac beta-adrenergic inotropism. OBJECTIVE: To study sympathetic presynaptic and post-synaptic functions after chronic nitric oxide synthesis blockade with NG-nitro-L-arginine-methyl-ester (L-NAME, for 40 days) in association with renin-angiotensin system blockade (during the last 12 days) in order to evaluate the possible physiological interactions between these systems. METHODS: Haemodynamic parameters in conscious rats were assessed. Release of noradrenaline from isolated atria and cardiac beta-adrenergic-adenylyl cyclase pathway in rats of sham-treated and L-NAME-treated groups, with or without losartan or enalaprilat treatment, were assessed. RESULTS: L-NAME-treated rats developed a time-dependent increase in blood pressure associated with increased plasma adrenaline levels whereas plasma noradrenaline and cardiac catecholamine levels were similar to those in sham-treated rats. Field-stimulated release of noradrenaline, cardiac beta-adrenoceptor density and affinity and isoproterenol-stimulated formation of cyclic AMP were similar in sham and L-NAME-treated rats. However, Gpp(NH)p, NaF and forskolin-stimulated adenylyl cyclase activity were greater in L-NAME rats although Gs and Gi protein levels were similar in sham-treated and L-NAME-treated rats. Losartan and enalaprilat treatments exerted equipotent angiotensin-pressor response blockade and hypotensive effects whereas catecholamine levels were not altered. Interestingly, only losartan treatment acted to reduce the increased Gs-adenylyl cyclase activity in L-NAME rats, without alteration of G protein levels. CONCLUSIONS: The nitric oxide synthase blockade-induced hypertension seems to be associated with increased adrenal-medullary system and renin-angiotensin system activities. The increased Gs-adenylyl cyclase activity after chronic inhibition of formation of nitric oxide suggests that nitric oxide plays a modulatory role in formation of cyclic AMP, to which angiotensin II seems to contribute through an angiotensin II type 1 receptor-mediated mechanism.

Adenylyl Cyclases↗

PubMed1998

Enhanced inhibition by melatonin of alpha-adrenoceptor-induced aortic contraction and inositol phosphate production in vascular smooth muscle cells from spontaneously hypertensive rats.

OBJECTIVE: To test the hypothesis that the enhanced inhibition by melatonin of the norepinephrine-induced vasoconstriction and formation of inositol phosphate in spontaneously hypertensive rats are mediated by its antioxidant effect METHODS: Aortic rings from spontaneously hypertensive rats and age-matched Wistar-Kyoto rats were used for measuring vascular contraction forces. Cultured aortic smooth muscle cells were prelabelled with myo-[2-3H]-inositol for evaluation of formation of inositol phosphate after exposure to agonist or antagonist Basal or forskolin-induced formation of cyclic AMP was evaluated using a [3H]-cyclic AMP assay system. Oxygen-derived free radicals were generated with a hypoxanthine and xanthine oxidase system. RESULTS: The inhibition of the norepinephrine-induced aortic contraction by melatonin was more potent in spontaneously hypertensive than it was in Wistar-Kyoto rats. The inhibition of the norepinephrine-induced formation of inositol phosphate by 0.3-300 micromol/l melatonin was also greater in smooth muscle cells from spontaneously hypertensive rats than it was in those cells from Wistar-Kyoto rats. In contrast, the inhibition of the norepinephrine-induced formation of inositol phosphate in smooth muscle cells from spontaneously hypertensive and Wistar-Kyoto rats by 2-iodomelatonin, an agonist of melatonin receptors, was not different. Prazosin, but not yohimbine, eliminated or partially inhibited the norepinephrine-induced formation of inositol phosphate in smooth muscle cells from Wistar-Kyoto rats or from spontaneously hypertensive rats, respectively. In the presence both of prazosin and of melatonin, the norepinephrine-induced production of inositol phosphate was abolished in smooth muscle cells from spontaneously hypertensive rats. Furthermore, superoxide dismutase significantly inhibited the norepinephrine-induced aortic contraction and formation of inositol phosphate in smooth muscle cells from spontaneously hypertensive rats, but not in those cells from Wistar-Kyoto rats. In contrast, catalase had no effect on the norepinephrine-induced formation of inositol phosphate and vascular contraction either in cells from spontaneously hypertensive rats or in cells from Wistar-Kyoto rats. Hypoxanthine-xanthine oxidase induced formation of more inositol phosphate in smooth muscle cells from spontaneously hypertensive rats than it did in those from Wistar-Kyoto rats. Melatonin and superoxide dismutase similarly inhibited the hypoxanthine-xanthine oxidase-induced formation of inositol phosphate more in cells from spontaneously hypertensive rats than it did in those from Wistar-Kyoto rats. However, melatonin had no effect either on basal or on the forskolin-induced formation of cyclic AMP in smooth muscle cells from rats of both strains. CONCLUSION: The enhanced inhibitory effect of melatonin on the norepinephrine-induced cellular production of inositol phosphate in spontaneously hypertensive rats was not mediated by melatonin receptors or alpha-adrenoceptors. Rather, the antioxidant effect of melatonin could become important in spontaneously hypertensive rats, which are suspected to have a lower cellular content of antioxidants or a greater sensitivity to superoxide anions, or both, of the vascular tissue.

