Alpha-adrenergic Responsiveness Research Articles

Detubularization-Induced Contractile Response Change of the Ileum following Ileocystoplasty

We reported previously that following ileocystoplasty the structure and pharmacologic response of the implanted ileum changes towards that of the bladder. Specifically, the relaxation response to alpha adrenergic (methoxamine) and purinergic (ATP) stimulation reverses to a contractile response one month after the ileal segment is surgically made part of the urinary bladder. The present study was designed to investigate possible signals for this change and also to determine whether bladder responses would mimic the ileum if surgically interposed into the ileal stream. Rabbits in group 1 underwent bladder interposition into the functioning terminal ileum, rabbits in group 2 underwent tubularized ileocystoplasty and rabbits in group 3 underwent detubularized ileocystoplasty with urinary diversion. Twelve rabbits survived and were available for evaluation; five in group 1, three in group 2 and four in group 3. Analysis was done six weeks after surgery. In group 1 animals, the interposed bladder showed epithelial changes towards ileum and also a change in its in-vitro contractile responses towards that of ileum. In group 2 animals the tubular cystoplastic ileum showed minimal functional and morphologic changes. In group 3 animals, the defunctionalized, detubular cystoplastic ileum showed alpha adrenergic and purinergic response changes towards bladder. These results indicate that detubularization with interruption in the arrangement of smooth muscle fibers as well as the breach in the integrity of neuronal connections is likely to be the primary signal for the change in the ileum towards bladder induced by cystoplasty. The results can not rule out reinnervation of the intestinal segment by bladder nerves. In addition these data demonstrate that the pharmacologic response of the bladder changes towards the ileum within six weeks after the bladder is surgically made part of the ileum.

Altered coupling of alpha 1-adrenergic receptor-G protein in rat parotid during aging.

A possible role for altered signal transduction mechanisms in impaired alpha 1-adrenergic-stimulated secretory function during aging was investigated in parotid cells prepared from adult (6 mo) and old (24 mo) rats. Compared with adults, epinephrine-stimulated 45Ca2+ efflux and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] production were reduced 31 and 36% in cells of old rats, respectively. There was a highly significant correlation between 45Ca2+ efflux and Ins(1,4,5)P3 production. In saponin-permeabilized cells, no significant differences in Ins(1,4,5)P3-stimulated 45Ca2+ efflux in adult and old preparations were observed. When G proteins were stimulated by guanosine 5'-O-(3-thiotriphosphate) or NaF, no age differences in Ins(1,4,5)P3 production were detected. Stimulation of phosphoinositide-specific phospholipase C (PLC) by CaCl2 in adult and old cells was also comparable. Moreover, no differences in immunolabeled common alpha (GTP binding site), Gi alpha, PLC-gamma, or PLC-delta could be detected in either cytosol or membranes of adult and old preparations. In the absence of 5'-guanylylimidodiphosphate [Gpp(NH)p], no age-related changes in epinephrine competition for [3H]prazosin binding sites were observed. Approximately 30% of the agonist binding sites existed in a high-affinity form at both ages. Gpp(NH)p caused large rightward shifts of epinephrine displacement curves in adult membranes (converting all binding sites to the low-affinity form), but not old. Moreover, epinephrine was much more effective in stimulating G protein low-Km GTPase in parotid membranes from adult than old rats. These data suggest that age-related impairments in alpha 1-adrenergic responsiveness are mediated, at least in part, by the functional alterations in the coupling of G proteins with alpha 1-adrenergic receptors.

