HORMONES AS LONG-TERM ERROR SIGNALS FOR THE SYMPATHETIC NERVOUS SYSTEM: IMPORTANCE OF A NEW PERSPECTIVE

1. A hormonal-sympathetic reflex model for long-term control of arterial pressure is presented. It is hypothesized that the hormonal-sympathetic reflex regulates arterial pressure during chronic dietary salt loading by decreasing sympathetic tone. This sympathetic response is mediated by an increase in plasma vasopressin (AVP) and a decrease in plasma angiotensin (AngII). 2. Three new models of neurogenic salt-dependent hypertension are presented. All models are theoretically based on an impaired hormonal-sympathetic reflex. 3. In the first model, sympathetic responsiveness is ‘clamped’ by long-term α-adrenergic blockade with prazosin. Prazosin treated rats exhibit marked salt-dependent hypertension despite normal suppression of the renin-angiotensin system. 4. In the second model, the ability of the central nervous system to respond to salt-induced changes in AVP and AngII concentrations was prevented by long-term administration of antagonists selective for the AVP-V₁ and AT₁. This ‘clamp’ of the afferent hormonal signal resulted in salt-dependent hypertension identical in magnitude to that observed in prazosin treated rats. 5. In the third model, the long-term arterial pressure responses to increasing dietary salt were examined in sino-aortic denervated (SAD) rats. SAD rats exhibited salt-dependent hypertension, of lesser magnitude than that observed with ‘clamped’ afferent and efferent pathways of the hormonal-sympathetic reflex. 6. A primary role for hormonal ‘error signals’ is presented and the impact this perspective has on past and future investigations of central mechanisms of long-term arterial pressure regulation is discussed.     

Does enhanced sympathetic tone contribute to angiotensin II hypertension in rats?

To determine whether enhanced sympathetic tone contributes to the maintenance of chronic angiotensin II (A II, 10 ng/min i.v. for 10 days) hypertension in rats, sympathetic activity was assessed in hypertensive and control rats by measuring norepinephrine (NE) turnover (alpha-methyl-p-tyrosine) in peripheral organs and by measuring depressor responses to ganglionic blockade in conscious rats. Pressor responses to methoxamine (1-8 micrograms/min) and arginine vasopressin (0.5-4 ng/min) were also obtained in rats with ganglionic blockade. Chronic A II infusion produced significant hypertension (mean +/- S.E. tail cuff pressure: 176 +/- 5 vs. 134 +/- 2 mm Hg in controls; n = 23 each group) but there were no significant differences in NE turnover in heart, kidney, skeletal muscle, or intestine in hypertensive rats compared with controls. Ganglionic blockade produced a significantly larger decrease in mean arterial pressure in A II-treated rats when compared with controls (73 +/- 7 vs. 38 +/- 2 mm Hg, n = 18 for each group). Dose-response curves for methoxamine and vasopressin were not significantly different between groups. The results suggest that the maintenance of chronic A II hypertension does not involve postsynaptic interactions between A II and the sympathetic system. The NE turnover data do not support the hypothesis that rats with chronic A II hypertension have enhanced sympathetic tone.     

VASOPRESSIN COMPENSATES FOR ACUTE LOSS OF SYMPATHETIC PRESSOR TONE IN SPONTANEOUSLY HYPERTENSIVE RATS

1. The aim of this study was to examine the pressor response of vasopressin (AVP) to an acute fall in blood pressure induced by ganglion blockade. 2. Aortic catheters were implanted in spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP), normotensive Wistar-Kyoto (WKY), black-hooded Wistar (BHW) and Sprague-Dawley (SD) rats, aged 5–7 weeks and 7–9 months, for direct measurement of mean arterial pressure (MAP) under conscious, resting conditions. The ganglion blocking agent pentolinium was administered intra-arterially, followed by an AVP receptor antagonist specific for the pressor effect of AVP. The basal level of MAP attained with each drug was recorded. 3. In the adult SHR and SHRSP with established hypertension, acute ganglion blockade caused MAP to fall to a similar extent as in WKY, suggesting that the level of sympathetic pressor tone was similar in all three strains. Administration of the AVP antagonist alone did not affect resting MAP. During ganglion blockade, however, it caused a further reduction of MAP in WKY, SHR and SHRSP, the magnitude of which was greater in the hypertensive strains. After both drugs, the total fall in MAP and the residual MAP were significantly greater in the hypertensive rats. 4. In young rats, AVP had little effect on MAP, even during ganglion blockade. The residual level of MAP after both drugs was greater in the hypertensive strains. 5. The extent to which AVP can compensate for an acute fall in MAP increases with age and the development of hypertension. This tends to mask the loss of sympathetic mediated pressor tone after ganglion blockade. By preventing this compensation we have shown that the sympathetically mediated component of blood pressure is elevated in SHRSP with established hypertension.     

