Two-kidney One-clip Research Articles

Adrenomedullin gene delivery attenuates renal damage and cardiac hypertrophy in Goldblatt hypertensive rats.

Adrenomedullin (AM) is a potent vasodilator and natriuretic peptide that plays an important role in cardiovascular function. In this study, we employed a somatic gene delivery approach to explore its potential protective role in renovascular hypertension. A single tail vein injection of adenovirus harboring the human AM gene significantly blunted a blood pressure increase that lasted for more than 3 wk in two-kidney one-clip (2K1C) hypertensive rats. The expression of human AM mRNA was detected in the kidney, adrenal gland, heart, lung, and liver, and immunoreactive human AM was detected in the plasma and urine of 2K1C rats after human AM gene delivery. A maximal blood pressure difference of 28 mmHg was observed 10 days after AM gene delivery, compared with that in rats injected with the control virus carrying the LacZ gene. Human AM gene delivery significantly attenuated increases in the ratio of left ventricular weight to heart weight, cardiomyocyte diameter, and fibrosis in the heart, as well as glomerular sclerosis, tubular injuries, and protein casts in the kidney. The beneficial effects of AM gene delivery were accompanied by increased urinary cAMP levels, indicating activation of AM receptors. These findings provide new insights into the role of AM in renovascular hypertension and may have significance in therapeutic applications in cardiovascular diseases.

Greater blood pressure-lowering effect of the renin inhibitor EMD 58265 than an angiotensin-converting enzyme inhibitor in two-kidney one-clip Goldblatt rabbit.

1. Renin inhibitors may be more advantageous than either angiotensin-converting enzyme (ACE) inhibitors or angiotensin (Ang) antagonists in blocking the renin-angiotensin system (RAS) because they do not allow accumulation of either AngI or AngII in plasma. 2. Effects of i.v. administration of two human renin inhibitors (EMD 58265 and U 71038) were compared with the ACE inhibitor enalaprilat on mean blood pressure (BP), renal blood flow (RBF) and plasma AngI and AngII in the anaesthetized two-kidney one-clip Goldblatt rabbit. 3. At doses of 2-2.5 mg/kg, i.v., EMD 58265 and 5-10 mg/kg, i.v., U 71038, both drugs decreased BP approximately 10 mmHg more than enalaprilat (2-4 mg/kg, i.v.) when given either before or after the ACE inhibitor. None of the three agents had any significant effect on RBF in the face of the lowered BP; however, renal vascular resistance was decreased. A higher dose of enalaprilat (10 mg/kg, i.v.) had no further effect on BP than the lower doses but did cause a marked increase in RBF. 4. Both renin inhibitors markedly decreased plasma AngI, but the high basal level of AngII was less consistently and only modestly affected. Enalaprilat, in either the low dose range or at the high dose, was also not effective in significantly decreasing AngII. 5. The results indicate that renin inhibition in the rabbit with a high circulating AngII level is more effective in lowering BP than ACE inhibition. A high dose of the ACE inhibitor may be required to block the intrarenal RAS, which may account for the increase in RBF.

The antihypertensive effect of garlic ( Allium sativum) in the rat two-kidney–one-clip Goldblatt model

A study was designed to elucidate the antihypertensive effect of garlic in the two-kidney–one-clip (2K-1C) Goldblatt model. Since the hypertension in this model depends largely on the increasing concentrations of vasopressor agents (prostaglandins and angiotensin II) there is a strong indication that reducing these factors could contribute in controlling the pathological rise in blood pressure. In this study, single or multiple doses of 0.5 ml of aqueous extract of garlic were given orally to 2K-1C rats. The data shows that the single dose of garlic used had a maximum antihypertensive effect 2–6 h after administration. The residual effect of this single dose continued for up to 24 h. The multiple dose of garlic appeared to be effective in restraining the expected rise in blood pressure that normally occurs in 2K-1C rats. Switching multiple-dose treatments halfway through the experiment further strengthened the findings. The study suggests that garlic does have an effective antihypertensive ability, and may be used as a supplementary and natural remedy in cases of unilateral renovascular hypertension.

Lessons from rat models of hypertension: from Goldblatt to genetic engineering.

