Increased renal neuroleptic binding in spontaneously hypertensive rats

The present experiments demonstrate high affinity stereospecific binding of the dopaminergic ligand [3H]spiroperidol to rat renal membranes. The binding was saturable, regionally distributed, and showed the same specificity as the caudate [3H]spiroperidol site for displacement by dopaminergic antagonists. Since there is an association between hypertension and abnormalities of renal blood flow, which appears to be regulated in part by dopamine, [3H]spiroperidol binding was measured in kidneys of spontaneously hypertensive rats. In two independent experiments renal cortical [3H]spiroperidol stereospecific binding was increased in spontaneously hypertensive rats.     

Hypotensive effects of diltiazem hydrochloride in the normotensive, spontaneously hypertensive and renal hypertensive rats (author's transl)

In conscious and anesthetized normotensive rats, intravenous administration of diltiazem (0.1--3 mg/kg) produced a dose-related decrease in blood pressure. Administration of diltiazem (1--50 mg/kg) into the duodenum of anesthetized rats also reduced the blood pressure in a dose related manner. In parallel with the change in blood pressure, the heart rate increased in conscious rats and decreased in anesthetized animals. Such an increase in the heart rate was suppressed by pretreatment with propranolol. Similarly, in conscious spontaneously hypertensive rats (SHR), diltiazem dose-dependently decreased the blood pressure and increased the heart rate after intravenous administration (0.03--1 mg/kg). Oral administration of diltiazem (100 mg/kg) also reduced the blood pressure of SHR. In addition, the progressive increase in blood pressure in young SHR was significantly suppressed by chronic oral administration of diltiazem (30 mg/kg). The blood pressure in conscious renal hypertensive rats was also decreased with diltiazem (50 mg/kg p.o.). On the other hand, it was demonstrated that the pressor responses to norepinephrine and angiotensin II in the anesthetized normotensive rats were non-competitively inhibited by intravenous administration of diltiazem at a dose which had no effect on the blood pressure.     

Cardiovascular responses in spontaneously hypertensive rats with acute renal failure

Cardiovascular status and reactivity have been investigated in spontaneously hypertensive rats (SHR) with glycerol-induced acute renal failure. SHR with acute renal failure had significantly lower mean arterial blood pressures and heart rates. The pressor responses to noradrenaline and the chronotropic responses to right cervical sympathetic and vagal nerve stimulation were diminished in uraemic SHR compared to control SHR. The cardiovascular depression observed in SHR with acute renal failure was similar to that previously noted in normotensive rats with acute renal impairment.     

Clonidine and a novel clonidine analog AL-12 cause sympathoinhibition in spontaneously hypertensive and diabetic spontaneously hypertensive rats

This study examined the sympathoinhibitory effects of clonidine and a novel clonidine analog, AL-12, in rat models of genetic hypertension and a combined state of genetic hypertension and diabetes. Rats in the treatment groups were given either clonidine or AL-12 while the respective control groups received either saline or Tween 80 for 6 days. Physiological data were collected during this period, which was followed by acute studies on day 7 when bolus administrations (i.v.) of graded doses of noradrenaline, phenylephrine and methoxamine were carried out. It was observed that in AL-12-treated nondiabetic spontaneously hypertensive rats (SHR), the pressure responses to all adrenergic agonists were greater (p < 0.05) in the treated group, while in the diabetic SHR rats a larger pressure response was observed only to noradrenaline (p < 0.05). In nondiabetic SHR rats treated with clonidine, a greater (p < 0.05) pressure response was observed only in the case of phenylephrine. In the diabetic SHR rats treated with clonidine, the pressure responses to the adrenergic agonists were similar (p > 0.05) in the treated and its control animals except that methoxamine caused a greater (p < 0.05) pressure response in the control group. The data obtained suggest that clonidine and AL-12 act possibly via vascular alpha1 and alpha2 adrenoceptors present at both pre- and postsynaptic locations.     

