Sodium responsiveness of central alpha 2-adrenergic receptors in spontaneously hypertensive rats

The responsiveness of central nervous system alpha 2-adrenergic receptors in the neural control of renal function was compared in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) on normal or high sodium intake (3-4 weeks of 1% NaCl for drinking). The responsiveness of central alpha 2-adrenergic receptors was determined by comparing among groups the dose-response curves for the effects of cumulative intracerebroventricular injections of guanabenz (5, 25, and 125 micrograms) on changes in mean arterial pressure, renal sympathetic nerve activity, and urinary sodium excretion. Guanabenz altered mean arterial pressure similarly in SHR on normal or high sodium intake and in WKY on normal or high sodium intake. High sodium intake shifted the guanabenz-renal sympathetic nerve activity and guanabenz-urinary sodium excretion dose-response curves to the left in SHR and to the right in WKY. The dose-response curves between SHR and WKY on normal sodium intake were similar. Surgical renal denervation or pretreatment with an alpha 2-adrenergic receptor antagonist (rauwolscine, 30 micrograms i.c.v.) attenuated the ability of guanabenz to inhibit renal sympathetic nerve activity or increase urinary sodium excretion in SHR and WKY on either normal or high sodium intake. We conclude that the responsiveness of central nervous system alpha 2-adrenergic receptors regarding the neural control of renal function is increased by high sodium intake in conscious SHR, but not in conscious normotensive WKY.     

Decrease in alpha 1-adrenoceptor reserve in mesenteric arteries isolated from spontaneously hypertensive rats

The characterization of alpha-adrenoceptor-mediated contractile responses and the effects of the calcium channel blocker nifedipine on these responses were investigated in mesenteric arterial strips from 13-week-old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Contractile responses to the alpha-adrenoceptor agonists phenylephrine and clonidine were mediated through the activation of alpha 1-adrenoceptors. The dose producing a half-maximum response (ED50) for the agonists was higher in SHR than in WKY. Affinities of alpha 1-adrenoceptors were similar between the two strains. When arterial strips from both strains were treated with the same concentration of phenoxybenzamine, the maximum response to each agonist was weaker in SHR. The alpha 1-adrenoceptor occupancy-response relationship for phenylephrine was hyperbolic and less steep in SHR, while the relationship for clonidine was linear in SHR but not in WKY. Alpha 1-adrenoceptor occupancy at a half-maximum response to each agonist was greater in SHR. Nifedipine inhibited the maximum responses to the agonists more profoundly in SHR than in WKY. This inhibition was greater in the response to clonidine than in the response to phenylephrine in both strains. When the maximum response to phenylephrine was reduced to the same extent in both strains by treatment with different concentrations of phenoxybenzamine, the responses to phenylephrine were more susceptible to inhibition by nifedipine. Under these conditions, the effects of nifedipine were similar between SHR and WKY. These results suggest that alpha 1-adrenoceptor reserve is reduced in SHR mesenteric artery compared with WKY, which may be responsible for the greater inhibition by nifedipine of the alpha 1-adrenoceptor-mediated contractions in SHR.     

Enhanced inhibitory effect of alpha 2-adrenoceptor stimulation on the formation of cAMP in glomeruli of spontaneously hypertensive rats.

Renal alpha 2-adrenoceptors are known to be increased in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). To investigate whether this difference affects the second messenger system, we examined the effect of alpha 2-adrenoceptor stimulation on the formation of cAMP in microdissected glomeruli and proximal convoluted tubules obtained from the kidneys of SHR and WKY. The formation of glomerular cAMP, which was stimulated by parathyroid hormone (PTH), was inhibited by alpha 2-adrenoceptor stimulation. In contrast, the inhibitory effect of alpha 2-adrenoceptor stimulation on PTH-induced cAMP formation in proximal convoluted tubules was not significantly different between SHR and WKY. These results confirm the inhibitory action of alpha 2-adrenoceptors on the formation of cAMP in glomeruli and proximal tubules and suggest that the greater inhibitory effect on glomerular cAMP formation in SHR may reflect an increase in alpha 2-adrenoceptor density in SHR kidneys.     

Platelet alpha 2-adrenoceptor density in pregnancy-induced hypertensive patients: effect of epidural analgesia.