Animals↗

PubMed1998

Role of NO and angiotensin II in the early development of endothelial functions impairment and cardiac hypertrophy in deoxycorticosterone acetate-salt hypertension.

This study was designed to investigate the effects of chronic inhibition of NO synthesis as well as chronic angiotensin receptor blockade with losartan in the development of hypertension, on mesenteric arterial bed reactivity as well as on the development of cardiac and kidney hypertrophy in deoxycorticosterone-salt (DOCA) hypertension. Uninephrectomized rats were divided in four experimental groups all receiving saline water to drink and treated or not with losartan over a period of 9 days. Two of these groups were administered DOCA, one of which received also N(G)-nitro-L-arginine-methyl ester (L-NAME) to drink. A third group received only L-NAME, while another group received only saline. Systolic blood pressure was similarly increased in L-NAME, DOCA, DOCA-L-NAME groups. Cardiac and kidney weights were increased in DOCA but significantly reduced in DOCA-L-NAME. Losartan prevented the development of hypertension in all groups and also prevented cardiac and kidney hypertrophy in DOCA. The hyperreactivity of mesenteric arteries to phenylephrine, measured in the presence of indomethacin, was endothelium-dependent in both L-NAME groups but not in DOCA rats. Pretreatment with BQ 123 did not modify these endothelium-dependent responses in L-NAME rats. Chronic losartan prevented endothelium-dependent phenylephrine hyperreactivity only in DOCA, whereas only the removal of the endothelium attenuated the responsiveness in both L-NAME-treated groups. Vasorelaxations to acetylcholine and isoproterenol were attenuated in the three hypertensive groups and were normalized only in DOCA and L-NAME treated with losartan. In summary, in all hypertensive groups, blood pressure was normalized by losartan independently of its effects on endothelial functions. In DOCA, losartan normalized the phenylephrine hyperreactivity through an endothelial-dependent mechanism. However, in L-NAME-treated groups an endothelial-derived contracting factor, other than angiotensin II, endothelin, or vasoconstrictor prostanoids, appears to be activated. Both NO and angiotensin II seem to play a role in the early development of hypertension and organ hypertrophy in DOCA hypertension.

Angiotensin II↗

PubMed1998

Different effects of nifedipine and amlodipine on circulating catecholamine levels in essential hypertensive patients.

