Reduced number of adrenal angiotensin II receptors in the spontaneously hypertensive rat

[¹²⁵I]angiotensin II binding to adrenal subcellular particles was compared between spontaneously hypertensive and Wistar-Kyoto normotensive control rats. The number of angiotensin II receptors was reduced in adrenals of spontaneously hypertensive rats (P < 0.05) without a change in the affinity of angiotensin II for the binding sites at animal ages of 5, 10 and 15 weeks. This decline of receptor content antedated the abrupt rise in blood pressure noted between 5 and 10 weeks. The data suggest the presence of an alteration of the receptor number in the renin-angiotensin- aldosterone system in the spontaneously hypertensive rat.     

Increased number of beta-adrenergic receptors in the hypertrophied myocardium.

Development of cardiac hypertrophy is associated with depletion of endogenous catecholamine stores and increased inotropic response to exogenous catecholamines. A biochemical basis for these changes is provided by the observation that the number of cardiac beta-adrenergic receptors - as reflected in specific [3H]dihydroalprenolol binding - is increased in hypertrophy without a change in the affinity of dihydroalprenolol for the binding sites or in the capacity of isoproterenol to displace dihydroalprenolol. This change in beta-receptor numbers may be an important adaptive mechanism for preserving the contractile performance of the hypertrophied myocardium.     

Decreased number of beta-adrenergic receptors in hypertensive vessels.

Responsiveness to inotropic agents is altered in hypertension and may contribute to its initiation and maintenance. A biochemical basis for this change was provided by the observation that the number of beta-adrenergic receptors, as reflected in specific [3H]dihydroalprenolol binding, was diminished in both arteries and veins of spontaneously hypertensive rats. There was no change in the affinity of dihydroalprenolol for the binding sites or in the capacity of isoproterenol to displace dihydroalprenolol. The decline in beta-adrenergic receptor numbers is not secondary to blood pressure elevation but may, instead, contribute to the pathogenesis of hypertension.     

Decreased number of beta-adrenergic receptors in hypertensive vessels

Responsiveness to inotropic agents is altered in hypertension and may contribute to its initiation and maintenance. A biochemical basis for this change was provided by the observation that the number of β-adrenergic receptors, as reflected in specific [³H]dihydroalprenolol binding, was diminished in both arteries and veins of spontaneously hypertensive rats. There was no change in the affinity of dihydroalprenolol for the binding sites or in the capacity of isoproterenol to displace dihydroalprenolol. The decline in β-adrenergic receptor numbers is not secondary to blood pressure elevation but may, instead, contribute to the pathogenesis of hypertension.     

Ontogenetic development of isoproterenol subsensitivity of myocardial adenylate cyclase and beta-adrenergic receptors in spontaneously hypertensive rats

[3H]Dihydroalprenolol binding and adenylate cyclase activity in the myocardial membranes of Kyoto Wistar normotensive rats and spontaneously hypertensive rats were compared at various stages of postnatal development ranging from 2 to 36 weeks. Basal as well as agonist-stimulated myocardial adenylate cyclase activity was consistently decreased in spontaneously hypertensive rats as compared to normotensive rats as early as 2 weeks of age with significant differences (P < 0.05) observed after 6 weeks of age. When results were expressed as percent stimulation over the basal activity, only isoproterenol plus GTP-stimulated enzyme activity was reduced by 25--30% in spontaneously hypertensive rats, suggesting a specific loss of stimulation by isoproterenol in hypertensive animals. The number of [3H]dihydroalprenolol binding sites of KD for dihydroalprenolol binding were comparable between spontaneously hypertensive and normotensive rats at 3, 6 and 12 weeks of age. The competition of isoproterenol with [3H]dihydroalprenolol for the specific binding sites showed that the affinity of isoproterenol binding was decreased 3--4-fold in spontaneously hypertensive compared with normotensive rats. With postnatal development in age, basal as well as agonist-stimulated activities decreased progressively in both spontaneously hypertensive and normotensive rats. Similarly, the number of [3H]dihydroalprenolol binding sites decreased with the development in age, whereas affinity of dihydroalprenolol binding increased up to 12 weeks of age. These results therefore suggest that adenylate cyclase activity and the number of beta-adrenergic receptors in rat heart, decrease with age and that in hypertension, specific decrease in isoproterenol stimulation of cyclase appears at all stages of development.     

