Chronic Stage Of Hypertension Research Articles

Asymptomatic Striatocapsular slit-like Hemorrhage as a Severity Marker in Patients with Hypertensive Angiopathy

BackgroundConcomitant asymptomatic striatocapsular slit-like hemorrhage (SSH) is occasionally found in patients of spontaneous intracerebral hemorrhage (ICH), but was seldomly described in the literature. In this study, we described the clinico-radiological features of asymptomatic SSH in ICH patients with hypertensive microangiopathy. Methods and Results246 patients with strictly deep or mixed deep and lobar ICH/microbleeds were included. SSH was defined as hypointense lesions involving the lateral aspect of lentiform nucleus or external capsule in slit shape (>1.5 cm) on susceptibility-weighted imaging without history of associated symptoms. Demographics and neuroimaging markers were compared between patients with SSH and those without. Patients with SSH (n=24, 10%) and without SSH had comparable age (62.0 ± 12.6 vs. 62.3 ± 13.5, p = 0.912) and vascular risk factor profiles including the diagnosis of chronic hypertension, diabetes, and dyslipidemia (all p>0.05). SSH was associated with more common lobar microbleeds (79.2% vs 48.2%, p = 0.005), lacunes (75% vs. 41.4%, p = 0.002) and higher white matter hyperintensity (WMH) volumes (24.1 [10.4–46.3] vs. 13.9 [7.0–24.8] mL, p = 0.012) on MRI, as well as more frequent left ventricular hypertrophy (LVH) (50.0% vs. 20.5%, p = 0.004) and albuminuria (41.7% vs. 19.4%, p = 0.018). In multivariable analyses, SSH remains independently associated with LVH (p = 0.017) and albuminuria (p = 0.032) after adjustment for age, sex, microbleed, lacune and WMH volume. ConclusionsAsymptomatic SSH is associated with more severe cerebral small vessel disease-related change on brain MRI, and hypertensive cardiac and renal injury, suggesting a more advanced stage of chronic hypertension.

Abstract TP342: Asymptomatic Striatocapsular Slit-Like Hemorrhage as a Severity Marker in Patients With Hypertensive Intracerebral Hemorrhage/Microbleeds

Background: Concomitant asymptomatic striatocapsular slit-like hemorrhage (SSH) is occasionally found in patients of hypertensive intracerebral hemorrhage (ICH), but was seldom reported. The correlation between hypertension severity and cerebral hemorrhagic pattern has not been well investigated, either. In this study, we described the clinico-radiological features of previous asymptomatic SSH in ICH patients with hypertensive angiopathy. Methods: 246 patients with strictly deep or mixed deep and lobar ICH/CMBs were included. SSH was defined as hypointense lesions involving the lateral aspect of lentiform nucleus or external capsule in slit shape (>1.5cm) on susceptibility-weighted imaging without history of associated symptoms (Figure 1). Demographics and neuroimaging markers were compared between patients with SSH and those without. The association between SSH and left ventricular hypertrophy (LVH) or proteinuria was investigated in univariable and multivariable logistic regression models. Results: Patients with SSH (n=24, 10%) and without SSH (n=222, 90%) had comparable age (62.0 ± 12.6 vs. 62.3 ± 13.5, p=0.912) and vascular risk factor profiles (all p>0.05). SSH was associated with more common lobar CMBs (79.2% vs 48.2%, p=0.005), lacunes (75% vs. 41.4%, p=0.002) and higher white matter hyperintensity (WMH) volumes (12.0 [7.7-26.8] vs. 8.7 [4.3-16.1] mL, p=0.016) on MRI, as well as more frequent LVH (50.0% vs. 20.3%, p=0.004) and proteinuria (41.7% vs. 19.4%, p=0.018). In multivariable analyses, SSH remains independently associated with LVH (Odds ratio 2.8 [1.1-7.3], p=0.033) and proteinuria (Odds ratio 2.6 [1.0-6.6], p=0.041) after adjustment for age, sex, CMBs, lacune and WMH volume. Conclusions: Asymptomatic SSH is associated with more severe cerebral small vessel disease-related change on brain MRI, and hypertensive cardiac and renal injury, suggesting a more advanced stage of chronic hypertension.