Alpha-1 adrenergic receptor number and receptor density in isolated hepatocytes from foetal, juvenile and adult rats

Alpha-1 adrenergic receptor number was defined by [ 3H]-prazosin binding in crude membrane preparations of hepatocytes and in intact hepatocytes isolated from foetal (day 22 of gestation), juvenile (12 days old), adult female and adult male (90–150 days old) rats and compared with the alpha-1 adrenergic response (measured by epinephrine stimulated glucose liberation in presence of the beta-antagonist propranolol). The alpha-1 receptor number (expressed as fmol bound [ 3H]-prazosin/mg membrane protein or as receptor number/cell) increases in an age-dependent fashion reaching the highest values in hepatocytes of adult female and male rats. Statistically significant differences could be found between foetal, juvenile and adult rat hepatocytes. No differences in [ 3H]-prazosin binding were observed between hepatocytes of adult female and adult male rats. The receptor density (expressed as receptor number/μm 2 cell surface), however was found to be equal in juvenile and adult rats. There are no differences of alpha-1 adrenergic response in juvenile, adult female and adult male rat hepatocytes, whereas the values in foetal hepatocytes were significantly lower. So the biological response is closely correlated with the receptor density and not with the receptor number per cell.

Intra-abdominal sepsis and adrenergic receptor response.

This study measured the adrenergic receptor response of 13 patients with severe intra-abdominal sepsis, who required laparotomy and an open abdominal closure with Marlex mesh. The source of the sepsis was gram-negative organisms of intestinal origin. There were seven survivors and six nonsurvivors. When the patients were stratified into survivors and nonsurvivors, the Septic Severity Score, the APACHE II score, the Acute Physiological Score, and the Glasgow Coma Scale score results were not significantly different between groups. The alpha-2 and beta-1 adrenergic receptor responses were measured in the adipose tissue of the abdominal wall and the small bowel mesentery on day 1 of admission to the intensive care unit. The results demonstrated that the alpha-2 and beta-1 receptors of the nonsurvivors had a significantly decreased receptor response with desensitization and down regulation. The alpha-2 and beta-1 receptors of the survivors had an increased response with hypersensitization and up regulation. This study indicates that the adrenergic receptor pattern is distinctly different between survivors and nonsurvivors with severe abdominal gram-negative sepsis. The pattern differences occurred early (within 24 hours) when the patients had similar physiologic profiles. It is concluded that adrenergic receptor response may be a biologic indicator of the magnitude of the septic injury and a predictor of outcome.

Augmentation of baroreflex-mediated bradycardia in conscious pregnant rats.

The goal of the present study was to examine baroreflex control of heart rate during pregnancy in chronically instrumented unrestrained rats. The same rats (n = 6) were studied before conception, again on gestational days 5, 12, and 19, and last on postpartum day 6; thus each rat served as its own control. Time control experiments were also conducted in a separate group of virgin rats (n = 7). Resting mean arterial pressure decreased by 10 mmHg on gestational day 19 (P less than 0.01 vs. prepregnant), and heart rate significantly increased by approximately 10% relative to time control rats. Dose-response curves were constructed for methoxamine and sodium nitroprusside comparing the various dosages with systemic pressor and depressor responses, respectively. The dose-response relationship for methoxamine was shifted to the right in gravid rats of 19 gestational days (P less than 0.03 vs. prepregnant), indicating an attenuation of alpha-adrenergic receptor-mediated pressor responsiveness. In contrast, depressor responses to sodium nitroprusside were not significantly altered in pregnancy. Baroreflex-mediated bradycardia was unchanged until gestational day 19, when enhanced bradycardia responses to methoxamine were observed. Baroreflex-mediated tachycardic responses elicited by sodium nitroprusside were not affected at any stage of pregnancy. Baroreflex control of heart rate did not change significantly with either increases or decreases of blood pressure in time control experiments. We conclude that during late pregnancy in conscious rats 1) resting blood pressure decreases and heart rate increases, 2) systemic pressor responses to methoxamine are diminished, and 3) baroreflex-mediated bradycardia is enhanced.

Drop in the "atypical" beta-adrenergic response and modification of the beta/alpha 2-adrenoceptor balance in fat cells from aging rabbits.