The chronic infusion of hexamethonium and phenylephrine to effectively clamp sympathetic vasomotor tone. A novel approach

There are several ways to assess the sympathetic nervous system (i.e. , nerve recording, sympathectomy, etc.), each of which has its own limitations. The present study was conducted to establish a standard, testable chronic ganglionic blockade protocol with a fixed level of adrenergic vasomotor tone. Rats were instrumented with radio telemetry pressure transducers and venous catheters for continuous measurement of arterial pressure and infusion of pharmacologic agents, respectively. After 3 days of control measurements, rats were infused for 9 days with a continuous dose of the ganglionic blocking agent, hexamethonium and the alpha-adrenergic agonist, phenylephrine. In this way, sympathetic tone was effectively "clamped," which maintained a normal level of arterial pressure. Control pressure between hexamethonium + phenylephrine (HEX + PE) treated rats (101+/-2 mm Hg) and saline (VEHICLE) treated rats (101+/-2 mmHg) was not different. By day 9 of the infusion, there was no difference in arterial pressure between groups (VEHICLE: 101+/-3 mm Hg, HEX + PE: 103+/-3 mm Hg) or from the control period, although heart rate was significantly less in HEX + PE rats (VEHICLE: 406+/-9 beats/min vs. HEX + PE: 343+/-6 beats/min). The effectiveness of this technique was validated by measuring cardiac baroreceptor reflex sensitivity, as well as the pressor response to the direct ganglionic stimulating agent, 1, 1-dimethyl-4-phenylpiperazinium iodide (DMPP). Compared to VEHICLE rats, HEX + PE rats showed no tachycardic response to depressor stimuli and an absence of a pressor response to DMPP. We conclude that this protocol is a useful technique to chronically, yet reversibly, block the sympathetic nervous system in experimental settings.     

Salt enhances responsiveness of terminal aortic vascular bed to sympathetic activity

Objective: Haemodynamic and laboratory examinations were performed in 27 essential hypertensives. The participation of the sympathetic system was estimated from the percentage decrease in regional vascular resistance caused by 1 mg prazosin, during varied salt intake (50–80 mEq sodium per day for 9 weeks, followed by 220–250 mEq sodium per day for 10 days), with or without benidipine. Results: During low salt intake, terminal aortic and renal resistances were decreased by prazosin, but superior mesenteric resistance remained unchanged. In the salt-sensitive patients, whose mean arterial pressure increased more than 5 mmHg with salt repletion, salt loading increased superior mesenteric and renal resistances but did not change terminal aortic resistance. This salt-induced vasoconstriction of renal and superior mesenteric arteries is not related to an increase in sympathetic activity, because both plasma noradrenaline concentrations and the percentage decrease in these regional vascular resistances by prazosin remained unchanged after salt loading. On the other hand, terminal aortic area demonstrated an increase in responsiveness to noradrenaline (increased response to prazosin) with salt loading in spite of unchanged terminal aortic resistance. This salt-induced increase in sympathetic responsiveness in the terminal aortic area was inhibited with the addition of benidipine, which abolished development of salt-induced hypertension and its accompanying haemodynamic responses. Received: 15 April 1996 / Accepted in revised form: 29 October 1996     

Renal denervation causes chronic hypotension in rats: role of beta1-adrenoceptor activity

