Biomedical subjects

B B Hoffman

Publications and source records attributed to B B Hoffman.

At least 19 recordsLinked to original sources

PubMed1992

Atenolol compared with nifedipine: effect on cognitive function and mood in elderly hypertensive patients.

OBJECTIVE: To compare the effects of atenolol and nifedipine on mood and cognitive function in elderly hypertensive patients. DESIGN: Randomized, double-blind, crossover trial. PATIENTS: Thirty-one elderly volunteers (7 women and 4 men) 60 to 81 years of age with mild to moderate hypertension were recruited from the general community and a Veterans Affairs hospital hypertension clinic. Six volunteers withdrew at early phases of the study for reasons unrelated to adverse drug effects. INTERVENTIONS: Participants had 2 weeks of placebo, to 6 weeks of titration with atenolol or nifedipine, and weeks of treatment followed by similar periods with the other drug. MEASUREMENTS: Psychometric tests designed to assess mood and cognitive function. RESULTS: In the group first treated with nifedipine, the summed recall score on the Buschke selective reminding test (a test of verbal learning and memory) decreased by 9.3 words (95% CI, 2.8 to 15.6 words), or 0%, during nifedipine treatment compared with placebo (P = 0.031). The group first treated with atenolol showed no improvement in summed recall scores when results seen during atenolol therapy and placebo administration were compared (P = 0.10); however, this group had an improvement of 16.1 words (CI, 5.6 to 26.5 words), or of 16%, when the atenolol score was compared with the nifedipine score (P = 0.026). In the group first treated with nifedipine, 6 of 11 patients 55%) showed a decrease of 5 words or more during nifedipine therapy compared with placebo, whereas only 1 of the 14 patients (7%) in the group first treated with atenolol showed a similar decrease (P less than 0.01). On the digit symbol test (a psychomotor test), patients treated first with atenolol tended to improve, whereas patients treated first with nifedipine tended to decline. The difference between nifedipine and atenolol, in terms of the change from the score seen during placebo, was 4.3 codings (CI, 0.7 to 7.9 codings) or 10% (P = 0.043). No statistically significant differences were seen between nifedipine and atenolol therapy regarding the other measures of psychomotor ability, sustained attention, motor performance, verbal fluency, or abstract reasoning, and no effects of either drug on mood or psychopathologic symptoms were noted. CONCLUSIONS: Although atenolol and nifedipine are generally free of gross effects on cognition or mood, nifedipine may subtly impair learning and memory in some elderly hypertensive patients.

Affect↗

PubMed1992

Activation of alpha-1 adrenergic receptors modulates the control of left/right sidedness in rat embryos.

Presomite stage rat embryos were cultured for 45-49 hr with medium containing various adrenergic agonists and antagonists. L-Norepinephrine but not D-norepinephrine (several orders of magnitude less potent than the L-isomer at alpha-1 adrenergic receptors) resulted in a dose-dependent increase of situs inversus similar to that found for phenylephrine, an alpha-1 adrenergic agonist. Prazosin, an alpha-1 adrenergic antagonist, inhibited phenylephrine-induced situs inversus in a dose-dependent manner. Neither dexmedetomidine, an alpha-2 adrenergic agonist, nor isoproterenol, a beta adrenergic agonist, caused situs inversus. These results provide pharmacological evidence that stimulation of alpha-1 but not of alpha-2 and beta adrenergic receptors modulates the control of left/right sidedness in rat embryos.

Adrenergic alpha-Agonists↗

PubMed1992

Prolonged activation of inhibitory somatostatin receptors increases adenylate cyclase activity in wild-type and Gs alpha-deficient (cyc-) S49 mouse lymphoma cells.