OBJECTIVES: Although pregnancy induced hypertension (PIH) is an important and relatively common medical problem, its pathophysiology remains unresolved and the search for a biochemical marker that precedes the hemodynamic abnormalities of PIH continues. Since human platelets contain alpha 2-adrenoceptors, these receptors were measured in women with PIH to determine whether patients with PIH have alpha 2-adrenoceptor abnormalities that might cause or exacerbate the hypertensive process. The effect of epidural analgesia upon blood pressure and its relation to changes in platelet alpha 2-adrenoceptor density were also investigated. DESIGN: Biochemical measurements and radioligand binding assays in platelets were performed on 33 patients with the criteria for PIH and on 26 healthy pregnant women. RESULTS: Blood pressure was significantly elevated in hypertensive women when compared with normotensive pregnant women although, in this group, blood pressure returned to normal levels in response to epidural analgesia. In drug-free hypertensive patients, the specific binding of 3H-yohimbine to platelet membranes increased significantly compared with that in control pregnant subjects. In contrast, the dissociation constant was not significantly different in the two groups. Furthermore, alpha 2-adrenoceptor density in the group with PIH returned to normal levels in response to epidural analgesia. CONCLUSION: Our findings indicate that PIH is characterized by an exaggerated response of platelet alpha 2-adrenoceptor density to a rise in blood pressure and that this alteration could be significant in the pathogenesis of hypertension. Furthermore, human alpha 2-adrenoceptors undergo regulatory mechanisms similar to those recently described for adrenergic receptors in a variety of animal models.     

Arterial baroreceptor reflex function in borderline hypertensive rats.

With increased dietary NaCl intake (8% NaCl), the borderline hypertensive rat develops hypertension, thus expressing the phenotype of the spontaneously hypertensive parent. Since arterial baroreceptor reflex function is impaired in the spontaneously hypertensive parent, it was the objective of this study to examine arterial baroreceptor reflex function in the borderline hypertensive rat made hypertensive by increased dietary NaCl intake. Borderline hypertensive rats were fed either 1% or 8% NaCl from age 4 to 16 weeks. Borderline hypertensive rats fed 8% NaCl (n = 10) were hypertensive compared with borderline hypertensive rats fed 1% NaCl (n = 11) (141 +/- 3 versus 120 +/- 4 mm Hg, p less than 0.01). They were chronically instrumented for the recording of arterial pressure, heart rate, and renal sympathetic nerve activity. The percent change from control in heart rate and renal sympathetic nerve activity resulting from increases (phenylephrine) and decreases (nitroglycerine) in arterial pressure were measured in conscious freely moving animals. With respect to arterial baroreceptor reflex control of heart rate, 8% NaCl borderline hypertensive rats had a similar range (75 +/- 4%) and maximal gain (-2.72 +/- 0.24%/mm Hg) as 1% NaCl borderline hypertensive rats (70 +/- 4%; -2.78 +/- 0.50%/mm Hg). With respect to arterial baroreceptor reflex control of renal sympathetic nerve activity, 8% NaCl borderline hypertensive rats had values for range (205 +/- 22%) and maximal gain (-3.92 +/- 0.93%/mm Hg) that were not significantly different from those for 1% NaCl borderline hypertensive rats (167 +/- 33%, -2.76 +/- 0.62%/mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Central alpha 2-adrenergic stimulation increases neurointermediate lobe immunoreactive beta-endorphin in spontaneously hypertensive rats

A possible influence of the central alpha 2-adrenergic system on beta-endorphin was examined in rat anterior pituitary, neurointermediate lobe, and plasma. The concentration of beta-endorphin in anterior pituitary, neurointermediate lobe, and plasma was determined by radioimmunoassay 15 minutes after subcutaneous injection of clonidine in 14-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Clonidine reduced the concentration of the plasma beta-endorphinlike immunoreactivity in SHR and to a lesser extent in WKY. No significant changes in the concentration of beta-endorphinlike immunoreactivity were observed in anterior pituitary. Clonidine increased the concentration of neurointermediate lobe beta-endorphinlike immunoreactivity in SHR in a dose-related manner but did not affect the concentration in WKY. Administration of yohimbine (1 mg/kg) completely blocked the clonidine-induced increase of neurointermediate lobe beta-endorphinlike immunoreactivity in SHR, while prazosin (1 mg/kg) had no effect. These data suggest that the central alpha 2-adrenergic activation increases the neurointermediate lobe concentration of beta-endorphinlike immunoreactivity in SHR by suppressing beta-endorphin release from the neurointermediate lobe into the circulation.     