Effect of acute unilateral renal denervation on renal hemodynamics in spontaneously hypertensive rats

1 This study was undertaken to characterize the renal responses to acute unilateral renal denervation in anaesthetized spontaneously hypertensive rats (SHR) by examining the effect of acute unilateral renal denervation on the renal hemodynamic responses to a set of vasoactive agents and renal nerve stimulation. 2 Twenty-four male SHR rats underwent acute unilateral renal denervation and the denervation was confirmed by significant drop (P < 0.05) in renal vasoconstrictor response to renal nerve stimulation along with marked diuresis and natriuresis following denervation. After 7 days treatment with losartan, the overnight fasted rats were anaesthetized (sodium pentobarbitone, 60 mg kg(-1) i.p.) and renal vasoconstrictor experiments were performed. The changes in the renal vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by renal nerve stimulation or intrarenal administration of noradrenaline, phenylephrine, methoxamine and angiotensin II. 3 The data showed that there was significantly (all P < 0.05) increased renal vascular responsiveness to the vasoactive agents in denervated rats compared to those with intact renal nerves. In losartan-treated denervated SHR rats, there were significant (all P < 0.05) reductions in the renal vasoconstrictor responses to neural stimuli and vasoactive agents as compared with that of untreated denervated SHR rats. 4 The data obtained in denervated rats suggested an enhanced sensitivity of the alpha(1)-adrenoceptors to adrenergic agonists and possible increase of AT(1) receptors functionality in the renal vasculature of these rats. These data also suggested a possible interaction between sympathetic nervous system and renin-angiotensin system in terms of a crosstalk relationship between renal AT(1) and alpha(1)-adrenoceptor subtypes.     

Effect of clonidine on renal sodium handling in spontaneously hypertensive rats

Up-regulation of kidney α2-adrenoceptor expression has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). This study was carried out to evaluate renal sodium excretion in response to clonidine administration in SHR and control normotensive Wistar-Kyoto (WKY) rats. SHR and WKY rats (12-week-old) were placed in metabolic cages for 4 days: the first 2 days in control conditions and the following 2 days under oral clonidine treatment (100 μg/kg body weight). Clonidine produced a similar reduction in systolic blood pressure values in SHR and WKY rats, although SHR remained hypertensive. At the end of the study SHR and WKY rats presented similar noradrenaline plasma levels. However, noradrenaline kidney tissue levels were significantly higher in SHR compared to WKY rats. Under control conditions, SHR presented lower urine flow compared to WKY rats. Clonidine produced a significant decrease in urine flow in WKY rats but not in SHR. Furthermore, clonidine also produced a significant reduction in urinary sodium, potassium, and creatinine excretion in WKY rats, but had no effect in SHR. In conclusion, in SHR the reduction in systolic blood pressure and sympathetic activity produced by clonidine was not accompanied by a decrease in urine volume and sodium excretion.     

Structural changes in the renal vasculature in the spontaneously hypertensive rat: no effect of angiotensin II blockade

1. There is strong evidence for a renal basis to the development of hypertension in the spontaneously hypertensive rat (SHR). Alterations of the SHR renal vasculature, including the glomerulus, may be involved in the initiation and maintenance of hypertension in this animal model. 2. The arterial walls of pre-glomerular vessels of the SHR are hypertrophied compared with WKY vessels. Unlike other vascular beds in the SHR, this hypertrophy is independent of angiotensin II (AngII). 3. Glomerular number and volume are similar between SHR and the normotensive Wistar-Kyoto (WKY) rats. These results provide no support for the theory that a reduced filtration surface area within the kidneys of the SHR contributes to the elevated blood pressure in these animals. 4. Intrarenal hypertrophy may have similar haemodynamic consequences to clipping of the main renal artery, as in Goldblatt hypertension. Further analysis of the role of pre-glomerular arterial hypertrophy is warranted to determine its involvement in the initiation and maintenance of hypertension in the SHR.     