Many cells develop enhanced adenylate cyclase activity after prolonged exposure to drugs that acutely inhibit the enzyme and it has been suggested that this adaptation may be due to an increase in Gs alpha. We have treated wild-type and Gs alpha-deficient cyc- S49 mouse lymphoma cells with a stable analogue (SMS 201-995) of the inhibitory agonist somatostatin. After incubation with SMS for 24 h, the forskolin-stimulated cAMP synthetic rate in intact cyc- cells was increased by 76%, similar to the increase found in the wild-type cells. Forskolin-stimulated adenylate cyclase activity in the presence of Mn2+ was also increased in membranes prepared from SMS-treated cyc- cells; however, guanine nucleotide-mediated inhibition of adenylate cyclase activity was not changed despite a small decrease in inhibitory Gi alpha subunits detected by immunoblotting. Pretreatment of cyc- cells with pertussis toxin prevented SMS from inducing the enhancement of forskolin-stimulated cAMP accumulation in intact cells. After chronic incubation of cyc- cells with SMS, exposure to N-ethylmaleimide, which abolished receptor-mediated inhibition of cAMP accumulation, did not attenuate the enhanced rate of forskolin-stimulated cAMP synthesis compared to N-ethylmaleimide-treated controls. These results with cyc- cells demonstrate that an adaptive increase in adenylate cyclase activity induced by chronic treatment with an inhibitory drug can occur in the absence of expression of Gs alpha.

Adenylyl Cyclases↗

PubMed1992

Adaptive increase in adenylyl cyclase activity in NG108-15 and S49 cells induced by chronic treatment with inhibitory drugs is not due to a decrease in cyclic AMP concentrations.

NG108-15 neuroblastoma x glioma hybrid cells and S49 lymphoma cells exhibit an enhancement in adenylyl cyclase activity after chronic treatment with receptor agonists that acutely inhibit the enzyme. Using agonists that activate five distinct inhibitory receptors in NG108-15 cells, we have found that there is a correlation between the extent of acute inhibition of prostaglandin E1 (PGE1)-stimulated cAMP accumulation and efficacy for induction of enhanced PGE1 stimulation of cAMP accumulation after chronic treatment and withdrawal. Chronic treatment with dideoxyadenosine, which acutely inhibits adenylyl cyclase activity by a mechanism independent or cell surface receptors or pertussis toxin-sensitive G proteins, did not induce enhanced PGE1 stimulation of cAMP accumulation in NG108-15 cells or forskolin stimulation of cAMP accumulation in S49 cells. While control basal cAMP concentrations were acutely decreased by carbachol in NG108-15 cells and by somatostatin in S49 cells, when the cAMP concentrations were maintained above the control basal values with a phosphodiesterase inhibitor, chronic treatment with these inhibitory drugs nonetheless resulted in enhanced cAMP responses in both NG108-15 and S49 cells. These results provide evidence that the initial decrement in cAMP concentrations caused by inhibitory drug is not the requisite signal for inducing the subsequent sensitization of adenylyl cyclase in NG108-15 and S49 cells but that activation of a pertussis toxin-sensitive G protein is involved in the development of this important adaptation.

Adaptation, Biological↗

PubMed1992

Comparison of vasodilatory responses to nitroglycerin and its dinitrate metabolites in human veins.

Independent of the route of nitroglycerin administration, substantial amounts of 1,2-glyceryl dinitrate (1,2-GDN) and 1,3-glyceryl dinitrate (1,3-GDN) metabolites accumulate in humans. Thus far their pharmacologic activity in comparison to nitroglycerin in humans is unknown. To compare the venodilatory potency of nitroglycerin and of 1,2-GDN and 1,3-GDN in vivo, cumulative dose-response curves were established in nine healthy volunteers by use of the dorsal hand vein compliance technique. Separated by a washout period, two of the three venodilators were infused in randomized order after preconstriction with phenylephrine. Values for maximum vasodilation were similar for all compounds: nitroglycerin, 109%; 1,2-GDN, 100%; and 1,3-GDN, 106%. The respective values for the dose rate exerting 50% of maximum vasodilation were 5.1, 43, and 60 ng/min, indicating that the dinitrates were about 10 times less potent than nitroglycerin (p < 0.001) but not significantly different from each other. The findings support the hypothesis that activity of nitroglycerin metabolites is related to the number of nitrate groups in the molecule and are in agreement with lower dinitrate potencies found in animal experiments.