Hypothalamic microinjection of alpha 2-adrenoceptor agonists causes greater sympathoinhibition in spontaneously hypertensive rats on high NaCl diets

We tested the hypothesis that in NaCl-sensitive spontaneously hypertensive rats (SHR-S) maintained on high NaCl diets, sympathoinhibitory neurons in the anterior hypothalamic area display increased responsiveness to alpha 2-adrenergic receptor stimulation, giving rise to exaggerated depressor responses. Clonidine (0.6-2.5 micrograms) was microinjected directly into the anterior hypothalamic area of SHR-S maintained for 2 weeks on high (8%) and normal (1%) NaCl diets, and blood pressure and heart rate responses were monitored. Controls were NaCl-resistant SHR (SHR-R) and normotensive Wistar-Kyoto (WKY) rats. Clonidine microinjection into the anterior hypothalamic area resulted in dose-dependent rapid-onset depressor and bradycardic responses that were significantly greater in SHR-S fed on a high NaCl diet. In SHR-R and WKY rats, the high NaCl diet had no significant effect on blood pressure or heart rate responses to clonidine. Further studies demonstrated that the response to microinjection of clonidine into the rat anterior hypothalamic area was location-specific, since injections into surrounding hypothalamic nuclei gave a longer latency in the onset of either depressor and bradycardic responses or pressor and tachycardic responses. The response of clonidine was blocked by concurrent microinjection of the selective alpha 2-adrenergic antagonist rauwolscine but not by the alpha 1-adrenergic antagonist prazosin, confirming that the response was alpha 2-adrenoceptor-specific. Microinjection of the selective alpha 2-agonist guanabenz into the anterior hypothalamic area produced depressor and bradycardic responses in SHR-S and Sprague-Dawley rats, while microinjection of the selective alpha 1-agonist phenylephrine into the anterior hypothalamic area had no effect on either blood pressure or heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

The frequency of alpha 2-adrenoceptor restriction fragment length polymorphisms in normotensive and hypertensive humans.

OBJECTIVE: To examine the frequency of distribution of allelic polymorphisms of the alpha 2-adrenoceptor gene in normotensive and hypertensive humans. DESIGN: The frequency of alpha 2-adrenoceptor genotypes was compared in the two groups using the chi 2-test. SETTING: The Midwest Hypertension Research Center Outpatient Clinic of Creighton University School of Medicine. STUDY PARTICIPANTS: History was taken from and physical examination performed on each of the 60 hypertensive and 47 normotensive adults. METHODS: DNA was extracted from leukocytes from each participants. Twenty restriction endonucleases were used and one restriction fragment length polymorphism (RFLP) was found using a 950-bp restriction fragment from the coding region of the human platelet alpha 2-adrenoceptor gene (ADRA2R) and Bsu36I restriction endonuclease. This probe and Bsu36I restriction endonuclease, in addition to another restriction endonuclease (Dra I), were then used in the study. RESULTS: Three genotype patterns were found. Homozygotes for the Bsu36I RFLP have either a unique 12-kb or a unique 5.8-kb band. Heterozygotes have both bands. The frequency of this alpha 2-adrenoceptor RFLP was calculated. In hypertensives the frequencies of the 12- and 5.8-kb alleles were 0.52 and 0.48, compared with 0.45 and 0.55, respectively, in normotensive, a difference that was not statistically significant. CONCLUSIONS: The frequency of the Bsu36I RFLP involving an alpha 2-adrenoceptor gene in hypertensives did not differ significantly from that in normotensives. A genetic linkage study is now under way to test for an association of the Bsu36I RFLP of the alpha 2-adrenoceptor gene with essential hypertension in families.     

