Dysfunctional presynaptic alpha 2-adrenoceptors expose facilitatory beta 2-adrenoceptors in the vasculature of spontaneously hypertensive rats.

Previous studies on spontaneously hypertensive rats (SHR) have yielded inconsistent information about functional aberrations of the presynaptic alpha 2- and beta 2-adrenoceptor-mediated modulation of sympathetic neurotransmitter release. In the present investigation we studied the capacity of presynaptic beta 2-adrenoceptors that enhance noradrenaline (NA) release in the portal vein of freely moving, unanesthetized SHR and normotensive Wistar rats (WR) using the beta 2-selective agonist fenoterol. The results show that the presynaptic beta 2-adrenoceptor population in SHR responds to significantly lower dosages of fenoterol than that in WR. The reason for this enhanced action, however, could not be attributed to the beta 2-adrenoceptor itself, nor to a diminished neuronal uptake of NA, but to a diminished responsiveness of the presynaptic alpha 2-adrenoceptor. Stimulation of presynaptic alpha 2-adrenoceptors with oxymetazoline (45 micrograms/min) decreased basal NA levels by 46% in WR and by 3% in SHR. Blockade of alpha 2-adrenoceptors, using 0.5 mg/kg yohimbine, induced a 4.86-fold rise in the basal NA level in WR but only a 1.89-fold rise in SHR. A subsequent dose of fenoterol, however, resulted in a further 2.5- and 2.6-fold rise in WR and SHR, respectively, indicating that there is a normal presynaptic beta 2-adrenoceptor population in the vasculature of SHR.     

Propranolol and atenolol inhibit norepinephrine spillover rate into plasma in conscious spontaneously hypertensive rats

Summary Radiotracer techniques capable of measuring norepinephrine clearance and spillover rate into plasma were used to test the hypothesis that the antihypertensive effects of propranolol and atenolol in conscious spontaneously hypertensive rats are associated with an inhibition of norepinephrine release from postganglionic sympathetic neurons. The 10%–15% fall in mean arterial pressure produced over 4 h by propranolol (1, 3.3 and 10 mg/kg, s. c.) and atenolol (1, 3.3 and 10 mg/kg, s. c.) was not dose-related, and only the largest dose of propranolol caused a significant bradycardia. Each dose of atenolol significantly lowered heart rate. The decrease in blood pressure caused by propranolol and atenolol was not related to the decrease in heart rate. Both propranolol and atenolol inhibited norepinephrine clearance by 12% to 16%. The 1 mg/kg doses of propranolol and atenolol significantly suppressed norepinephrine spillover rate by 21 % and 32%, respectively, at 4 h postinjection. As the dose of propranolol was increased, the inhibition of norepinephrine spillover was reversed as plasma epinephrine concentration rose by 125%. The suppression of norepinephrine spillover rate caused by atenolol was more persistent but did diminish after the 10 mg/kg dose, when plasma epinephrine concentration was elevated by 55%. Both drugs suppressed plasma renin concentration, but the inhibition of norepinephrine spillover rate by propranolol and atenolol was not related to the fall in plasma renin concentration. By comparison, treatment with the adrenergic neuron blocking agent bretylium (5, 10, 20 and 40 mg/kg, s. c.) elicited a dose-related vasodepression with no change in heart rate or plasma renin concentration. The 10 mg/kg dose of bretylium inhibited norepinephrine spillover rate by 40%, but increasing the dose did not produce a further suppression of norepinephrine spillover rate. Bretylium caused a dose-related elevation of plasma epinephrine concentration (354% increase at 40 mg/kg). In a separate study, propranolol (10 mg/kg) and bretylium (40 mg/kg) significantly increased epinephrine spillover rate by 85% and 118%, respectively. Based on these data, we conclude that the -adrenoceptor antagonists lower blood pressure by inhibiting norepinephrine release from postganglionic sympathetic neurons. Send offprint requests to T. K. Keeton at the above address     

The measurement of norepinephrine clearance and spillover rate into plasma in conscious spontaneously hypertensive rats