Adult↗

PubMed1992

Vascular reactivity to phenylephrine and angiotensin II: comparison of direct venous and systemic vascular responses.

The objective of this study was to determine the relationship between peripheral venous responsiveness (use of the dorsal hand vein compliance technique) and systemic vascular responsiveness (measurement of blood pressure changes) to phenylephrine and angiotensin II in humans. There was a significant correlation (r = 0.70, p less than 0.02) between the dose causing a 20 mm increase in mean arterial pressure and the dose producing half-maximal response in the hand vein (log ED50) for phenylephrine but not for angiotensin II. There was no correlation between the systemic responses to angiotensin II and phenylephrine, but there was a significant correlation (r = 0.70, p less than 0.02) between the log ED50 measurements for phenylephrine and angiotensin II in the hand vein experiments. These findings suggest that systemic and hand vein responsiveness to phenylephrine are similar. Consequently, in evaluating alpha-adrenergic receptor mediated responses, the dorsal hand vein compliance approach offers a satisfactory alternative to the use of systemic hemodynamic changes.

Adult↗

PubMed1992

Responsiveness of superficial hand veins to alpha-adrenoceptor agonists in insulin-dependent diabetic patients.

1. Diabetic autonomic neuropathy causes loss of sympathetic cardiovascular control and is associated with increased vascular sensitivity to catecholamines. Supersensitivity to catecholamines could be due to either a postsynaptic increase in vascular sensitivity or to decreased catecholamine uptake into peripheral sympathetic nerve endings. 2. To differentiate between these possible mechanisms we have measured the responsiveness in vivo to noradrenaline and phenylephrine with local infusions into peripheral veins of diabetic patients with and without symptomatic autonomic neuropathy and of healthy control subjects. The dorsal hand vein compliance technique was used. 3. Symptomatic diabetic patients required significantly lower doses of noradrenaline for half-maximal venoconstriction (ED50) (geometric mean 2.14 ng/min) than control subjects (geometric mean 6.61 ng/min, P = 0.032), but there was no difference in the results from the phenylephrine dose-response curves between the groups. There were no differences in venous responsiveness to noradrenaline or phenylephrine between the asymptomatic diabetic group and the control group. However, in the asymptomatic diabetic group, postural blood pressure change (an index of loss of sympathetic control) was correlated with the ED50 for noradrenaline (r = 0.74, P = 0.014), but not with the ED50 for phenylephrine. In the control group the ED50 values for noradrenaline and phenylephrine were correlated with each other (r = 0.81, P = 0.0005). 4. Both vasopressor drugs act on vascular alpha-adrenoceptors, but only noradrenaline is taken up into peripheral sympathetic nerve endings. Our results suggest that, in diabetic patients, vascular supersensitivity to catecholamines is primarily determined by decreased neuronal catecholamine uptake. A postsynaptic increase in vascular alpha-adrenoceptor stimulation does not appear to be prominent in diabetic autonomic neuropathy.

Adrenergic alpha-Agonists↗

PubMed1992

Beta adrenergically mediated cardiac chronotropic and vascular smooth muscle responses during propranolol therapy and withdrawal in young and elderly persons.