Chronic ethanol feeding potentiates alpha1-adrenoceptor responsiveness in SHR aortas

Previous studies including ours demonstrated a hypotensive response to ethanol in spontaneously hypertensive rats (SHRs). In this study, we investigated whether this hypotensive effect of ethanol involves alterations in vascular alpha1-adrenergic receptor responsiveness. The contractile responses to the alpha1-receptor agonist phenylephrine were evaluated in aortic rings obtained from pair-fed SHRs receiving liquid diet with or without ethanol (2.5% or 5%, w/v) for 3 months. The responses were measured in aortas with and without endothelium to determine the role of the endothelium in the observed responses. The liquid diet intake was similar in the control and ethanol groups throughout the study whereas the body weight was significantly reduced by ethanol. Cumulative addition of phenylephrine (1 x 10(-9)-1 x 10(-4) M) caused concentration-related contractile responses. These responses were significantly reduced after endothelium denudation suggesting a role for the endothelium in the modulation of alpha1-receptor responsiveness. Ethanol (2.5% and 5%) caused significant and concentration-related increases in the contractile responses elicited by phenylephrine but not KCl. The maximum contraction (Emax) caused by phenylephrine in rings obtained from SHRs treated with 2.5% and 5% ethanol amounted to 413.6 +/- 26.3 and 513.0 +/- 46.7 mg tension/mg tissue, respectively, compared with 383.6 +/- 35.2 mg tension/mg tissue in control rings. The enhancement of alpha1 contractions by ethanol was virtually abolished in rings pretreated with the alpha1-receptor antagonist prazosin, suggesting upregulation of alpha1-receptors in aortas of ethanol-fed rats. Endothelium denudation also abolished ethanol-evoked increases in phenylephrine contractions. These findings suggest that chronic ethanol feeding upregulates aortic alpha1-receptors, which may be a consequence of chronic alpha1-receptor blockade by ethanol. The latter may account, at least in part, for the hypotensive response elicited by ethanol in SHRs.     

Presynaptic alpha 2-adrenoceptor mediated regulation of norepinephrine release in perfused mesenteric vasculatures in young and adult spontaneously hypertensive rats

The present study was designed to evaluate the role of the presynaptic alpha 2-adrenoceptor in the pathogenesis of hypertension. Norepinephrine overflow during sympathetic nerve stimulation and its changes by presynaptic alpha 2-adrenoceptor inhibition were examined in the perfused mesenteric vasculatures of young and adult spontaneously hypertensive rats (SHR) compared with age-matched Wistar Kyoto rats (WKY). Electrical sympathetic nerve stimulation caused significantly greater overflow of endogenous norepinephrine from the adrenergic nerve terminals in young SHR than in age-matched WKY. Yohimbine, an alpha 2-adrenoceptor blocking agent, facilitated norepinephrine overflow from the adrenergic nerve terminals. The effects of yohimbine on norepinephrine overflow and pressor responses to electrical nerve stimulation were less in young SHR than in age-matched WKY. Norepinephrine overflow in adult SHR was similar to that in adult WKY, and differences in the effect of yohimbine on norepinephrine overflow between SHR and WKY were not marked at this chronic stage. These results suggest that enhanced norepinephrine overflow in the mesenteric vasculatures can be observed only in young SHR; this may be due in part to an impaired negative feed-back mechanism on the nerve terminals by presynaptic alpha 2-adrenoceptors.     

Reduced beta 2-adrenoceptor responsiveness in exercise-induced asthma

Beta-adrenoceptor responsiveness was studied both in vivo and in vitro in patients with exercise-induced asthma (EIA), asthmatic patients without EIA (NEIA), and control subjects. All subjects were age- and sex-matched and without medication at least one week prior to the tests. In vivo, beta-adrenoceptor responsiveness was evaluated by plasma concentration-effect studies for intravenously infused isoprenaline (0.02-0.1 micrograms X kg-1 X min-1). Mainly beta 2-adrenoceptor mediated responses to isoprenaline, ie, decreases in diastolic blood pressure and increases in plasma cyclic AMP, were reduced in EIA patients but not in NEIA patients. Heart rate and plasma glycerol responses to isoprenaline did not differ between the groups. In vitro, the beta 2-adrenoceptor mediated accumulation of cyclic AMP in lymphocytes stimulated by isoprenaline was attenuated (p less than 0.05) in EIA patients, whereas the beta 2-adrenoceptor responsiveness of lymphocytes from NEIA patients was normal. Thus, beta 2-adrenoceptor mediated responses were reduced both in vivo and in vitro in EIA patients, but not in NEIA patients. This finding that beta 2-adrenoceptor responsiveness was reduced only in a subgroup of asthmatic patients could explain some of the controversies in the literature concerning beta-adrenoceptor function in asthma.     