Previous studies have shown a strong reduction of catecholamine-induced lipolysis in perirenal white fat cells in aging rabbits. The molecular basis of this observation was explored on scapular and perirenal adipocytes from 45 and 300- to 500-day-old rabbits. ACTH and forskolin were used to define the maximal lipolytic potencies of the adipocytes. beta-Adrenergic responsiveness was explored with isoproterenol and specific agonists of the "atypical" beta-adrenoceptor (beta-AR) (BRL37344 and (+/-)CGP12177); beta 1/beta 2-ARs were identified with [125I]cyanopindolol. alpha 2-adrenergic responses were evaluated with the full alpha 2-agonist, UK14304. The alpha 2 AR number was determined with the alpha 2-antagonist radioligand [3H]RX821002. Whatever the fat deposit, the relative order of lipolytic potency of the beta-agonists was: isoproterenol greater than BRL37344 greater than (+/-)CGP12177. As previously reported for catecholamines, the maximal lipolytic response initiated by isoproternol decreased with aging; the stronger reduction was observed in perirenal adipocytes compared to subscapular adipocytes. The most striking observation concerns the parallel and complete disappearance of the lipolytic responses induced by the atypical beta-agonists (BRL37344 and (+/-)CGP12177) and the preservation of a residual action of isoproterenol (30% of that described in young animals) which was attributed to the stimulation of beta 1/beta 2-ARs. The number of beta 1/beta 2-AR binding sites was practically equivalent whatever the fat deposite and the age of the animals. alpha 2-Adrenergic responsiveness and alpha 2-adrenergic receptor number were increased with aging in the various deposits but the stronger changes were observed in the perirenal adipocytes where epineprine initiated a biphasic effect on lipolysis (antilipolytic and then lipolytic). To conclude, the reduction of catecholamine-induced lipolysis observed in the rabbit fat cells with aging can be explained by changes in the atypical beta-AR/alpha 2-AR balance. First, a loss of responsiveness to the atypical beta-adrenergic agents was observed (it is impossible for the moment to distinguish between the loss of atypical beta-AR binding sites and their putative uncoupling from the adenylate cyclase system) whereas beta 1/beta 2-AR-mediated responses were maintained. Second, an increment of alpha 2-adrenergic responsiveness and of the alpha 2-AR binding sites accompanied aging and fattening. In the absence of, or after a strong reduction of the atypical beta-AR component of the lipolytic response in fat cells of aged rabbits, epinephrine exerts a biphasic effect on lipolysis, demonstrating the changes occurring in the atypical beta-AR/alpha 2-AR balance.(ABSTRACT TRUNCATED AT 400 WORDS)

Drop in the "atypical" beta-adrenergic response and modification of the beta/alpha 2-adrenoceptor balance in fat cells from aging rabbits

Previous studies have shown a strong reduction of catecholamine-induced lipolysis in perirenal white fat cells in aging rabbits. The molecular basis of this observation was explored on scapular and perirenal adipocytes from 45 and 300- to 500-day-old rabbits. ACTH and forskolin were used to define the maximal lipolytic potencies of the adipocytes. beta-Adrenergic responsiveness was explored with isoproterenol and specific agonists of the "atypical" beta-adrenoceptor (beta-AR) (BRL37344 and (+/-)CGP12177); beta 1/beta 2-ARs were identified with [125I]cyanopindolol. alpha 2-adrenergic responses were evaluated with the full alpha 2-agonist, UK14304. The alpha 2 AR number was determined with the alpha 2-antagonist radioligand [3H]RX821002. Whatever the fat deposit, the relative order of lipolytic potency of the beta-agonists was: isoproterenol greater than BRL37344 greater than (+/-)CGP12177. As previously reported for catecholamines, the maximal lipolytic response initiated by isoproternol decreased with aging; the stronger reduction was observed in perirenal adipocytes compared to subscapular adipocytes. The most striking observation concerns the parallel and complete disappearance of the lipolytic responses induced by the atypical beta-agonists (BRL37344 and (+/-)CGP12177) and the preservation of a residual action of isoproterenol (30% of that described in young animals) which was attributed to the stimulation of beta 1/beta 2-ARs. The number of beta 1/beta 2-AR binding sites was practically equivalent whatever the fat deposite and the age of the animals. alpha 2-Adrenergic responsiveness and alpha 2-adrenergic receptor number were increased with aging in the various deposits but the stronger changes were observed in the perirenal adipocytes where epineprine initiated a biphasic effect on lipolysis (antilipolytic and then lipolytic). To conclude, the reduction of catecholamine-induced lipolysis observed in the rabbit fat cells with aging can be explained by changes in the atypical beta-AR/alpha 2-AR balance. First, a loss of responsiveness to the atypical beta-adrenergic agents was observed (it is impossible for the moment to distinguish between the loss of atypical beta-AR binding sites and their putative uncoupling from the adenylate cyclase system) whereas beta 1/beta 2-AR-mediated responses were maintained. Second, an increment of alpha 2-adrenergic responsiveness and of the alpha 2-AR binding sites accompanied aging and fattening. In the absence of, or after a strong reduction of the atypical beta-AR component of the lipolytic response in fat cells of aged rabbits, epinephrine exerts a biphasic effect on lipolysis, demonstrating the changes occurring in the atypical beta-AR/alpha 2-AR balance.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic modulation of extrarenal potassium disposal in men with end-stage renal disease.