OBJECTIVE: To compare the acute and chronic effects of nifedipine retard (NPA), nifedipine gastrointestinal therapeutic system (NGITS) and amlodipine at trough and peak plasma concentrations of drug on blood pressure and heart rate, and on plasma norepinephrine and epinephrine levels in patients with mild-to-moderate hypertension (diastolic blood pressure 95-115 mmHg). DESIGN AND METHODS: After 3-4 weeks' placebo treatment, patients of both sexes were randomly allocated to be administered 10 or 20 mg NPA twice a day, 30 or 60 mg NGITS once a day, and 5 or 10 mg amlodipine once a day for 6 weeks. Initially, for the first 2 weeks, the lowest dose of each drug was used, but higher doses were administered after 2 weeks if sitting diastolic blood pressure was > 90 mmHg. Patients were evaluated after administration of the first dose and after 6 weeks' therapy in a hospital setting. Blood samples were taken for high-performance liquid chromatography measurement of catecholamine and drug levels at various intervals for a period covering trough to peak drug level ranges. RESULTS: Administration of all three drugs reduced clinic blood pressure to the same level after 6 weeks' therapy, but heart rate was increased slightly only with amlodipine (P < 0.05). Administration of NPA reduced blood pressure more abruptly whereas administrations of NGITS and amlodipine induced smoother falls after acute and chronic treatments: a significant increase in heart rate was observed with amlodipine after chronic treatment. Both acute and chronic treatments with NPA (n = 19) increased norepinephrine levels (P < 0.01) transiently (2-4 h). In contrast, administration of NGITS (n = 22) did not increase norepinephrine levels and even induced a slight but significant decrease in norepinephrine levels 5-6 h after chronic treatments. Although administration of amlodipine (n = 22) did not increase norepinephrine levels transiently either after acute or after chronic administration, it did induce a sustained rise in basal norepinephrine levels by more than 50% after chronic therapy (P < 0.01). Plasma epinephrine levels were not increased by any of the treatments and even a slight decrease was observed 4 h after administration of a dose following chronic treatments with NGITS and amlodipine (P < 0.05). CONCLUSIONS: The transient increase in norepinephrine levels observed with NPA and the sustained increases in norepinephrine levels observed after chronic treatment with amlodipine suggest that sympathetic activation occurs with those two drugs. The lack of increase in norepinephrine levels after administration of NGITS suggests that this formulation does not activate the sympathetic system. The lowering of epinephrine levels after administrations of NGITS and amlodipine suggests that inhibition of release of epinephrine by the adrenal medulla occurs with longer-acting dihydropyridine formulations.

Adult↗

PubMed1998

Different effects of nifedipine and amlodipine on circulating catecholamine levels in essential hypertensive patients.

Adult↗

PubMed1997

Reflex adrenal medullary secretion during coronary occlusion mediated by cardiac receptors with afferent vagal fibres in the rat.

The relative contribution of ventricular receptors and sinoaortic baroreceptors to the reflex release of adrenaline upon coronary occlusion was studied in anaesthetised rats submitted to a 30-min occlusion of the left coronary artery. Arterial adrenaline concentrations, heart rate and blood pressure were evaluated in control and sham-operated rats, and following sinoaortic denervation (SAD), bilateral vagotomy with and without SAD, ventricular application of lidocaine, neonatal treatment with capsaicin and cervical section of teh spinal cord. In all groups submitted to coronary ligation, blood pressure decreased sharply upon ligation and remained significantly reduced throughout occlusion while heart rate changes were not significant. In control rats, arterial adrenaline concentrations were significantly increased 15 and 30 minutes following coronary occlusion. The increase in adrenaline concentrations observed upon coronary ligation following SAD was not different from that of the control group. On the other hand, vagotomy with or without SAD, ventricular application of lidocaine, neonatal capsaicin treatment and spinal section all greatly reduced the increase in plasma adrenaline values. These results suggest that a large part of the reflex release of adrenaline upon coronary occlusion is mediated by ventricular receptors with unmyelinated vagal afferent fibres.

Adrenal Medulla↗

PubMed1997

Canine adrenal catecholamine response to VIP is blocked by PACAP-(6-27) in vivo.

