Program Director, Kansas City University of Medicine and Biosciences College of Osteopathic Medicine
Seven days following injection erectile dysfunction age 27 buy generic kamagra gold 100 mg online, after the area is reshaven erectile dysfunction and diabetes type 2 buy kamagra gold 100 mg without prescription, the test article is applied topically and an occluded patch is applied for 48 hours erectile dysfunction injection test buy kamagra gold 100mg line. In cases where the test article at the given concentration is nonirritating erectile dysfunction treated by buy cheap kamagra gold 100mg on-line, the area is pretreated with 10% sodium lauryl sulfate 24 hours before the patch is applied to produce a mild inflammatory response. Two weeks following topical application, the animals are challenged on the shaven flank with a nonirritating concentration of the test article, which remains under an occluded patch for 24 hours. Then, after 24 and 48 hours, the test site is examined for signs of erythema and edema, two well-recognized indicators of cutaneous inflammation and contact dermatitis. However, the endpoints for evaluation in the guinea pig assays are visual and subjective, and it is difficult to assess irritating or colored compounds using these models. Over the past 20 years, efforts have been made to develop and establish more quantitative and immunologically based assay methods in other species, focusing mainly on the mouse, again primarily because of the availability of reagents and techniques to conduct mechanistic studies. Gad and coworkers (1986) developed the mouse ear swelling test, which uses a quantitative measurement of ear thickness as an endpoint. Animals are sensitized by topical application of the test article for four consecutive days to abdominal skin that has been prepared by intradermal injection of adjuvant and tape stripping. On Day 10, the animals are challenged by topical application of the test article to one ear and vehicle to the contralateral ear. A positive response is considered anything above a 20% increase in thickness of the treated ear over the control ear. Thorne and colleagues (1991) showed that dietary supplementation with vitamin A enhanced the mouse ear swelling assay in the absence of adjuvants, injections, or occlusive patches. The assays described above evaluate the elicitation phase of the response in previously sensitized animals. In this assay, the induction phase of contact sensitization is measured by the incorporation of 3H-thymidine into proliferating lymphocytes in lymph nodes draining the site where the test article has been applied. Animals are dosed by topical application of the test article to the ears for three consecutive days. The animals are rested for two days and then injected intravenously with 20 Ci of 3 H-thymidine. Five hours later, animals are sacrificed, the draining lymph nodes are dissected out, and single-cell suspensions are prepared and radioassayed. As an example, some compounds capable of producing contact sensitization also induce IgE production and subsequent respiratory hypersensitivity. Assessment of Contact Hypersensitivity in Humans Human testing for contact hypersensitivity reactions is by skin patch testing. Patch testing allows for the diagnostic production of acute lesions of contact hypersensitivity by the application of a suspected allergen to the skin. Patches containing specified concentrations of the allergen in the appropriate vehicle are applied under an occlusive patch for 48 hours in most test protocols. Once the patch is removed and enough time elapses for the signs of mechanical irritation to resolve (approximately 30 minutes), the area is read for signs of erythema, papules, vesicles, and edema. Generally, the test is read again at 72 hours and, in some cases, signs may not appear for up to one week or more. Like predictive testing in animal models, there are many variations in attempts to increase the sensitivity of these procedures. These include preparation of the induction site by either tape-stripping, the application of an irritating concentration of sodium lauryl sulfate, or use of high concentrations of the test article for induction of sensitization. Assessment of Autoimmune Responses As described in the preceding section, exaggerated immune responses can be mediated by two entirely different types of interactions between the immune system and xenobiotics. One type of interaction was described in the preceding section in which the xenobiotic is a hapten, and the immune system plays an active role in eliciting a hypersensitivity response. The immune system can also be a passive target for the enhancing effects of drugs and chemicals, such as occurs when a xenobiotic mimics or causes the aberrant production of immunomodulatory cytokines, or when a xenobiotic disrupts the regulatory mechanisms which serve to protect self (ie, disrupt a suppressor mechanism). Additional mechanisms were presented above in the subsection "Autoimmunity" under "Immune-Mediated Disease. Moreover, the existence of environmental adjuvants is controversial and/or poorly studied. In the context of testing strategies, the situation with autoimmunity is much more complex than with hypersensitivity responses. Animal models exist for a number of autoimmune diseases, and autoimmunity has been clearly demonstrated in humans. Therefore, the existence of autoimmune disease and the expected consequences cannot be denied. However, the ability of drugs and chemicals to exacerbate or trigger autoimmune disease in either animal models or humans is poorly understood. In fact, of all the possible consequences of immunotoxicity, autoimmunity is unquestionably the least understood. Primarily because of the strong genetic component in the susceptibility to autoimmunity, deciphering the exact role of xenobiotics in the induction of these conditions has proven to be very difficult. The following is a brief review of some of the currently used methods of predicting the potential of a xenobiotic to trigger or exacerbate autoimmunity leading to an inappropriate immune response to self-tissue antigens that can be associated with the generation of autoantibodies and/or autoreactive T cells. As emphasized throughout this chapter, immunotoxicology has evolved to the point where an ever-increasing number of studies are being conducted to characterize the immunotoxicity of a variety of xenobiotics using standard immunotoxicological parameters. Depending on the specific drug/chemical, the exposure conditions, the species being tested and the immune parameter being measured, the outcomes can be manifested as decreases, increases, or no effect. While there is no question that the most frequent observation has been immune suppression, there is also no doubt that some examples of immune stimulation have been reported, a profile consistent with the concept of immunotoxicology existing as a continuum.