In normal subjects, beta-adrenergic stimulation lowers the serum potassium, whereas alpha-stimulation raises it. Epinephrine, a mixed alpha and beta agonist, acutely lowers the blood potassium in normal subjects, but not in patients with end-stage renal disease. This study was designed to determine whether the resistance to the hypokalemic effect of epinephrine in dialysis patients is due to a blunted beta-adrenergic response, or to an augmented alpha-adrenergic response. The infusion of epinephrine at low doses (0.01 microgram/kg/min) produced a significant increase in serum potassium in hemodialysis patients (+0.21 +/- 0.07 mmol/liter, P less than 0.05), as compared to a nonsignificant decrease (-0.06 +/- 0.04 mmol/liter) in normal subjects. Epinephrine at high physiologic doses (0.04 microgram/kg/min) failed to significantly change the serum potassium in the dialysis patients (-0.10 +/- 0.14 mmol/liter), but substantially lowered serum potassium in the controls (-0.64 +/- 0.10 mmol/liter, P less than 0.001). There was no significant correlation (r = 0.03) between the baseline serum potassium concentration and the magnitude of change during epinephrine infusion. Epinephrine infusion (0.04 microgram/kg/min) during beta-blockade with propranolol produced a greater rise in serum potassium in the dialysis patients as compared to the controls (+0.69 +/- 0.11 vs. +0.32 +/- 0.11 mmol/liter, P less than 0.05). Epinephrine infusion (0.01 microgram/kg/min) during alpha-blockade with phentolamine resulted in similar changes in serum potassium in dialysis patients and in normal control (-0.10 +/- 0.12 vs. -0.10 +/- 0.06 mmol/liter). Moreover, phentolamine reversed the increase in serum potassium observed in dialysis patients during the infusion of epinephrine following beta-blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Participation of Endothelium-Derived Relaxing Factor and Role of Cyclic GMP in Inhibitory Effects of Endothelium on Contractile Responses Elicited by α-Adrenoceptor Agonists in Rat Aorta

The participation of NO production and the role of cyclic GMP in inhibitory function of endothelium were investigated in rat aortic rings exposed to alpha-adrenoceptor agonists. Both endothelium and 8-Br cyclic GMP (in endothelium-denuded rings) depressed more markedly not only maximal contractions but also equipotent contractions elicited by two partial agonists (indanidine and B-HT 920) than responses to the full agonist phenylephrine. The influence of endothelium on maximal responses to the three agonists was abolished by both the nitric oxide (NO)-synthase inhibitor NG-nitro-L-arginine methylester (L-NAME, 30 microM) and by the guanylate cyclase inhibitor methylene blue (methylene blue, 0.3 and 1 microM). Both endothelium and 8-Br cyclic GMP (in endothelium-denuded rings) increased the EC50 value of phenylephrine. This effect was more pronounced in the case of endothelium (10-fold), however, than in the case of 8-Br cyclic GMP (fourfold at 30 microM), and the rightward shift produced by endothelium remained significant (twofold) in the presence of L-NAME or methylene blue. In addition, the effect of 8-Br cyclic GMP on phenylephrine-induced contractions was considerably enhanced in the presence of endothelium or after partial alkylation of receptors by phenoxybenzamine in endothelium-denuded rings. These results indicate that the L-arginine-NO-cyclic GMP pathway accounts for most of the inhibitory influence of endothelium on alpha-adrenergic responses in aortic rings. They indicate differential effects of cyclic GMP depending on the agonist and show that 8-Br cyclic GMP does not impair the basal inhibitory effect of endothelium on aortic contraction to alpha-adrenergic agonists.

