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Human subjects with impaired baroreflex function cannot buffer rises or falls in blood pressure (BP), thus allowing BP effects of endogenous or environmental stimuli that previously escaped detection to emerge dramatically. Studies in these patients led us to discover that water ingestion induced a robust increase in BP and vascular resistance. Here, using a mouse model of baroreflex impairment, we show that the increase in blood pressure after water ingestion is mediated through sympathetic nervous system activation and that the osmosensitive transient receptor potential vanilloid 4 channel (Trpv4) is an essential component of the response. Although portal osmolality decreases after water ingestion in both wild-type and Trpv4(-/-) mice, only the wild-type animals show a pressor response. The same volume of physiological saline does not elicit an increase in BP, suggesting osmolality as the stimulus. The osmopressor response to water, and Trpv4 thus represent new factors now implicated in the physiology of BP regulation.
Stimulation of beta-adrenergic receptors (betaARs) causes apoptosis in adult rat ventricular myocytes (ARVMs). The role of reactive oxygen species (ROS) in mediating betaAR-stimulated apoptosis is not known. Stimulation of betaARs with norepinephrine (10 micromol/L) in the presence of prazosin (100 nmol/L) for 24 hours increased the number of apoptotic myocytes as determined by TUNEL staining by 3.6- fold. The superoxide dismutase/catalase mimetics Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP; 10 micromol/L) and Euk-134 decreased betaAR-stimulated apoptosis by 89+/-6% and 76+/-10%, respectively. Infection with an adenovirus expressing catalase decreased betaAR-stimulated apoptosis by 82+/-15%. The mitochondrial permeability transition pore inhibitor bongkrekic acid (50 micromol/L) decreased betaAR-stimulated apoptosis by 76+/-8%, and the caspase inhibitor zVAD-fmk (25 micromol/L) decreased betaAR-stimulated apoptosis by 62+/-11%. betaAR-stimulated cytochrome c release was inhibited by MnTMPyP. betaAR stimulation caused c-Jun NH2-terminal kinase (JNK) activation, which was abolished by MnTMPyP. Transfection with an adenovirus expressing dominant-negative JNK inhibited betaAR-stimulated apoptosis by 81+/-12%, and the JNK inhibitor SP600125 inhibited both betaAR-stimulated apoptosis and cytochrome c release. Thus, betaAR-stimulated apoptosis in ARVMs involves ROS/JNK-dependent activation of the mitochondrial death pathway.
We examined the relative roles of the mitogen-activated protein kinases (MAPK) in mediating the alpha1-adrenergic receptor (alpha1-AR) stimulated hypertrophic phenotype in adult rat ventricular myocytes (ARVM). Norepinephrine (NE; 1 microM) in the presence of the beta -AR antagonist propranolol (Pro; 2 microM) caused activation of Ras (>six-fold), MAPK/ERK kinase 1 and 2 (MEK1/2, >10-fold) and extracellular signal-regulated kinases 1 and 2 (ERK1/2, approximately 30-fold) within 5 min, as determined by kinase activity assays and Western blots using phospho-specific antibodies. Conversely, p38 and c-Jun amino-terminal kinases (JNK) were not activated by NE/Pro. Activated MEK1/2 signals remained detectable at 2 h, and activated ERK1/2 remained detectable at 48 h. The alpha1-AR selective inhibitor prazosin (100 nM) completely inhibited the NE/Pro-stimulated activation of Ras, MEK1/2 and ERK1/2. The MEK inhibitor PD98059 caused a concentration-dependent inhibition of NE/Pro-stimulated protein synthesis (as assessed by [3H]leucine incorporation and cellular protein accumulation) and ERK1/2 activation, with approximately 50% inhibition at a concentration between 10 and 50 microM, which is consistent with the known IC50 values of PD98059 for MEK1 (4 microM) and MEK2 (50 microM). Thus, these data show that alpha1-AR stimulated hypertrophy in ARVM is dependent on the MEK1/2-ERK1/2 signaling pathway.
Norepinephrine (NE) causes hypertrophic growth of cardiac myocytes via stimulation of alpha1-adrenergic receptors (alpha1-AR). Reactive oxygen species (ROS) can act as signaling molecules for cell growth. Accordingly, we tested the hypothesis that ROS mediate alpha1-AR-stimulated hypertrophic growth in adult rat ventricular myocytes (ARVM). NE increased the level of intracellular ROS as assessed by lucigenin chemiluminescence or cytochrome c reduction, and this effect was prevented by the superoxide dismutase (SOD)-mimetic MnTMPyP. NE also caused the induction of MnSOD mRNA. alpha1-AR stimulation with NE (1 microM) in the presence of propranolol (2 microM) for 48-96 h caused a hypertrophic growth phenotype characterized by a 36+/-3% increase in 3H-leucine incorporation, a 49+/-14% increase in protein accumulation, a six-fold induction of atrial natriuretic peptide mRNA, actin filament reorganization, and the induction of MnSOD mRNA. These responses were all prevented by pretreatment with the alpha1-AR-selective antagonist prazosin (100 n M) or the SOD-mimetics MnTMPyP (50 microM) and Euk-8 (100 microM). MnTMPyP had no effect on alpha1-AR-stimulated 3H-inositol phosphate turnover or the hypertrophic phenotype caused by the protein kinase C activator phorbol-12-myristate-13-acetate. Thus, ROS play a critical role in mediating the hypertrophic growth response to alpha1-AR-stimulation in ARVM.
