Sex hormones change adrenoceptors in blood vessels of the spontaneously hypertensive rat.

In this study we investigated how male sex hormones, which increase blood pressure in the spontaneously hypertensive rat (SHR), affect adrenergic receptors in the cardiovascular system. Testosterone treatment significantly increased blood pressure in male SHRs (P < 0.05). Testosterone treated male SHRs also showed a significant increase (P < 0.05) in total apparent numbers of alpha 1 adrenoceptors in tail artery preparations as compared to controls. Gonadectomy attenuated blood pressure and caused a decrease in the total apparent number of alpha 1 adrenoceptors in tail artery preparations (P < 0.05). Testosterone replacement therapy in these gonadectomized rats reversed this decrease in apparent number of alpha 1 adrenoceptors to control values. KD values for dihydroalprenolol, isoproterenol, prazosin and norepinephrine were not significantly different between treatment groups. These results indicate that sex hormones (androgens) modulate numbers of alpha 1 adrenoceptors in the cardiovascular system of the male SHR.

Intracoronary PGE2 and veratrine inhibits renin release in conscious dogs via chemosensitive ventricular afferents.

1. Prostaglandins (PG) and veratrum alkaloids stimulate ventricular sensory receptors with non-myelinated vagal afferents and mediate inhibitory circulatory responses. 2. The present study in conscious instrumented dogs was carried out to determine the effects of intracoronary artery infusions of veratrine (Ver-IC) and PGE2 (PGE2-IC) on plasma renin activity (PRA). 3. A 15-20 mmHg decrease in arterial pressure was produced during Ver-IC (0.2-0.8 micrograms/kg per min) and PGE2-IC (10-50 ng/kg per min), but there was no change in PRA or heart rate. 4. In contrast, significant increases in PRA (+3.51 +/- 0.37 ng angiotensin I/mL per h; P less than 0.01) and heart rate (+38.5 +/- 6.2 beats/min; P less than 0.001) were elicited in response to a 15-20 mmHg decrease in arterial pressure produced by intravenous infusions of nitroprusside. 5. Pharmacological blockade of afferent fibres in the pericoronary region of the left main coronary artery during Ver-IC resulted in significant hypotension-induced increases in PRA (P less than 0.001) and heart rate (P less than 0.001), thus removing the inhibitory influence of chemosensitive ventricular afferents. 6. Therefore, intracoronary veratrum alkaloids and prostaglandins inhibit hypotension-induced increases in PRA and heart rate in the conscious dog. This is mediated by chemosensitive receptors located in the left ventricular myocardium along with afferent nerves in the pericoronary region and cervical vagi.

Serum magnesium increases following severe hemorrhage in dogs blocked by verapamil treatment.

The opening of voltage sensitive calcium channels is an important event in the progression of irreversible shock, allowing the entry of toxic amounts of calcium (Ca2+) into the cells. Because intracellular magnesium (Mg2+) can efflux through these same channels, changes in serum Mg2+ may reflect the patency of these channels. In this study, electrolytes and selected serum enzymes were monitored in chronically instrumented conscious dogs to follow the progression of shock following a fixed volume hemorrhage. Plasma enzymes indicative of liver damage were elevated only in the terminal phase of hemorrhagic decompensation. A significant increase in serum Mg2+ was evident 60 min following hemorrhage, even though arterial pressure was still recovering. Serum Mg2+ continued to rise throughout the recovery and decompensating phases of shock. Verapamil treatment, which increased survival time and survival rate, significantly attenuated the changes in serum Mg2+ which normally followed hemorrhage. These results indicate that serum Mg2+ may be a useful indicator of the severity and the progression of hemorrhagic shock.

Verapamil treatment of canine hemorrhagic shock.

The entry of calcium (Ca++) into ischemic cells is the first of a series of steps leading to irreversible cellular damage. This study examined the ability of verapamil, which may delay or diminish the injury-induced influx of Ca++, to prolong survival in three groups of chronically instrumented dogs subjected to a single, rapid hemorrhage. In untreated animals (group 1, N = 6), hemorrhage decreased mean arterial blood pressure from 101 +/- 3 mm Hg to 23 +/- 2 mm Hg. Following hemorrhage, arterial pressure recovered to 61 +/- 5 mm Hg before the secondary fall (decompensation) occurred. As decompensation progressed, arterial pressure fell to 25 mm Hg, and the animals were euthanized. In group 2 (N = 6), verapamil treatment (2 mg bolus, 1 mg/hr infusion) was initiated 30 minutes before the hemorrhage. This treatment significantly increased both the time to decompensation (184 +/- 15 minutes vs 72 +/- 9 minutes) and survival time (262 +/- 20 minutes vs 128 +/- 8 minutes). Arterial pressure recovery during the first 60 minutes following hemorrhage, however, was not affected by the verapamil pretreatment. Verapamil treatment immediately after the hemorrhage (group 3, N = 4) increased the survival rate to 75% (three of four animals). These results indicate that calcium channel blockade may be a useful initial intervention in the treatment of hemorrhagic shock.