Regional variation in adipose tissue lipolysis in lean and obese men.

Biopsies of adipose tissue were obtained from two subcutaneous regions (abdominal and femoral) in a sample of 54 men (32 obese and 22 lean subjects). Clonidine-induced antilipolysis in femoral adipose cells was similar in both groups, whereas subcutaneous abdominal adipocytes of obese individuals showed a higher alpha 2-adrenergic response than did subcutaneous abdominal adipose cells from lean subjects. In addition, epinephrine had a biphasic effect in subcutaneous abdominal adipocytes from obese individuals, as it induced antilipolysis at low concentrations, and a net lipolytic response at higher doses. In contrast, the physiological amine promoted lipolysis in subcutaneous abdominal adipose cells of lean subjects. Epinephrine- and clonidine-induced antilipolysis of subcutaneous abdominal adipocytes was positively associated with the level of subcutaneous abdominal fat measured by computed tomography (CT). Finally, men with a high alpha 2-adrenergic response of subcutaneous abdominal fat cells were fatter than those with a low alpha 2-adrenergic component. These results suggest that, in men with a wide range of body fatness, variations in the lipolytic response of subcutaneous abdominal adipose cells to epinephrine appear to involve changes in the functional balance between alpha 2- and beta-adrenoceptors.

Adrenergic regulation of lipolysis in human fat cells during exercise

The adrenergic regulation of lipolysis was studied, before and after 30 min of submaximal exercise, in isolated adipocytes removed from the abdominal and gluteal regions of healthy non-obese men and women. Noradrenaline-induced lipolysis was significantly enhanced in gluteal adipocytes from men but not in women after exercise. However, the pure beta-adrenergic responsiveness was equally increased in gluteal adipocytes of both sexes after exercise, as judged by the effect of isoprenaline. Furthermore, the alpha 2-adrenergic anti-lipolytic responsiveness was more apparent after exercise in females than in males thereby counter-balancing the increase in the beta-adrenergic effect in the gluteal region in the former. The increased beta-adrenergic responsiveness induced by exercise in gluteal adipocytes of males could be mimicked by agents acting at the levels of adenylate cyclase, coupling proteins, phosphodiesterase, and protein kinase and seems to be due to an adaptive enhancement at the hormone-sensitive-lipase level. There was no change in the stoichiometric properties of beta-adrenoceptors of gluteal adipocytes after exercise. Abdominal adipocytes of both sexes were four to five times more responsive to noradrenaline than gluteal ones. However, exercise induced no further enhancement of the catecholamine-stimulated lipolysis rate in fat cells from this site. Thus, the influence of exercise on catecholamine-stimulated lipolysis is regional and sex dependent. Men, but not women, have a greater ability to adapt lipolysis to increasing energy demands during exercise that are due to an acute increase in the effectiveness of the hormone-sensitive lipase complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic exposure to neuropeptide Y determines cardiac alpha 1-adrenergic responsiveness

The onset of sympathetic innervation induces a developmental change in the cardiac alpha 1-adrenergic chronotropic response from an increase to a decrease in rate. The mechanism by which innervation induces this alteration is unknown. Neuropeptide Y (NPY), which is found abundantly in cardiac sympathetic nerve terminals, was considered as a possible mediator for this effect. Chronic conditioning by NPY in noninnervated myocyte cultures stimulated the effect of sympathetic innervation in inducing the alpha 1-inhibitory chronotropic response. Chronic conditioning by the NPY antagonist PYX-2 blocked the effect of innervation. Thus endogenous NPY may modulate alpha 1-adrenergic responsiveness during the ontogeny of cardiac sympathetic innervation.