Over the past 50 years various animal models of hypertension have been developed, predominantly in the rat. In this review we discuss the use of the rat as a model of hypertension, and evaluate what these models have taught us. Interestingly, the spontaneously hypertensive rat (SHR) is by far the most widely used rat model, although it reflects only a rare subtype of human hypertension, i.e. primary hypertension that is inherited in a Mendelian fashion. Many other aspects of the etiology of hypertension are found in other rat models, but these models are less frequently employed. The widespread use of the SHR suggests that this rat model is often chosen without considering alternative (and possibly better suited) models. To illustrate the importance of the choice for a particular model, we compared the natural history and response to antihypertensive drugs in different rat models of hypertension (SHR, Dahl, deoxycorticosterone acetate (DOCA)-salt, two-kidney one-clip, transgenic TGR(mRen2)27. This revealed that the outcome of hypertension can be similar in some respects, as all models exhibit cardiac hypertrophy, and all demonstrate impaired endothelium-dependent relaxations. However, the more severe forms of end-organ damage such as heart failure, stroke and kidney failure, occur only in some models and then only in a subset of the hypertensive rats. The effects of antihypertensives varies even more in the different models: antihypertensive treatment only attenuates end-organ damage if it decreases blood pressure. Moreover, if a given antihypertensive is effective, it sometimes even attenuates end-organ damage in nonhypotensive doses. On the other hand, some agents do decrease blood pressure but do not prevent end-organ damage (e.g. hydralazine in SHR). Furthermore, not all classes of antihypertensives are equally effective in all rat models of hypertension: endothelin-receptor antagonists are not effective in SHR, but have beneficial effects in the DOCA-salt model. The comparison of models, and the comparison of treatment effects suggests that end-organ damage critically depends upon not only on the stress imposed by high blood pressure and its underlying biochemical disturbance, but also upon the ability of the organism to recruit adequate 'coping' mechanisms. These coping mechanisms deserve greater attention, as failure to recruit such mechanisms may indicate an increased risk. The current development of transgenic techniques will provide new opportunities, to develop specific models to address this balance between stress and coping.

Hypotensive effects of peptide T in conscious rats.

1. The present study investigated the effects of peptide T on mean arterial blood pressure (MAP) in conscious normotensive Sprague-Dawley (SD) rats, spontaneously hypertensive rats (SHR) and two-kidney one-clip (2K1C) hypertensive rats. 2. Peptide T was infused via the left jugular vein at a rate of 1 mg/kg per h in SD, SHR and 2K1C rats and then at doses of 0.1, 0.25, 0.5, 1 and 5 mg/kg per h in SHR, with 0.9% saline as a sham control in SHR and 2K1C. Mean arterial pressure was measured directly before, during and after infusion. 3. Peptide T (1 mg/kg per h) decreased blood pressure in both SHR (P < 0.01) and 2K1C (P < 0.05). In normotensive SD rats the fall in MAP approached statistical significance (P = 0.06). The effect of peptide T was not significantly different in normotensive compared with hypertensive rats. Saline infusion had no effect. The blood pressure lowering effect of peptide T appeared to be dose-dependent in SHR.

Effects of niflumic acid on α 1-adrenoceptor-induced vasoconstriction in mesenteric artery in vitro and in vivo in two-kidney one-clip hypertensive rats

The influence of niflumic acid (3 and 10 μM), a Cl − channel antagonist, on cirazoline-induced vasoconstriction in isolated perfused mesenteric artery (5 ml/min) from two-kidney one-clip (2K1C) hypertensive and sham normotensive rats was examined. In addition, the effect of a single i.v. bolus injection of niflumic acid (3 mg/kg) on cirazoline-mediated reduction in vascular conductance in superior mesenteric artery was determined in pentobarbital-anaesthetized hypertensive and normotensive rats. Bolus injections of cirazoline induced a dose-dependent transient increase in the perfusion pressure in vitro. In the presence of niflumic acid, cirazoline-mediated vasoconstriction was significantly inhibited. Cirazoline-induced vasoconstriction in isolated mesenteric beds was also significantly inhibited following perfusion with Cl −-free buffer. Pre-perfusion of mesenteric blood vessels with Cl −-free buffer resulted in a significantly greater inhibition of cirazoline-mediated vasoconstriction in sham normotensive rats than in hypertensive rats. We found that in Cl −-free buffer, cirazoline-mediated vasoconstriction could be further inhibited by niflumic acid. Intravenous infusion of cumulative doses of cirazoline in vivo caused a dose-dependent decrease in superior mesenteric vascular conductance. Pretreatment with niflumic acid significantly impaired cirazoline-mediated decreases in vascular conductance. Our results indicate that chloride ions play an important role in α 1-adrenoceptor-mediated vasoconstriction in mesenteric blood vessels. In addition, the contribution of chloride ions in α 1-adrenoceptor-mediated vasoconstriction in blood vessels from hypertensive rats appears to be reduced.

