Propranolol-induced alterations in the pathophysiology of spontaneously hypertensive rats

Male and female, spontaneously hypertensive rats (SHR) were treated with propranolol (14 weeks) when they became 1, 4 and 8 months old prior to, during the steep ascent, and when severe high blood pressure becomes established. Propranolol prevented the usual increase in blood pressure at an early age but did not effectively lower blood pressure at all age levels. Propranolol-treated SHR manifested marked alterations in pituitary, adrenal, thymus, heart and gonadal weights. Despite progressively increasing hyperlipidemia and hyperglycemia, there were no significant differences between lipid, glucose, BUN, or serum enzyme levels in treated vs nontreated SHR. Circulating aldosterone and corticosterone levels were reduced in propranolol-treated SHR. Male SHR, treated or untreated, developed severe cardiovascular-renal lesions when they became 8 months old; none of the female SHR manifested any pathologic changes. It is suggested that the anti-hypertensive effects of propranolol were partially mediated by hormonal as well as by hemodynamic mechanisms.     

Age-related alterations in epicardial arteries of spontaneously hypertensive rats

Proximal portions of the left coronary arteries were examined microscopically in aging female normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). The age-related intimal alterations in SHR were largely limited to endothelial cells, which demonstrated a proliferation of organelles (most notably Weibel-Palade bodies). In the media, degenerative alterations appeared to be most marked near the medio-adventitial junction. Compared to WKY and increasing with age, the media of the SHR epicardial artery demonstrated an accumulation of extracellular elements that included basement membrane-like material, collagen fibers and debris. Complex carbohydrates, as determined with the silver methenamine reaction, were noted to accumulate in a lamellar fashion. Smooth muscle cells demonstrated an age-related tendency (which was exaggerated in SHR) toward development of invaginations and irregular profiles. These observations indicate that age-related structural alterations in epicardial arteries of SHR are progressive, and they support the concept that structural alterations in SHR coronary arteries may represent accelerated aging phenomena.     

Puberty and ovulatory release of gonadotropins in spontaneously hypertensive rats

The age at vaginal opening, estrous cyclicity, serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (PRL) on the day of proestrus, and number of ova and ovarian weight as measured on the day of estrus in spontaneously hypertensive (SH) and genetically matched normotensive Wistar Kyoto (WKY) female rats were compared. In SH rats, there was a significant delay in the vaginal opening, but the regular 4-day estrous cycle followed afterwards. No significant changes were observed in the afternoon increase in serum LH, FSH and PRL on the day of proestrus in SH and WKY rats, although the basal levels of LH and PRL in the morning (11:00 h) were lower in SH rats than in WKY rats. The mean number of ova in SH rats was also less than in WKY rats, whereas the ovarian relative weight was similar in both species of rats. It can be said that SH rats undergo certain, but not critical, endocrine and/or neuroendocrine changes related to reproduction.     

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.     

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.     

Reduced number of beta-adrenergic receptors in the myocardium of spontaneously hypertensive rats.

Inotropic response to β-adrenergic stimulation of the myocardium is decreased in hypertension. A biochemical basis for this decrease was provided by the observation that the number of β-adrenergic receptors — as reflected in specific [³H]dihydroalprenolol binding — was diminished in the myocardium of spontaneously hypertensive rats without a 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 and may be related to increased sympathetic drive in spontaneously hypertensive rats.     

Intact hindquarter vascular responses of young spontaneously hypertensive rats to norepinephrine and tyramine

Intact hindquarter vascular responses to abdominal aortic injections of subpressor doses of norepinephrine (0.01, 0.02, 0.03 μg) or tyramine (5, 10, 15 μg) were examined in young ($\text{2}\text{1}\text{2}\text{–3}\text{months}$) spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) normotensives to ascertain whether altered vascular response to catecholamines in SHR could be detected in the presence of relatively constant systemic arterial perfusion pressure. Increases in vascular resistance (Δ mmHg. min/ml) and total decreases in blood flow volume (Δ ml) were determined by using electromagnetic flowmetry and blood flow integration techniques. Under a resting condition the abdominal aortic flow rate (ml/min) was similar between the SHR (8.7 ± 0.5) and WKY control (9.1 ± 0.5), whereas hindquarter vascular resistance was greater (73.8%) in SHR than in WKY normotensives (P < 0.05). The increase in vascular resistance in response to a low dose of norepinephrine (0.1 μg) was greater (85%) in SHR than in WKY rats (P < 0.05) and at higher doses of norepinephrine (0.02, 0.03 μg) there was a tendency of greater increase in resistance (20–30%) in SHR (0.05 < P < 0.1). Tyramine at all doses tested produced greater increases (50–66%) in resistance in SHR compared to WKY normotensives (P < 0.05). On the other hand, the decreases in the integrated total blood flow volume passing to the hindquarters after norepinephrine or tyramine administration at all doses were less (27–46%) in SHR than in WKY control (P < 0.05). The data demonstrate increased catecholamine vasoconstrictor responses in the intact hindquarters of SHR with attenuated blood flow volume decreases due to the higher resting vascular resistance, supporting the contention that the elevated vascular resistance in SHR may be attributed to vasoconstrictor hyperresponsiveness of catecholamines.     