Summary The clearance of norepinephrine from plasma and the spillover rate of norepinephrine into plasma were determined in conscious unrestrained spontaneously hypertensive rats by measuring the concentrations of ³H-norepinephrine and norepinephrine in arterial plasma after 90 min of i. v. infusion with ³H-norepinephrine. In 50 conscious spontaneously hypertensive rats treated with saline (control animals), the following basal values were obtained: plasma norepinephrine concentration = 149 ± 5 pg/ml; plasma epinephrine concentration = 61 ± 4 pg/ml; norepinephrine clearance = 188 ± 4 ml min-1 kg-1; and norepinephrine spillover rate = 27.5 ± 0.8 ng min-1 kg^–1. A significant portion of infused ³H-norepinephrine appeared to be cleared from the plasma by the uptake, process, since desipramine decreased norepinephrine clearance by 32%. The vasodilating agents hydralazine and minoxidil produced dose-related increases in norepinephrine spillover rate and plasma norepinephrine concentration, but the percent increases in norepinephrine spillover rate exceeded the percent increases in plasma norepinephrine concentration because of concomitant increases in norepinephrine clearance, particularly after treatment with minoxidil. The increase in norepinephrine clearance caused by hydralazine and minoxidil probably resulted from the increase in cardiac output and resultant increase in hepatic and/or pulmonary blood flow. Adrenal secretion of norepinephrine did not appear to contribute to the elevation in norepinephrine spillover rate elicited by hydralazine and minoxidil. Chlorisondamine suppressed norepinephrine spillover rate by 77%, in association with a 70% decline in plasma epinephrine concentration, whereas bretylium lowered norepinephrine spillover rate by only 41%, with no change in plasma epinephrine concentration. The decrements in norepinephrine clearance caused by chlorisondamine (–23%) and bretylium (–15%) were more or less proportional to the magnitude of the vasodepression caused by these drugs. Both norepinephrine spillover rate and clearance fell in a dose-related fashion after treatment with clonidine. After treatment with the sympathoinhibitory agents chlorisondamine, bretylium and clonidine, the percent decreases in norepinephrine spillover rate always exceeded the percent decreases in plasma norepinephrine concentration. Based on these observations, we conclude that norepinephrine spillover rate provides a more accurate measurement of the activity of the peripheral sympathetic nervous system than does plasma norepinephrine concentration in conscious spontaneously hypertensive rats.Send offprint requests to T. K. Keeton at the above address     

Response of plasma norepinephrine concentration to the vasodepression caused by beta-adrenoceptor antagonists in the conscious spontaneously hypertensive rat

The subcutaneous administration of a single dose of the beta-adrenoceptor antagonists atenolol, betaxolol, oxprenolol, pindolol, propranolol, or sotalol to conscious spontaneously hypertensive rats (SHR) lowered mean arterial pressure (MAP) by 15-20%, but this vaso-depression was not accompanied by a rise in plasma norepinephrine (NE) concentration. When MAP was decreased at the same rate and to the same extent with the vasodilator minoxidil, plasma NE concentration increased 50-75%. Atenolol, betaxolol, propranolol, and sotalol lowered heart rate, whereas oxprenolol, pindolol, and minoxidil elicited a tachycardia. Atenolol (-48%), betaxolol (-63%), and propranolol (-29%) significantly suppressed plasma renin activity (PRA), and minoxidil elevated PRA by 150-315%. Pindolol (+37%) caused a nonsignificant increase in PRA, and oxprenolol (-23%) and sotalol (-17%) produced nonsignificant decreases in PRA. Because the beta-adrenoceptor antagonists did not increase plasma NE concentration, whereas an equivasodepressor dose of minoxidil did, we conclude that plasma NE concentration is inappropriately low relative to the decrease in MAP caused by beta-adrenoceptor antagonists in the conscious SHR. In addition, the diverse effects of the beta-adrenoceptor antagonists on PRA in SHRs indicate that a suppression of renin release cannot account for either the decrease in MAP caused by these drugs or the failure of plasma NE concentration to increase when MAP is decreased by beta-adrenoceptor antagonists.     

Alpha2-adrenoceptors in platelets of spontaneously hypertensive rats

Alpha 2-adrenoceptors were studied in platelets of stroke-prone spontaneously hypertensive rats (SpSHR) and of normotensive Wistar Kyoto control rats (WKY). In platelets of female SpSHR with established hypertension but not in those of normotensive WKY, specific binding of the alpha 2-adrenoceptor ligand, [3H]yohimbine, was found. Compared with human platelets (KD and B max about 3 nM and 200 fmol/mg protein, respectively), [3H]yohimbine binding to SpSHR platelets was of lower affinity (KD about 20 nM) and of lower capacity (B max about 30 fmol/mg protein). The potency orders of alpha-adrenoceptor agonists (clonidine greater than adrenaline greater than phenylephrine) and antagonists (yohimbine greater than or equal to phentolamine much greater than prazosin) in competing with [3H]yohimbine indicated that the binding sites in SpSHR platelets are of the alpha 2-adrenoceptors type. Similar data were obtained in platelets of 7-9 week old hypertensive rats without established hypertension. Furthermore, adrenaline inhibited SpSHR but not WKY platelet adenylate cyclase. This inhibition, which was smaller than in human platelets, was also found in platelets of 4 week old SpSHR but not in the corresponding control rats. The data show that in SpSHR alpha 2-adrenoceptors can appear, which may play a significant role in the pathogenesis of hypertension.     