1. Renal denervation (RDNX) chronically lowers mean arterial pressure (MAP) in normal rats but mechanisms leading to this hypotensive response remain unknown. 2. We hypothesized that this sustained decrease in arterial pressure was because of a loss of beta1-adrenoceptor mediated renin secretion. Male Sprague-Dawley rats were assigned to sham (SHAM; n = 9), unilateral (UniRDNX; n = 9), or bilateral (RDNX; n = 10) renal denervation groups and instrumented for telemetric MAP measurements, plasma renin concentration (PRC) measurements and intravenous infusion. Twenty-four h MAP, heart rate, sodium and water balances were recorded 5 days before, 3 days during and 3 days after 1-adrenoceptor blockade with atenolol. 3. The 5-day control MAP was significantly lower in RDNX (97 +/- 1 mmHg) compared to SHAM (105 +/- 2 mmHg) and UniRDNX (102 +/- 2 mmHg) rats. No significant differences in basal PRC were observed between RDNX (2.2 +/- 0.3 ngAng1/mL per h), UniRDNX (2.6 +/- 0.4 ng/Ang1/mL per h) and SHAM (2.6 +/- 0.4 ngAng1/mL per h) rats. By day 1 of atenolol, PRC was significantly lower in UniRDNX rats (1.8 +/- 0.2 ngAg1/mL per h) compared to control values, but was unchanged during atenolol infusion in the other groups. By day 3 of atenolol, MAP was significantly decreased in all groups, but the absolute levels of MAP remained statistically different between RDNX (87 +/- 1 mmHg) and SHAM (91 +/- 1 mmHg) groups. 4. We conclude that the arterial pressure lowering effect of RDNX is not solely dependent on the loss of neural control of renin release.     

Enhanced sympathetic neurotransmission in the tail artery of 1,3-dipropyl-8-sulphophenylxanthine (DPSPX)-treated rats.

1. Sympathetic neurotransmission and noradrenaline content of the tail artery of Wistar rats treated for 7 days with the adenosine antagonist, 1,3-dipropyl-8-sulphophenylxanthine (DPSPX), were examined. 2. Systolic blood pressure of the DPSPX-treated rats (164.0 +/- 2.9 mmHg; n = 6) was significantly greater than saline-treated controls (140.0 +/- 2.8 mmHg; n = 5) after 7 days treatment. 3. The pressor responses of the arterial rings to transmural nerve stimulation (65 V, 0.1 ms, 4-64 Hz, for 1 s) were markedly enhanced in the DPSPX-treated compared with the saline-treated animals. Both noradrenergic and purinergic components of perivascular sympathetic neurotransmission were enhanced during DPSPX-induced hypertension. 4. Vasoconstrictor responses to exogenous noradrenaline (0.1-300 microM) and adenosine 5'-triphosphate (0.01-3 mM) were unaffected after DPSPX treatment, indicating prejunctional alteration of sympathetic cotransmission during DPSPX-induced hypertension. 5. Acute exposure to DPSPX (10 microM) did not modify vasoconstrictor responses to transmural nerve stimulation, thus supporting the claim that the enhancement of sympathetic neurotransmission only results from long-term DPSPX treatment. 6. The noradrenaline content of the tail arteries of DPSPX-treated (4.498 +/- 0.26 ng cm-1; n = 4) was significantly greater than saline-treated (3.440 +/- 0.30 ng cm-1; n = 5) animals. 7. These findings show that chronic inhibition of the actions of endogenous adenosine by DPSPX results in an elevation of systolic blood pressure accompanied by enhanced sympathetic cotransmission and enhanced noradrenaline content of the rat tail artery.     

Mechanisms for linking high salt intake to vascular tone: role of Na(+) pump and Na(+)/Ca²(+) exchanger coupling

Excessive salt intake is a major risk factor for hypertension. However, the underlying molecular relationship between salt and hypertension is not fully understood. Recently discovered cardiotonic steroids, such as endogenous ouabain and other steroids, have been proposed as candidate intermediaries. Plasma cardiotonic steroids are significantly elevated in patients with essential hypertension and in salt-dependent hypertensive animals. Generally, it is believed that cardiotonic steroids inhibit Na(+) pump activity and lead to an increase in the cytosolic Na(+) concentration. Cellular Na(+) accumulation raises the cytosolic Ca2(+) concentration through the involvement of Na(+)/Ca2(+) exchanger type 1 (NCX1). In isolated arteries from α2 Na(+) pump knockout mice (α2(+/-)), myogenic tone is increased, and NCX inhibitor normalizes the elevated myogenic tone in α2(+/-) arteries. The NCX inhibitor lowers arterial blood pressure in salt-dependent hypertensive rats but not in other types of hypertensive rats or in normotensive rats. Furthermore, smooth muscle-specific NCX1 transgenic mice are hypersensitive to salt, whereas mice with smooth muscle-specific knockout of NCX1 (NCX1(SM-/-)) have low salt sensitivity. These results suggest that functional coupling between the vascular α2 Na(+) pump and NCX1 is a critical molecular mechanism for salt-induced blood pressure elevation.     