Two-kidney one-clip is a pertinent approach to integrate arterial hypertension in animal models of stroke: Serial magnetic resonance imaging studies of brain lesions before and during cerebral ischemia

Although chronic arterial hypertension (CAH) represents the major comorbid factor in stroke, it is rarely integrated in preclinical studies of stroke. The majority of those investigations employ spontaneously hypertensive rats (SHR) which display a susceptibility to ischemic damage independent of hypertension. Here, we used a renovascular model of hypertension (RH) to examine, with magnetic resonance imaging (MRI), brain alterations during the development of hypertension and after brain ischemia. We also examined whether MRI-derived parameters predict the extent of ischemia-induced brain damage. RH was induced according to the two-kidney one-clip model and multiparametric MRI was performed at 3, 6, 9, and 12 weeks after hypertension and also at 10, 50, and 60 min following stroke. Blood pressure values increased progressively and reached a plateau at 6 weeks after RH induction. At 12 weeks, all hypertensive animals displayed spontaneous brain lesions (hemorrhages, deep and cortical lesions, ventricular dilatation), increased apparent diffusion coefficient (ADC) values in the corpus callosum and higher fractional anisotropy in the cortex. Following ischemia, these animals showed larger brain lesions (406 ± 82 vs. 179 ± 36 mm3, p < 0.002) which correlated with ADC values at chronic stage of hypertension. This model of hypertension displays many characteristics of the neuropathology of human CAH. The use of this model in stroke studies is relevant and desirable.

Deletion of interleukin-6 prevents cardiac inflammation, fibrosis and dysfunction without affecting blood pressure in angiotensin II-high salt-induced hypertension.

Inflammation has been proposed as a key component in the development of hypertension and cardiac remodeling associated with different cardiovascular diseases. However, the role of the proinflammatory cytokine interleukin-6 in the chronic stage of hypertension is not well defined. Here, we tested the hypothesis that deletion of interleukin-6 protects against the development of hypertension, cardiac inflammation, fibrosis, remodeling and dysfunction induced by high salt diet and angiotensin II (Ang II). Male C57BL/6J and interleukin-6-knock out (KO) mice were implanted with telemetry devices for blood pressure (BP) measurements, fed a 4% NaCl diet, and infused with either vehicle or Ang II (90 ng/min per mouse subcutaneously) for 8 weeks. We studied BP and cardiac function by echocardiography at baseline, 4 and 8 weeks. Myocyte cross-sectional area (MCSA), macrophage infiltration, and myocardial fibrosis were also assessed. BP increased similarly in both strains when treated with Ang II and high salt (Ang II-high salt); however, C57BL/6J mice developed a more severe decrease in left ventricle ejection fraction, fibrosis, and macrophage infiltration compared with interleukin-6-KO mice. No differences between strains were observed in MCSA, capillary density and MCSA to capillary density ratio. In conclusion, absence of interleukin -6 did not alter the development of Ang II-high salt-induced hypertension and cardiac hypertrophy, but it prevented the development of cardiac dysfunction, myocardial inflammation, and fibrosis. This indicates that interleukin-6 plays an important role in hypertensive heart damage but not in the development of hypertension.