Prostaglandins modulate hormonal effects on rabbit myometrial alpha 1-adrenergic responses.

Estrogen increases the alpha 1-adrenergic contractile sensitivity of the rabbit uterus. Since estrogen treatment increases prostaglandin (PG) production by the perfused rabbit uterus, and PGs contribute to the alpha 1-adrenergic contractile response, we postulated that estrogen's effects on PG production or response may play a role in the increased alpha 1-adrenergic sensitivity induced by estrogen. We studied the effects of the eicosanoid synthesis inhibitor meclofenamate (60 microM) on the response to epinephrine (10(-9)-10(-5) M) of uterine strips from ovariectomized, mature, and estrogen-treated rabbits in terms of both contractile response and PGE2 and PGF2 alpha production. We also measured the contractile response to PGE2 and PGF2 alpha (both 10(-10)-10(-5) M) and KCl (70 mM) of uterine strips from these groups. We found that in the ovariectomized rabbits, meclofenamate decreased PG production, but did not alter the alpha 1-adrenergic sensitivity. In the mature rabbit uterus, meclofenamate decreased both PGE2 and PGF2 alpha production and reduced the alpha 1-adrenergic sensitivity. In the estrogen-treated rabbit uterus, meclofenamate decreased PGF2 alpha, but not PGE2, production and did not alter the alpha 1-adrenergic sensitivity. Finally, meclofenamate reduced the contractile response to KCl in all three groups, and exposure to PGE2 increased the contractile response to KCl in both the mature and estrogen-treated rabbits. We conclude that PGs play a role in the increase in the alpha 1-adrenergic sensitivity of the uterus in mature rabbits, and that this may be the result of an estrogen-mediated alteration in the postreceptor effects of PGs.

Melatonin‐induced relaxation of rat aorta: Interaction with adrenergic agonists

The influence of melatonin on alpha- and beta-adrenergic responses of vascular smooth muscle ex vivo were examined in these experiments. Melatonin caused a dose-dependent relaxation of precontracted (30 mM KCl) vascular smooth muscle. This response was not affected by the removal of vascular endothelium. Melatonin (10 nM) reduced the efficacy, but not potency, of the contractile responses to methoxamine and clonidine. Melatonin had no effect on the vascular beta-adrenergic response to isoproterenol. Pretreatment of vascular rings with lithium sulfate (0.1 mM) completely blocked the relaxation in response to melatonin, suggesting that the inositol phosphate pathway may be involved in this relaxation. Furthermore, pretreatment of vascular rings with phorbol 12-myristate-13-acetate, an activator of protein kinase C, antagonized the relaxation response to melatonin. Pharmacologic doses of melatonin (0.1 mM) slightly impaired the vascular smooth muscle response to calcium. These data indicate that melatonin per se is capable of relaxing vascular smooth muscle and that low doses of melatonin impair alpha-1 and alpha-2 adrenergic responses without changes in the beta adrenergic response of vascular smooth muscle.

Responsiveness of peripheral veins to vasodilators and the effect of nifedipine on alpha-adrenergic responsiveness in hypertension.

Vasodilators have varying hemodynamic properties that may be important in determining their efficacy for different disorders. We used the dorsal hand vein technique to measure the effects of several vasodilators infused locally and to measure the action of systemically administered nifedipine. The venodilatory effects of hydralazine, verapamil, diazoxide, and nitroglycerin were determined in peripheral veins of healthy subjects. The potency (ED50, the dose producing half-maximal response) was as follows: nitroglycerin (0.0007 micrograms/min) greater than verapamil (6.5 micrograms/min) greater than diazoxide (75 micrograms/min) greater than hydralazine (660 micrograms/min). The effect of oral nifedipine on alpha-adrenergic responsiveness of hand veins was determined. Nifedipine given in therapeutic doses for the treatment of hypertension was associated with a threefold increase in the ED50 for phenylephrine (92 to 277 ng/min; p less than 0.05) and norepinephrine (2.9 to 11.5 ng/min; p less than 0.05). Therapeutic doses of nifedipine are associated with measurable shifts in the dose-response curves to these two alpha-adrenergic agonists in the hand vein. The hand vein technique can be used not only to compare the potency of locally infused drugs but also to measure venous effects of vasoactive drugs at therapeutic concentrations achieved after systemic administration.