Effects of birth on baroreceptor-mediated changes in heart rate variability in lambs and fetal sheep

1. In adult unanaesthetized sheep, there is a V-shaped relationship between mean arterial pressure (MAP) and heart rate variability (HRV), measured in both time and frequency domains. In contrast, in fetal sheep, there is only a positive direct relationship between MAP and HRV, which is determined by the cardiac vagus. We postulated that by the time lambs were 8-10 days old, the 'adult like' V-shaped relationship between MAP and HRV would be present and it may appear at or after birth. To test these hypotheses, experiments were performed in six chronically catheterized fetal sheep (aged 132-138 days gestation), 10 newborn sheep (within 10 h of birth) and 10 lambs (aged 8-10 days). The relationships between MAP and HRV (in both time and frequency domains) were studied before and during beta-adrenoreceptor blockade with propranolol and before and during cardiac vagal blockade with atropine. 2. In 8-10-day-old lambs, V-shaped relationships between MAP and HRV (measured in both time and frequency domain) were obtained. The negative limb of this V-shaped relationship between MAP and HRV was present after cardiac vagal blockade. The positive slope of the V was present after beta-adrenoreceptor blockade. 3. In 4-h-old newborn sheep, there was no relationship between MAP and HRV (measured in the time domain), but between 7 and 10 h of age a negative relationship was found during treatment with atropine and a positive relationship was found during beta-adrenoreceptor blockade, when HRV was measured in both time and frequency domains. 4. As described previously, there was only a positive relationship between MAP and HRV in fetal sheep, which was abolished by atropine but not affected by beta-adrenoreceptor blockade. 5. Thus, until relatively late in fetal life, baroreceptor- modulated changes in efferent cardiac sympathetic tone, determined by measuring the effects of autonomic blockade on HRV, could not be elicited, although reflex vagal pathways were active. By 7-10 h after birth, baroreceptor-modulated changes in efferent cardiac sympathetic tone were present. It was possible using measurements of HRV made in the time domain to show that these baroreceptor-modulated cardiac sympathetic effects became stronger over the first 10 days of life (P < 0.01). These studies are the first to show that the influence of baroreceptor-mediated changes in cardiac sympathetic tone on HRV increases in early life. This is probably because maturation of sympathetic innervation of the fetal sheep heart is occurring at this age.     

Effect of cold on fetal heart rate and its variability

1. The effects of cold saline (25 mL) injected over the fetal skin on fetal heart rate (HR) and HR variability (HRV), measured as the coefficient of variation (CV) in pulse interval (PI) and by power spectral analysis (PSA), were measured in 10 chronically catheterized fetal sheep aged 140-144 days. To determine the extent to which effects on HR and HRV were mediated by the sympathoadrenal neuroendocrine axis and the cardiac vagus, experiments were performed before and after beta-adrenoreceptor blockade with propranolol (n = 12 fetuses) or before and after cardiac vagal blockade with atropine (n = 4 fetuses). 2. Injection of ice-cold saline over the skin caused an immediate rise in mean arterial pressure (MAP) from 46+/-1 to 55+/-1 mmHg (P < 0.001) and HR from 156+/-2 to 182+/-2 b.p.m. (P < 0.001). Heart rate variability, measured as CV of PI, rose from 3.5+/-0.2 to 8.0+/-0.2% (P < 0.001) and total power spectral density (PSD) increased from 78+/-6 to 278+/-16 units (P < 0.001) as measured by PSA. Within 100s, MAP, HR and HRV had returned to baseline. 3. Beta-adrenoreceptor blockade abolished all these changes in HR, HRV and PSD, but had no effect on changes in MAP. Atropine had no demonstrable effect on the responses to cold. 4. Therefore, the increase in fetal MAP, HR and HRV that occurred with stimulation of peripheral thermoreceptors was the result of increased activity of the sympathetic nervous system. Alterations in efferent cardiac vagal tone were not involved in the cardiac response to cold.     

