Sympathetic hyperactivity and relative NO deficiency are characteristic alterations in both genetic and salt hypertension. The contribution of these abnormalities to blood pressure (BP) maintenance can be determined in conscious rats using a consecutive blockade of particular vasoactive systems. Thus, the contribution of pressor effects of angiotensin II to the maintenance of high BP is usually small, but the role of renin-angiotensin system in the development of hypertension mediated by central and peripheral effects of angiotensin II on sympathetic activity is highly important. This is even true in angiotensin-dependent hypertension of heterozygous Ren-2 transgenic rats in which sympathetic hyperactivity is increasing with age. Central sympathoexcitation in this hypertensive model can be inhibited by lower losartan doses than peripheral angiotensin II-dependent vasoconstriction. This experimental model also yielded important knowledge on nephroprotective effects of new therapeutic drugs - endothelin receptor type A blockers. A considerable part of sympathetic vasoconstriction is dependent on the interaction of Ca2+ sensitization (RhoA/Rho kinase pathway) and Ca2+ influx (through L-VDCC). The blockade of these pathways prevents a major part of sympathetic vasoconstriction. Ca2+ sensitization seems to be attenuated in genetic hypertension in order to compensate increased Ca2+ influx. In contrast, enhanced Ca2+ sensitization is a hallmark of salt sensitivity in Dahl rats in which salt hypertension is dependent on increased Ca2+ influx. The attention should also be paid to the impairment of arterial baroreflex sensitivity which permits enhanced BP responses to pressor or depressor stimuli. Some abnormalities can be studied in blood vessels isolated from hypertensive rats but neither conduit arteries nor mesenteric resistance arteries represent the vascular beds decisive for the increased peripheral resistance and high BP. Keywords: Sympathetic vasoconstriction, NO-dependent vasodilatation, Calcium sensitization, Calcium influx, Arterial baroreflex, Spontaneously hypertensive rats, Salt hypertensive Dahl rats, Ren-2 transgenic rats, RAS blockade, SNS blockade, NOS inhibition, Endothelin, Vascular contraction and relaxation, Isolated conduit and resistance arteries, EDCF, PGI2, BKCa channels.

• MeSH
• Hypertension * physiopathology   metabolism   MeSH
• Blood Pressure physiology   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Renin-Angiotensin System physiology   MeSH
• Sympathetic Nervous System * physiopathology   metabolism   MeSH
• Vasodilation * physiology   drug effects   MeSH
• Vasoconstriction * physiology   drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND: The consequences at the molecular level and the mechanisms involved in a possible cardioprotective effect of antihypertensive treatment are not yet fully understood. Here, the efficacy of pyridostigmine (PYR) and trandolapril (TRA) as antihypertensive and antihypertrophic agents was investigated and compared in hypertensive SHR and normotensive WKY rats. In parallel, we investigated the effects of these drugs on myocardial β-adrenergic and cholinergic signaling pathways and protein expression profiles. METHODS: Age-matched male SHR and WKY rats were chronically (8 weeks) treated with PYR or TRA in drinking water. Blood pressure (BP) and heart rate (HR) were monitored telemetrically prior to tissue sampling for biochemical analysis. Baroreceptor reflex sensitivity (BRS) and methylatropine HR response as a measure of vagal tone were evaluated in separate groups of animals. RESULTS: PYR slightly lowered BP and HR in SHR rats during the dark phase of the day, while TRA effectively reduced BP during the light and dark phases without affecting HR. PYR enhanced BRS and improved vagal tone. There were no significant alterations in myocardial β-adrenergic and cholinergic signaling, with the exception of decreased forskolin-stimulated adenylyl cyclase (AC) activity in SHR rats, which was restored by TRA. Proteomic analysis revealed numerous differences induced by both treatments. Notable were changes in TGFβ-related signaling pathways as well as proteins involved in modifying hemodynamic parameters and cardiac hypertrophy. CONCLUSIONS: PYR is able to slightly decrease BP and HR in SHR rats but effectively increase BRS through vagal potentiation. The specific differences in protein expression profiles in rat myocardium induced by treatment with PYR and TRA reflect different mechanisms of action of these two agents at the molecular level.