Whereas this conclusion may ultimately prove to be correct in any particular case erectile dysfunction doctor manila purchase kamagra gold 100mg with amex, it is not warranted solely on the basis of the 2 parallel lines erectile dysfunction watermelon purchase cheap kamagra gold line. The same admonition applies to any pair of parallel "effect" curves or any other pair of toxicity or lethality curves erectile dysfunction drugs buy cheap kamagra gold american express. The plot is of log dosage versus percentage of population responding in probit units erectile dysfunction treatment testosterone order kamagra gold with american express. The quantitative comparisons described above have been used mainly after a single administration of chemicals. A measure of the degree of accumulation of a chemical and/ or its toxic effects can also be estimated from quantal toxicity data. Theoretically, if no cumulative effect occurs over the doses, the chronicity index will be 1. Thus, for example, if an estimate of human exposure to a pesticide residue yielded a value of 0. This value indicates that the estimate of daily exposure under the described set of conditions is 1/1000 the estimated daily dose that would cause evident toxicity in 10% of exposed animals. One can then compare the potency and maximal efficacy of the 2 chemicals to produce a toxic effect. Chemical A is said to be more potent than chemical B because of their relative positions along the dosage axis. Potency thus refers to the range of doses over which a chemical produces increasing responses. Chemicals A and B have equal maximal efficacy, whereas the maximal efficacy of C is less than that of D. The living matter that is injured is termed the uneconomic form (or undesirable), and the matter protected is called the economic form (or desirable). They may be related to each other as parasite and host or may be 2 tissues in 1 organism. This biological diversity interferes with the ability of ecotoxicologists to predict the toxic effects of a chemical in 1 species (humans) from experiments performed in another species (laboratory animals). However, by taking advantage of the biological diversity, it is possible to develop chemicals that are lethal for an undesired species and harmless for other species. In agriculture, for example, there are fungi, insects, and even competitive plants that injure the crop, and thus selective pesticides are needed. Similarly, animal husbandry and human medicine require chemicals, such as antibiotics, that are selectively toxic to the undesirable form but do not produce damage to the desirable form. Drugs and other chemicals used for selective toxic purposes are selective for 1 of 2 reasons. Either (1) the chemical is equally toxic to both economic and uneconomic cells but is accumulated mainly by uneconomic cells or (2) it reacts fairly specifically with a cytological or a biochemical feature that is absent from or does not play an important role in the economic form (Albert, 1973). Selectivity resulting from differences in distribution usually is caused by differences in the absorption, biotransformation, or excretion of the toxicant. The selective toxicity of an insecticide spray may be partly due to a larger surface area per unit weight that causes the insect to absorb a proportionally larger dose than does the mammal being sprayed. The effectiveness of radioactive iodine in the treatment of hyperthyroidism (as well as its thyroid carcinogenicity) is due to the selective ability of the thyroid gland to accumulate iodine. A major reason why chemicals are toxic to one, but not to another, type of tissue is that there are differences in accumulation of the ultimate toxic compound in various tissues. This, in turn, may be due to differences in the ability of various tissues to transport or biotransform the chemical into the ultimate toxic product. Selective toxicity caused by differences in comparative cytology is exemplified by a comparison of plant and animal cells. Plants differ from animals in many ways-for example, absence of a nervous system, an efficient circulatory system, and muscles as well as the presence of a photosynthetic mechanism and cell walls. The fact that bacteria contain cell walls and humans do not has been utilized in developing selective toxic chemotherapeutic agents, such as penicillin and cephalosporins, that kill bacteria but are relatively nontoxic to mammalian cells. Selective toxicity can also be a result of a difference in biochemistry in the 2 types of cells. For example, bacteria do not absorb folic acid but synthesize it from p-aminobenzoic acid, glutamic acid, and pteridine, whereas mammals cannot synthesize folic acid but have to absorb it from the diet. Thus, sulfonamide drugs are selectively toxic to bacteria because the sulfonamides, which resemble p-aminobenzoic acid in both charge and dimensions, antagonize the incorporation of p-aminobenzoic acid into the folic acid molecule-a reaction that humans do not carry out. Species Differences Although a basic tenet of toxicology is that "experimental results in animals, when properly qualified, are applicable to humans," it is important to recognize that both quantitative and qualitative differences in response to toxic substances may occur among different species. As discussed above, there are many reasons for selective toxicity among different species. Even among phylogenetically similar species (eg, rats, mice, guinea pigs, and hamsters), large differences in response may occur.