The goal of the present study was to characterize the adrenal catecholamine response to exogenous vasoactive intestinal peptide (VIP) in anesthetized dogs. We studied the potential involvement of mechanism(s) mediated by muscarinic receptors, L-type Ca2+ channels, VIP-ergic receptors, or pituitary adenylate cyclase-activating peptide (PACAP) receptors. The study consisted of five groups: a vehicle control group receiving VIP (5 micrograms) in the presence of saline and four drug-treated groups receiving VIP (5 micrograms) in the presence of either atropine (500 micrograms), nifedipine (50 micrograms), [Lys1,Pro2,5,Arg3,4,Tyr6]VIP (50 micrograms), or PACAP-(6-27) (50 micrograms). All drugs were locally infused to the left adrenal gland. Plasma catecholamine concentrations were measured in adrenal venous and aortic blood by a high-pressure liquid chromatography-electrochemical method. In the control group, VIP produced a significant increase in adrenal catecholamine output. Neither atropine, nifedipine, nor[Lys1,Pro2,5,Arg3,4,Tyr6]-VIP significantly affected the medullary response to VIP. In the presence of PACAP-(6-27), however, the catecholamine response to VIP was attenuated by approximately 77% (P < 0.05). The present study suggests that adrenal catecholamine secretion induced by exogenous VIP may be mediated by a PACAP-related mechanism, most probably through a PACAP type I receptor, in anesthetized dogs. The data also indicate that neither muscarinic receptors, VIP-ergic receptors, nor dihydropyridine-sensitive L-type Ca2+ channels are operative in the adrenal catecholamine response to exogenous VIP in vivo.

Adrenal Glands↗

PubMed1997

Effects of renin-angiotensin blockade on sympathetic reactivity and beta-adrenergic pathway in the spontaneously hypertensive rat.

As interactions between the renin-angiotensin and sympathetic nervous systems have been suggested in the pathogenesis of hypertension, we wanted to investigate the effect of chronic renin-angiotensin blockade with losartan and enalaprilat on the sympathetic reactivity to hypotension and on the cardiac beta-adrenergic-coupled adenylyl cyclase pathway in 12-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Both treatments, exerting equipotent shifts of angiotensin-pressure responses, lowered blood pressure and attenuated cardiac hypertrophy similarly in SHR. The nitroprusside-induced hypotension was similar in both strains, but the associated increases in plasma catecholamines and heart rate were higher in SHR. In SHR treated with losartan and enalaprilat, the nitroprusside-induced hypotension was greater and associated with markedly attenuated increases in norepinephrine and heart rate. The binding affinity of cardiac beta-adrenoceptors was significantly lower, and beta2-adrenoceptor subtype was dominant in untreated SHR in contrast to WKY, in which beta1-adrenoceptor subtype was dominant. Enalaprilat treatment increased total beta-adrenoceptor density, whereas both treatments restored the binding affinity and beta1- and beta2-adrenoceptor proportions to normal in SHR. Isoproterenol-, guanylylimidodiphosphate [Gpp(NH)p]-, and forskolin-stimulated adenylyl cyclase reactivity was increased in SHR. Enalaprilat restored adenylyl cyclase reactivity to normal in SHR and reduced the sensitivity (EC50) of Gpp(NH)p-induced cAMP formation in both strains. The present study supports the possibility that functional alterations of the renin-angiotensin and sympathetic systems are involved in hypertension in SHR. The antihypertensive action of losartan and enalaprilat in SHR may be partly mediated through the normalization of sympathetic hyperreactivity and the restoration of beta-adrenergic signaling pathway sensitivity.

Adenylyl Cyclases↗

PubMed1996

Effects of chronic treatment with losartan and enalaprilat on [3H]-norepinephrine release from isolated atria of Wistar-Kyoto and spontaneously hypertensive rats.