The effects of estradiol and mestranol on alpha-adrenoceptors in select regions of the rat brain.

The role of estrogens in modulating the concentration of CNS alpha-adrenoceptors has not been elucidated nor has it been determined how different estrogenic compounds affect these receptors. In this study brain alpha-1 and alpha-2-adrenoceptor binding was measured in female rats treated with estradiol and/or the synthetic estrogen mestranol. Rats treated biweekly for 12 weeks with mestranol (50 micrograms/100 g b.wt.) had a significant reduction in the apparent number of alpha-2-adrenoceptors in the frontal cortex and nucleus tractus solitarius (NTS), while apparent numbers of both alpha-1 and alpha-2-adrenoceptors were depressed in the locus coeruleus. Estradiol treatment (50 micrograms/100 g b.wt.) caused a significant elevation in apparent alpha-1-adrenoceptor numbers in the NTS relative to control. Alpha-adrenoceptor numbers in the rostral and caudal hypothalamus were not affected by either steroid treatment. These results suggest that regulation of apparent numbers of alpha-1 and alpha-2-adrenoceptors in the CNS depends on the type of estrogen used for treatment.

Single hemorrhage: a clinically relevant canine model of hemorrhagic shock.

Clinically encountered hemorrhagic shock is usually caused by a single, rapid hemorrhage secondary to trauma. Experimental models of shock, however, have utilized anesthetic agents and hemorrhage protocols which may compromise the clinical relevance of their findings. This report characterizes the response of conscious, splenectomized dogs to a single hemorrhage of varying rates and volumes, uncomplicated by the presence of anesthetic agents. The duration of a 40 ml kg-1 hemorrhage affected the magnitude of blood pressure recovery, but did not alter the decompensating drop in blood pressure. The shortest hemorrhage duration was chosen for further study, as the blood pressure profile for this hemorrhage duration demonstrated most clearly the recovery, plateau, and decompensation phases. Increasing the hemorrhage volume to 43 ml kg-1 caused a reproducible decrease in the magnitude of the blood pressure recovery, the time to decompensation, and the time to death. Splenectomized dogs, then, demonstrate a reproducible response to a fixed-volume hemorrhage, making chronically instrumented conscious dogs a good animal model with which to study the progression of hypovolemic shock.

Endothelium-dependent relaxation in estrogen-treated spontaneously hypertensive rats.

Female spontaneously hypertensive rats (SHR) were injected subcutaneously with mestranol twice a week for 12 weeks. Isolated segments of thoracic aorta were then used to generate relaxation response curves to acetylcholine or ATP after precontraction with phenylephrine. Estrogen treatment attenuated the development of hypertension. Further, augmented endothelium-dependent relaxation to acetylcholine was seen in the estrogen-treated SHR. There was no difference, however, in the relaxation produced by ATP. Since the relaxation of both acetylcholine and ATP is endothelium-dependent, these findings suggest that different mechanisms may be involved in the relaxation produced by acetylcholine and ATP.

Prevention of "irreversible" hemorrhagic shock by the preservation of cellular integrity.

The clinically encountered state of hypovolemic shock results from a series of metabolic and cardiovascular responses to tissue hypoperfusion. Recent advances have increased our understanding of the consequences of tissue hypoxia, and identified at the cellular level those changes which cause the damage to be "irreversible", or refractory to treatment. To be successful, therapeutic interventions should be designed to 1) limit, if not reverse, the subcellular alterations in membrane stability and mitochondrial function which herald the transition from compensated to decompensated shock, and 2) re-hydrate the individual to restore normal circulatory dynamics and to prevent further cellular damage. It is proposed that calcium channel blocking agents and/or high energy phosphate compounds may delay the positive feedbacks which cause irreversible tissue damage, and thus may be useful initial interventions in the treatment of hypovolemic shock.

Myocardial adrenergic receptors and adenylate cyclase in the developing spontaneously hypertensive rat.

Cardiac membrane preparations from developing spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (0 to 125 days of age) were analyzed for the apparent numbers of alpha- and beta-adrenergic receptors and adenylate cyclase activities in an attempt to correlate biochemical changes with the reported functional changes occurring with the development of hypertension in the SHR. Although the apparent number of alpha- and beta-adrenergic receptors were similar in both strains of rats, isoproterenol-stimulated adenylate cyclase activities were significantly higher (P less than 0.05) in the prehypertensive SHRs when compared to WKY rats and declined to lower values as hypertension appeared. The percent stimulation produced by isoproterenol remained similar in cardiac membranes from normotensive WKY rats at all ages of development whereas this percent stimulation was 40% higher at birth in the SHRs and declined to approximately one half the original value by 100 days of age (P less than 0.05). The elevated adenylate cyclase activity observed during the prehypertensive state may contribute to the genesis of hypertension.