Receptor autoradiography of mu and delta opioid peptide receptors in spontaneously hypertensive rats.

The receptor autoradiographic distribution of opioid peptide receptors in spontaneously hypertensive rats (SHR) was compared to that of Sprague-Dawley (SD) rats, using the highly selective mu and delta opioid receptor ligands, [3H]DAGO (Tyr-D-Ala-Gly-NMe-Phe-Gly-ol) and [3H]DPDPE ([D-Pen2,D-Pen5]enkephalin), respectively. Although the distribution of these binding sites was similar in both strains, SHR showed significantly higher binding densities of mu receptors in 16 of 27 areas examined. These included the patch and matrix components of the caudate-putamen (CPu), olfactory tubercle, endopiriform nucleus, anterior cingulate cortex, ventral tegmental area lateroposteral thalamic nucleus and the ventral part of the dentate gyrus. In contrast, SHR had lower [3H]DAGO binding sites in the CA1 of the hippocampus. Conversely, SHR showed higher binding densities of delta receptors in 7 of 20 areas examined, including the CPu, CA2 and CA3 areas of the hippocampus and the central grey. High-to-low lateromedial gradients of striatal delta receptors were observed in both strains. Because opioid peptides are known to participate in locomotive behavior in rodents and in the control of blood pressure, the present results support a role of opioid peptidergic systems in the manifestation of hyperactivity and hypertension observed in SHR.     

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.     

Pathological alterations of astrocytes in stroke-prone spontaneously hypertensive rats under ischemic conditions

Stroke-prone spontaneously hypertensive rats (SHRSP/Izm) develop severe hypertension, and more than 95% of them die of cerebral stroke. We showed the vulnerability of neuronal cells of SHRSP/Izm rats. Furthermore, we analyzed the characteristics of SHRSP/Izm astrocytes during a stroke. It is known that the proliferating ability of SHRSP/Izm astrocytes is significantly enhanced compared with those in the normotensive Wistar Kyoto rats (WKY/Izm) strain. Conversely, the ability of SHRSP/Izm astrocytes to form tight junctions (TJ) was attenuated compared with astrocytes from WKY/Izm rats. During the stress of hypoxia and reoxygenation (H/R), lactate production, an energy source for neuronal cells, decreased in SHRSP/Izm astrocytes in comparison with the WKY/Izm strain. Moreover, during H/R, SHRSP/Izm astrocytes decreased their production of glial cell line-derived neurotrophic factor (GDNF) in comparison with WKY/Izm astrocytes. Furthermore, SHRSP/Izm rats decreased production of l-serine, compared with WKY/Izm rats following nitric oxide (NO) stimulation. Additionally, in H/R, astrocytes of SHRSP/Izm rats expressed adhesion molecules such as VCAM-1 at higher levels.It is possible that all of these differences between SHRSP/Izm and WKY/Izm astrocytes are not associated with the neurological disorders in SHRSP/Izm. However, attenuated production of lactate and reduced GDNF production in astrocytes may reduce required energy levels and weaken the nutritional status of SHRSP/Ism neuronal cells. We suggest that the attenuation of astrocytes’ functions accelerates neuronal cell death during stroke, and may contribute to the development of strokes in SHRSP/Izm. In this review, we summarize the altered properties of SHRSP/Izm astrocytes during a stroke.     

Selective proliferation of brain kappa opiate receptors in spontaneously hypertensive rats

The binding of tritiated ligands for various opiate receptor subtypes to brain membranes prepared from spontaneously hypertensive rats and normotensive Wistar-Kyoto rats was determined. The density (Bmax) or the apparent dissociation constant (Kd) for the binding of the mu-ligand (naltrexone) and delta-ligand (Tyr-D-Ser-Gly-Phe-Leu-Thr) to brain membranes of hypertensive and normotensive rats did not differ. However, the Bmax for the binding of kappa-ligand (ethylketocyclazocine, EKC) to brain membranes after the suppression of mu and delta-sites by 100 nM each of unlabeled D-Ala2-MePhe4-Gly-ol5-enkephalin and D-Ala2-D-Leu5-enkephalin, respectively, was significantly greater in hypertensive rats compared to normotensive rats. The Kd values for the binding of 3H-EKC in the two groups did not differ. The binding of 3H-EKC in brain regions was in the order: hypothalamus greater than midbrain greater than striatum greater than cortex greater than pons + medulla. The increase in the binding of 3H-EKC in the brain of hypertensive rats compared to normotensive rats was due to increased binding in the hypothalamus and cortex. These results provide for the first time evidence of selective proliferation of kappa-opiate receptors in the brain of hypertensive rats, and suggest that brain kappa-opiate receptors may play an important role in the pathophysiology of hypertension.     