POSSIBLE INVOLVEMENT OF INOSITOL-LIPID METABOLISM IN MALIGNANT HYPERTHERMIA

Alpha-adrenoceptor stimulation may induce malignant hyperthermia (MH) in vivo. Consequently, we have investigated the effects of the alpha-adrenoceptor agonist phenylephrine and, for comparison, the effects of the beta-adrenoceptor agonist isoproterenol on inositol-lipid metabolism of malignant hyperthermia susceptible (MHS) and healthy control (MHN) swine. The experiments were performed on electrically stimulated (frequency 0.2 Hz) trabeculae isolated from the right ventricles of the hearts of MHS and MHN animals. After labelling with [3H]inositol for 6 h, different inositol phosphates were measured by high pressure liquid chromatography, including inositol 1-phosphate, inositol 1,4-bisphosphate, inositol 1,3,4-trisphosphate, inositol 1,4,5-trisphosphate (1,4,5-IP3) and inositol 1,3,4,5-tetrakisphosphate. After stimulation with isoproterenol, the inositol phosphate content did not increase or vary between muscle from MHS and MHN animals. In contrast, all inositol phosphates increased after stimulation with phenylephrine in both muscle types, the effects being greater in MHS than in MHN, especially as regards 1,4,5-IP3 content. As 1,4,5-IP3, a presumed second messenger, has been shown to mobilize intracellular calcium, it is concluded that an enhanced alpha-adrenergic response is involved in the development of MH.

Spontaneously hypertensive rats demonstrate increased renal vascular alpha 1-adrenergic receptor responsiveness

To determine alpha 1-adrenergic receptor responsiveness of the renal vasculature in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), phenylephrine (2.5 or 5.0 micrograms.kg-1.min-1 iv) or saline was infused. Effective renal blood flow (ERBF) and glomerular filtration rate were determined by p-aminohippuric acid and inulin clearances, respectively. Peritubular capillary, proximal tubular, and stop-flow pressures (SFP) were measured by micropuncture. Phenylephrine decreased ERBF (6.27 +/- 0.48 to 4.55 +/- 0.65 ml.min-1.g-1; P less than 0.05) and increased arterial pressure and SFP (31.5 +/- 0.9 to 34.2 +/- 1.0 mmHg) in SHR. It only increased arterial pressure and ERBF in WKY without changing SFP. Afferent arteriolar resistance (RA) and glomerular capillary pressure (PG) remained unchanged, whereas efferent resistance (RE) decreased in WKY; in contrast, RA, RE, and PG increased in SHR (RA 21.2 +/- 2.0 to 38.1 +/- 7.1 mmHg.ml-1.min.g, RE 6.9 +/- 0.6 to 13.9 +/- 3.8 mmHg.ml-1.min.g; and PG 49.6 +/- 0.9 to 53.7 +/- 1.1 mmHg; all P less than 0.05). These data demonstrated increased SHR afferent and efferent arteriolar responsiveness; WKY efferent arteriolar hyperresponsiveness was not observed. The findings support the concept of augmented intrarenal vascular alpha 1-adrenergic responsiveness in hypertension that may predispose to subsequent glomerular hypertension.

Cluster analyses of cardiovascular responsivity to three laboratory stressors.