HYPOTHALAMIC ANTIHYPERTENSIVE EFFECT OF METOPROLOL IN CHRONIC AORTIC COARCTATED RATS

1. The aim of the present study was to investigate the possible hypothalamic antihypertensive effect of metoprolol and its action on aminergic neurotransmission in sham-operated (SO) rats and aortic coarctated (ACo) rats at a chronic hypertensive stage using the microdialysis technique. 2. Hypothalamic metoprolol concentrations and their cardiovascular effects were measured after the intravenous administration of 3 mg/kg metoprolol. Based on metoprolol concentrations reached in the anterior hypothalamus, in a second experiment the anterior hypothalamus of SO and ACo animals was perfused with Ringer's solution containing approximately 7.5 microg/mL metoprolol. The cardiovascular effects of metoprolol perfusion and changes in hypothalamic dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindol acetic acid (5-HIAA) levels were measured during the perfusion. 3. After i.v. administration of metoprolol, a greater hypotensive effect was observed in ACo rats than in SO animals (Delta mean arterial pressure (MAP) -23.8 +/- 2.1 vs-13.8 +/- 1.3 mmHg, respectively; n = 5 for both groups). Metoprolol rapidly reached the central nervous system (CNS) in both groups of rats and its levels were similar in SO and ACo rats. Intrahypothalamic perfusion with metoprolol induced a significative decrease in blood pressure in ACo animals (DeltaMAP -13.3 +/- 1.5 mmHg; n = 5; P < 0.05 vs Ringer perfusion), but not in SO rats (DeltaMAP 3.4 +/- 2.7 mmHg; n = 5). Metoprolol perfusion reduced hypothalamic levels of DOPAC in ACo rats (65 +/- 7% of basal levels; n = 5; P < 0.05 vs Ringer perfusion), but not in SO animals (87 +/- 5% of basal levels; n = 5). There were no changes in hypothalamic concentrations 5-HIAA observed in either experimental group. 4. In conclusion, metoprolol exerts a greater hypotensive effect in chronic ACo animals, suggesting a participation of beta-adrenoceptors in the maintenance of the hypertensive stage. Metoprolol distribution in the CNS is not affected by ACo. The hypotensive effect of metoprolol perfusion in ACo rats suggested that hypothalamic beta-adrenoceptor blockade is part of the antihypertensive effect of metoprolol in chronic ACo rats. The effects of metoprolol on DOPAC levels suggest a reduction of dopamine turnover in hypertensive animals, but not in SO rats.

Hypothalamic Antihypertensive Effect of Irbesartan in Chronic Aortic Coarctated Rats

The aim of the present work was to study the central and plasma pharmacokinetics of irbesartan (IRB) and its possible hypothalamic antihypertensive effect in sham-operated (SO) and aortic-coarctated (ACo) rats at a chronic hypertensive stage using the microdialysis technique. Anesthetized Wistar rats were used 42 days after ACo or SO. For the study of plasma pharmacokinetics, a vascular shunt probe was inserted into the carotid artery. In a separated experiment, a concentric probe was placed into the anterior hypothalamus for the study of IRB distribution in the central nervous system. Based on the hypothalamic concentrations of IRB reached in ACo rats, the anterior hypothalamus of SO and ACo animals was perfused with a Ringer solution containing approximately 6 µg·ml^–1 of the drug. IRB (10 mg·kg^–1 i.v.) induced a late decrease of heart rate (HR) in ACo animals (ΔHR: –42 ± 10 bpm, n = 5, p < 0.05 vs. SO rats) but not in SO rats (ΔHR: 11 ± 13 bpm, n = 5). Systemic administration of the drug reduced the mean arterial pressure (MAP) of both experimental groups, but the hypotensive effect was greater in ACo (ΔMAP: –39.9 ± 5.0 mm Hg, n = 5, p < 0.05 vs. SO rats) than in SO rats (ΔMAP: –25.4 ± 2.1 mm Hg, n = 5). A similar pharmacokinetic profile was observed in both experimental groups. Hypothalamic distribution of IRB was greater in ACo (AUC: 730 ± 130 ng·ml^–1 h^–1, n = 5, p < 0.05 vs. SO rats) than in SO animals (AUC: 283 ± 87 ng·ml^–1 h^–1, n = 5). The IRB hypothalamic perfusion induced an antihypertensive effect in ACo (ΔMAP: –15.1 ± 1.0 mm Hg, n = 5, p < 0.05 vs. Ringer perfusion) but not in SO rats. In conclusion, the chronic aortic coarctation did not modify the plasma pharmacokinetics of IRB, but it increased the distribution of the drug in the central nervous system. The greater hypotensive effect of IRB observed in ACo animals suggests the involvement of AT1 receptors in the maintenance of the hypertensive stage in chronic ACo rats. The hypotensive effect of IRB in ACo animals could be explained, at least in part, due an action on the anterior hypothalamic angiotensin system.