Propranolol in conscious spontaneously hypertensive rats

The disposition of dl-propranolol was studied in spontaneously hypertensive rats (SHR), both after subcutaneous (s.c.) and intracerebroventricular (i.c.v.) injection of 1 mg/kg. 1. Upon s.c. injection propranolol appeared rapidly in plasma. A maximum concentration of 374 +/- 33 ng/ml (N = 10) was reached 5 min after injection. After a distribution phase with a half-life of t 1/2 alpha = 17 min propranolol was eliminated with a t 1/2 beta = 59 min. 2. Both propranolol and its metabolites were taken up rapidly into all tissues studied. Highest concentrations (10.4 +/- 1.5 micrograms/g, N = 5) were found in lungs 30 min after injection. 3. Neither propranolol nor its metabolites accumulated in any of the tissues examined. 4. Upon i.c.v. injection of propranolol, a maximal concentration of 573 +/- 47 ng/ml (N = 3) was reached in plasma already 2 min after injection. In this case t 1/2 alpha was 13 min and t 1/2 beta was 80 min. 5. Dialysis experiments indicated that propranolol is bound to plasma proteins for 92% in the concentration range of 20--100 ng/ml. With increasing concentrations binding diminishes progressively. At the highest concentration tested (345 ng/ml) only 76% was bound. It is concluded that s.c. and i.c.v. injection of an identical dose of propranolol gives a similar plasma concentration-time profile. Moreover, it is suggested that the pharmacokinetic behaviour of propranolol in SHR does not explain the delayed antihypertensive effect of this drug.     

Influence of adrenodemedullation on beta 2- and beta 3-adrenoceptors mediating relaxation of oesophageal smooth muscle of spontaneously hypertensive rats.

1. In oesophageal smooth muscle strips from spontaneously hypertensive rats (SHR) of 8-10 and 22-24 weeks of age, respectively, beta-adrenoceptor-mediated relaxation was investigated, by use of the beta-agonists, (-)-isoprenaline and fenoterol (both in the absence and presence of the beta 2-selective antagonist ICI 118,551) and the selective beta 3-agonist, BRL 37,344. 2. In preparations from 8-10 week SHR, (-)-isoprenaline- and fenoterol-induced concentration-response curves (CRCs) were hardly antagonized by ICI 118,551 at concentrations up to 1 microM, indicating only a minor contribution of beta 2-adrenoceptors. pA2-values for ICI 118,551 of 5.30 ((-)-isoprenaline as agonist) and 5.46 (fenoterol as agonist), estimated from the shifts at the highest (10-100 microM) antagonist concentrations, are consistent with affinity at a beta 3-adrenoceptor, similar to that in Wistar rat oesophageal smooth muscle. 3. In 8-10 week SHR, adrenodemedullated at 4 weeks of age (SHR-ADM4) the potency of fenoterol was markedly increased and CRCs were shallow. In addition, ICI 118,551 (0.1 microM) now produced a clear rightward shift accompanied by a steepening of the CRC. A marked further shift was observed only at 100 microM of the antagonist. The data are compatible with the involvement of both beta 2- and beta 3-adrenoceptors. 4. In 22-24 week animals, the same differences between SHR and SHR-ADM4 were observed with fenoterol as in 8-10 week animals, though beta-adrenoceptor responsiveness was slightly decreased. The potency of ICI 118,551 at beta 3-adrenoceptors (pA2 = 5.11) was significantly different from the pA2 value of 5.46 obtained with the younger animals. 5. Responses to the beta 3-adrenoceptor agonist, BRL 37,344, were similar in Wistar rat and SHR preparations. In 8-10 week SHR, a small decrease in the maximal response was observed, which in animals of 22-24 weeks of age was accompanied by a small decrease in the pEC50 value as well. 6. The results clearly indicate that beta 2-adrenoceptors in SHR oesophageal muscularis mucosae are desensitized, whereas beta 3-adrenoceptor-mediated responses are unaffected and similar to the responses observed in the Wistar rat oesophagus. The functional presence of beta 2-adrenoceptor-responses in SHR-ADM4 suggests a major role for adrenal-derived adrenaline in the desensitization of the beta 2-adrenoceptor-population.     