Effects of uninephrectomy on renal structural properties in spontaneously hypertensive rats

1. To investigate effects of a reduction in nephron numbers on renal structural properties in hypertension, either unilateral nephrectomy (UNX) or sham operation (SO) was performed at 5 weeks of age in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (n = 9 for each operation for each strain). 2. At 10-12 weeks of age, flow-pressure (F-P) and pressure-glomerular filtration rate (P-GFR) relationships were determined for maximally vasodilated, perfused kidneys. Kidneys were then perfusion fixed for histological analysis. 3. In the SO groups, the slope of F-P (minimal renal vascular resistance, reflecting overall luminal dimensions of pre- and post-glomerular vasculature) was greater in SHR than in WKY rats. The threshold pressure for beginning filtration at P-GFR (preglomerular to post-glomerular vascular resistance ratio) was higher in SHR than in WKY rats, but the slope of P-GFR (glomerular filtration capacity) did not differ between the two strains. These results suggest that vascular narrowing occurred, especially in the preglomerular resistance vessels in the kidneys of SHR, although glomerular filtration capacity was normal. 4. In UNX animals, the following results were obtained: (i) the slope of F-P was not affected in either strain; (ii) the pressure for beginning filtration at P-GFR was unchanged in WKY rats, but was decreased in SHR; (iii) the slope of P-GFR increased in WKY rats, but a compensatory adaptive increase was missing in SHR; and (iv) histologically, small increases in the luminal cross-sectional area of interlobular arteries and glomerular tuft area were observed in both strains. However, the increase in vascular lumen was more pronounced in SHR, whereas glomerular enlargement was greater in WKY rats. 5. These results suggested that UNX attenuates vascular narrowing of the preglomerular resistance vessels and glomerular structural adaptations to UNX (i.e. increased filtering capacity and glomerular enlargement) are impaired in SHR.     

Investigation of the mechanism(s) of 8-OH-DPAT-mediated inhibition of plasma insulin in spontaneously hypertensive rats.

1. Effects of the prototype selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-dipropylamino)tetralin (8-OH-DPAT), were studied on the glycaemia and insulinaemia in conscious spontaneously hypertensive (SH) rats concurrently with blood pressure (BP) and heart rate (HR); underlying mechanism(s) were investigated in anaesthetized and pithed SH rats and in the perfused rat pancreas. 2. Intravenous (i.v.) injections of 8-OH-DPAT (150 micrograms kg-1, i.v.) into fasted conscious but not anesthetized SH rats increased glycaemia; glucose-stimulated (i.v. glucose tolerance test) plasma insulin levels were significantly inhibited in both cases without significant changes in glucose tolerance. Metabolic changes were associated with prominent decreases in BP and HR. 3. No inhibitory effect of 8-OH-DPAT, 150 micrograms kg-1 i.v., on glucose-stimulated plasma insulin was observed in pithed SH rats; in contrast, clonidine (8 micrograms kg-1 i.v.), produced marked inhibition of insulin levels in association with glucose intolerance. Neither compound decreased BP; rather, pronounced vasopressor effects were observed. 4. In the isolated perfused pancreas of the rat, 8-OH-DPAT, at 10(-8) and 10(-7) M, concentrations known to activate 5-HT1A receptors in vitro, failed to modify glucose-stimulated insulin release. Inhibition (39 +/- 7%) was seen only at a high concentration of 10(-6) M. 5. The present data suggest that like the cardiovascular effects of 8-OH-DPAT, the inhibition of glucose-stimulated insulin release is mediated via the central nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional evidence of alpha1D-adrenoceptors in the vasculature of young and adult spontaneously hypertensive rats.

The role of alpha1D-adrenoceptors in the vasculature of spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY), of different ages was assessed in pithed rats by the use of the selective alpha1D-adrenoceptor antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-8-azaspiro [4.5]decane-7,9-dione dihydrochloride). BMY 7378 displaced the pressor effect of phenylephrine in young pre-hypertensive pithed SHR rats, but produced no effect in young WKY rats (dose ratio of 3.4 and 1.6, respectively), while in adult rats BMY 7378 produced a greater shift in the phenylephrine response curve than in younger animals (dose ratio of 3.2 and 6.2 in WKY and SHR, respectively). The presence of alpha1D-adrenoceptors in the vasculature of pre-hypertensive rats, suggests its role in the pathogenesis/maintenance of increased blood pressure.     

Effects of manidipine hydrochloride on the renal microcirculation in spontaneously hypertensive rats.