Effects of vasodilator drugs on venous tone in conscious rats

The dose-response effects of vasodilator drugs, nitroglycerin, sodium nitroprusside and hydralazine, on mean arterial pressure (MAP) and mean circulatory filling pressure (MCFP), an index of body venous tone, were investigated in conscious, unrestrained, intact rats as well as in rats treated with the ganglionic blocker, hexamethonium. The effects of these drugs were compared with those of the vehicle, normal saline, in control rats. In intact rats, i.v. infusion of nitroglycerin did not alter MAP while i.v. infusions of nitroprusside or hydralazine caused dose-dependent decreases in MAP. After ganglionic blockade, all three drugs decreased MAP. In intact rats, nitroglycerin and sodium nitroprusside did not affect MCFP but hydralazine increased MCFP. After treatment with hexamethonium, all three drugs decreased MCFP. The decreases in MCFP caused by nitroglycerin and nitroprusside, but not that by hydralazine, were significantly greater than the corresponding changes in control rats. Thus, in intact rats, the direct venodilator actions of nitroprusside and nitroglycerin were masked by endogenous sympathetic tone. When sympathetic nerve activity was attenuated, both nitroprusside and nitroglycerin have venodilator effects. Hydralazine, on the other hand, had insignificant venodilator effect both in the presence and absence of sympathetic reflexes.     

Alpha-fluoromethylhistidine, an inhibitor of histamine biosynthesis, causes arterial hypertension

In this study we assessed the cardiovascular response to 13 days of irreversible inhibition of the enzyme histidine-decarboxylase (HD) with alpha-fluoromethylhistidine (AFMH). Age-matched untreated rats were used as controls. Tail-cuff mean arterial pressure (MAP) and heart rate (HR) rose progressively in AFMH-treated rats, reaching maximal values during the study period by the 13th day of treatment. There was a reduction in urinary histamine at the day 7 and 13, and of sodium excretion at the day 7 of treatment, while the renal catecholamine excretion was increased at both days of treatment, suggesting an increase of sympathetic activity. At the 13th day of treatment, there was an activation of the renin-angiotensin-aldosterone system. In addition, the cardiovascular responses to footshock stress were determined in rats treated intraperitoneally (i.p.) or intracerebroventricularly (i.v.t.) with a single dose of AFMH. Peripheral sympathetic facilitation was found, as the hemodynamic response to footshock stress was significantly enhanced after i.p. administration, but not after i.v.t. administration of AFMH. Our results suggest that conditions of peripheral histamine deficiency may result in sympathetic facilitation, arterial hypertension and tachycardia in the rat.     

Effects of a peripherally acting alpha 2-adrenoceptor antagonist (L-659,066) on hemodynamics and plasma levels of catechols in conscious rats

L-659,066 is a new alpha 2-adrenoceptor antagonist which does not enter the central nervous system after systemic administration and therefore can be used to examine effects of blockade of peripheral alpha 2-receptors on hemodynamics and plasma levels of catechols. After i.v. administration to conscious rats, L-659,066 produced dose-related, small decreases in mean arterial pressure (MAP) and large increases in heart rate (HR), arterial plasma levels of norepinephrine (NE), and levels of the intraneuronal NE metabolite, dihydroxyphenylglycol (DHPG). After administration of L-659,066, HR, but not MAP, was strongly correlated with NE levels (r = 0.93, P less than 0.001). Levels of DHPG and dihydroxyphenylalanine (DOPA) also were strongly correlated with NE levels (r = 098 and r = 0.71). After comparison with responses during hypotension induced by the vasodilator, nitroprusside, the results indicated that L-659,066 increases sympathetically mediated NE release and catecholamine turnover due to inhibition of presynaptic alpha 2-receptors as well as due to reflexive sympathetic activation related to blockade of alpha 2-receptors on arterial smooth muscle cells.     