The present study was designed to evaluate the effect of chronic treatment with losartan, an AT1 angiotensin II receptor antagonist, and enalaprilat, an angiotensin converting enzyme inhibitor, on the presynaptic modulation of [3H]-norepinephrine release from isolated atria of spontaneously hypertensive rats (SHR) and their respective control, the Wistar-Kyoto rats (WKY). The rats received either losartan (5 mg/kg/day) or enalaprilat (1 mg/kg/day) for 12 days by means of osmotic minipumps. The atria were isolated and incubated with [3H]-norepinephrine and the release of radioactivity was used as an index of norepinephrine release. The experimental protocol consisted of two electrical stimulations and the drugs were administered 20 min before the second stimulation. The modulatory action of angiotensin II (0.01 and 1 mumol/L), the alpha 2-adrenoceptor agonist, oxymetazoline (1 mumol/L), the alpha 2-adrenoceptor antagonist, idazoxan (1 mumol/L) and the beta 2-adrenoceptor agonist fenoterol (1 mumol/L) were tested. The results show that losartan or enalaprilat both similarly reduced the blood pressure in SHR. However, only the chronic losartan treatment, and not enalaprilat, abolished the facilitatory effect of exogenously administered angiotensin II on the release of radioactivity. The prejunctional alpha 2- and beta 2-adrenoceptor modulatory mechanisms were not altered by either chronic treatments. Similarly, the facilitatory effect of angiotensin II was blocked by acute administration of losartan but not by enalaprilat. Finally, the facilitatory action of bradykinin on the release of radioactivity was unchanged by chronic enalaprilat treatment. These results confirm the presence of facilitatory AT1 angiotensin II receptors on sympathetic nerve terminals of rat atria. These results also confirm that sympathetic nerve terminal blockade by losartan or the blockade of endogenous angiotensin II formation by enalaprilat are likely to participate in the antihypertensive action of AT1 angiotensin II receptor antagonists and angiotensin converting enzyme.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Inhibition by cyclic AMP of basal and induced inositol phosphate production in cultured aortic smooth muscle cells from Wistar-Kyoto and spontaneously hypertensive rats.

OBJECTIVE: To investigate inositol phosphate formation and its modulation by the cyclic AMP (cAMP) pathway in cultured aortic smooth muscle cells from spontaneously hypertensive rats (SHR). METHODS: Phenylephrine was used to stimulate inositol phosphate formation in cultured aortic smooth muscle cells from SHR and Wistar-Kyoto (WKY) rats. The smooth muscle cells from passages 6-14 were prelabelled with myo-[2-3H]-inositol (1.9 x 10(5) Bq/ml for 24 h) and inositol phosphate formation was measured after exposure to agonist for 45 min. (-)isoproterenol or forskolin-induced cAMP formation was also evaluated using a radioimmunoassay method. RESULTS: The basal level of inositol phosphate formation in smooth muscle cells from SHR was higher than that observed in smooth muscle cells from WKY rats. Phenylephrine increased the formation of inositol phosphates in a concentration-dependent manner (0.1-100 mumol/l). In the presence of 100 mumol/l phenylephrine, the increase in inositol phosphate formation was significantly greater in smooth muscle cells from SHR (214 +/- 6%) than that observed in smooth muscle cells from WKY rats (156 +/- 8%). When the cells were pretreated with 1 mmol/l 8-bromoadenosine 3':5'-cyclic monophosphate or with 10 mumol/l forskolin for 45 min, the basal production of inositol phosphates in smooth muscle cells both from SHR and from WKY rats was significantly and similarly decreased by about 20%. In the presence of 1 mmol/l 8-bromoadenosine 3':5'-cyclic monophosphate, 100 mumol/l phenylephrine-induced inositol phosphate formation was similarly decreased by 33 +/- 4 and 30 +/- 3% in smooth muscle cells from SHR and from WKY rats, respectively, whereas, in the presence of 10 mumol/l forskolin, inositol phosphate formation was reduced by 25 +/- 3 and 27 +/- 5%, respectively, in those cells. In contrast, isoproterenol induced less inhibition of phenylephrine-induced inositol phosphate formation in smooth muscle cells from SHR (14 +/- 2%) than it did in those from WKY rats (25 +/- 4.5%). Although there was no significant difference in basal or forskolin-induced cAMP accumulation between smooth muscle cells from SHR and those from WKY rats. (-)isoproterenol-induced cAMP accumulation was significantly lower in smooth muscle cells from SHR. CONCLUSION: A marked inhibitory effect of cAMP on the alpha 1-adrenoceptor-mediated inositol phosphate signal transduction pathway was demonstrated in smooth muscle cells of SHR and of WKY rats. Decreased cAMP formation with beta-adrenergic stimulation and increased inositol phosphate formation with alpha-adrenergic stimulation in SHR smooth muscle cells may both contribute to the dominant alpha 1-adrenergic activity observed in SHR.