Anterior hypothalamic β‐adrenoceptors in chronic aortic‐coarctated hypertensive rats: An interaction with central angiotensin II receptors

1. The aim of the present study was to investigate the activity of anterior hypothalamic beta-adrenoceptors and angiotensin (Ang) II receptors on blood pressure in normotensive rats and aortic-coarctated (ACo) animals at a chronic stage of hypertension. A possible interaction between beta-adrenoceptors and AngII pressor activity was also investigated. 2. Injection of isoproterenol (0.1-10 nmol) in the anterior hypothalamic area induced a dose-dependent decrease in mean arterial pressure (MAP) in sham-operated (SO), but not in ACo, animals. Isoproterenol (1 nmol) reduced blood pressure in SO rats (DeltaMAP -10.1+/-1.4 mmHg; n=10) but not in ACo animals (DeltaMAP -0.9+/-1.6 mmHg; n=10; P<0.05 vs SO rats). Whereas previous administration of atenolol (40 nmol) enhanced the cardiovascular effect of isoproterenol (1 nmol) in ACo rats but not in SO animals, propranolol (40 nmol) prevented the hypotensive action of isoproterenol in both experimental groups. Intrahypothalamic administration of clenbuterol decreased MAP in a dose-dependent manner; however, the depressor response to clenbuterol (10 nmol) was greater in ACo rats than in SO rats (DeltaMAP -26.8+/-3.2 vs -14.4+/-2.4 mmHg, respectively; n=5 for both; P<0.05). When AngII (50 ng) was injected into the anterior hypothalamic area, a greater pressor response was observed in ACo rats than in SO rats (DeltaMAP 19.6+/-1.1 vs 11.3+/-0.6 mmHg, respectively; n=5 for both; P<0.05). Atenolol (40 nmol) pretreatment partially and significantly prevented the pressor response to AngII in ACo rats, but not in SO rats. 3. In conclusion, these results provide pharmacological evidence for the existence of a beta1-adrenoceptor-mediated pressor mechanism in the anterior hypothalamic area of ACo rats that is absent in SO rats. The enhanced depressor beta2-adrenoceptor activity observed in chronic ACo rats could be a compensatory adjustment to pressor beta1-adrenoceptor activity. Conversely, pressor overactivity of AngII was observed in the anterior hypothalamic area of ACo rats at a chronic hypertensive stage; this enhancement could be explained, at least in part, by the pressor beta1-adrenoceptor activity.

GABA-A Function and Receptor Binding in the Paraventricular Nucleus in Chronic Renal Wrap Hypertension

P48 The onset of renal wrap hypertension is associated with a reduced tonic GABA inhibition in the paraventricular nucleus (PVN) on the sympathetic nervous system. This reduced functional inhibition occurs without a change in GABA-A receptor binding in the PVN. The goal of the present study was to determine if GABAergic transmission and GABA binding is altered in chronic renal wrap hypertensive rats. Sprague-Dawley rats were made hypertensive or sham-operated. Four weeks later, animals were prepared with femoral artery catheters for the measurement of arterial pressure. Subgroups were also prepared with bilateral cannulae directed at the PVN. The renal wrap rats had higher mean arterial pressure (MAP): 139±4 mmHg vs.113±2 mmHg, but heart rate (HR) was not different (354±12 bpm vs. 369±6 bpm) as compared to control animals. Administration of the GABA-A antagonist, bicuculline, into the PVN caused a greater increase in MAP and HR in wrap animals (25±2 mmHg and 150±30 bpm) compared to sham operated rats (16±2 mmHg and 89±12 bpm). GABA-A binding sites in the PVN were estimated using in vivo autoradiography. [3H]-Flunitrazepam was used as the receptor ligand. Magnocellular neurons of the PVN showed a higher density of receptors than other areas of the nucleus. However, the number of binding sites was not different between normotensive and hypertensive rats in either the high density (1825±56 vs. 1756±41 fmol/mg protein) or low density (1454±26 vs. 1433±57 fmol/mg protein) regions of PVN. These data indicate that the inhibition by GABA in the PVN is augmented in the chronic stage of hypertension, and appears to be unrelated to a change in the number of GABA binding sites. The increased GABAergic inhibition is in contrast to the reduced inhibition that has been observed during the onset of hypertension.