Increased beta 2-adrenoceptor number in peripheral sympathetic ganglia of spontaneously hypertensive rats

We determined beta-adrenoceptor concentrations in sympathetic ganglia from adult Spontaneously Hypertensive Rats (SHR) and Wistar-Kyoto (WKY) control rats by quantitative autoradiography. Adjacent tissue sections were incubated with [125I]iodocyanopindolol, with or without excess of unlabeled (-)-propranolol, the beta 1-antagonist CGP 20712A or the beta 2-antagonist ICI 118,551. Most beta-adrenoceptors were of the beta 2-type. Their concentration was higher in the superior cervical and stellate ganglia of SHR when compared to normotensive WKY. Our results indicate that beta 2-adrenoceptor stimulation may be enhanced in sympathetic ganglia of SHR, and could play a role in the maintenance of their increased sympathetic activity.     

Increased vascular beta2-adrenoceptor responsiveness in autonomic dysfunction

Responsiveness to the vasopressor, vasodepressor and chronotropic effects of several sympathomimetic amines was assessed in 12 patients with severe autonomic dysfunction and in 8 age-matched control subjects. The patients with autonomic dysfunction showed a profound increase in responsiveness to both isoproterenol and phenylephrine as compared with control subjects. The mean bolus dose of isoproterenol required to increase heart rate by 25 beats/min was 0.9 + 0.2 microgram in the patients and 5.4 + 2.1 micrograms in the control subjects. The dose of isoproterenol required to reduce mean blood pressure by 25 mm Hg was 0.3 + 0.2 and 5.2 + 1.8 micrograms, respectively. Thus, although there is a 6-fold increase in responsiveness to the chronotropic effect of isoproterenol in autonomic dysfunction, the responsiveness to the drug's depressor effect is increased 17-fold. This enhanced depressor sensitivity is quite marked, even with oral beta-adrenoceptor agonists. Beta-adrenoceptor agonists must be used with caution in conditions associated with autonomic dysfunction if dangerous hypotension is to be avoided.     

Renal manifestations of NaCl sensitivity in borderline hypertensive rats

Compared with the normotensive Wistar-Kyoto rat, the spontaneously hypertensive rat exhibits exaggerated alterations in renal sympathetic nerve activity and excretory function during volume expansion (exaggerated natriuresis) and environmental stress (antinatriuresis). The borderline hypertensive rat is the first filial offspring of the spontaneously hypertensive rat and the Wistar-Kyoto rat and develops hypertension with increased dietary NaCl intake. The present investigation sought to determine whether the dietary NaCl intake-induced transition from the normotensive state of the Wistar-Kyoto parent to the hypertensive state of the spontaneously hypertensive parent in the borderline hypertensive rat was accompanied by a similar transition of the renal sympathetic nerve activity and excretory responses to volume expansion and environmental stress. Borderline hypertensive rats fed a 1% NaCl diet remained normotensive and exhibited renal sympathetic nerve activity and excretory responses to volume expansion and environmental stress that were similar to those of their Wistar-Kyoto parent. Borderline hypertensive rats fed an 8% NaCl diet developed hypertension and exhibited responses that were similar to those of their spontaneously hypertensive parent. Thus, the dietary NaCl intake-induced transition from the normotensive state of the Wistar-Kyoto parent to the hypertensive state of the spontaneously hypertensive parent in the borderline hypertensive rat was accompanied by a similar transition of the renal sympathetic nerve activity and excretory responses to volume expansion and environmental stress. The results suggest that increased dietary NaCl intake is able to induce or unmask the capabilities for these responses, which are genetically conveyed to the borderline hypertensive rat by the spontaneously hypertensive rat parent in latent forms.     