The functional role of PI3K in maintenance of blood pressure and baroreflex suppression in (mRen2)27 and mRen2.Lewis rat

The phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway in brain of spontaneously hypertensive rats, but not Wistar-Kyoto (WKY) rats, contributes to elevated mean arterial pressure (MAP). The role of PI3K in the regulation of blood pressure or autonomic function in the nucleus tractus solitarii (NTS) is yet to be established in other Ang II-dependent models of hypertension. Thus, we microinjected PI3K inhibitors, wortmannin or LY294002, into the NTS, and measured MAP, baroreflex sensitivity (BRS) for heart rate (HR) control, and HR variability (HRV) in mRen2.Lewis congenic and (mRen2)27 transgenic rats. Bilateral NTS microinjections of wortmannin (100 nmol/L; 50 nL) reduced MAP in (mRen2)27 and mRen2.Lewis rats (33 ± 5 mm Hg, n = 7, and 32 ± 6 mm Hg, n = 9, respectively) for approximately 90 minutes. Spectral and sequence analysis showed improvements in spontaneous BRS and HRV (50%-100%) after treatment in both hypertensive strains. Injections of wortmannin into NTS of Hannover Sprague-Dawley or Lewis control rats failed to alter MAP, BRS, or HRV. In mRen2.Lewis, but not in control Lewis rats, LY294002 (50 μmole/L) reduced MAP and increased BRS and HRV similar to wortmannin. Thus, the pharmacologic blockade of the PI3K signaling pathway in NTS reveals an important contribution to resting MAP and BRS in rats with overexpression of the Ren2 gene.     

Effects of medullary alpha2-adrenoceptor blockade in the rat

The effect of alpha2-adrenoceptor blockade in the medulla was studied in pentobarbital anesthetized rats in which arterial blood pressure, heart rate and renal sympathetic nerve activity were analysed. Three series of experiments were performed: (1) i.c. administration of alpha2-adrenoceptor antagonists with different subtype affinities; (2) i.v. administration of methoxy-idazoxan to study its effects on neuronal activity into the rostral ventral medulla; (3) microinjections of methoxy-idazoxan in rostral ventral medulla and nucleus tractus solitarii. Methoxy-idazoxan (0.1-3 microg x kg(-1) i.c., n=5), but not saline, rauwolscine, BRL 44408 (2-[2H-(1,3,dihydroisoindol)methyl]-4,5dihydroimidazol) or ARC 239 (2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquilindione) (each at 10-100 microg x kg(-1) i.c., n=5-5-6-5, respectively), increased mean arterial blood pressure, heart rate and renal nerve activity (+19+/-6 mm Hg, +72+/-22 beats x min(-1), +43+/-9%) and blocked the sympatho-inhibitory action of clonidine (10 microg x kg(-1) i.v.). In further experiments, methoxy-idazoxan, BRL 44408 and the highest dose of rauwolscine i.c., reversed the clonidine-induced sympatho-inhibition (order of potency: methoxy-idazoxan>BRL4440>rauwolscine, n=6 each), whereas ARC 239 (n=5) or saline (n=7) did not. Methoxy-idazoxan i.v. (n=7, 10-100 microg x kg(-1)) increased the renal sympathetic nerve and rostral ventral medulla neuronal activity and the heart rate (+36+/-7%, +66+/-29% and +18+/-9 beats x min(-1)) without a significant effect on mean arterial blood pressure. Microinjection of methoxy-idazoxan (1 nmol/40 nl) into the rostral ventral medulla reversed the effect of clonidine microinjected into the same site (2 nmol/40 nl, n=5). In another group of rats (n=8), methoxy-idazoxan increased mean arterial blood pressure, heart rate and renal nerve activity (+16+/-2 mm Hg, +42+/-7 beats x min(-1), +24+/-5%) and blocked the effect of clonidine i.v. (10 microg x kg(-1)). Bilateral microinjections into the nucleus tractus solitarii (n=5) did not alter mean arterial blood pressure but decreased heart rate and sympathetic nerve activity (-30+/-16 beats x min(-1), -20+/-14%). Our results offer direct in vivo evidence for the main role of the alpha2A/D-adrenoceptors located in the ventral pressor area. The data show that the sympathy-excitatory effect of alpha2-adrenoceptor antagonists is due to the blockade of a tonic activation of these alpha2A/D-adrenoceptors present in the rostral ventral pressor area.     