Isoproterenol-induced cardiac failure in the spontaneously hypertensive rat.

Thirty-one age-matched, conscious, virgin, male Sprague-Dawley rats and spontaneously hypertensive rats (SHRs) were individually injected with a single subcutaneous dose of 85 mg/kg dl-isoproterenol to determine the degree and time course of drug-induced cardiac failure and functional recovery. At 24 hr and 1 week postisoproterenol, rats were anesthetized and prepared for the recording of cardiac output and arterial pressure. Calculated cardiac index was used to determine normal cardiac function. Following that measurement, a 2-min, 15.3 ml/min infusion of Tyrode's solution was performed via a right jugular vein cannula. Volume-loaded peak-cardiac outputs and peak stroke volumes were also used as indices of cardiac function. Twenty-four hours after the injection of isoproterenol to he normotensive Sprague-Dawley rats, cardic failure was evident only during the stress of volume loading. Normal cardiac index was unaffected, but peak cardiac output and peak stroke volume were depressed. By 1 week after isoproterenol, the volume loaded measures of cardiac function had returned to normal. Interestingly, by 1 week postisoproterenol, total peripheral resistance was reduced. This reduced vascular resistance may have aided myocardial repair. At 24 hr postisoproterenol, the volume loaded peak cardiac outputs and peak stroke volumes in the SHRs were reduced to the same degree as in the Sprague-Dawley rats. Here, also, no change in normal cardiac index occurred. In the SHRs, however, total peripheral resistances were elevated at both 24 hr and 1 week. These increases in resistance appeared to impair the myocardial healing process, as both normal cardiac index and volume-loaded peak cardiac output and peak stroke volume were depressed at 1 week postisoproterenol. In normotensive and hypertensive rats, different vascular responses to isoproterenol or its initial cardiac effects may determine the duration and eventual degree of cardiac failure.

Histopathologic changes in aging male vs female spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) were autopsied at timed intervals from weaning to 28 months. Blood pressure reached 180 to 240 mm Hg after 4 months and was maintained. After 20 months, male SHR began to die of myocardial infarction. A survey was made of the histopathologic changes associated with increasing blood pressure and age. Histopathologic changes appeared in males when they became 8 months old; degenerative changes did not appear in female SHR until 12 to 15 months. Degenerative changes consisted of pituitary basophilia, fatty liver, islet hyperplasia and beta cell degranulation which preceded and became exacerbated with worsening hypertension. Intimal fibrino hyalin lesions of the gonads, polyarteritis nodosa, myocardial infarction, and cerebral edema were more severe in males vs females. Female SHR live significantly longer than males (e.g., 28 to 34 months). Hypertension and longevity may be under separate genetic control in SHR.

The hemodynamics of isoproterenol-induced cardiac failure in the rat.

In virgin, male Sprague-Dawley rats, subcutaneous injections of 2.5 mg/kg or 250 mg/kg isoproterenol increased heart rate and aortic dF/dt and decreased total peripheral resistance. The net systemic response was an arterial hypotension. The larger dose of isoproterenol initially produced a greater hypotension; reflex compensatory responses followed. Cardiac failure occurred by 24 hours post-isoproterenol. The extent of cardiac failure was isoproterenol dose dependent. By gross inspection of the epicardial surface of the hearts of the isoproterenol-treated rats, anatomical injury also appeared to be isoproterenol dose dependent. The data presented in this study support the existing theory that isoproterenol-induced myocardial damage is due to a relative myocardial hypoxia produced by artereial hypotension and myocardial hyperactivity. The data also indicate that reflex responses to arterial hypotension occur and may be detrimental. Cardiac failure is produced by massive quantities of isoproterenol, and the degree of cardiac failure is dose dependent.

Pathophysiological differences between obese and non-obese spontaneously hypertensive rats.

A genetic variant of the spontaneously hypertensive rat (SHR) has been produced which becomes markedly obese as well as hypertensive, i.e. Obese/SHR weigh 800 g as against 300 g for non-obese cohorts. Serum enzymes (CPK, SGOT, SGPT and LDH) are frequently abnormally elevated, concomitantly with a high incidence of myocardial necrosis. Obese/SHR are hyperlipidaemic with severe fatty infiltration of the liver; they are hyperglycaemic with enormous islets of Langerhans and extensive beta-cell degranulation; despite elevated blood urea nitrogen (BUN) levels, they manifest little or no renal damage. Measurement of corticosterone, deoxycorticosterone (DOC) and aldosterone in Obese/SHR demonstrate marked hyper-responsiveness to moderate stress. Circulating prolactin levels are lower in Obese and non-obese/SHR compared to SHR, but Obese/SHR manifest unusually high increases incirculating prolactin levels in response to stress. Obese/SHR are hyperinsulinaemic and have subnormal growth-hormone levels. Desite mild hypertension, hyperglycaemia and hyperlipidaemia, Obese/SHR show no evidence of atheromatous change but do develop early polyarteritis nodosa. It is believed that the genetically programmed hypertension and hyperglycaemia is mediated by increased DOC, aldosterone and corticosterone production respectively, and that the obesity, hypertension, and diabetes in Obese/SHR may be likened to human Cushing's disease.