Haemodynamic responses to conflict stress in borderline hypertensive rats

Chronic exposure to a shock-shock conflict paradigm (2 h/day, 5 days/week for 12 weeks [1]) produces hypertension in the borderline hypertensive rat (BHR), a cross between the spontaneously hypertensive rat (SHR) and the Wistar-Kyoto rat (WKY). The purpose of the present study was to characterize the regional haemodynamic responses which take place during conflict-stress. A pulsed Doppler flowmeter and miniature probes implanted on the left renal and superior mesenteric arteries and the abdominal aorta were used to record changes in regional flow velocity. Recording of mean arterial pressure (MAP) allowed changes in regional resistance to be calculated. The first conflict session produced intense splanchnic and renal vasoconstriction and hindquarter vasodilation. Pressor responses were moderate. A second group of BHRs was studied during conflict sessions 17-18, prior to the development of hypertension. This group exhibited faster habituation to the stress than the group studied during the first conflict session: MAP and mesenteric resistance returned more rapidly towards pre-stress levels. Relative to naive control rats, this group exhibited a larger peak MAP and less tachycardia in response to a neutral stressor (air-jet stress) and a smaller reduction in renal resistance in response to ganglionic blockade. These data suggest that in this model, pressure load per se is moderate. More attention should be directed towards the role of trophic effects of the neurohumoral factors responsible for the pronounced constriction of splanchnic and renal vasculature in producing hypertension.     

Adipocyte responsiveness to norepinephrine in spontaneously hypertensive rats

The present study describes the effect of norepinephrine on lipolysis and adenylate cyclase activity in adipocytes from Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats. The adipocytes were incubated in the presence of norepinephrine (10(-7) to 10(-4) mol/L) and the lipolytic activity was measured according to the accumulation of glycerol after one hour incubation. The results showed that norepinephrine induced a lower lipolytic activity in adipocytes from SH rats. cAMP-phosphodiesterase activities in adipocyte homogenates from WKY and SH rats were the same for both preparations. The effect of norepinephrine (10(-7) to 10(-4) mol/L) on adenylate cyclase activity in fat cell membranes from SH rats was decreased compared with WKY fat cell membranes. Adenylate cyclase activities in the presence of 10 mmol/L NaF were the same in both preparations. beta-receptor characteristics were examined, and the data demonstrate a statistically significant decrease in beta-receptor density in fat cell membranes from SH rats. The dissociation constants (Kd) were the same for WKY and SH preparations. This article suggests that adipocyte responsiveness to norepinephrine is decreased in SH rats. The decreased response to norepinephrine may be explained by a lower beta-receptor density in fat cell membranes from SH rats.     

Enhanced myogenic responsiveness of renal interlobular arteries in spontaneously hypertensive rats.

We recently demonstrated that the interlobular artery (ILA) constricts in response to elevating renal arterial pressure (RAP), suggesting that the ILA contributes to renal autoregulation. In the present study, we examined the segmental myogenic responsiveness of the ILA in kidneys from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). The tapered nature of the ILA allowed us to characterize the regional responsiveness, using the basal diameter to define segments as either proximal (greater than 60 microns), intermediate (40-60 microns), or distal (less than 40 microns). At 80 mm Hg, segmental diameters were similar in WKY and SHR arteries (proximal, 76.0 +/- 3.1 versus 71.6 +/- 3.5 microns; intermediate, 48.2 +/- 1.4 versus 48.1 +/- 1.7 microns; distal, 30.7 +/- 0.9 versus 27.9 +/- 1.3 microns for WKY and SHR, respectively). In both strains, intermediate and distal segments exhibited graded reductions in diameter as RAP was elevated, whereas proximal segments did not. Pressure-induced decrements in the diameters of distal ILA segments were similar in WKY (-24 +/- 2%) and SHR (-20 +/- 2%; p greater than 0.1). The intermediate ILA of SHR exhibited an augmented myogenic responsiveness, constricting at lower RAP levels and exhibiting greater maximal decrements in diameter at 180 mm Hg (i.e., -19 +/- 2% and -12 +/- 2% for SHR and WKY, respectively; p less than 0.05). Nifedipine (1.0 microM) reduced pressure-induced vasoconstriction of intermediate and distal ILA segments by 56 +/- 11% and 79 +/- 7%, respectively, in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of acute NaCl depletion on NaCl-sensitive hypertension in borderline hypertensive rats.