Amlodipine preserves the glomerular number in spontaneously hypertensive rats

The calcium channel blockers have individual pharmacological and therapeutic properties that may vary, but as a group, they are effective antihypertensive agents in patients with renal disease. Their effects on the kidney may extend beyond BP reduction alone. Fifteen one-year-old male spontaneously hypertensive rats (SHR) were separated in three groups: Initial control group (IC), Final control group (FC, SHR received standard rat chow and fresh water ad libitum during 15 weeks), Amlodipine group (Aml, SHR) received 0.2 mg/kg/day of amlodipine in addition to food and water during 15 weeks. The glomerular number was estimated using the disector method. In the Control group, the BP level increased almost 20 per cent in the first six weeks (from 186 +/- 11 to 223 +/- 16 mmHg, p<0.01) and then BP level increased almost 15 percent until week 15 (from 223 +/- 16 to 258 +/- 20 mmHg, p<0.01). In the same period, the Aml group showed a progressively low BP, reaching a level almost 50 per cent lower in the week 15 than in the week 1 (from 190 +/- 15 to 101+/-8 mmHg, p<0.01). Amlodipine treatment significantly decreased the serum creatinine, more than 12 per cent lower than the FC group (from 70.4 +/- 6.2 to 61.4 +/- 5.2 micromol/L, p<0.05). However, proteinuria was not different when groups were compared. The FC group reached a glomerular number almost 20 percent smaller than the IC and Aml groups (from 35 x 10(3) +/- 7 x 10(3) in IC group, 34 x 10(3) +/- 4 x 10(3) in Aml group to 27 x 10(3) +/- 3 x 10(3) in FC group, p<0.05). A possible protective effect of amlodipine against the loss of glomeruli in SHR is a major additional action of amlodipine in the treatment of hypertension mainly when the renal lesion already exists.     

Photon radiation-induced structural and functional changes in the myocardium of hypertensive spontaneously hypertensive rats

Hypertensive SHR rates were irradiated with orange-red light using a Korobkov photon light-emitting diode matrix with a maximum radiation at 612 nm; irradiation was performed daily for 1 h for 13 days. After the course of irradiation, the rhythmoinothropic characteristics of the cardiac papillary muscle significantly improved. Morphological analysis revealed active rearrangement in myocytes, which were observed primarily in the structure of the sarcoplasmic reticulum (SR), whose relative area increased more than twice compared to the control. Apparently, photon therapy of hypertensive rats normalizes calcium homeostasis in myocytes and improves the calcium-transport function of SR. The normalization of structural and functional characteristics of the myocardium with hypertensive rates may result from an increase in the SR buffer capacity and activation of SR Ca²⁺-ATPase. Furthermore, qualitative and quantitative changes in the proportion of capillaries, myofibrils, and mitochondria in myocytes indicate the development of adaptive-compensatory processes leading to the activation of biosynthetic processes and an increase in the energy potential of the myocardium.     

Down-regulation of endothelin receptors in the ventrolateral medulla of spontaneously hypertensive rats.

The binding of [125I] sarafotoxin 6b (SRT 6b) and [125I] endothelin-1 (ET-1) to endothelin (ET) receptors of neuronal membranes prepared from cerebral cortex and ventrolateral medulla of 8 week old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats was determined. [125I] SRT 6b bound to the membranes of cerebral cortex and ventrolateral medulla at a single high affinity site. The binding of [125I] SRT 6b in the cerebral cortex was found to be similar in SHR and WKY rats. However, in the ventrolateral medulla [125I] SRT 6b binding was found to be significantly lower in SHR as compared to WKY rats. The decreased binding was due to decrease (48%) in the Bmax values in SHR rats as compared to WKY rats. The Kd values were similar in SHR and WKY rats. [125I] ET-1 also bound to the membranes of cerebral cortex and ventrolateral medulla at a single high affinity site. The binding of [125I] ET-1 in the cerebral cortex was found to be similar in SHR and WKY rats. However, in the ventrolateral medulla [125I] ET-1 binding was found to be significantly lower in SHR as compared to WKY rats. The decreased binding was due to 36% decrease in the Bmax values in SHR rats as compared to WKY rats. The Kd values were similar in SHR and WKY rats. It is concluded that the population of ET receptors is less in the ventrolateral medulla of SHR rats and may be contributing to the regulation of blood pressure.     

Lower number of atrial natriuretic peptide receptors in thymocytes and spleen cells of spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) have a much lower number of atrial natriuretic peptide (ANP) receptors in thymus and spleen from young and adult animals than age-matched normotensive controls. In spite of this low receptor concentration, the ANP-stimulated cyclic GMP response in isolated thymocytes and spleen cells from SHR was similar to that of normotensive control rats. Alterations in ANP receptor concentration in thymus and spleen of SHR may be related to the immune abnormalities described in these animals, and to the pathophysiology of genetic hypertension.     