Aging is associated with diminished beta-adrenergic responsiveness in a variety of tissues. Desensitization of tissues secondary to the age-associated increase in sympathetic nervous system activity has been proposed as a potential explanation for diminished beta-adrenergic responsiveness. If this hypothesis is correct, then beta-blockade in older people might be expected to reverse the blunted beta-adrenergic responses of tissues having diminished responsiveness. Cardiac chronotropic responses to bolus isoproterenol (ISO) doses and ISO-induced venous smooth muscle dilatation in superficial hand veins were examined in 8 young (26.2 +/- 2.6 yrs) and 9 elderly (68.0 +/- 2.2 yrs) healthy subjects before, during, and 3 and 7 days following 2 weeks of treatment with propranolol. Baseline cardiac chronotropic responsiveness, CD25, was 1.55 +/- 0.77 mcg in the young and 5.97 +/- 2.77 mcg in the elderly subjects (p less than .01), increasing to 84 +/- 56 mcg and 194 +/- 172 mcg during treatment with propranolol. At 3 and 7 days following withdrawal of propranolol, CD25s were respectively 1.24 +/- 0.79 (p = .14) and 1.10 +/- 0.42 (p = .04) in the young and 5.63 +/- 2.34 (p = .31) and 4.85 +/- 2.37 (p = .05) in the elderly subjects. In contrast, there was no decrease in the ED50 or increase in Emax for ISO-induced venodilation of hand veins following propranolol withdrawal. These results demonstrate that both young and elderly subjects have similar increases in cardiac chronotropic responsiveness following discontinuation of beta-blockade and do not support the concept that desensitization is responsible for the diminished beta-adrenergic responsiveness seen with aging.

Adult↗

PubMed1992

Bradykinin-induced venodilation is not impaired with aging in humans.

The aim of this study was to determine whether there is an age-related decline in vascular responsiveness to bradykinin, whose vasodilatory action is mediated chiefly through endothelium-derived relaxing factor (EDRF). Dose-response curves for bradykinin were constructed using the dorsal hand vein compliance technique in veins preconstricted with phenylephrine in 27 volunteers (16 male, 11 female) aged 18 to 81 years. At the end of the bradykinin study, 12 subjects had a single infusion of a high dose of isoproterenol. There was no correlation between age and the EMAX or the log ED50 for bradykinin, although the same subjects showed a correlation between age and EMAX for isoproterenol, as previously found. There was no significant difference in either the EMAX or the log ED50 between male and female subjects. The results suggest that bradykinin-induced vasodilation is independent of age or gender.

Adolescent↗

PubMed1992

Desensitization of beta-adrenoceptor- and prostaglandin E1 receptor-mediated human vascular smooth muscle relaxation.

Regulation of beta-adrenoceptors in animal tissues and human cell cultures has been extensively described; on the other hand, relatively little is known about regulation of beta-adrenoceptors in human tissues in vivo. Both beta-adrenoceptors and the prostaglandin E1 (PGE1) receptors stimulate vasodilation. We wondered if prolonged infusion of isoproterenol or PGE1 would cause desensitization of smooth muscle relaxation and used the dorsal hand-vein compliance technique to investigate this question. After constructing a dose-response curve to either the beta-agonist isoproterenol or to PGE1 in a phenylephrine preconstricted vein, isoproterenol (271 ng/min), PGE1 (956 pg/min), or saline was infused for 4 h in separate experiments. There was no change in the ED50 or Emax for either isoproterenol or PGE1 after saline infusion. After a 4-h infusion of isoproterenol, the maximal vasodilator response to isoproterenol was significantly (p less than 0.01) attenuated from 61 +/- 33% to 19 +/- 10%, while the ED50 significantly increased (p less than 0.01) from a geometric mean of 37 to 197 ng/min. After infusion of isoproterenol, the mean maximum PGE1-induced venorelaxation of 129 +/- 29% was modestly but significantly (p less than 0.05) blunted to 96 +/- 35%, while the ED50 of PGE1 increased significantly (p less than 0.01) from a geometric mean of 81 to 398 pg/min. A 4-h infusion of PGE1 significantly (p less than 0.01) attenuated the maximum response to PGE1 from 73 +/- 35 to 28 +/- 16%. The maximal vasodilatory response to isoproterenol was also significantly blunted (p less than 0.05) from 62 +/- 35 to 42 +/- 41%, with no change in ED50.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗

PubMed1992

Desensitization of nitrate-induced venodilation: reversal with oral N-acetylcysteine in humans.