Alpha 1-adrenoceptor subtypes mediating adrenergic vasoconstriction in kidney, one-clip Goldblatt and deoxycorticosterone acetate-salt hypertensive rats.

We characterised the functional alpha 1-adrenoceptors involved in mediating adrenergic vasoconstrictor responses in kidney of two-kidney one-clip (2K1C) Goldblatt and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In sodium pentobarbital-anaesthetised rats, frequency- and dose-dependent renal vasoconstrictor responses were obtained by direct electrical renal nerve stimulation, close renal arterial administration of phenylephrine (PE), and methoxamine. Administration of amlodipine, a dihydropyridine calcium channel antagonist (bolus dose of 200 and 400 micrograms/kg and an infusion of 50 and 100 micrograms/kg/h, respectively) and the alpha 1-adrenoceptor antagonist 5-methylurapidil (5 micrograms/kg plus 1.25 micrograms/kg/h and twice this dose) suppressed renal nerve-, PE-, and methoxamine-induced vasoconstrictions 14-70% (p < 0.05-0.001) in 2K1C Goldblatt and DOCA-salt hypertensive rats. The alpha 1B-adrenoceptor alkylating agent, chloroethylclonidine (5 micrograms/kg plus 1.25 micrograms/kg/h and twice this dose) caused significant attenuation (p < 0.001) of renal nerve-induced vasoconstriction by 19-23% in DOCA-salt hypertensive rats but did not affect PE- and methoxamine-induced vasoconstriction in either 2K1C Goldblatt or DOCA-salt hypertensive rats. In contrast, in 2K1C Goldblatt rats vasoconstrictor responses were potentiated by renal nerve stimulation and methoxamine. The data show that the functional renal postjunctional alpha 1-adrenoceptors on the vasculature of both hypertensive models are primarily of the alpha 1A-subtype, as reflected by their sensitivity to amlodipine and 5-methylurapidil. Moreover, an interaction appears to occur between the alpha 1-adrenoceptor subtypes at renal vessels in 2K1C Goldblatt hypertensive rats.

Renal Vasodepressor Mechanism: Characterization by Chemical Medullectomy

The features of hypertension produced in the rat by chemical medullectomy with 2-bromoethylamine hydrobromide are described. This procedure partially prevents the fall in blood pressure that occurs when the constriction is removed from the renal artery of rats with two-kidney one-clip Goldblatt hypertension. In normal rats, chemical medullectomy causes a moderate but consistent blood pressure elevation that is dose related and associated with elevation of peripheral resistance; the venous side of the circulation is normal. The hypertension is not associated with sodium retention or with activation of the renin angiotensin system. Although vasopressin levels are elevated, the rise is only modest, and blood pressure is not reduced by a vascular AVP antagonist. It is concluded that chemical medullectomy removes the source of a humoral substance that has been shown by other workers to carry out a vasodepressor role. The chemical medullectomy model therefore offers new insights into the renomedullary vasodepressor system.

Role of sodium and renal prostaglandin E2 in the maintenance of hypertension in the chronic phase of two-kidney one-clip renovascular hypertension in rabbits.