Seventy-three young normotensive male subjects were tested with an experimental protocol that included a reaction time, a mental arithmetic, and a cold pressor task. Physiological variables that were recorded included heart rate, stroke volume, pre-ejection period, blood pressure, total peripheral resistance, and respiratory sinus arrhythmia. In order to identify subgroups of subjects who differed in their pattern of autonomic responses to the tasks, the physiological change scores from baseline to the tasks for each subject were entered into a cluster analysis for each task. Ward's method was used as the clustering algorithm. The cluster analyses identified four clusters for the reaction time and mental arithmetic tasks, and five clusters for the cold pressor task. Although there was a wide range of patterns exhibited by cluster subgroups, most subjects who were reactive to the tasks showed response patterns that were qualitatively similar to the pattern of overall mean response by all subjects, albeit varying considerably in terms of quantitative response. Little evidence was generated for the consistency of extreme beta-adrenergic response from one task to another, although significant consistency was noted when milder beta-responders were included in the comparisons. Some consistency of alpha-adrenergic response noted across tasks, as well as significant consistency of being relatively nonreactive to the tasks.

Alpha-adrenoceptor-mediated increase in cytosolic free calcium in isolated cardiac myocytes

The effect of alpha-adrenoceptor stimulation on the concentration of cytosolic free calcium ( Ca i 2+ ) was determined by measuring indo-1 fluorescence in isolated ventricular cardiomyocytes from normal and streptozotocin-diabetic rat; 1.3 × 10 5 alpha 1-adrenoceptors per normal myocyte and an unaltered number of these receptors in cells from diabetic rats were detected using the alpha 1-selective ligand WB-4101. Under basal conditions, Ca i 2+ was found to be 154 ± 4 n m ( n = 34) reaching a value of 192 ± 10 n m ( n = 15) after stimulation of myocytes with a maximal dose of methoxamine for 5 min. Under the same conditions the leakage of dye produced a significantly smaller increase of basal values to 169 ± 5 n m ( n = 17). Indo-1 loaded cells did not respond to beta-stimulation unless in the presence of KCl (50 m m), demonstrating the specificity of methoxamine action. Treatment of cells with nifedipine or chelation of extracellular calcium by EGTA did not modify the alpha-adrenergic response. Experiments with cardiomyocytes from streptozotocin-diabetic rats showed an unaltered modulation of Ca i 2+ by both alpha- and beta-receptor stimulation.It is concluded that signalling by alpha 1-adrenoceptors in ventricular cardiomyocytes results in mobilization of intracellular calcium stores.

Regulation of venous alpha-adrenergic responses in older humans

Decreased adrenergic responsiveness in human aging could be a result of downregulation mediated by the age-related increase in sympathetic nervous system (SNS) tone. If so, suppression of SNS tone in elderly subjects should upregulate adrenergic responsiveness into the range observed for younger subjects. To test this hypothesis, we examined alpha 1 (phenylephrine)- and alpha 2 (clonidine)-adrenergic agonist-mediated venoconstriction in a group of 15 older healthy subjects (age 59-73 yr) during placebo and when SNS tone was suppressed by guanadrel (15 mg twice daily for 3 wk). During guanadrel compared with placebo 1) there were decreases in plasma norepinephrine (NE) levels (1.47 +/- 0.07 to 0.80 +/- 0.06 nM; P less than 0.001) and in the extravascular NE release rate derived from [3H]NE kinetics (11.8 +/- 1.4 to 6.1 +/- 1.0 nmol.min-1.m-2; P = 0.01), suggesting suppression of SNS tone; 2) there was an augmented clonidine-mediated venoconstriction response [analysis of variance (ANOVA) P = 0.01]; and 3) there was no detectable change in phenylephrine-mediated venoconstriction (ANOVA P = 0.60). When compared with previous results from young subjects, maximal alpha 2-adrenergic venoconstriction during guanadrel was decreased in the elderly compared with the young, although their response appeared to be appropriately upregulated by the decrease in SNS tone. The lack of an age-related decrease in alpha 1-adrenergic venoconstriction, together with the lack of upregulation of this response during guanadrel, suggests that regulation of this alpha 1-adrenergic response is impaired in the older group.