Decreased density of alpha 2-adrenoceptors in medulla oblongata of spontaneously hypertensive rats

To study the role of medullary alpha-adrenoceptors in hypertension, we compared specific binding of [3H]prazosin and [3H]clonidine in different brain regions of spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP), and normotensive Wistar-Kyoto rats (WKY). As compared with age-matched WKY, Bmax values for specific [3H]clonidine binding in the medulla oblongata were significantly lower in SHR and SHRSP at 16-24 weeks of age. In the SHRSP medulla oblongata, the decrease was more prominent in dorsomedial and ventrolateral regions than in the ventromedial region. Density of alpha 2-adrenoceptor binding sites was also decreased in the medulla oblongata of young (4-5-week-old) SHRSP. In contrast, there was no difference in Kd and Bmax values for medullary [3H]prazosin binding between WKY and SHRSP. The dorsomedial and ventrolateral regions of the SHRSP medulla oblongata showed significantly lower levels of norepinephrine (NE). Thus, the present study demonstrates that there is a specific loss of alpha 2-adrenoceptors in the medulla oblongata of SHR and SHRSP that may be partly involved in the pathogenesis of spontaneous hypertension.     

Decreased density and sensitivity of alpha 2-adrenoceptors in the brain of spontaneously hypertensive rats.

The specific binding of the agonist [corrected], [3H]clonidine, to neural membranes and clonidine-induced mydriasis were used to evaluate the density and sensitivity [corrected] of alpha 2-adrenoceptors in the brain of spontaneously hypertensive rats (SHR) and sex- and age-matched normotensive Wistar-Kyoto (WKY) rats. In hypertensive rats (SHR) the density of alpha 2-adrenoceptors was reduced in the cerebral cortex, hypothalamus and medulla oblongata (20-27%), as was the dose-pupillary response curve for clonidine (1.8-fold). The results demonstrated that this model of genetic hypertension is associated with desensitization of alpha 2-adrenoceptors in the brain.     

Cardiovascular effects of cannabinoids in conscious spontaneously hypertensive rats

BACKGROUND AND PURPOSE: In anaesthetized spontaneously hypertensive rats (SHR), there is evidence for up-regulation of cannabinoid (CB1) receptors: antagonism of CB1 receptors causes a rise in blood pressure, and administration of the endocannabinoid, anandamide, or inhibition of anandamide degradation causes hypotension. These findings have led to the suggestion that the endocannabinoid system may be a therapeutic target in hypertension. However, since the cardiovascular responses to cannabinoids are substantially influenced by anaesthesia, the purpose of this study was to assess regional haemodynamic responses to cannabinoid receptor stimulation and inhibition in conscious SHR. EXPERIMENTAL APPROACH: Cardiovascular responses to i.v. administration of anandamide, the cannabinoid receptor agonist, WIN 55212-2, and the CB(1) receptor antagonist, AM 251, were measured in male SHR, Wistar Kyoto rats and outbred Wistar rats, chronically instrumented for recording renal, mesenteric and hindquarters haemodynamics in the conscious, freely-moving state. KEY RESULTS: Hypotensive responses to anandamide and WIN 55212-2 only occurred in SHR, but these were relatively modest and not associated with CB1 receptor-mediated vasodilatation. In SHR only, anandamide caused bradycardia, which was inhibited by AM 251. Furthermore, a pressor response to CB1 receptor antagonism occurred only in SHR, but was not associated with vasoconstriction. Moreover, there was some evidence for CB1 receptor-mediated vasoconstrictor actions of anandamide in SHR, which was not seen in the normotensive strains. CONCLUSIONS AND IMPLICATIONS: The results are consistent with activation of CB1 receptors in SHR by endogenous ligands exerting an antihypertensive effect, but the findings do not indicate enhanced CB1 receptor-mediated vasodilator mechanisms in SHR.     

Involvement of beta 2-adrenoceptors in the regional haemodynamic responses to bradykinin in conscious rats.