In membranes erectile dysfunction in middle age buy kamagra gold 100 mg otc, the polar head groups are oriented toward the outer and inner surfaces of the membrane free erectile dysfunction drugs buy kamagra gold 100mg on-line, whereas the hydrophobic tails are oriented inward and face each other to form a continuous hydrophobic inner space erectile dysfunction za order kamagra gold no prescription. Numerous proteins are inserted or embedded in the bilayer erectile dysfunction by age order kamagra gold online, and some transmembrane proteins traverse the entire lipid bilayer, functioning as important biological receptors or allowing the formation of aqueous pores, ion channels, and transporters. The fatty acids of the membrane do not have a rigid crystalline structure but are semifluid at physiological temperatures. Overall, hydrophobic interactions are the major driving force in the formation of membrane lipid bilayers, and the fluid character of membranes is determined largely by the structure and relative abundance of unsaturated fatty acids. The more unsaturated fatty acids the membranes contain, the more fluid-like they are, facilitating more rapid active or passive transport. The membrane barrier is differentially permeable and regulates what enters into or exits from cells. Toxicants cross membranes Cytoplasm Phospholipid Intergral proteins Cholesterol Ion channel Ligand (Receptors, Transporters) Figure 5-2. The ionized form usually has low lipid solubility and thus does not permeate readily through the lipid domain of a membrane. There may be some transport of organic anions and cations (depending on their molecular weight) through the aqueous pores, but this is a slow and inefficient process. In contrast, the nonionized form of weak organic acids and bases is lipid soluble to some extent, resulting in diffusion across the lipid domain of a membrane. The rate of movement of the nonionized form is proportional to its lipid solubility such that the extent to which a compound is nonionized determines its diffusion. The molar ratio of ionized to nonionized molecules of a weak organic acid or base in solution depends on the ionization constant, which is defined as the pH at which a weak organic acid or base is 50% ionized (denoted as pKa or pKb for acids and bases, respectively). Like pH, pKa and pKb are defined as the negative logarithm of the ionization constant of a weak organic acid or base. An organic acid with a low pKa is relatively a strong acid, and one with a high pKa is a weak acid. The numerical value of pKa does not indicate whether a chemical is an organic acid or a base. Knowledge of the chemical structure is required to distinguish between organic acids and bases. Lipid solubility is generally determined by the octanol/water partition coefficient, P, which is defined as the ratio of the concentration of neutral compound in organic and aqueous phases under equilibrium conditions. It is usually expressed in logarithmic form as log P, and numerous examples are listed in Table 5-1. The log P is an extremely informative physicochemical parameter relative to assessing potential membrane permeability, with positive values associated with high lipid solubility. There are a variety of experimental methods for empirical determination of log P, along with computational tools that can be used to predict log P for any chemical (Mannhold et al. The effect of pH on the degree of ionization of an organic acid (benzoic acid) and an organic base (aniline) is illustrated in. At pH 4, exactly 50% of benzoic acid is ionized and 50% is nonionized because this is the pKa of the compound. As the pH increases, more and more protons are neutralized by hydroxyl groups, and benzoic acid continues to dissociate until almost all of it is in the ionized form. As the pH increases, ions from aniline continue to dissociate until almost all the aniline is in the nonionized form, which is the aniline base. As transmembrane passage is largely restricted to the nonionized form, benzoic acid is more readily translocated through a membrane from an acidic environment, whereas more aniline is transferred from an alkaline environment. Filtration When water flows in bulk across a porous membrane, any solute small enough to pass through the pores flows with it. One of the main differences between various membranes is the size of these channels. In renal glomeruli, a primary site of filtration, these pores are relatively large (about 70 nm) allowing molecules smaller than albumin (approximately 60 kDa) to pass through. The complex subsequently traverses to the other side of the membrane, where the substance is released. Afterward, the carrier returns to the original surface to repeat the transport cycle. Facilitated Diffusion Facilitated diffusion applies to carriermediated transport that exhibits the properties of active transport except