The peripheral renin-angiotensin system is not involved in the hypertension of sheep exposed to prenatal dexamethasone

1. Fetal exposure to an adverse intrauterine environment has been linked with cardiovascular and metabolic disease later in life. We have shown previously, in sheep, that brief exposure (48 h) to maternally administered dexamethasone (0.28 mg/kg per day) at 27 days of gestation (prenatal treatment group (PTG) 1; term approximately 150 days), but not at 64 days of gestation (PTG2), produced hypertensive offspring at 40 months of age. The present study aimed to determine whether the elevated blood pressure in these sheep was associated with an altered peripheral renin-angiotensin system (RAS). 2. Measurements of the basal levels of the RAS components (renin, angiotensinogen, angiotensin (Ang) I, angiotensin- converting enzyme (ACE), AngII and Ang-(1-7)) were made. In addition, we studied the effect of a peripherally administered AngII type 1 (AT1) receptor antagonist (irbesartan at 1.02 mg/kg per h) on mean arterial pressure (MAP) over 4.5 h. 3. There was no significant difference in basal plasma concentrations of the components of the RAS measured between control (n = 7) and PTG1 (n = 5) or PTG2 (n = 6) animals. The MAP in PTG1 was significantly higher than in the control group during both vehicle infusion and AT1 receptor blockade. The effect of 4.5 h irbesartan (1.02 mg/kg per h) infusion on blood pressure was similar between the groups. 4. In conclusion, intrauterine exposure for 48 h to maternally administered dexamethasone at 27 days of gestation caused elevated blood pressure in adult sheep that does not appear to be associated with an alteration in the peripheral RAS.     

Augmented sensory-motor vasodilatation of the rat mesenteric arterial bed after chronic infusion of the P1-purinoceptor antagonist, DPSPX.

1. The effect of long-term antagonism of P1-purinoceptors on vascular function was examined in the perfused mesenteric arterial bed isolated from rats which had received constant infusion of either the non-selective P1-purinoceptor antagonist, 1-3-dipropyl-8-sulphophenylxanthine (DPSPX, 30 micrograms kg-1 h-1, i.p.) or saline for seven days. Sympathetic and sensory-motor neurotransmission, smooth muscle and endothelial function were assessed. 2. Basal tone was similar in mesenteric arterial preparations from control and DPSPX-treated rats. Continuous perfusion with methoxamine (7-70 microM) induced similar increases in tone in control and DPSPX-treated preparations. In the presence of guanethidine (5 microM), electrical field stimulation (EFS; 1-12 Hz, 60V, 0.1 ms, 30 s) elicited frequency-dependent vasodilatation due to activation of sensory-motor nerves. In tissues from DPSPX-treated rats the nerve-mediated vasodilator responses were markedly augmented at all frequencies. Maximal relaxation at 8 Hz was 38.34 +/- 4.76% (n = 5) in controls and 65.92 +/- 3.68% (n = 5) after DPSPX-treatment (P < 0.01). Adenosine (3 microM) inhibited the frequency-dependent sensory-motor neurotransmission similar in preparations from controls and DPSPX-treated rats. 3. In raised-tone preparations calcitonin gene-related peptide (CGRP; 5,15 and 50 pmol), the principal vasodilator transmitter of sensory-motor nerves in rat mesenteric arteries, produced similar relaxations in control and DPSPX-treated preparations. Vasodilator responses to the sensory neurotoxin capsaicin (50 and 500 pmol) were also similar between the groups. 4. Assay of tissue CGRP levels of the superior mesenteric artery by enzyme-linked immunosorbent assay showed no significant difference in tissue levels of CGRP in controls, 120.25 +/- 26.34 pmol g-1 tissue (n = 6) and with DPSPX-treatment, 82.12 +/- 24.42 pmol g-1 tissue (n = 6). 5. In raised-tone preparations dose-dependent endothelium-dependent vasodilatation to acetylcholine and ATP, and endothelium-independent vasodilatation to sodium nitroprusside were similar in control and DPSPX-treated preparations. 6. EFS (4-32 Hz, 90V, 1 ms, 30 s) elicited frequency-dependent vasoconstriction due to activation of sympathetic nerves which was similar in controls and in DPSPX-treated preparations. Adenosine (10 and 30 microM) inhibited sympathetic neurotransmission similarly in control and DPSPX-treated preparations. Dose-dependent vasoconstriction to noradrenaline (NA) and ATP, and to KCI (0.15 mmol) was similar between the groups. 7. High performance liquid chromatographic analysis of tissue NA showed no significant difference in NA content of the superior mesenteric artery from DPSPX-treated (1.38 +/- 0.09 ng mg-1, n = 6) and control rats (1.46 +/- 0.17 ng mg-1, n = 6). 8. In conclusion, in rats with hypertension due to 7 days treatment with the P1-purinoceptor antagonist, DPSPX, there is an increase in sensory-motor vasodilatation of the mesenteric arterial bed. There is no change in sympathetic nerve, endothelial or smooth muscle function. Augmented sensory-motor neurotransmission, which does not involve a change in postjunctional responsiveness to CGRP or in the CGRP content of sensory-motor nerves, could be a compensatory change in response to the DPSPX- induced hypertension.     