To study the role of sodium and renal prostaglandin E2 in the chronic phase of two-kidney one-clip renovascular hypertension, urinary excretion rates of sodium and prostaglandin E2 were measured in rabbits with hypertension induced by left renal artery constriction during alteration in sodium intake. The arterial blood pressure, the increasing rate of body weight and sodium balance during alteration in sodium intake were directly proportional to the amount of sodium intake in the hypertensive rabbits, but not in the control ones. Plasma renin activity and plasma aldosterone concentration, which had no significant difference between hypertensive and control rabbits, were inversely proportional to the amount of sodium intake in both rabbits. Urinary excretion rates of sodium in the clipped kidneys of the hypertensive rabbits were significantly lower than the control values in all dietary regimens (p less than 0.01). Urinary excretion rates of sodium in the nonclipped kidneys were not significantly higher and in the total kidneys were significantly lower than the corresponding control values during sodium load (p less than 0.01). Urinary excretion rates of prostaglandin E2 were inversely proportional to the amount of sodium intake in both groups. Urinary excretion rates of prostaglandin E2 in the clipped kidneys were significantly lower than the control values in all dietary regimens (p less than 0.001). Urinary excretion rates of prostaglandin E2 in the nonclipped kidneys were significantly higher during sodium restriction (p less than 0.01) but not during sodium load than the control values. Furthermore, urinary excretion rates of prostaglandin E2 in the total kidneys were significantly lower than the control values in all dietary regimens (p less than 0.01). These results suggest that two-kidney one-clip renovascular hypertension in rabbits seems to be partly sodium-dependent in the chronic phase because the nonclipped kidney fails to excrete sodium sufficiently. There may also be disorders of renal prostaglandin E2 metabolism influencing these disorders of sodium in the nonclipped kidneys.

Divided Renal and Caval Vein Plasma Renin Activity in Two-Kidney Two-Clip Hypertension in Rabbits and Variations of Blood Pressure, Plasma Volume and Renal Function Following Unilateral Nephrectomy

Determinations were made of peripheral plasma renin activity, blood pressure, plasma volume and blood urea nitrogen in rabbit models of two-kidney one-clip, two-kidney two-clip or one-kidney one-clip hypertension that were created by staged operation to produce functionally significant renal artery stenosis. The plasma renin activity in the divided renal veins and inferior caval vein was also measured in animals with two-kidney two-clip hypertension.In rabbits with two-kidney two-clip hypertension the plasma renin activity was significantly higher in the renal vein on the more involved side and comparable in the renal vein on the less involved side and the inferior caval vein. This response pattern of renin secretion, unilateral hypersecretion with contralateral suppression, was identical with that observed in animals with two-kidney one-clip hypertension. In animals with one-kidney one-clip hypertension there was a marked increase in plasma volume and blood urea nitrogen. The renovascular hypertension was in decreasing order of severity in animals with one-kidney one-clip hypertension, those with two-kidney two-clip hypertension and those with two-kidney one-clip hypertension.

Partition of carotid baroreceptor response in two-kidney renal hypertensive dogs.

This study evaluated the mechanism of carotid sinus baroreceptor resetting in two-kidney one-clip Goldblatt hypertension in dogs by partitioning the resetting between carotid sinus wall compliance and receptor neural elements. With dogs under halothane anesthesia, the left renal artery was constricted 70-80% with a Goldblatt clamp without disturbing the contralateral kidney. Ten weeks later, when mean blood pressure had risen to 151 +/- 6 mmHg (means +/- SE) compared with 105 +/- 5 mmHg in controls, we measured simultaneously whole nerve action potentials (N) and carotid sinus volume (V) during step changes in intrasinus pressure (P). Hypertensive N vs. P relationship was sigmoid shaped and shifted toward the P-axis compared with controls. Hypertensive V vs. P relationship was not significantly different from controls. The hypertensive N vs. V relationship derived from the composite plots of N vs. P and V vs. P was sigmoid shaped and shifted toward the V-axis compared with controls. These results suggest that the resetting of baroreceptors is due to changes in receptor properties rather than carotid sinus wall compliance.

Failure of naloxone to influence surgical reversal of two-kidney, one-clip hypertension in the rat.

The rapid fall in blood pressure after removal of the constricting clip in two-kidney one-clip (2K-1C) hypertension in the rat is not fully explained by inhibition of the renin-angiotensin system or change in sodium balance. It has been postulated that compounds released in the renal venous effluent following unclipping of 2K-1C rats have a central opiate-like action and endogenous opioids are recognized to have profound hypotensive properties. To investigate this, we removed the clip from, or performed a sham operation in, early phase (less than 6 weeks) 2K-1C hypertensive rats during an infusion of naloxone, an opioid antagonist, or vehicle alone. The infusion of naloxone did not affect the pattern of blood pressure fall in either unclipped or sham-operated rats. Both naloxone-treated and control groups were similarly normotensive at 24 hr postoperation, the MAP being significantly lower than in the sham-operated groups, which regained previously hypertensive levels. Heart rate was unchanged 24 hr postoperatively in all groups. Morphine-induced bradycardia and hypotension were significantly reduced by naloxone infusion. Thus, naloxone infusion had no effect on blood pressure or heart rate in either the sham-operated or the unclipped groups, indicating that endogenous opioids do not have a major role in the reversal of renovascular hypertension under these circumstances.