OBJECTIVES: The borderline hypertensive rat (BHR) is the first generation offspring of a mating between a female spontaneously hypertensive rat and a male normotensive Wistar-Kyoto rat. With increased dietary NaCl intake, the BHR develops hypertension and augmented cardiovascular and renal responses to acute environmental stress. This investigation sought to examine the role of extracellular fluid volume (ECFV) in these changes. DESIGN: Three groups of 16-week-old BHR were studied: (1) rats on a 1% NaCl diet for 12 weeks; (2) rats on an 8% NaCl diet for 12 weeks; and (3) rats on an 8% NaCl diet for 12 weeks plus furosemide (50 mg/kg, i.p., twice daily) for the preceding 2 days. METHODS: Rats were chronically instrumented for the measurement of mean arterial pressure (MAP), heart rate and renal hemodynamic, excretory and sympathetic nerve activity responses to acute environmental stress (acute air jet stress). ECFV was measured as inulin space. RESULTS: BHR fed an 8% NaCl diet had increased MAP, urinary sodium excretion and ECFV compared with those fed a 1% NaCl diet; they also exhibited augmented pressor, tachycardic, renal sympathetic nerve excitatory and antinatriuretic responses to acute environmental stress. When 8% NaCl-diet BHR were treated with furosemide for 2 days, arterial pressure, urinary sodium excretion, ECFV and cardiovascular and renal responses to acute environmental stress returned to values seen in 1% NaCl-diet BHR. CONCLUSIONS: The hypertension and increased cardiovascular and renal responses to acute environmental stress produced by increased dietary NaCl intake in BHR derive from a central nervous system site of action via a mechanism(s) related to ECFV and/or sodium.     

Role of renal alpha 2-adrenergic receptors in spontaneously hypertensive rats

To identify a physiological role for renal alpha 2 adrenergic receptors, renal vascular and tubular responses to administration of graded frequencies of renal nerve stimulation or graded doses of adrenergic agonists were determined in anesthetized spontaneously hypertensive, Wistar-Kyoto, and Sprague-Dawley rats. Renal vasoconstrictor responses to renal nerve stimulation and alpha 1-adrenergic receptor agonists (norepinephrine, phenylephrine) were inhibited by an alpha 1-adrenergic receptor antagonist (prazosin) but not by an alpha 2-adrenergic receptor antagonist (rauwolscine). A semilog plot of renal vasoconstrictor responses a fraction of control renal blood flow versus agonist dose (in nanograms) was linear with the slope, k, taken as the fractional decrease in renal blood flow per nanogram. The alpha 2-adrenergic receptor agonists (clonidine, guanabenz) produced minimal renal vasoconstrictor responses (fractional decrease in renal blood flow per nanogram: norepinephrine, 0.011; phenylephrine, 0.003; clonidine, 0.00087; guanabenz, 0.000037). The small renal vasoconstrictor responses to clonidine and guanabenz were more inhibited by rauwolscine than by prazosin. Low frequency renal nerve stimulation produced antidiuresis and antinatriuresis without decreasing glomerular filtration rate or renal blood flow. The antidiuretic and antinatriuretic responses were inhibited by prazosin but unaffected by rauwolscine. The magnitude of the renal vascular and tubular responses and their adrenergic receptor mediation were not different between spontaneously hypertensive, Wistar-Kyoto, and Sprague-Dawley rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

alpha2-adrenoceptor agonists as nasal decongestants

Nasal congestion, one of the major disease features of rhinitis, is induced by the filling of venous sinusoids causing mucosal engorgement with resultant obstruction of nasal airflow. The only available drugs that directly target the underlying vascular features driving nasal obstruction are the sympathomimetic alpha-adrenoceptor agonists due to their vasoconstrictor action. However, standard decongestants are nonselective alpha-adrenoceptor agonists, which have the potential for side-effects liabilities such as hypertension, stroke, insomnia and nervousness. In the present study, the effects of nonsubtype selective alpha(2)-adrenoceptor agonists BHT-920 and PGE-6201204 were evaluated in several isolated nasal mucosa contractile bioassays including dog, pig and monkey, and in a real-time tissue contractility assay using isolated pig nasal explants for BHT-920. The decongestant activity of PGE-6201204 was evaluated in vivo in a cat model of experimental congestion. Our results showed that alpha(2)-adrenoceptor agonists (1) contract nasal mucosa of different species, (2) exert a preferential vasoconstrictor effect on the capacitance vessels (veins and sinusoids), and (3) elicit decongestion. In conclusion, a selective alpha(2)-adrenoceptor agonist causing constriction preferentially in the large venous sinusoids and veins of nasal mucosa and producing nasal decongestion is expected to show efficacy in the treatment of nasal congestion without the characteristic arterio-constrictor action of the standard nonselective sympathomimetic decongestants.