• Keywords
• SHR and WKY rats, acetylcholinesterase, cholinergic signaling, hypertension, myocardial proteome, pyridostigmine, trandolapril,
• Publication type
• Journal Article MeSH

Recently, we demonstrated that chronic blockade of the renin-angiotensin system (RAS) lowered the blood pressure (BP) of adult Ren-2 transgenic rats (TGR) mainly through the attenuation of central sympathoexcitation. However, the participation of central and peripheral mechanisms in the development of high BP in immature TGR remains unclear. In the present study, 6-week-old heterozygous TGR males were chronically treated with intracerebroventricular (ICV) or intraperitoneal (IP) infusions of the AT1 receptor inhibitor losartan (1 or 2 mg/kg/day) for 4 weeks. The influence of these treatments on sympathetic- and angiotensin II-dependent BP components (BP response to pentolinium or captopril, respectively) as well as on BP response to exogenous angiotensin II were determined to evaluate the participation of central and peripheral RAS in hypertension development. Chronic IP losartan administration (1 or 2 mg/kg/day) lowered the BP of immature TGR by reducing both sympathetic and angiotensin II-dependent BP components. The central action of IP-administered losartan was indicated by a reduced BP response to acute ICV angiotensin II injection. Chronic ICV administration of a lower losartan dose (1 mg/kg/day) reduced only the sympathetic BP component, whereas a higher ICV administered dose (2 mg/kg/day) was required to influence the angiotensin II-dependent BP component. Accordingly, chronic ICV losartan administration of 2 mg/kg/day (but not 1 mg/kg/day) attenuated the BP response to acute intravenous angiotensin II application. In conclusion, central sympathoexcitation seems to play an important role in hypertension development in immature TGR. Central sympathoexcitation is highly susceptible to inhibition by low doses of RAS-blocking agents, whereas higher doses also affect peripheral angiotensin II-dependent vasoconstriction.

• Keywords
• Ren-2 transgenic rats, angiotensin II, hypertension, intracerebroventricular, losartan,
• MeSH
• Angiotensin II * MeSH
• Hypertension * MeSH
• Blood Pressure physiology   MeSH
• Rats MeSH
• Losartan pharmacology   therapeutic use   MeSH
• Rats, Transgenic MeSH
• Renin-Angiotensin System MeSH
• Renin metabolism   MeSH
• Vasoconstriction MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Angiotensin II * MeSH
• Losartan MeSH
• Renin MeSH

Salt hypertensive Dahl rats are characterized by sympathoexcitation and relative NO deficiency. We tested the hypothesis that the increased blood pressure (BP) response to fasudil in salt hypertensive Dahl rats is due to augmented calcium sensitization in the salt-sensitive strain and/or due to their decreased baroreflex efficiency. BP reduction after acute administration of nifedipine (an L-type voltage-dependent calcium channel blocker) or fasudil (a Rho kinase inhibitor) was studied in conscious intact rats and in rats subjected to acute NO synthase inhibition or combined blockade of the renin-angiotensin system (captopril), sympathetic nervous system (pentolinium), and NO synthase (L-NAME). Intact salt-sensitive (SS) Dahl rats fed a low-salt diet had greater BP responses to nifedipine (-31 ± 6 mmHg) or fasudil (-34 ± 7 mmHg) than salt-resistant (SR) Dahl rats (-16 ± 4 and -17 ± 2 mmHg, respectively), and a high-salt intake augmented the BP response only in SS rats. These BP responses were doubled after acute NO synthase inhibition, indicating that endogenous NO attenuates both calcium entry and calcium sensitization. Additional pentolinium administration, which minimized sympathetic compensation for the drug-induced BP reduction, magnified the BP responses to nifedipine or fasudil in all groups except for salt hypertensive SS rats due to their lower baroreflex efficiency. The BP response to the calcium channel blocker nifedipine can distinguish SS and SR rats even after calcium sensitization inhibition by fasudil, which was not seen when fasudil was administered to nifedipine-pretreated rats. Thus, enhanced calcium entry (potentiated by sympathoexcitation) in salt hypertensive Dahl rats is the abnormality that is essential for their BP increase, which was further augmented by increased calcium sensitization in salt-sensitive Dahl rats.

• Keywords
• Baroreflex efficiency, Fasudil, Nifedipine, Nitric oxide, Rho kinase, Sympathetic tone, Voltage-dependent calcium channels,
• MeSH
• Hypertension * drug therapy   MeSH
• Blood Pressure MeSH
• Rats MeSH
• Sodium Chloride, Dietary * MeSH
• Rats, Inbred Dahl MeSH
• Calcium MeSH
• Vasoconstriction MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Sodium Chloride, Dietary * MeSH
• Calcium MeSH