Effect of vasopressin blockade on blood pressure in conscious rats with malignant two-kidney Goldblatt hypertension.

The role of vasopressin (VP) in maintaining blood pressure in malignant two-kidney one-clip Goldblatt hypertension in chronically catheterized conscious rats was investigated by studying the effect of two structurally different VP pressor antagonists. Injections of either 20 micrograms/kg of dPTyr(Me)AVP or 10 micrograms/kg of d(CH2)5Tyr(Me)AVP failed to alter mean arterial pressure or heart rate, although both antagonists completely inhibited the pressor response elicited by exogenous VP. These results suggest, that VP is not involved as a pressor hormone in the maintenance of high blood pressure in this type of experimental hypertension.

Effect of unclipping on pressor responses in rats with renovascular hypertension.

Pressor responses to angiotensin II and noradrenaline have been examined in two models of renovascular hypertension (two-kidney one-clip and one-kidney one-clip) before and 24 h after removal of the renal artery clip to examine the possible role of pressor hyper-responsiveness in the maintenance of hypertension. Early and chronic hypertension was studied to assess the part played by progressive structural hypertrophy. Plasma renin concentration was elevated in early two-kidney hypertensive rats, whereas it was similar to that in age-matched normal rats in early one-kidney and chronic two-kidney hypertensive rats. Twenty-four hours after unclipping plasma renin concentration was the same in all groups. Unclipping restored blood pressure to normal levels by 24 h, whereas sham-operated animals remained hypertensive. Angiotensin II responses in both early and chronic two-kidney one-clip hypertensive rats were lower than in age-matched normal rats. In unclipped rats responses were similar to those in normals. One-kidney hypertensive rats had similar angiotensin II responses to normal rats and there was no change with unclipping. Blockade of endogenous angiotensin II production by converting enzyme inhibition resulted in similar angiotensin II responses in hypertensive and unclipped groups. In normal rats, angiotensin II responses were inversely related to plasma renin concentration (r = -0.47, P less than 0.001). Angiotensin II responses in hypertensive and unclipped rats were found to show a similar relationship to plasma renin concentration as normal rats. Noradrenaline responses in hypertensive rats were similar to those in age-matched normals and there was no significant change with unclipping.(ABSTRACT TRUNCATED AT 250 WORDS)

Cation excretion and kallikrein secretion by the rat parotid gland in various hypertensive models.

The major salivary glands are distinguished by a high kallikrein content, localized particularly in regions with intense electrolyte transport (the apical border of striated duct cells and the luminal border of the main excretory ducts). For this reason we used the parotid gland as a test model for investigations on electrolyte (sodium and potassium) and kallikrein transport in various forms of experimental hypertension [spontaneously hypertensive rats, renovascular (two-kidney one-clip) hypertension, and deoxycorticosterone trimethylacetate (DOCA)-salt hypertension]. As compared with values for the controls, the sodium concentration in parotid saliva was decreased in all hypertensive models studied, indicating enhanced sodium reabsorption in the glandular duct system. In DOCA-salt hypertension the flow rate dependency of the sodium concentration was preserved. In contrast, in genetic and renovascular hypertension, the decreased sodium concentration was independent of the salivary flow rate. Salivary potassium concentration showed an inverse relationship to sodium level and was slightly increased in DOCA-salt and renovascular hypertension. In genetic hypertension potassium concentration in saliva was lowered. Salivary kallikrein activity was enhanced in all forms of hypertension studied, with the highest increase in genetic hypertension (factor 3.5), followed by DOCA-salt hypertension (factor 3.0) and finally by renovascular hypertension (factor 2.5). The pathogenesis of the exaggerated kallikrein secretion observed in hypertension is discussed with regard to a counterregulatory mechanism as well as sympathicoadrenergic activation.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent arteriolar diameter in DOCA-salt and two-kidney one-clip hypertensive rats.