Lipolysis and beta-adrenergic receptor binding on adipocytes of spontaneously hypertensive rats

Adipocytes from spontaneously hypertensive rats demonstrated a blunted lipolytic response to isoproterenol and dibutyryl cyclic AMP. (-)-[3H]Dihydroalprenolol binding was examined in adipocytes from normotensive and spontaneously hypertensive rats. Increasing concentrations of isoproterenol decreased total (-)-[3H]dihydroalprenolol binding to intact cells from normotensive rats, and the efficacy of competition was decreased in adipocytes from spontaneously hypertensive rats. Scatchard analysis indicated that the number of (-)-[3H]dihydroalprenolol binding sites and the affinity of dihydroalprenolol binding were comparable between normotensive and spontaneously hypertensive rats. Isoproterenol- and Gpp(NH)p-stimulated adenylate cyclase activity was consistently depressed in adipocyte membranes from spontaneously hypertensive rats as compared to normotensive rats. No difference in fluoride-stimulated adenylate cyclase activity was observed. The blunted lipolytic and cyclic AMP response to isoproterenol in these cells suggest a postreceptor lesion of the lipolytic pathway (possibly the guanine nucleotide regulatory protein) in adipocytes from spontaneously hypertensive rats. The blunted lipolytic response to dibutyryl cyclic AMP suggests defective regulation of lipolytic enzymes at the protein kinase-hormone-sensitive lipase level.     

Brain somatostatin receptors in spontaneously hypertensive rats: an autoradiographic study.

The apparent densities of brain somatostatin (SRIF) receptor sites were compared in adult spontaneously hypertensive rats (SH) and their normotensive genetic counterparts (Wistar-Kyoto; WKY) using quantitative receptor autoradiography. Globally, the distribution of brain [125I][Tyr0, D-Trp8]SRIF14 binding sites was very similar in both strains. However, apparent densities of specific labeling were either higher (subfornical organ, 3.2 x; locus coeruleus, 1.9 x; lateroanterior hypothalamic nucleus, 1.3 x) or lower (basolateral amygdaloid nucleus, 0.8 x; spinal trigeminal sensory nucleus, 0.6 x) in SH than WKY rats in areas especially relevant to CNS cardiovascular integration. This provides further evidence for the possible involvement of brain SRIF neurons in cardiovascular regulation.     

Susceptibility to systolic dysfunction in the myocardium from chronically infarcted spontaneously hypertensive rats

We explored whether the hypertensive heart is susceptible to myocardial dysfunction in viable noninfarcted tissue post-myocardial infarction (MI), the potential mechanisms thereof, and the impact of these changes on pump function. Six to seven months after the ligation of the left anterior descending coronary artery, left ventricular (LV) myocardial systolic function, as assessed from the percent shortening of the noninfarcted lateral wall segmental length determined over a range of filling pressures (ultrasonic transducers placed in the lateral wall in anaesthetized, open-chest, ventilated rats) and the percent thickening of the posterior wall (echocardiography), was reduced in infarcted spontaneous hypertensive rats (SHR-MI) (P < 0.05) but not in normotensive Wistar-Kyoto (WKY-MI) animals compared with corresponding controls [SHR-sham operations (Sham) and WKY-Sham]. This change in the regional myocardial function in SHR-MI, but not in WKY-MI, occurred despite a similar degree of LV dilatation (increased LV end-diastolic dimensions and volume intercept of the LV end-diastolic pressure-volume relation) in SHR-MI and WKY-MI rats and a lack of difference in LV relative wall thinning, LV wall stress, apoptosis [terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling (TUNEL)], or necrosis (pathological score) between SHR-MI and WKY-MI rats. Although the change in regional myocardial function in the SHR-MI group was not associated with a greater reduction in baseline global LV chamber systolic function [end-systolic elastance (LV E(es)) and endocardial fractional shortening determined in the absence of an adrenergic stimulus], in the presence of an isoproterenol challenge, noninfarct-zone LV systolic myocardial dysfunction manifested in a significant reduction in LV E(es) in SHR-MI compared with WKY-MI and SHR and WKY-Sham rats (P < 0.04). In conclusion, these data suggest that with chronic MI, the hypertensive heart is susceptible to the development of myocardial dysfunction, a change that cannot be attributed to excessive chamber dilatation, apoptosis, or necrosis, but which in turn contributes toward a reduced cardiac adrenergic inotropic reserve.     