Changes in the morphology and location of arterial lesions in virgin and breeder Sprague-Dawley and spontaneously hypertensive rats (SHR) to adrenal regeneration hypertension.

Repeatedly bred, spontaneously hypertensive rats (SHR), unlike breeder Sprague-Dawley (S-D) rats, develop intimal hyalin lesions of the small sized gonadal arteries exclusively. When subjected to adrenal regeneration hypertension (ARH), breeder SHR develop aortic sclerosis identical to the arteriosclerosis which appears in breeder S-D rats. virgin and breeder S-D and SHR were subjected to ARH and were killed 8 weeks later. ARH caused a much greater increase in the blood pressure of S-D than in SH rats. Circulating levels of aldosterone, deoxycorticosterone, and corticosterone were significantly lower in the ARH-treated S-D and SH rats. The regenerated adrenal cortices of the S-D rats manifested extensive lipid depletion indicative of active synthesis and discharge; the regenerated cortices of SHR were replete with lipid suggestive of depressed steroidogenesis. The diverse morphology and anatomical location of arterial lesions in virgin vs breeder SR may be related to adrenal steroidogenesis.

Inhibition of the development of spontaneous hypertension in SH rats by gonadectomy or estradiol.

Young male and female rats that become spontaneously hypertensive when they mature were gonadectomized at 30 days of age while they were still normotensive. Gonadectomy retarded the usual steep ascent of blood pressure up to 120 days of age. Ovariectomized females "escaped" from this inhibiting effect, and blood pressure rose to severely high levels, i.e., 210 mm Hg, from 150 to 240 days. Treatment with testosterone or estradiol demonstrated that estradiol was particularly effective in inhibiting the usual rise in blood pressure in intact (sham-operated) or gonadectomized males and females. Although effectively lowering blood pressure, estradiol also caused increased pituitary and adrenal weights, hyperlipidemia, and increased circulating levels of corticosterone and DOC.

Aldosterone, deoxycorticosterone, corticosterone, and prolactin changes during the lifespan of chronically and spontaneously hypertensive rats.

Male and female spontaneously hypertensive rats (SHR), which develop hypertension spontaneously with maturation, were autopsied at select time intervals from weaning to 28 months. Their blood pressure began to rise steeply at 4--5 weeks, reaching a zenith of 180--240 mm Hg after 4 months. Elevated blood pressures were maintained in both sexes. After 20 months, the male SHR began to die of myocardial infarction and hypotensive crisis. Heart and adrenal gland weight increased progressively not only during the phase of rapidly rising blood pressure but also during the period of plateaued but sustained high blood pressure. RIA of plasma levels of aldosterone, deoxycorticosterone, corticosterone, and PRL, under both quiescent and mildly stressful conditions, demonstrated that the pituitary-adrenal axis of SHR progressively increases its propensity to respond to stress with maturation. This capacity to respond to stress was maintained despite the severe high blood pressure and the attainment of relative old age, i.e. 2 yr. An incremental change in circulating PRL, corticosterone, and aldosterone as early as 2 months of age, when blood pressure levels are beginning to rise, suggests that there may be some connection between the genetically programmed pathogenesis of the spontaneous hypertension and the progressively increasing (with age) sensitivity of the pituitary-adrenal axis to stress.

Protection against high-pressure oxygen seizures by amino-oxyacetic acid.

A variety of autonomic blocking agents, general anesthetics, and anticonvulsants have been shown to offer protection from seizures caused by hyperbaric oxygen. Amino-oxyacetic acid (AOAA) has been shown to offer rats only minimal protection from such seizures. This study investigated whether AOAA protected cats and mice from hyperbaric-oxygen-induced seizures. Cats and mice were exposed to 100% oxygen at 5 ATA until seizures occurred or for a period of up to 60 min. Approximately half of the animals were pretreated with AOAA either 30 or 240 min before oxygen exposure. Results showed that the interval between exposure and grand mal seizures increased significantly in cats pretreated 30 or 240 min before exposure with 17 to 25 mg/kg AOAA; the number of cats remaining seizure-free for 60 min also increased markedly. However, mice received little protection even at doses up to 40 mg/kg. At higher doses the AOAA itself caused seizures even in the absence of hyperbaric oxygen.