GABA-A Function and Receptor Binding in the Paraventricular Nucleus in Chronic Renal Wrap Hypertension

P48 The onset of renal wrap hypertension is associated with a reduced tonic GABA inhibition in the paraventricular nucleus (PVN) on the sympathetic nervous system. This reduced functional inhibition occurs without a change in GABA-A receptor binding in the PVN. The goal of the present study was to determine if GABAergic transmission and GABA binding is altered in chronic renal wrap hypertensive rats. Sprague-Dawley rats were made hypertensive or sham-operated. Four weeks later, animals were prepared with femoral artery catheters for the measurement of arterial pressure. Subgroups were also prepared with bilateral cannulae directed at the PVN. The renal wrap rats had higher mean arterial pressure (MAP): 139±4 mmHg vs.113±2 mmHg, but heart rate (HR) was not different (354±12 bpm vs. 369±6 bpm) as compared to control animals. Administration of the GABA-A antagonist, bicuculline, into the PVN caused a greater increase in MAP and HR in wrap animals (25±2 mmHg and 150±30 bpm) compared to sham operated rats (16±2 mmHg and 89±12 bpm). GABA-A binding sites in the PVN were estimated using in vivo autoradiography. [3H]-Flunitrazepam was used as the receptor ligand. Magnocellular neurons of the PVN showed a higher density of receptors than other areas of the nucleus. However, the number of binding sites was not different between normotensive and hypertensive rats in either the high density (1825±56 vs. 1756±41 fmol/mg protein) or low density (1454±26 vs. 1433±57 fmol/mg protein) regions of PVN. These data indicate that the inhibition by GABA in the PVN is augmented in the chronic stage of hypertension, and appears to be unrelated to a change in the number of GABA binding sites. The increased GABAergic inhibition is in contrast to the reduced inhibition that has been observed during the onset of hypertension.

Chymase is activated in the hamster heart following ventricular fibrosis during the chronic stage of hypertension

Chronic pressure overload induces cardiac tissue remodeling. Chymase is known to regulate matrix metabolism and angiotensin II formation. In the present study, we investigated the pathophysiological functions of chymase in the pressure-overloaded hamster heart induced by a two-kidney, one-clip (2K1C) hypertension procedure. Fibrosis and apoptosis were observed in the pressure-overloaded hearts of 2K1C hamsters 32 weeks after clipping, but these histological changes were not detected at 16 weeks. Heart chymase-like activity of 2K1C hamsters at 32 weeks increased 5.2-fold compared with that at 16 weeks, while angiotensin-converting enzyme was not activated. Chymase might be involved in cardiac tissue remodeling during the chronic stage of hypertension.

副腎再生高血圧症

In young rats consuming 1% NaCl drinking solution, unilateral nephrectomy and bilateral adrenal enucleation caused a hypertension. Plasma corticosterone concentration in hypertensive rats was not significantly higher than that of normotensive control rats in early hypertensive or chronic hypertensive stage. At the end of experiment, each rat received an intravenous injection of 0.4 microCi/g of 3H-lysine and was sacrificed 2 hours after the injection. Incorporation of 3H-lysine into collagen or elastin of the mesenteric artery and heart in hypertensive rats was greater than that of normotensive rats. Administration of phenoxybenzamine hydrochloride lower the blood pressure of hypertensive rats and reduced the incorporation of 3H-lysine into collagen and elastin of the mesenteric artery and heart. From these findings, increased protein synthesis of collagen and elastin in hypertensive rats appears to play an important role for the maintenance of adrenal regeneration hypertension.

Arteriolar changes in developing and chronic stages of two-kidney, one clip hypertension.