Inhibitors of prostaglandin synthesis reverse the effects of chronic beta-receptor blockade to attenuate adrenergic neurovascular transmission in dogs

The effects of acute and chronic treatment with beta-adrenergic receptor blocking drugs on peripheral adrenergic neurovascular transmission were investigated. Experiments were performed using the blood perfused gracilis muscle preparation in control dogs and in animals treated with single or repeated doses of beta-receptor antagonists. After 7 days of d,l-propranolol, l-propranolol, or atenolol administration, the arterial pressor response to sympathetic nerve stimulation was significantly reduced in treated dogs (p less than 0.05) when compared with control- or d-propranolol-treated animals. In comparison, acute beta blockade produced by a single intravenous dose of propranolol had no effect on the pressor response to nerve stimulation. Inhibition of fatty acid-cyclooxygenase activity by indomethacin or piroxicam enhanced the vasoconstrictor response to sympathetic nerve stimulation in chronic d,l-propranolol-, l-propranolol-, and atenolol-treated dogs, but had no effect on vascular neurotransmission in control-, chronic d-propranolol-, or acutely d,l-propranolol-treated animals. The vasoconstrictor response to intraarterial phenylephrine was not significantly altered by chronic propranolol treatment, and measurement of norepinephrine overflow during sympathetic nerve stimulation failed to reveal any difference in neurotransmitter release between control- and propranolol-treated dogs. The results indicate that chronic but not acute beta-adrenergic receptor blockade alters signaling at the neurovascular synapse to diminish adrenergic transmission. This effect does not appear to result from a change in postsynaptic alpha 1 receptors or from a decrease in norepinephrine release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Topics on the Na+/Ca2+ exchanger: role of vascular NCX1 in salt-dependent hypertension

Excess salt intake is a major risk factor for hypertension. However, the molecular mechanisms underlying salt-dependent hypertension remain obscure. Our recent studies using selective Na(+)/Ca(2+) exchange inhibitors and genetically engineered mice provide compelling evidence that salt-dependent hypertension is triggered by Ca(2+) entry through Na(+)/Ca(2+) exchanger type 1 (NCX1) in arterial smooth muscle. Endogenous cardiac glycosides, which may contribute to salt-dependent hypertension, seem to be necessary for NCX1-mediated hypertension. Intriguingly, recent studies by Dostanic-Larson et al. using knock-in mice with modified cardiac glycoside binding affinity of Na(+),K(+)-ATPases demonstrate that this binding site plays an important physiological role in blood pressure control. Thus, when cardiac glycosides inhibit Na(+),K(+)-ATPase in arterial smooth muscle cells, the elevation of local Na(+) on the submembrane area is believed to facilitate Ca(2+) entry through NCX1, resulting in vasoconstriction. This proposed pathway may have enabled us to explain how to link dietary salt to hypertension.     

The role of sympathetic nervous system in the action of dopamine and dobutamine on the function of circulatory system

To assess the role of peripheral structures of the sympathetic nervous system in the effects of dopamine and dobutamine on some functions of the cardiovascular system, experiments were carried out on anesthetized rabbits in which the blood flow in calf muscles was measured, during rest and during evoked twitches, using the method of 133Xe clearance. The arterial blood pressure and ECG were simultaneously recorded. A complete reversal of the action of dopamine on the arterial blood pressure and heart rate, after sympathetic nerve endings blockade, indicates an important role for the undisturbed neurotransmission in revealing hypotensive properties of this amine. In the action of dobutamine on blood pressure, heart rate and muscle blood flow, the blockade of peripheral structures of the sympathetic nervous system is of minor importance.