1. Bradykinin can release neuronal calcitonin gene-related peptide (CGRP) and adrenal medullary catecholamines, both of which could contribute to its cardiovascular effects in vivo. Therefore, in the main experiment, regional haemodynamic responses to bolus injections of bradykinin (3 nmol kg-1, i.v.) were assessed in the same chronically-instrumented, conscious, Long Evans rats in the absence and in the presence of human alpha-CGRP [8-37] or ICI 118551, antagonists of CGRP1-receptors and beta 2-adrenoceptors, respectively. The selected doses of these antagonists caused specific inhibition of responses mediated by exogenous human alpha-CGRP and beta 2-adrenoceptor agonists, respectively. 2. Bradykinin administered alone as an i.v. bolus had a slight pressor effect accompanied by a marked tachycardia. There were early (at about 30 s) increases in flow and conductance in the mesenteric vascular bed, and delayed (at about 90 s), but qualitatively similar, changes in the hindquarters vascular bed. There were only slight increases in flow and conductance in the renal vascular bed. 3. Human alpha-CGRP [8-37] had no statistically significant effects on the responses to bolus doses of bradykinin. However, in the presence of ICI 118551, the pressor effect of bradykinin was significantly enhanced while its tachycardic effect was significantly suppressed. The hindquarters vasodilator effect of bradykinin was converted to a vasoconstriction and there was a slight renal vasoconstriction, but the mesenteric vasodilator effect of bradykinin was unchanged by ICI 118551. 4. In subsidiary experiments, in other animals, it was found that infusion of bradykinin (36 nmol kg-1 min-1) elicited a pattern of haemodynamic responses similar to that seen with bolus injections and, as in the latter case, the hindquarters hyperaemic vasodilation was inhibited by ICI 118551. In the presence of mecamylamine (at a dose sufficient to block reflex heart rate responses to rises or falls in arterial blood pressure) bolus injection or infusion of bradykinin still elicited increases in renal, mesenteric and hindquarters blood flow. However, in additional experiments in adrenal demedullated rats (n = 4) the hindquarters hyperaemic effect of bradykinin was absent, although the mesenteric hyperaemic effect remained. 5. The results indicate that the increase in hindquarters blood flow following administration of bradykinin in vivo is largely due to activation of beta 2-adrenoceptors by catecholamines released subsequent to direct stimulation of the adrenal medulla by the peptide. However, the bradykinin-induced increase in mesenteric blood flow does not depend on this mechanism.     

Ketanserin stabilizes blood pressure in conscious spontaneously hypertensive rats

1. It has been demonstrated that blood pressure variability (BPV) is increased in hypertension and related to organ damage. It will be important to lower BPV in the treatment of hypertension. The present study was designed to investigate the effect of ketanserin, a 5-HT2A receptor antagonist with a weak alpha1-adrenoceptor blocking effect, on BPV in conscious spontaneously hypertensive rats (SHR). 2. It was found that ketanserin decreased blood pressure (BP) and BPV in SHR when administered intravenously (3 mg/kg, i.v.). Ketanserin decreased BPV, but not the BP level, when administered intracerebroventricularly (50 microg/rat, i.c.v.). 3. Prazosin, an alpha1-adrenoceptor antagonist, lowered BP but did not affect BPV when given either i.v. (0.5 mg/kg) or i.c.v. (30 microg/rat). Ritanserin (0.625 mg/kg, i.v.; 40 microg/rat, i.c.v.), a 5-HT2A receptor antagonist, decreased BPV only when administered i.c.v. and did not modify the BP level. 4. Ketanserin enhanced arterial baroreflex function in SHR when given either i.v. or i.c.v. 5. The stabilizing effect of ketanserin on BP was persistent when administered intragastrically. This administration route is similar to oral administration clinically. 6. It is concluded that ketanserin is an antihypertensive agent with an effect of reducing BPV. This effect is mainly mediated by central 5-HT2A receptors and is probably attributable to the restoration of arterial baroreflex function.     

Central alpha 2-adrenoceptor-mediated pressor response to clonidine in conscious, spontaneously hypertensive rats.