Animals↗

PubMed1996

Cardiovascular responses to intrathecal neuropeptide gamma in conscious rats: receptor characterization and mechanism of action.

1. In the conscious rat, cardiovascular responses to intrathecally (i.t.) administered neuropeptide gamma (NP gamma) were studied prior to and after the i.t. pretreatment with selective antagonists at NK1 ((+/-)-CP 96345 and RP 67580), NK2 (SR 48968) and NK3 (R 486) receptors. Pretreatment with a mixture of peptidase inhibitors (phosphoramidon, captopril, bacitracin, phenanthroline) was also tested to ascertain whether or not the effect of NP gamma was mediated by a metabolite. The involvement of peripheral catecholamines was examined with intravenous injection of alpha-adrenoceptor (phentolamine) and beta-adrenoceptor (propranolol) antagonists. 2. NP gamma (0.078-78 nmol) induced dose-dependent increases in heart rate (HR) and mean arterial blood pressure (MAP). The highest dose of 78 nmol did not induce an increase of MAP greater than that with 7.8 nmol but was preceded by a transient decrease of MAP (1-3 min). No desensitization was observed when three injections of 7.8 nmol NP gamma were given at 90 min intervals. 3. Cardiovascular and behavioural (biting/scratching) effects evoked by 0.78 nmol NP gamma were significantly reduced by the NK1 antagonists, (+/-)-CP 96345 (65 nmol) or RP 67580 (7.8 and 78 nmol). However, cardiovascular responses to NP gamma were not affected by (+/-)-CP 96345 (6.5 nmol), SR 48968 (7.8 and 78 nmol) or R 486 (25 nmol). Pretreatment with peptidase inhibitors significantly enhanced the cardiovascular and behavioural responses to NP gamma. 4. The pressor response to 7.8 nmol NP gamma was converted to a vasodepressor response by pretreatment with phentolamine (2 mg kg-1, i.v.) while the chronotropic response was markedly reduced by propranolol (2 mg kg-1, i.v.). 5. These results suggest that the cardiovascular responses to i.t. NP gamma are mediated by NK1 receptors in the spinal cord leading to the peripheral release of catecholamines from sympathetic fibres or the adrenal medulla. It is unlikely that the spinal action of NP gamma results from its metabolic conversion into neurokinin A or another major metabolite.

Animals↗

PubMed1995

C-type natriuretic peptide and brain natriuretic peptide inhibit adenylyl cyclase activity: interaction with ANF-R2/ANP-C receptors.