In spontaneously hypertensive rats alterations in aortic wall properties precede development of hypertension

In hypertension arterial wall properties do not necessarily depend on increased blood pressure alone. The present study investigates the relationship between the development of hypertension and thoracic aortic wall properties in 1.5-, 3-, and 6-mo-old spontaneously hypertensive rats (SHR); Wistar-Kyoto rats (WKY) served as controls. During ketamine-xylazine anesthesia, compliance and distensibility were assessed by means of a noninvasive ultrasound technique combined with invasive blood pressure measurements. Morphometric measurements provided in vivo media cross-sectional area and thickness, allowing the calculation of the incremental elastic modulus. Extracellular matrix protein contents were determined as well. Blood pressure was not significantly different in 1.5-mo-old SHR and WKY, but compliance and distensibility were significantly lower in SHR. Incremental elastic modulus was not significantly different between SHR and WKY at this age. Media thickness and media cross-sectional area were significantly larger in SHR than in WKY, but there was no consistent difference in collagen density and content between the strains. Blood pressure was significantly higher in 3- and 6-mo-old SHR than in WKY, and compliance was significantly lower in SHR. The findings in this study show that in SHR, in which hypertension develops over weeks, alterations in functional aortic wall properties precede the development of hypertension. The decrease in compliance and distensibility at a young age most likely results from media hypertrophy rather than a change in intrinsic elastic properties.     

Vasopressin receptors and inositol trisphosphate production in blood vessels of spontaneously hypertensive rats

To understand the regulation of vasopressin (AVP) receptors in spontaneous hypertension, we investigated the pressor response of AVP in the perfused mesenteric vasculature, AVP binding sites in the membrane preparation of the same vascular bed, and the production of inositol trisphosphate (InsP3) stimulated by AVP in the aorta of spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), and Wistar rats (WR) at different ages (4-16 weeks). Plasma AVP concentrations were similar in SHR, WKY, and WR at all ages. The density of AVP vascular binding sites was significantly higher in WKY than in SHR and WR at 12 weeks. Receptor affinity was similar in all strains. The pressor response of the mesenteric vasculature to AVP was similar in the three strains of rats at 4 weeks (prehypertensive stage) and increased progressively in SHR compared with WKY and WR at 8 and 12 weeks of age by 43 and 35%, respectively, and by more than 80% at 16 weeks of age (established hypertensive stage). There was no difference in vascular sensitivity to AVP. A significantly increased pressor response to a supramaximal dose of norepinephrine was also found at 16 weeks in SHR, but not in younger rats. InsP3 production in the aorta in response to AVP was increased in SHR at 8, 12, and 16 weeks, compared with WKY and WR. These results suggest that the vascular response to AVP is increased in SHR, in spite of decreased or normal density of binding sites compared with WKY or WR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise training increases acetylcholine-stimulated endothelium-derived nitric oxide release in spontaneously hypertensive rats

This study investigated the effects of exercise training on the regional release of endothelium-derived nitric oxide (EDNO) in spontaneously hypertensive rats (SHR). Male SHR and Wistar-Kyoto rats were divided into control and training groups, respectively. The training groups received moderate exercise by running on a drum exerciser for 60 min/day, 5 days/week for 10 weeks. At the end of experiments, thoracic aortae and common carotid arteries were excised. Acetylcholine (ACh)-induced relaxing responses due to EDNO release were evaluated in the presence of indomethacin. Vascular relaxing responses to A23187 or to sodium nitroprusside (SNP) were also studied. Our results indicated that after training, (1) the vascular sensitivity of thoracic aortae to ACh-induced relaxation was elevated when indomethacin was present; this effect was absent in the common carotid artery and it was abolished by adding N-nitro-L-arginine, and (2) no significant changes in SNP- or A23187-induced vascular relaxing responses, both being nonreceptor-mediated processes, were observed. We can conclude that for both hypertensive and normotensive rats, exercise training may increase receptor-mediated agonist-stimulated EDNO release in the thoracic aorta, but not in the common carotid artery.