The objective of this study was to determine whether the dorsal hand vein could be used as a model to study tolerance to oral nitrates, and whether oral N-acetylcysteine (NAC) could reverse tolerance if present. Dose-response curves to nitroglycerin were constructed for 11 normotensive volunteers before and during treatment with a sustained-release formulation of isosorbide dinitrate, 80 mg, three times daily for 7 days and followed by concurrent treatment with NAC at a mean dose of 150 mg/kg/day, in divided doses, for 2 days. In separate studies, dose-response curves were constructed for seven normotensive volunteers before and after treatment with oral NAC at the same dose for 2 days. Nitroglycerin's Emax was significantly attenuated from 115 +/- 36 to 77 +/- 22% after treatment with isosorbide dinitrate alone (p < 0.009). Concurrent treatment with NAC reversed this decrease, as nitroglycerin's Emax of 108 +/- 26% during coadministration of isosorbide dinitrate and NAC was not different from its Emax in the control period. There was also no difference in the dose of phenylephrine required to cause 80% of maximal venoconstriction throughout the study. These studies demonstrate that smooth muscle tolerance to nitrates can be demonstrated in medium-sized veins in humans. In addition, high-dose oral NAC can reverse existing tolerance to oral nitrates in human veins. These results indicate that the dorsal hand vein compliance technique is a good model for the clinical investigation of tolerance to nitrates in humans.

Acetylcysteine↗

PubMed1992

Prolonged activation of alpha 1 adrenoceptors induces down-regulation of protein kinase C in vascular smooth muscle.

Sustained exposure of vascular smooth muscle to catecholamines results in desensitization of alpha 1-adrenoreceptor-mediated vascular smooth muscle contraction. The present study was designed to determine the effects of prolonged exposure of blood vessels to catecholamines on protein kinase C (PKC) activity. Incubation of rat aortic smooth muscle with 10 microM norepinephrine (NE) for 4 h resulted in a threefold decrease in sensitivity of the contractile response of rat aortic smooth muscle to the phorbol ester 4 beta-phorbol 12,13-dibutyrate (PDBu); this loss in sensitivity was dependent on the presence of endothelium. NE induced a 45% decrease in enzymatic activity of the soluble and particulate forms of PKC. With [3H]PDBu used to label phorbol ester receptor binding sites in the aorta, there was a 34% decrease in [3H]PDBu binding sites in NE-treated blood vessels without change in binding affinity for the ligand. To determine whether this loss in enzymatic activity and [3H]PDBu binding resulted from a decrease in the quantity of the enzyme, Western blot analyses were performed using a monoclonal antibody (MoAb) against PKC. This approach confirmed the presence of an 80-Kd immunoreactive PKC in the soluble fraction of rat aortic smooth muscle and demonstrated a 44% decrease in the amount of PKC in blood vessels after sustained exposure to catecholamines. Our results demonstrate that prolonged activation of alpha-adrenoceptors in blood vessels leads to down-regulation of PKC which may contribute to desensitization of contraction mediated by vasoconstrictors.

Animals↗

PubMed1992

Age-related changes in adenosine and beta-adrenoceptor responsiveness of vascular smooth muscle in man.

1. Ageing is associated with a decline in beta-adrenergic responsiveness in several tissues. Reduced beta-adrenoceptor mediated smooth muscle relaxation in aged man has been demonstrated using the dorsal hand vein technique. Isoprenaline and adenosine activate adenylate cyclase through separate membrane bound receptors to induce vasodilatation. 2. To determine the specificity of reduced beta-adrenergic responsiveness in smooth muscle of aged man, and possible sites of the defect responsible, venodilatory responses to isoprenaline, a beta-adrenoceptor agonist and adenosine were determined in nine young (age 26 +/- 3 years: mean +/- s.d.) and eight elderly (age 70 +/- 5 years), healthy male volunteers. Veins were partially constricted with the alpha 1-adrenoceptor agonist phenylephrine and increasing doses of adenosine (5 to 1220 micrograms min-1) or isoprenaline (271 ng min-1) were infused. 3. Maximal dilatation induced by isoprenaline was 83 +/- 26% in the young and 51 +/- 34% in the elderly, P = 0.02. Maximal dilatation induced at the highest dose of adenosine (1220 micrograms min-1) was similar in young and elderly: 79 +/- 25% vs 88 +/- 28%, P = 0.26. 4. Adenosine venodilatation was measured before and after infusions of theophylline (6.8 to 135 micrograms min-1) for 30 min in six subjects. Adenosine responsiveness was unchanged following theophylline: 48 +/- 16% to 49 +/- 40%, P = 0.44. 5. The results suggest that the age-associated reduced responsiveness of the beta-adrenergic system in human vascular smooth muscle is not shared by venodilatation mediated by adenosine.