BACKGROUND - beta-Adrenergic receptor (beta-AR) stimulation increases apoptosis in adult rat cardiac (ventricular) myocytes (ARVMs) via activation of adenylyl cyclase. beta(2)-ARs may couple to a G(i)-mediated signaling pathway that can oppose the actions of adenylyl cyclase.
METHODS AND RESULTS - In ARVMs, beta-AR stimulation for 24 hours increased the number of apoptotic cells as measured by flow cytometry. beta-AR-stimulated apoptosis was abolished by the beta(1)-AR-selective antagonist CGP 20712A (P<0.05 versus beta-AR stimulation alone) but was potentiated by the beta(2)-AR-selective antagonist ICI 118,551 (P<0.05 versus beta-AR stimulation alone). The muscarinic agonist carbachol also prevented beta-AR-stimulated apoptosis (P<0.05 versus beta-AR stimulation alone), whereas pertussis toxin potentiated the apoptotic action of beta-AR stimulation (P<0.05 versus beta-AR stimulation alone) and prevented the antiapoptotic action of carbachol.
CONCLUSIONS - In ARVMs, stimulation of beta(1)-ARs increases apoptosis via a cAMP-dependent mechanism, whereas stimulation of beta(2)-ARs inhibits apoptosis via a G(i)-coupled pathway. These findings have implications for the pathophysiology and treatment of myocardial failure.
The role of the central nervous system in the pressor effect of nicotine is not well understood. In this study, we evaluated the cardiovascular effects of nicotine in the lower brainstem of normotensive and hypertensive rats. Microinjection of nicotine (0.012-3696 pmol/60 nl) into the nucleus of the solitary tract and area postrema of Sprague-Dawley (SD), Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) decreased blood pressure and heart rate. In contrast, administration of similar doses of nicotine within the rostral ventrolateral medulla (RVLM) evoked a long-lasting pressor and tachycardic effect. This pressor effect was completely abolished by prior microinjection of hexamethonium. In SHR the depressor and bradycardic responses in the nucleus of the solitary tract and area postrema were similar to those of normotensive animals. The pressor effect in the RVLM, however, was more pronounced in the SHR than in WKY or SD rats. In additional experiments, the changes produced by intra-RVLM administration of nicotine on renal sympathetic nerve activity, blood pressure and heart rate were evaluated before and after equidepressor intravenous doses of either clonidine, labetalol or prazosin. The prior administration of labetalol antagonized the pressor effect of nicotine in the three strains of rats (SHR, 82 +/- 6%; SD, 96 +/- 4%; WKY, 83 +/- 9%). Prazosin inhibited the nicotine pressor response by 69% in SHR, by 44% in SD and by 70% in WKY. Clonidine had no effect on nicotine response in the three groups of rats. In conclusion, nicotine administration within the RVLM increases renal sympathetic nerve activity and blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Monitoring expression of c-fos and other immediate-early genes has proven a useful method for determining potential sites of action of antipsychotic drugs. Most studies of the effects of antipsychotic drugs on immediate-early gene expression have focused on the basal ganglia and allied cortical regions. We now report that clozapine administration markedly increases both the number of cells expressing Fos protein-like immunoreactivity and the amount of Fos protein in the thalamic paraventricular nucleus, but not the contiguous mediodorsal thalamic nucleus. Comparable doses of several dopamine D2-like antagonists, including raclopride, sulpiride, remoxipride and haloperidol, did not induce Fos expression in the paraventricular nucleus. However, loxapine and very high doses of haloperidol resulted in a small but significant increase in paraventricular nucleus Fos expression. The dopamine D1 receptor antagonist SCH23390 did not induce Fos in the paraventricular nucleus or alter the magnitude of the clozapine-elicited increase in Fos expression. The serotonergic 5-hydroxytryptamine2a/2c antagonist ritanserin, alone or in combination with sulpiride, did not increase Fos expression in the paraventricular nucleus. Similarly, the 5-hydroxytryptamine2:D2 antagonist risperidone did not change the amount of Fos protein in the paraventricular nucleus. Neither the alpha 1 adrenergic antagonist prazosin nor the muscarinic cholinergic antagonist scopolamine mimicked the effect of clozapine. The key placement of the paraventricular nucleus as an interface between the reticular formation and forebrain dopamine systems suggests that this thalamic nucleus may be an important part of an extended neural network subserving certain actions of antipsychotic drugs.
Animal studies have suggested that vasoconstrictor alpha-2 adrenoreceptors exist on vascular smooth muscle cells. We tested this hypothesis in a patient with severe autonomic failure who demonstrated a pressor response to oral clonidine (a selective alpha-2 adrenoreceptor partial agonist). After clonidine 0.8 mg orally, mean arterial pressure rose by 54 mm Hg. After pretreatment with prazosin (a selective alpha-1 adrenoreceptor antagonist) and confirmation of alpha-1 blockade, clonidine 0.8 mg still raised mean arterial pressure by 43 mm Hg. After pretreatment with yohimbine (a selective alpha-2 adrenoreceptor antagonist), clonidine 0.8 mg elevated mean arterial pressure by 13 mm Hg. Since alpha-1 antagonism does not block, and alpha-2 antagonism does not block the pressor effect of clonidine, we conclude that clonidine raised blood pressure in this severely affected autonomic failure patient by vascular alpha-2 adrenoreceptor stimulation. Thus, this provides pharmacological evidence that postjunctional vascular smooth muscle alpha-2 adrenoreceptors exist in man and can modulate blood pressure.