We wished to clarify the effects of a newly developed calcium antagonist, manidipine hydrochloride (HCl), on renal microcirculation in hypertensive rats by using the micropuncture technique. Oral administration of manidipine HCl for 2 months reduced systemic blood pressure (BP), did not change the single-nephron glomerular filtration rate (SNGFR), but increased the SNG plasma flow (SNGPF). Moreover, the glomerular transcapillary hydraulic pressure difference (delta P), which is assumed to be the parameter most related to development of glomerulosclerosis, was significantly reduced. Both afferent and efferent arteriolar resistance (RA and RE) were reduced. Intravenous (i.v.) infusion of manidipine HCl (20 micrograms/kg) decreased systemic BP but did not change SNGFR, SNGPF, or delta P. Both RA and RE were also significantly decreased. These results indicate that chronic administration of manidipine HCl increases renal blood flow (RBF) by dilating the afferent arterioles and improves glomerular hypertension by dilating the efferent arterioles. Thus, manidipine HCl might be a beneficial antihypertensive agent for patients with renal diseases. Because acute i.v. infusion of manidipine HCl did not change delta P, apparently time must elapse before glomerular hypertension is corrected.     

Effect of carvedilol on renal hemodynamics and renal excretory function in spontaneously hypertensive rats

The effects of the novel antihypertensive agent, carvedilol, on renal hemodynamics and excretory function have been investigated and compared with the effects of labetalol in conscious, spontaneously hypertensive rats. Sustained intravenous infusion of carvedilol or labetalol at a rate of 10 micrograms/kg/min resulted in a significant decrease in blood pressure which was equivalent in magnitude for both drugs. Carvedilol had no effect on renal hemodynamic parameters; glomerular filtration rate, renal blood flow, and filtration fraction were unchanged. In contrast, labetalol decreased the glomerular filtration rate by 13% (p less than 0.01) and the filtration fraction was reduced from 28 to 24%. Inasmuch as renal blood flow was unchanged and perfusion pressure was reduced, both compounds decreased renal vascular resistance. Urine flow decreased and osmolality increased with both carvedilol and labetalol. However, excretion of electrolytes was affected differently with the two compounds. While sodium and potassium excretion were significantly decreased with labetalol, sodium and potassium excretion remained stable during carvedilol infusion, which represents an important beneficial effect for a potent systemic vasodilator. We conclude, therefore, that carvedilol does not compromise the renal autoregulatory integrity in hypertensive rats, and that the antihypertensive activity of the compound is associated with an apparent 'renal sparing' effect, in that the decrease in blood pressure does not compromise the urinary excretion of sodium.     

The symptoms of unilateral inflammation in spontaneously hypertensive,renal hypertensive and normotensive wistar kyoto and wistar rats

Widy-Tyszkiewicz E, Kohutnicka M, Mierzejewski P, Czlonkowski A. The symptoms of unilateral inflammation in spontaneously hypertensive, renal hypertensive and normotensive Wistar Kyoto and Wistar rats. Inflammopharmacology. 1994;2:337-343. Spontaneously hypertensive (SHR) and renal hypertensive (RHR), Wistar (NR) and Sham or Wistar Kyoto (WKY) rats were tested for clinical symptoms following inoculation with Freund’s adjuvant in the unilateral hind paw. In the present study, body weight change (during weeks 1–11) was examined once a week and inflammatory score of hindpaw twice a week. The body weight gain was increased in the WKY compared with NR/Sham, SHR and RHR groups. Inflammatory changes were also most profoundly exhibited in the NR/Sham, the SHR and the RHR, compared with the WKY rats. The data may reflect a genetic difference not necessarily related to elevated blood pressure.     

Differences in renal tubular Na-K-adenosine triphosphatase in spontaneously hypertensive and normotensive rats

Na-K-adenosine triphosphatase (ATPase) activity in seven specific renal tubular segments of 8-week-old spontaneously hypertensive rats (SHR) was compared with age-matched normotensive Wistar-Kyoto rats (WKY). Systolic blood pressure in 8-week-old SHR were significantly higher than in age-matched WKY. Na-K-ATPase activity in proximal convoluted tubule and outer and inner medullary collecting ducts was significantly higher in SHR than in WKY. On the other hand, medullary thick ascending limbs had reduced Na-K-ATPase activity in SHR. The possible role of the abnormal pattern of renal tubular Na-K-ATPase in the development of hypertension in SHR remains to be determined.