The afferent arteriolar diameter (dAA) was investigated during development of hypertensive renal disease in normal and uninephrectomized control rats, in chronic DOCA-salt (DOCA), post-DOCA (p-DOCA), and chronic two-kidney one-clip (2K-1C) hypertensive rats, and in post-two-kidney one-clip (p-2K-1C) normotensive rats. dAA was measured by the microsphere method. Nephron loss was present in the kidneys exposed to elevate blood pressure. The dAA was reduced from 19.9 to 17.2 micron in the DOCA group (P less than 0.001) and from 19.1 to 16.3 micron in the nonclipped kidneys in the 2K-1C group (P less than 0.001). The dAA increased from 19.9 to 20.7 micron in the p-DOCA group. Afferent arteriolar dilatation from 19.1 to 21.0 micron (P less than 0.001) was present about 50 days after clipping in the 2K-1C group; in the clipped kidneys the dAA returned to normal (18.9 micron) after declipping. No relation between the dAA and plasma renin concentration was observed. In all models dAA was the same in three cortical layers of equal thickness. Accordingly, chronic renal DOCA-salt hypertension constricts the afferent arteriole with angiotensin-independent mechanisms. Autoregulatory dilatation of the afferent arteriole seems to be maintained for at least 50 days. When the hypertension is moderate, dAA in damaged kidneys may be dilated.

Relative contribution of vasopressin and angiotensin II to the altered renal microcirculatory dynamics in two-kidney Goldblatt hypertension.

The renal microcirculation was assessed in non-clipped kidneys of 23 Munich-Wistar rats with two-kidney one-clip Goldblatt hypertension. Four weeks after placement of a renal arterial clip, mean systemic arterial pressure averaged 163 +/- 5 mm Hg in hypertensive rats as compared to 108 +/- 2 in sham-operated controls (n = 6 rats). Non-clipped kidneys in hypertensive rats were characterized by higher glomerular capillary hydraulic pressures, single nephron glomerular filtration rate, and afferent arteriolar resistance. The glomerular capillary ultrafiltration coefficient was significantly reduced in hypertensive rats. In 10 of these rats, intravenous infusion of the angiotensin antagonist, saralasin, or the converting enzyme inhibitor, SQ20881, led to significant reductions in systemic arterial pressure and in afferent and efferent arteriolar resistance, on average by 8 +/- 3%, 15 +/- 4%, 28 +/- 5%, respectively. These changes were associated with significant increase in glomerular plasma flow, while ultrafiltration coefficient remained unaffected. In the presence of saralasin or SQ20881, infusion of a specific antagonist of the vascular action of arginine vasopressin led to significant systemic but not renal vasodilation. Thus, whereas systemic arterial pressure fell further, on average by 23 +/- 2%, renal arteriolar resistance remained constant, resulting in marked reduction in glomerular capillary hydraulic pressures (by 18 +/- 2%) and glomerular plasma flow rate (by 28 +/- 10%). Because of these pronounced reductions in glomerular pressures and flows induced by vasopressin antagonist, single nephron glomerular filtration rate fell markedly in hypertensive rats (by 34 +/- 6%) despite normalization of ultrafiltration coefficient. When hypertensive rats (n = 7) were treated with vasopressin antagonist alone, a modest fall in systemic arterial pressure was again observed in the absence of changes in renal arteriolar resistance. Due to this selective extrarenal vasodilatory action of vasopressin antagonist, glomerular capillary hydraulic pressure, plasma flow rate, and single nephron glomerular filtration rate again fell markedly. When these vasopressin antagonist pre-treated hypertensive rats were given saralasin or SQ20881, marked reductions in renal arteriolar resistance were observed in association with a significant increase in glomerular plasma flow rate. These observations made during acute inhibition of angiotensin II and vasopressin indicate that both of these vasopressin hormones may play important roles in maintaining systemic hypertension in hypertensive rat. By virtue of its preferential constrictor effects on extrarenal rather than renal vasculature vasopressin serves to maintain high glomerular pressures and flows in the non-clipped kidney of Goldblatt hypertensive rats.

Renal nerves in the pathogenesis of hypertension in experimental animals and humans.