Adenosine↗

PubMed1992

Assessment of delta-opioid receptor activation by a series of peptides in cultured cells.

This study was designed to investigate the relative ability of a series of cyclic opioid peptides to initiate the first activation steps following their binding of delta-opioid receptors. The extent of stimulation of low Km guanosine-triphosphatase (GTPase activity) and inhibition of hormonally-stimulated cAMP accumulation in the NG108-15 (neuroblastoma-glioma) hybrid cell line were determined and compared for six closely related peptides. In addition, their binding affinity was assessed by competition with 3H-[D-Pen2D-Pen5]-enkephalin (3H-DPDPE) in membranes from these cells. All peptides tested elicited comparable maximal effects for both functional responses. Different potencies in stimulating the low Km GTPase was observed at sub-maximal agonist concentrations, although the shallow dose-response behavior did not allow accurate determination of ED50s. Estimation of ED50s for inhibition of cAMP accumulation could be made by curve fitting and were similar for four of these peptides, while DCDPE and 3R-methylDCDPE, the highest affinity analogs, were considerably more potent. In general, the observed differences in hormonal activity somewhat parallel the rank order of binding affinities, but no strict relationship was found between receptor binding and activation.

Amino Acid Sequence↗

PubMed1992

Inactivation of endothelial derived relaxing factor by oxidized lipoproteins.

Endothelial cell derived relaxing factor (EDRF) mediated relaxation of blood vessels is impaired in vessels exposed to lipoproteins in vitro and in arteries of hyperlipidemic humans and animals. To investigate the mechanism by which lipoproteins impair the effects of EDRF, which is likely nitric oxide (NO) or a related molecule, we have bioassayed EDRF/NO activity by measuring its ability to increase cGMP accumulation in rat fetal lung cultured fibroblasts (RFL-6 cells). Low density lipoprotein modified by oxidation (ox-LDL) induced a concentration-dependent inhibition of EDRF activity that had been released from bovine aortic endothelial cells (BAEC) stimulated with bradykinin or the calcium ionophore A23187. In addition, lipoproteins directly impaired authentic NO-induced stimulation of cGMP accumulation in the detector cells; stimulation by sodium nitroprusside was unaffected. Ox-LDL or oxidized HDL3 were highly potent in blocking NO-stimulated cGMP accumulation with EC50's of approximately 1 microgram/ml. Lipid extracted from ox-LDL blocked NO-stimulated cGMP accumulation to about the same extent as intact ox-LDL, while the protein component of ox-LDL did not inhibit the cGMP response. These results suggest that the lipid component of oxidized lipoproteins inactivate EDRF after its release from endothelial cells.

Animals↗

PubMed1992

Pharmacological tolerance to alpha 1-adrenergic receptor antagonism mediated by terazosin in humans.