that the substrate is not moved against an electrochemical or concentration gradient, and the transport process does not require the input of energy; that is, metabolic poisons do not interfere with this transport. Special Transport There are numerous compounds whose movement across membranes cannot be explained by simple diffusion or filtration. Some compounds are too large to pass through aqueous pores or too insoluble in lipids to diffuse across the lipid domains of membranes. Nevertheless, they are often transported very rapidly across membranes, even against concentration gradients. These systems are responsible for the transport (both influx and efflux) across cell membranes of many nutrients, such as sugars and amino and nucleic acids, along with numerous foreign compounds. Based on the sequencing of the human genome, there are at least 500 genes whose putative function involves membrane transport (Venter et al. Throughout this chapter, membrane-associated transporters known to contribute to the disposition and subsequent effects of xenobiotics will be emphasized. Importantly, the role of xenobiotic transporters in chemical disposition is an expanding research field, and new information regarding their function, molecular regulation, and genetic polymorphisms continues to inform and modify traditional concepts in toxicology.
Excitation of these neurons located in the cornea and the mucous membranes of the eye and the respiratory tract elicits irritation erectile dysfunction pump ratings buy kamagra gold 100 mg without a prescription, pain erectile dysfunction natural treatment options buy kamagra gold no prescription, lacrimation erectile dysfunction 50 years old cheap 100 mg kamagra gold fast delivery, bronchial secretion erectile dysfunction doctors buffalo ny order kamagra gold toronto, sneezing, coughing, and bronchospasm (Bessac and Jordt, 2010). If moderate, these responses are alerting and protective, but are incapacitating and detrimental when exaggerated at high exposure. Keap1 may be regarded as an intracellular sensor of similar chemicals, as covalent and/or oxidative modification of thiol groups in Keap1 triggers the adaptive electrophile stress response, which is cytoprotective. For example, covalent binding of aflatoxin 8,9-oxide to N-7 of guanine results in pairing of the adduct-bearing guanine with adenine rather than cytosine, leading to the formation of an incorrect codon and the insertion of an incorrect amino acid into the protein. Such events are involved in the aflatoxin-induced mutation of the Ras proto-oncogene and the p53 tumor suppressor gene (Eaton and Gallagher, 1994). Cross-linking imposes both structural and functional constraints on the linked molecules. Some target molecules are susceptible to spontaneous degradation after chemical attack. Subsequent fragmentation gives rise to hydrocarbons such as ethane and reactive aldehydes such as 4-hydroxynon-2-enal and malondialdehyde. Many of the products, such as the radicals and the,-unsaturated aldehydes, are reactive, whereas others, such as ethane, are nonreactive but are indicators of lipid peroxidation. F2-isoprostanes are stable peroxidation products of arachidonic acid; these are not only sensitive markers of lipid peroxidation but also potent pulmonary and renal vasoconstrictors (Basu, 2004). Apart from hydrolytic degradation by toxins and radiolysis, toxicant-induced fragmentation of proteins is not well documented. For instance, cytochrome P450 converts allyl isopropyl acetamide into a reactive metabolite, which alkylates the heme moiety of the enzyme. Arsine (AsH3) acutely induces heme release from oxyhemoglobin, which may underlie its hemolytic effect. Formation of a bulky Neoantigen Formation Whereas the covalent binding of xenobiotics or their metabolites is often inconsequential with respect to the function of the immune system, in some individuals these altered proteins, which carry the xenobiotic adduct as a hapten, evoke an immune response. Some chemicals (eg, dinitrochlorobenzene, penicillin, and nickel ion) are sufficiently reactive to bind to proteins spontaneously. Others may obtain reactivity by autooxidation to quinones (eg, urushiols, the allergens in poison ivy) or by enzymatic biotransformation (Park et al. Haptenized proteins released from cells may evoke antibodymediated (humoral) and/or T-cell-mediated (cellular) immune response. Antigen binding (as signal #1) and cell surface costimulatory molecules on T-helper cells (as signal #2) induce differentiation of B cells into plasma B cells that manufacture and secrete antibody. By binding to the antigen, the antibody assists in destruction of the antigen by phagocytosis; however, harmful consequences may also result. For example, when penicillin-bound proteins as antigens react with IgE-type antibodies on the surface of mast cells, the reaction triggers