The effect of chemical sympathectomy on cardiovascular parameters and the compensatory role of adrenal hormones, the renin-angiotensin system, and cardiovascular sensitivity to vasoconstrictors were studied in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Sympathectomy was induced in 20-week-old rats by daily intraperitoneal guanethidine administration (30 mg/kg b.w.) for 2 weeks. Basal blood pressure (BP), heart rate (HR), and restraint stress-induced cardiovascular changes were measured by radiotelemetry. The BP response to catecholamines was determined in rats with implanted catheters. Sympathectomy decreased BP only transiently, and after 14-day guanethidine treatment, BP returned to basal values in both strains. Sympathectomy permanently lowered HR, improved baroreflex sensitivity, and decreased the low-frequency domain of systolic blood pressure variability (a marker of vascular sympathetic activity). Guanethidine also attenuated the BP and HR responses to restraint stress. On the other hand, the BP response to catecholamines was augmented in sympathectomized rats, and this was not due to the de novo synthesis of vascular adrenergic receptors. Sympathectomy caused adrenal enlargement, enhanced the expression of adrenal catecholamine biosynthetic enzymes, and elevated plasma adrenaline levels in both strains, especially in WKY rats. Guanethidine also increased the plasma levels of aldosterone and corticosterone in WKY rats only. In conclusion, sympathectomy produced a transient decrease in BP, a chronic decrease in HR and improvement in baroreflex sensitivity. The effect of sympathectomy on BP was counteracted by increased vascular sensitivity to catecholamines in WKY rats and SHRs and/or by the enhanced secretion of adrenal hormones, which was more pronounced in WKY rats.

• Keywords
• Adrenal medulla, Blood pressure response, Catecholamines, Guanethidine, Vascular wall innervation,
• MeSH
• Baroreflex drug effects   MeSH
• Blood Vessels drug effects   innervation   physiopathology   MeSH
• Restraint, Physical MeSH
• Guanethidine pharmacology   MeSH
• Hypertension physiopathology   MeSH
• Cardiovascular Physiological Phenomena drug effects   MeSH
• Catecholamines metabolism   MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• Adrenal Glands growth & development   metabolism   physiopathology   MeSH
• Rats, Inbred SHR MeSH
• Rats, Inbred WKY MeSH
• Stress, Psychological MeSH
• Heart Rate drug effects   MeSH
• Sympatholytics pharmacology   MeSH
• Vasoconstrictor Agents pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Guanethidine MeSH
• Catecholamines MeSH
• Sympatholytics MeSH
• Vasoconstrictor Agents MeSH

OBJECTIVE: We evaluated the hypothesis that the development of renal dysfunction and congestive heart failure (CHF) caused by volume overload in rats with angiotensin II (ANG II)-dependent hypertension is associated with altered renal vascular responsiveness to ANG II and to epoxyeicosatrienoic acids (EETs). METHODS: Ren-2 transgenic rats (TGRs) were used as a model of ANG II-dependent hypertension. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF). Renal blood flow (RBF) responses were determined to renal arterial administration of ANG II, native 11,12-EET, an analog of 14,15-EETs (EET-A), norepinephrine (NE), acetylcholine (Ach) and bradykinin (Bk) in healthy (i.e., sham-operated) TGR and ACF TGR (5 weeks after ACF creation). RESULTS: Selective intrarenal administration of neither vasoactive drug altered mean arterial pressure in any group. Administration of ANG II caused greater decreases in RBF in ACF TGR than in sham-operated TGR, whereas after administration of NE the respective decreases were comparable in the 2 groups. Administration of Ach and Bk elicited significantly higher RBF increases in ACF TGR as compared with sham-operated TGR. In contrast, administration of 11,12-EET and EET-A caused significantly smaller RBF increases in ACF TGR than in sham-operated TGR. CONCLUSION: The findings show that 5 weeks after creation of ACF, the TGR exhibit exaggerated renal vasoconstrictor responses to ANG II and reduced renal vasodilatory responses to EETs, suggesting that both these alterations might play an important role in the development of renal dysfunction in this model of CHF.

• Keywords
• Acetylcholine, Angiotensin II, Aorto-caval fistula, Bradykinin, Congestive heart failure, Epoxyeicosatrienoic acid, Hypertension, Norepinephrine, Renal blood flow, Renal dysfunction, Renal vascular reactivity,
• MeSH
• Angiotensin II adverse effects   MeSH
• Pulmonary Artery abnormalities   physiopathology   MeSH
• Arterio-Arterial Fistula physiopathology   MeSH
• Hypertension chemically induced   complications   MeSH
• Rats MeSH
• Rats, Transgenic MeSH
• Renal Circulation drug effects   MeSH
• Heart Failure complications   physiopathology   MeSH
• Vasodilation drug effects   MeSH
• Vasoconstriction drug effects   MeSH
• Vasoconstrictor Agents pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Angiotensin II MeSH
• Vasoconstrictor Agents MeSH