Efferent renal innervation is composed of postganglionic sympathetic fibers to the renal arterioles, juxtaglomerular apparatus, and renal tubules. Increased efferent renal sympathetic nerve activity results in increased renal vascular resistance, renin release, and sodium retention. These responses from enhanced renal sympathetic activity contribute to normal cardiovascular homeostasis but could also facilitate the development of hypertension by shifting the arterial pressure-renal sodium excretion curve to the right. Accordingly, interruption of the renal nerves should prevent the development of hypertension in animal models in which increased sympathetic nervous system activity has been implicated. Renal denervation delays the development of hypertension and results in greater sodium excretion in the Okamoto and New Zealand spontaneously hypertensive rat and in the DOCA-salt-treated rat, suggesting that these responses are due, at least in part, to loss of efferent renal nerve activity. Similar sympathetically mediated renal vasoconstriction has been implicated in the pathogenesis of early essential hypertension in man. Recent studies indicate that the kidney is a sensory organ with mechano-receptive and chemoreceptive afferent renal nerves involved in renorenal and cardiovascular regulation. Renal denervation in established one-kidney one-clip and two-kidney one-clip Goldblatt hypertension in the rat and chronic coarctation in the dog results in an attenuation of the hypertension. The depressor effect of renal denervation in these models is not due to change in renin activity or sodium excretion but is associated with decreased activity of the sympathetic nervous system. These findings suggest that the afferent renal nerves contribute to the pathogenesis of renovascular hypertension by enhancing the activity of the sympathetic nervous system. The role of the afferent renal nerves in renovascular hypertension in humans warrants further study.

The importance of the renin-angiotensin system in the development and maintenance of hypertension in the two-kidney one-clip hypertensive rat.

1. Blood pressure, renin concentration and angiotensin II were measured in unanaesthetized two-kidney one-clip hypertensive rats at 1 and 2 days, at weekly intervals up to 10 weeks and at 15 and 20 weeks after clipping. 2. Compared with values in sham-operated rats, renin and angiotensin II were initially increased at 1-2 days but were then suppressed between 2 and 4 weeks to levels similar to that found in sham-operated rats. Between 5 and 20 weeks renin and angiotensin II increased again to high levels. 3. There was a significant correlation between angiotensin II and blood pressure in acute rats 1-2 days after clipping (P less than 0.05) and in chronic rats 8-20 weeks after clipping (P less than 0.001). There was no difference in the slope of the regression lines but the regression line for the chronic rats was shifted upwards in a parallel manner. 4. The acute hypotensive response (-20.3 +/- SD 24.9 mmHg) in 26 chronic rats given converting enzyme inhibitor was related to the basal renin and angiotensin II levels and followed the slope of the angiotensin II/blood pressure regression line for all chronic rats. Only one out of 26 rats reduced its blood pressure to normal levels. 5. In 12 rats at 4 weeks after clipping, when blood pressure was elevated but angiotensin II was suppressed, there was only a small fall in blood pressure (-7.1 +/- SD 7.2 mmHg). This also followed the angiotensin II/blood pressure regression line for chronic rats but at the lower end. Blood pressure again was not reduced to normal. 6. These results suggest that renin and angiotensin II are increased up to 20 weeks after clipping, that there is no change in the net vascular responsiveness to endogenous angiotensin II at any stage in this experimental model and that the acute effect of angiotensin II is determined solely by its position in the same dose-response curve. Also with the exception of 1-2 days immediately after clipping the acute effect of angiotensin II plays only a minor, though variable, role in the hypertension and that some other mechanism, as yet undetermined, is of greater importance and begins to have an effect as early as 2 weeks after clipping.

Behavioral responsiveness and habituation to discrete auditory and olfactory stimuli in spontaneously hypertensive, two-kidney one-clip hypertensive, and normotensive rats

Behavioral responsiveness and habituation to discrete stimuli were investigated in spontaneously hypertensive (SHR), two-kidney one-clip hypertensive (RHR), and normotensive rats (NR). Responsiveness to an auditory stimulus, as measured by amplitude and duration of the orienting response (OR), was enhanced in the SHR compared to the other two groups. In addition, the SHR needed more trials to attain the habituation criterion (Experiment 1). There were no differences between the groups in terms of the arrest response to an auditory stimulus (Experiment 2). The SHR exhibited increased amplitude and duration of the OR to an olfactory stimulus compared to the two other groups, but there was no difference in trials needed to attain habituation when this stimulus was repeated (Experiment 3). These data, together with previous behavioral and psychophysiological data, indicate increased general level of responsiveness in the SHR.