Minireview. Presynaptic receptors and alterations in norepinephrine release in spontaneously hypertensive rats

The ability of blood vessels to constrict to a given stimulus is significantly increased in spontaneously hypertensive rats (SHR). Such an increase in the vasoconstrictor responsiveness contributes to the elevated peripheral vascular resistance noted in SHR. The present review discusses evidence in support of the concept that an increased release of norepinephrine during sympathetic nerve stimulation may contribute to the increase in vasoconstrictor responsiveness and, subsequently, to an increase in vascular resistance in the SHR. Several studies suggest that the exocytotic release of norepinephrine from sympathetic nerves may be altered by endogenously occurring neurohumoral substances which produce their effects by interacting with presynaptic receptors located on postganglionic sympathetic nerves. Therefore, it is postulated that alterations in presynaptic regulation of norepinephrine release, resulting from changes in the functioning of one or more of these presynaptic receptors, may lead to a greater release of norepinephrine in the SHR. This review summarizes the results of studies evaluating presynaptic receptor mechanisms and norepinephrine release in the SHR. These studies suggest that norepinephrine release during sympathetic nerve stimulation is greater in the SHR and that alterations in some of the presynaptic receptor mechanisms may be responsible for this phenomenon.     

Skeletal muscle adaptation to physical training and beta-adrenergic blockade in spontaneously hypertensive rats

The effects of training alone or in combination with long-term, non-selective, beta-adrenergic blockade on histochemical and biochemical properties of fast-twitch [extensor digitorum longus muscle (EDL)] and slow-twitch [soleus muscle (Sol)] muscle were analyzed in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto strain rats (WKY). Fiber type distribution of Sol was drastically modified in SHR with fewer type I fibers and more type IIA fibers. No such histochemical alterations were observed in EDL. While prolonged swimming training remained ineffective in inducing both histochemical and biochemical improvement in WKY, SHR displayed a significant enhancement of capillarization and oxidative capacity in both Sol and EDL. However, in long-term beta-blocks rats training failed to improve significantly the oxidative capacity of SHR muscles, suggesting that beta-adrenoreceptor stimulation is necessary for a fully efficient adaptation of muscular metabolism to physical training.     

Relative systolic dysfunction in female spontaneously hypertensive rat myocardium.

Hypertension and exercise independently induce left ventricular (LV) remodeling and alter LV function. The purpose of this study was to determine systolic and diastolic LV pressure-volume relationships (LV-PV) in spontaneously hypertensive rats (SHR) with and without LV hypertrophy, and to determine whether 6 mo of exercise training modified the LV-PV in SHR. Four-month-old female SHR (n = 20), were assigned to a sedentary (SHR-SED) or treadmill-trained (SHR-TRD) group (approximately 60% peak O2 consumption, 5 days/wk, 6 mo), while age-matched female Wistar-Kyoto rats (WKY; n = 13) served as normotensive controls. The LV-PV was determined using a Langendorff isolated heart preparation at 4 (no hypertrophy: WKY, n = 5; SHR, n = 5) and 10 mo of age (hypertrophy: WKY, n = 8; SHR-SED, n = 8; SHR-TRD, n = 7). At 4 mo, the LV-PV in SHR was similar to that observed in WKY controls. However, at 10 mo of age, a rightward shift in the LV-PV occurred in SHR. Exercise training did not alter the extent of the shift in the LV-PV relative to SHR-SED. Relative systolic function, i.e., relative systolic elastance, was approximately 50% lower in SHR than WKY at 10 mo of age (P < 0.05). Doppler-derived LV filling parameters [early wave (E), atrial wave (A), and the E/A ratio] were similar between groups. LV capacitance was increased in SHR at 10 mo (P < 0.05), whereas LV diastolic chamber stiffness was similar between groups at 10 mo. Hypertrophic remodeling at 10 mo of age in female SHR is manifest with relative systolic decompensation and normal LV diastolic function. Exercise training did not alter the LV-PV in SHR.     

Expression of titin in the myocardium of spontaneously hypertensive rats during development of hypertrophy

Changes in the expression of titin N2B and N2BA isoforms in the left ventricle of the heart of spontaneously hypertensive rats during the development of hypertrophy have been analyzed by the methods of real-time polymerase chain reaction and SDS gel electrophoresis. It was shown that, in early terms of development of hypertrophy (15-week-old rats), an increase in the expression of mRNA of the titin gene and a decrease in the content of the protein itself occur. At a later stage of development (26-week-old rats), a decrease in the expression of titin at the level of both mRNA and protein was observed. The results obtained can be used in the development of methods for diagnosing the development of myocardial hypertrophy.     

Renal microvasculature in spontaneously hypertensive rats.

The renal microvasculature was studied in normotensive rats and in rats with spontaneous hypertension. The microvascular pattern was normal in both groups of animals, suggesting normal renin secretion. This may or may not indicate a role for renin in the cause of spontaneous hypertension.