Arteriolar internal and external diameters in the cremaster muscle of two-kidney, one clip hypertensive rats (2K1C) were measured in vivo with video microscopy, both before and after the topical application of adenosine (10(-4) M). Arteriolar density was determined by stereologic techniques. Mean arterial blood pressure was significantly elevated in the 2K1C rats, rising to 186 +/- 6 mm Hg by 8 weeks compared with 113 +/- 4 mm Hg in controls. Lumens of larger arterioles showed a structural reduction at 2 weeks of hypertension and remained at the same level through 8 weeks, while arterioles of control rats showed a progressive increase in diameter with age (101 +/- 6 microns in 2K1C vs. 158 +/- 8 microns in controls at 8 weeks after operation). Wall-to-lumen ratios of larger arterioles were significantly increased at 2, 4, and 8 weeks of hypertension, but cross-sectional wall area was significantly reduced at 8 weeks. Medial hypertrophy was not evident at any stage of hypertension. Arteriolar rarefaction of smaller arterioles was functional at 2 weeks and structural at 8 weeks of hypertension. Vascular tone of the smaller arterioles was elevated in the developing and chronic stages of hypertension. At 2 weeks of hypertension when the structural reduction in diameters of larger arterioles was progressing, the increased vasoconstriction and functional rarefaction may have contributed to the elevated resistance. At 8 weeks, the marked diameter reductions of larger arterioles (36% in first-order arterioles and 25% in second-order arterioles) account for most of the increased resistance to flow.

２腎性Ｇｏｌｄｂｌａｔｔ型高血圧犬におけるＭＫ‐０５２１の連続経口投与による降圧作用

MK-0521 and captopril were orally administered to acute (6 to 8 days after unilateral renal artery constriction) and chronic (2 to 2.5 months after the constriction) 2-kidney Goldblatt hypertensive dogs for 7 to 21 days. MK-0521 lowered the blood pressure to similar extents in the acute and chronic stages of hypertension. The antihypertensive effect of MK-0521 was dose-dependent and persistent even after its cessation. Captopril also produced an antihypertensive effect, although the effect in the chronic stage of hypertension was less prominent than that in the acute stage of hypertension. MK-0521 was more inhibitory on the renin-angiotensin system than captopril. In the acute stage of hypertension, the dogs treated with MK-0521 had increased angiotensin converting enzyme (ACE) activity, while they had decreased plasma angiotensin II level and elevated plasma angiotensin I level and plasma renin activity. These results clarified the inhibitory effect of MK-0521 on ACE. In contrast, in the chronic stage of hypertension, MK-0521 showed no depression of plasma angiotensin II. There were no significant changes in daily urinary volume, and renal clearances of sodium, potassium and creatinine. These results suggest that the major mechanism of the antihypertensive effect of MK-0521 in 2-kidney Goldblatt hypertensive dogs is an inhibition of the ACE. In addition, the different effects in the acute and chronic hypertensive dogs suggest that some differences exist in the mechanisms of maintaining blood pressure between the two stages of 2-kidney Goldblatt hypertensive dogs.

Elevated vascular angiotensin converting enzyme in chronic two-kidney, one clip hypertension in the dog.

The possible role of the vascular angiotensin converting enzyme (ACE) in the development of two-kidney, one clip (2-K, 1C) hypertensive dogs was studied in different blood vessels. Vascular ACE activity per mg protein differed in a variety of blood vessels; the activity appeared to vary inversely with the outer diameter of arteries. The systemic blood pressure in mongrel dogs increased after partial occlusion of the left renal artery, and the hypertension lasted for 8 months. Plasma renin activity (PRA) was raised only for the first 4 weeks after the operation and then returned to the original level in the chronic stage of hypertension. Plasma ACE activity did not alter during the experimental period. In contrast, ACE activities in the jejunal, pulmonary and renal arteries, aorta, lung and cerebral cortex, significantly increased in the chronic hypertensive stage (8 months after occlusion). The production of angiotensin II (ANG II) from ANG I was significantly greater in isolated arteries from 8-month hypertensive dogs than in those from normotensive dogs when assessed by the contractile responses to ANG I and ANG II. These results indicate that acceleration by increased vascular ACE activity of the production of ANG II in the vascular wall may contribute to the maintenance of hypertension in the chronic stage of 2-K, 1C hypertensive dogs having normal PRA and plasma ACE activity.

Vascular renin-angiotensin system in two-kidney, one clip hypertensive rats.