Pressor responses to intracerebroventricular (i.c.v.) injection of clonidine were investigated in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Clonidine (1-10 micrograms, i.c.v.) caused a dose-dependent pressor response and decrease in heart rate in both SHR and WKY. In SHR, low doses (1, 2.5 micrograms) but not high doses (5, 10 micrograms) of i.c.v.-clonidine induced a depressor response following the pressor response. Both pressor and depressor responses to i.c.v.-clonidine were significantly greater in SHR than in WKY. In both SHR and WKY, pressor responses to i.c.v.-clonidine were abolished by pentobarbital anesthesia, pretreatment with i.v.-furosemide (5 mg/kg), 24-hr water deprivation and pretreatment with i.c.v.-yohimbine (100 micrograms), but not by pretreatment with i.v.-yohimbine (100 micrograms) and i.c.v.-prazosin (10 micrograms). On the 1st day after surgery for arterial catheter implantation, SHR reduced their water intake, and i.c.v.-clonidine (5 micrograms) caused a slight pressor response, whereas the same dose of clonidine on the 7th day after surgery resulted in a marked pressor response. These results suggest that clonidine caused a central alpha 2-adrenoceptor-mediated pressor response, which is greater in SHR than in WKY and is sensitive to body fluid volume changes and anesthesia.     

Hypotensive effect of bunitrolol at low plasma concentrations in conscious, unrestrained spontaneously hypertensive rats

Effects of bunitrolol on mean arterial pressure (MAP) and heart rate (HR) were studied in conscious, unrestrained spontaneously hypertensive (SHR) rats at rest and during handling stress. Propranolol was employed as a reference drug. Plasma drug concentrations were determined to related with the cardiovascular effects of the drugs. Bunitrolol produced a tachycardia for the first 2 hr and a significant reduction in resting MAP at 3 and 4 hr after the oral dose (5 mg/kg) when plasma bunitrolol concentration was less than 10 ng/ml, indicating the difference between cardiac and vascular beta adrenoceptors in sensitivity to intrinsic sympathomimetic action or direct vasodilator action. Propranolol (5 mg/kg) produced no discernible effects on resting MAP and HR. Stress-induced tachycardia was significantly inhibited by both drugs throughout the experiment, while significant inhibition of hypertensive response was observed only at 4 hr after the treatment. Both bunitrolol and propranolol were rapidly absorbed from the gastrointestinal tract. Plasma half-life of these drugs were almost the same values of around 2 hr. These results indicate that dose size, plasma concentrations, and procedures and the timing of blood pressure measurement are the important factors to be considered when the antihypertensive effect of beta-blockers is studied in SHR rats.     

Acute arteriolar vasoconstriction following furosemide in conscious spontaneously hypertensive rats

In a previous study in conscious spontaneously hypertensive rats (SHR), we observed an immediate decrease in the cardiac index (CI) and an increase in the total peripheral resistance index (TPRI) following the administration of furosemide. The present study was designed to evaluate the regional hemodynamic effects and the involvement of sinoaortic baroreceptors in the increase in TPRI. In SHR instrumented for the measurement of central hemodynamics, 8 mg.kg-1 furosemide decreased CI from 31.0 +/- 2.5 ml.min-1.100 g bw-1 by 9.5 +/- 1.3 ml.min-1.100 g bw-1 (n = 7). TPRI increased maximally from 5.7 +/- 0.8 by 2.7 +/- 0.5 mm Hg.min.100 g bw.ml-1. The effect on TPRI was not affected by sinoaortic denervation (SAD) to abolish arterial baroreflexes. However, furosemide induced a significantly greater decrease in CI (-12.6 +/- 1.2 ml.min-1.100 g bw-1; n = 7) after SAD. Furosemide effectively reduced the mean arterial pressure in SAD SHR (-21 +/- 9 mm Hg) but not in sham-denervated SHR. Furosemide (8 mg.kg-1) reduced renal, mesenteric and hindquarter blood flow to a comparable extent (approximately 20%) in intact SHR. The reduction in renal flow at 3.5 min after injection (-17.9 +/- 4.1%; n = 8) was significantly greater than the reduction in mesenteric (-7.1 +/- 4.7%) and hindquarter blood flow (-4.2 +/- 3.7%), suggesting that the renal bed responds faster. Thereafter, the flow reductions in the three beds were not different. The results show that furosemide causes a general vasoconstriction in conscious SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hypotensive effect of combined beta1-adrenoceptor blockade and beta2-adrenoceptor stimulation in spontaneously hypertensive rats (SHR).

The effect on heart rate (HR) and blood pressure (BP) of metoprolol, propranolol and terbutaline, applied alone or in combinations was studied in spontaneously hypertensive rats. Terbutaline had little effect on BP and HR. Propranolol combined with terbutaline had no effect while metoprolol combined with terbutaline decreased BP by 48 mm Hg without affecting HR. Thus the beta2-mediated increase in peripheral vascular resistance after terbutaline was revealed by a drop in BP after beta1-blockade by metoprolol, but not when both beta1-and beta2-receptors were blocked by propranolol.