Biomedical subjects

A Sandoval

Publications and source records attributed to A Sandoval.

12 recordsLinked to original sources

PubMed1991

Potent inhibitory effects of suicide inhibitors of P450 isozymes on 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene initiated skin tumors.

A single dose of 1-ethynylpyrene (EP), 1-vinylpyrene (VP) or 2-ethynylnaphthalene (EN) was applied to the skin of SENCAR mice 5 min before an initiating dose of 7,12-dimethylbenz[a]anthracene (DMBA) or benzo[a]pyrene (B[a]P) and the development of skin tumors then promoted with biweekly topical applications of 12-O-tetradecanoylphorbol-13-acetate (TPA). The application of EP strongly inhibited the formation of skin tumors initiated by either DMBA or B[a]P in a dose-dependent manner. Application of 44 pmol of EP inhibited tumor initiation by 10 nmol of DMBA approximately 25%; application of 440 nmol of EP inhibited tumor initiation by 200 nmol of B[a]P approximately 51%. A high single dose of EP (4.4-44 mumol) nearly eliminated skin tumor initiation by either 10 nmol of DMBA or 200 nmol of B[a]P. Application of VP also inhibited the formation of skin tumors initiated by either DMBA or B[a]P in a dose-dependent manner, but higher doses of VP than of EP were required to produce comparable inhibitions. Application of 44 nmol of VP inhibited tumor initiation by 10 nmol of DMBA approximately 30%; application of 4.4 mumol of VP inhibited tumor initiation by 200 nmol of B[a]P approximately 56%. Application of EN yielded contrasting results. EN inhibited the formation of skin tumors initiated by 10 nmol of DMBA, but the observed dose-dependence was minimal; tumors were decreased about 40% by 3.3 mumol of EN and only about 65% by 132 mumol of EN. A high single dose of EN (132 mumol) increased both the mean number of tumors per mouse and the percentage of mice that developed tumors after initiation by 200 nmol of B[a]P. Topical application of 4.4 mumol of EP, 22 mumol of VP or 33 mumol of EN to the skin of SENCAR mice 5 min before a single initiation dose of 2.5 mumol of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) had a minimal inhibitory effect (14-28%) on the development of skin tumors produced by subsequent biweekly promotion with TPA. A single dose of 44 mumol of EP or 132 mumol of EN followed by biweekly applications of TPA did not produce skin tumors; however, a dose of 44 mumol of VP followed by promotion with TPA produced a low but significant number of skin tumors.(ABSTRACT TRUNCATED AT 400 WORDS)

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1990

Beta-adrenergic pathways in nonfailing and failing human ventricular myocardium.

beta-Adrenergic pathways in the human ventricular myocardium mediate the powerful positive inotropic effects of released neurotransmitters (norepinephrine) and circulating hormones (epinephrine) and the response to therapeutically administered beta-agonists. Two genetically and pharmacologically distinct receptors, beta 1 and beta 2, mediate the contractile effects of catecholamines in a similar manner. The biologic signal produced by the occupancy of beta-adrenergic receptors by catecholamine agonists is transduced, amplified, and regulated by a family of guanine nucleotide-binding proteins (G proteins), which serve both stimulatory and inhibitory functions. Although the major biochemical effector of beta-adrenergic receptors is the enzyme protein--coupled directly to ion channels that regulate inotropic and electrophysiological effects. In human ventricular myocardium, heart failure produces changes in the beta-adrenergic receptor pathways that have the collective effect of reducing the degree of inotropic stimulation that may be produced by a given amount of beta-agonist. These changes include downregulation of beta 1-adrenergic receptors, uncoupling of beta 2-adrenergic receptors, and an increase in the functional activity of the inhibitory G protein. These effects in turn are probably caused by exposure to increased amounts of neurotransmitter resulting from a complex series of changes in the cardiac sympathetic nervous system. Finally, the components of the beta-receptor-G protein system may be both acutely and chronically modulated by certain kinds of pharmacological therapy. These observations underscore the importance of the adrenergic nervous system in heart failure, and they create the potential for the development of new interventional strategies designed to alter the natural history of heart muscle disease and heart failure.

Adenylyl Cyclases↗

PubMed1989

Beta-adrenoceptor regulation in the human heart: can it be monitored in circulating lymphocytes?

In heart failure a decrease in cardiac beta-adrenoceptors presumably due to endogenous down-regulation by the elevated catecholamines is a general phenomenon. Thus, attempts have been made to assess beta-adrenoceptor function in patients with chronic heart failure in order to monitor the functional state of cardiac beta-adrenoceptors. The model most widely used is that of circulating lymphocytes that contain a homogeneous population of beta 2-adrenoceptors coupled to the adenylate cyclase/cyclic AMP system. The biochemical and pharmacological properties of beta 2-adrenoceptors present in lymphocytes are quite comparable to those of beta 2-adrenoceptors in the human heart, but clearly different from those of human cardiac beta 1-adrenoceptors. Furthermore, beta-adrenoceptor agonists and antagonists regulate lymphocyte beta 2- and cardiac beta 1- and beta 2-adrenoceptors in a subtype-selective fashion: while non-selective agonists (independent of exogenously applied or endogenously elevated) and antagonists affect both cardiac beta 1- and beta 2- as well as lymphocyte beta 2-adrenoceptors, beta 1-selective agonists and antagonists influence only cardiac beta 1-, but not cardiac and lymphocyte beta 2-adrenoceptors. Finally, direct comparison of lymphocyte and cardiac beta-adrenoceptor densities revealed that changes in lymphocyte beta 2-adrenoceptors are significantly correlated with changes in cardiac beta 2-adrenoceptors, but not related to changes in cardiac beta 1-adrenoceptors. Since beta 1-adrenoceptors predominate in all parts of the human heart, the use of lymphocyte beta 2-adrenoceptors as a tool for predicting the status of cardiac beta-adrenoceptors is, therefore, quite limited.

Humans↗

PubMed1974