The possible role of the renin-angiotensin system in the maintenance of hypertension in two-kidney, one clip hypertensive rats was studied. Plasma renin activity rose rapidly and markedly in association with the elevation of blood pressure and then decreased gradually, although blood pressure remained high. Renin activity in the lung, aorta, and mesenteric artery also increased with the development of hypertension and then decreased in a way similar to that of plasma renin activity at the chronic stage of hypertension. Plasma angiotensin converting enzyme activity did not change significantly until 16 weeks after unilateral renal artery clipping, whereas vascular angiotensin converting enzyme activity significantly increased at the chronic, but not the acute, stage of hypertension. In chronically renal hypertensive rats, 1-sarcosine, 8-isoleucine angiotensin II or enalapril, an angiotensin converting enzyme inhibitor, lowered the blood pressure and enalapril also lowered the angiotensin converting enzyme activity of vascular tissues. The constrictor effect of angiotensin I was greater in isolated arteries from chronically hypertensive rats than in those from age-matched normotensive rats. These results suggest that the vascular renin-angiotensin system plays an important role in the maintenance of two-kidney, one clip hypertension. Elevated vascular angiotensin converting enzyme activity appears to increase local production of angiotensin II, which results in vasoconstriction by acting directly and indirectly through adrenergic nerves on vascular smooth muscle.

Different effects of captopril on blood pressure in the acute and chronic two-kidney Goldblatt hypertensive dogs.

Captopril was administered to acute (8 to 14 days after unilateral renal artery constriction) and chronic (71 to 127 days after the constriction) two-kidney Goldblatt hypertensive dogs, and to normotensive ones for 21 days (oral administration of 10, 20 and 40 mg/kg/day, consecutively each 7-day period). The decrease of arterial blood pressure was remarkable in hypertensive animals with high plasma renin activity, but not in the normotensive animals. In the acute stage of hypertension, the antihypertensive effect of captopril was dose-dependent and persistent even after its cessation. In the chronic stage of hypertension, blood pressure also decreased, but the response was not dose-dependent and did not continue after cessation. Plasma renin activity rose in both hypertensive and normotensive animals during the treatment with captopril. There were no significant changes in heart rate, daily urinary volume, sodium balance, and renal clearances of sodium (CNa), potassium (CK), chloride (CCl) and creatinine (CCr). Circulating blood volume was also not altered. These results indicate that the main mechanism of antihypertensive effect of captopril in two-kidney Goldblatt hypertensive dogs is an inhibition of the angiotensin converting enzyme. In addition, the different effects in the acute and chronic hypertensive dogs suggest that some differences exist in the mechanism(s) of maintaining blood pressure between the two stages of two-kidney Goldblatt hypertension in dogs.

Changes in cardiac beta-adrenoceptor concentrations in spontaneously hypertensive and experimental renal hypertensive rats.

Cardiac beta-adrenoceptors were studied in membrane fractions from spontaneously hypertensive rats (SHR) and rats with two-kidney, one clip hypertension (2K, 1C HT), using radioligand binding method. beta-Adrenoceptor concentration measured by [3H]-dihydroalprenolol (DHA) binding was significantly lower in cardiac membranes from two months old SHR than those from Wistar-Kyoto rats (WKY) (38.2 +/- 2.6 vs 45.1 +/- 1.8 fmol/mg protein, means +/- SEM, p less than 0.05). Cardiac membranes from 2K, 1C HT rats had also a lower concentration of beta-adrenoceptors than those from the sham-operated control rats at a week after operation (30.9 +/- 2.2 vs 47.8 +/- 1.6 fmol/mg protein, p less than 0.01). But receptor affinity remained unchanged. These reduced concentrations of beta-adrenoceptors were restored to control levels at 12 months old in SHR and at 6 weeks after operation in 2K, 1C HT rats, although age-dependent decrease in beta-adrenoceptor was observed. The decrease in beta-adrenoceptor was associated with increase in plasma noradrenaline levels during the earlier stages of hypertension. But there is no correlation between beta-adrenoceptor concentrations and plasma noradrenaline levels in the chronic stages of hypertension. No significant difference was found in activities of 5'-nucleotidase, which is a marker enzyme of cell membrane, in membrane fractions between the hypertensive hearts and the controls, suggesting that the cardiac hypertrophy is not a determinant factor for change in beta-adrenoceptor. The observed decrease in beta-adrenoceptor concentration may reflect an increase in sympathetic nerve activity during development of hypertension. In the chronic stages of hypertension, additional factors may be involved in the restoration of beta-adrenoceptors.