C-type natriuretic peptide (CNP) and brain natriuretic peptide (BNP) are members of the natriuretic peptide family, which have been shown to interact with ANP-C/ANF-R2 receptors in addition to ANP-B receptor subtypes. The present study was undertaken to investigate if the interaction of CNP and BNP with ANP-C receptors results in the inhibition of adenylyl cyclase activity. CNP and BNP inhibited adenylyl cyclase activity in heart and brain striatal membranes in a concentration dependent manner with an apparent Ki between 0.1 and 1.0 nM. Maximal inhibition observed in heart membranes were about 25% and 35% for BNP and CNP respectively, however the inhibitions in brain striatal membranes were smaller (approximately 20%). The inhibition was dependent on the presence of guanine nucleotides and was attenuated by pertussis toxin treatment. In addition, CNP inhibited the stimulatory effect of isoproterenol on adenylyl cyclase, whereas CNP as well as BNP showed an additive effect with the inhibitory response of angiotensin II on adenylyl cyclase activity. When the combined effect of C-ANF4-23/BNP, C-ANF4-23/CNP and BNP/CNP at optimal concentrations was studied together on adenylyl cyclase activity, the percent inhibition remained the same for C-ANF4-23 and BNP or C-ANF4-23 and CNP, however, an additive inhibitory effect was observed for BNP and CNP. These results suggest that CNP and BNP like C-ANF4-23 interact with ANP-C receptors and result in the inhibition of adenylyl cyclase activity. On the other hand, CNP and BNP interact with the ANP-C receptor, however, the interaction may be different sites or there may be two subpopulations of ANP-C receptors specific for each of the peptides. These results indicate that BNP and CNP, like ANP and C-ANF4-23, inhibit the adenylyl cyclase/cAMP signal transduction system through an inhibitory guanine nucleotide regulatory protein, by interacting with ANP-C receptor subtypes.

Adenylyl Cyclase Inhibitors↗

PubMed1995

Alteration of prejunctional alpha 2-adrenergic autoinhibition in DOCA-salt hypertension.

The possible involvement of prejunctional alpha 2-adrenergic autoinhibition in hypertension is still controversial. The aim of this study was to determine the functional integrity of this regulatory mechanism in conscious DOCA-salt hypertensive rats, a model characterized by an increased sympathetic tone and reactivity. Basal and hemorrhage-induced increases in catecholamine and immunoreactive neuropeptide Y (NPY) levels were compared between control and yohimbine (alpha 2-adrenergic receptor antagonist) pretreated normotensive and DOCA-salt hypertensive rats. DOCA-salt hypertensive rats had higher basal norepinephrine levels (NE), as well as increased NE and epinephrine (EPI) responses to a 15-mL/kg hemorrhage as compared to control normotensive rats. In normotensive animals, yohimbine (0.5 mg/kg, intravenous [iv]) doubled plasma NE, EPI, and NPY levels in basal conditions and in response to the hemorrhage. In contrast, the same treatment had smaller or no effect on basal NE levels and on the hemorrhage-induced responses in DOCA-salt hypertensive rats, although basal EPI levels were increased in this group. These results therefore suggest a decreased function of the prejunctional alpha 2-adrenergic autoinhibitory mechanism at the level of sympathetic nerve terminals and adrenal medulla during sympathetic hyperactivity in DOCA-salt hypertension. This dysfunction could in part explain the hyperactivity and hyperreactivity of the sympathetic nervous system observed in this model, and thus contribute to the elevation of blood pressure in DOCA-salt hypertension.

Adrenal Medulla↗

PubMed1995

Altered calcium homeostasis in tail artery endothelial cells from spontaneously hypertensive rats.

Using the fura-2 fluorescence technique, the hypothesis that calcium homeostasis may be altered in vascular endothelial cells of spontaneously hypertensive rats (SHR) was examined. Endothelial cells (EC) were isolated from rat tail arteries and subcultured for up to three passages. The resting intracellular calcium ion concentration ([Ca2+]i) in EC from tail arteries was found to be significantly lower in SHR than that in normotensive Wistar-Kyoto (WKY) rats. Bradykinin and endothelin induced a lesser increase in [Ca2+]i in both the peak increase and the total amount of calcium increase during a defined period of time in tail artery EC from SHR, compared with the respective EC from WKY rats. However, there was no significant difference in angiotensin II induced increase in [Ca2+]i in tail artery EC between SHR and WKY rats. It is suggested that a lower resting [Ca2+]i and a selectively impaired stimulation-induced increase in [Ca2+]i in EC may contribute to the altered endothelium function in spontaneously hypertensive rats.

Angiotensin II↗