Chronic administration of alpha 1-receptor antagonists is associated with loss of clinical efficacy, especially in congestive heart failure, although the mechanism is uncertain. To evaluate changes in venous alpha 1-adrenoceptor responsiveness during chronic alpha 1-adrenoceptor blockade, dose-response curves to phenylephrine and angiotensin II were constructed in 10 healthy subjects before, during, and after administration of terazosin 1 mg orally for 28 d. Terazosin initially shifted the dose-response curve of phenylephrine to the right, with a significant increase in ED50 for phenylephrine from a control value of 102 to 759 ng/min on day 1 of terazosin (P < 0.001). However, by day 28, the dose-response curve had shifted back towards baseline with an ED50 of 112 ng/min. After discontinuing terazosin, the ED50 for phenylephrine remained near the baseline value, indicating no evidence of supersensitivity to phenylephrine. There was no change in responsiveness to angiotensin II during the course of treatment with terazosin. Plasma terazosin concentrations were stable throughout the period of drug administration. The mean Kd of terazosin was estimated as 11 +/- 15 nM in the first few days of treatment. This study demonstrates that pharmacological tolerance to the alpha 1-adrenoceptor blocking action of terazosin occurs in man and may be responsible for loss in efficacy with chronic therapy.

Adrenergic alpha-Antagonists↗

PubMed1992

Cardiovascular effects of omega-conopeptides in conscious rats: mechanisms of action.

We examined the effects of omega-conopeptides, a novel class of neuronal voltage-gated calcium channel antagonists, on hemodynamic responses in rats. Intravenous (i.v.) injections of SNX-111 (omega-conopeptide MVIIA) dose-dependently decreased arterial blood pressure (BP) in conscious rats. Intracerebroventricular (i.c.v.) SNX-111 injections (580 pmol) tended to increase BP and, after an initial decrease, to increase heart rate (HR). The dose-response curve for SNX-111 administered i.v. in conscious rats was biphasic. Beginning at subdepressor doses, SNX-111 caused a long-lasting blockade of pressor responses elicited by sympathetic nerve stimulation in pithed animals but did not prevent increases in BP evoked by exogenously administered norepinephrine (NE). Pretreatment of rats with histamine antagonists partially blocked the hypotensive effects of the higher (870 and 2,900 nmol/kg) doses of SNX-111. Substitution of alanine for arginine at position 10 ([Ala10]-MVIIA) markedly attenuated the histamine-mediated component of the vasodepressor response. Together, these findings indicate that SNX-111 administered i.v. decreases systemic BP by a combination of blockade of sympathetic neurotransmission and mast cell degranulation; the latter function appears to be dependent on the arginine residue in position 10 of the amino acid sequence of SNX-111.

Amino Acid Sequence↗

PubMed1992

Prolonged exposure to catecholamines enhances sensitivity of smooth muscle relaxation induced by sodium nitroprusside and atriopeptin.

Desensitization of alpha-1 adrenergic receptor-mediated contraction occurs in aortic smooth muscle from rats after in vitro exposure to norepinephrine (NE). The purpose of this study was to examine effects of pretreatment of blood vessels with catecholamines on relaxant responses of the vessels to sodium nitroprusside (SNP) and atriopeptin III (ANF). Vessels preincubated with NE for 4 hr had a markedly increased sensitivity to relaxation induced by SNP as compared to controls. The concentration of SNP giving half-maximal relaxation (log EC50) was -8.78 +/- 0.09 in the vessels pretreated with NE and -7.40 +/- 0.18 in controls (P less than .001). NE-treated vessels also had an increased sensitivity to ANF (EC50 -8.23 +/- 0.11 vs. -7.03 +/- 0.31, respectively; P less than .01). However, both desensitized and control vessels had similar sensitivity to relaxation induced by 8-bromo-cyclic GMP. The capacity of SNP to stimulate intracellular cyclic GMP accumulation in vessels pretreated with NE was greater than controls at a high concentration of SNP (10(-5) M.). However, there was no correlation between vasodilation induced by lower concentrations of SNP and stimulation of cyclic GMP accumulation in these blood vessels. Activity of soluble and particulate guanylate cyclase in NE-treated vessels was increased compared to controls. Changes in sensitivity of smooth muscle relaxation to SNP and ANF after prolonged exposure to catecholamines may relate to changes in capacity of the cyclic GMP system.

Animals↗