Decreased venous compliance in dogs with chronic renal hypertension.

Femoral vein (FV) pressure-volume relationships were measured in vitro in 14 dogs with chronic (more than 4 weeks), one-kidney perinephritic hypertension and in 13 unilaterally nephrectomized normotensive control dogs. Segments of FV were also examined histologically and analyzed for their water and electrolyte contents. Compared to controls: (I) the FV pressure-volume curves of hypertensive dogs were shifted toward the pressure axis (P is less than 0.05); (ii) calcaulated vagous compliance in the pressure range of 0-15 mm Hg was decreased (P is less than 0.05); and (iii) the water and sodium contents of vwins from hypertensive dogs were increased (P is less than 0.05). Histological examination of the FV from hypertensive and control dogs did not reveal significant differences. The findings indicate that the decreases in venous compliance that we have previously observed in the early stages (less than 4 weeks) of perinephritic hypertension in dogs persist into the chronic stage of hypertension. Venous wall "edema" may account for the decreased venous compliance in this form of hypertension.

Morphological studies on the autonomic nervous system of hypertensive rats. V. Various morphological observations on the superior cervical sympathetic ganglia of rats with experimentally induced hypertension.

1. Histometric, enzyme histochemical, and fluorescence and electron microscopic studies were performed on the superior cervical sympathetic ganglia of rats with experimentally induced hypertension and those of normotensive control rats. DOCA hypertension, renal infarction hypertension, and cerebral hypertension were induced in normotensive Wistar strain rats (with original blood pressures below 150 mmHg). The hypertensive animals were sacrificed and examined, some in the acute and some in the chronic stage of hypertension, and their ganglia were compared with those of normal controls. 2. The rats with DOCA implantation and l% saline ingestion developed sustained hypertension beginning after about three weeks of treatment and lasting till death (DOCA hypertension). The body weight of these animals was significantly lower than that of the controls through the experimental period. The rats with bilateral ligation of the posterior branches of the renal arteries became hypertensive within a few days after operation, and hypertension was maintained thereafter (renal infarction hypertension). The body weight of these animals was lower than that of the controls only in the acute stage. The rats with bilateral internal carotid artery dissection developed hypertension one week after operation (cerebral hypertension). It was slightly labile in the acute stage, but sustained in the chronic stage. No gross physical changes were found in this group. 3. Histometrically, the following findings were noted. The sympathetic ganglia of the rats with DOCA hypertension showed no remarkable changes in the acute stage, but the ganglia tended to increase in weight and the nerve cell bodies became significantly enlarged in the chronic stage. In the acute stage in rats with renal infarction hypertension, only the ganglia weighed more than those of the controls. However in the chronic stage, the weight and volume of the ganglia, and the size of the nerve cells and their nuclei, were significantly greater than those of the controls. The rats with cerebral hypertension in the acute stage had heavier ganglia and larger nuclei than normal rats. In the chronic stage, there was definite hypertrophy of both ganglia and neurons. 4. Enzyme histochemical findings were as follows.

Cardiovascular Effects of Acute and Chronic Stimulations of the Hypothalamic Defence Area in the Rat

AbstractIn experiments on rats long‐term intermittent stimulations of the hypothalamic defence area have been performed after that the characteristic responses to such stimulations had been explored in acute experiments. Weak topical stimulations of the defence area in rats induced an alerting response which was regularly accompanied by blood pressure and heart rate increases, increased muscle blood flow and decreased renal and gastrointestinal blood flows. When such weak intermittent stimulations of the hypothalamic defence area were continued for 12 hours daily during about four months the ‘resting’ blood pressure of a stimulated group of rats gradually rose, to become significantly different from that of a control group, which had been identically treated in all respects with exception of the intermittent hypothalamic stimulations. On the basis of these results it is discussed whether episodes of mental stress, which are often repeated during prolonged periods of time and which normally seem to excite the hypothalamic defence area, may act as an efficient “trigger” mechanism for gradually inducing a stage of chronic hypertension.