release of mast cell mediators (eg, histamine, leukotrienes), which in turn may cause bronchoconstriction (asthma), vasodilatation, and plasma exudation (wheal, anaphylactic shock). Without signal #2 (which verifies that the antigen detected is foreign) the T cell becomes functionally inert (anergic). Whereas this response is protective against virus-infected cells and tumor cells, it causes inflammation and cell injury in cells containing xenobiotic 64 neoantigens. This model describes the response to contact allergens, such as nickel and urushiols, and is the basis of detecting contact allergens in mice with the local lymph node assay. Regarding contact allergens, a new concept has emerged: to elicit allergic contact dermatitis chemicals should not only initiate formation of antigen-specific T cells (as described above) but also evoke a less specific inflammatory reaction (referred to as innate immune signal). The need for an innate immune signal may account for the observation that contact allergy may be facilitated by an injury evoking inflammatory response, such as toxic cell injury by an irritant chemical or microbial infection. The causative chemicals are typically nucleophiles, such as aromatic amines (eg, aminopyrine, clozapine, procainamide, and sulfonamides), hydrazines (eg, hydralazine and isoniazid), and thiols (eg, propylthiouracil, methimazole, and captopril). The reactive metabolites may also activate monocytes and thus promote the immune reaction. For example, some chemicals (eg, the ethylene glycol-derived Ca-oxalate, methotrexate, and acyclovir) form water-insoluble precipitates in renal tubules. The poorly water-soluble complex produced in renal tubules from melamine and its derivative cyanuric acid caused the renal injury observed in cats and dogs fed adulterated pet food (Dobson et al. By occupying bilirubin binding sites on albumin, compounds such as the sulfonamides induce bilirubin toxicity (kernicterus) in neonates. Carbon dioxide displaces oxygen in the pulmonary alveolar space and causes asphyxiation. Certain programs determine the destiny of cells-that is, whether they undergo division, differentiation (ie, express proteins for specialized functions), or apoptosis. Other programs control the ongoing (momentary) activity of differentiated cells, determining whether they secrete more or less of a substance, whether they contract or relax, and whether they transport and metabolize nutrients at higher or lower rates. For regulation of these cellular programs, cells possess signaling networks (such as those shown in. To execute the programs, cells are equipped with synthetic, metabolic, kinetic, transport, and energy-producing systems as well as structural elements, organized into macromolecular complexes, cell membranes, and organelles, by which they maintain their own integrity (internal functions) and support the maintenance of other cells (external functions). If the target molecule is involved in cellular regulation (signaling), dysregulation of gene expression and/or dysregulation of momentary cellular function occur primarily. The reaction of a toxicant with targets serving external functions can influence the operation of other cells and integrated organ systems. Toxicity Not Initiated by Reaction with Target Molecules Some xenobiotics not only interact with a specific endogenous target molecule to induce toxicity but also, instead, alter the biological microenvironment (see step 2b in. Receptor activation may ultimately lead to (1) altered gene expression that increases or decreases the quantity of specific proteins and/or (2) a chemical modification of specific proteins, typically by phosphorylation, which activates or inhibits proteins. The third step in the development of toxicity: alteration of the regulatory or maintenance function of the cell. Whereas desirable in the treatment of lymphoid malignancies, this is an unwanted response in many other conditions.
Many exocrine secretory cells are controlled by muscarinic acetylcholine receptors (item 11 in erectile dysfunction in diabetes pdf buy generic kamagra gold 100 mg on-line. Salivation erectile dysfunction treatment time cheap kamagra gold 100 mg overnight delivery, lacrimation trimix erectile dysfunction treatment order kamagra gold now, and bronchial hypersecretion after organophosphate insecticide poisoning are due to stimulation of these receptors erectile dysfunction melanoma purchase kamagra gold in united states online. In contrast, blockade of these receptors contributes to the hyperthermia characteristic of atropine poisoning. Kupffer cells, resident macrophages in the liver, secrete inflammatory mediators. Because Kupffer cells possess glycine receptors, that is, glycine-gated Cl- channels (item 4 in. The discovery that some sulfonamides produce hypoglycemia in experimental animals led to the development of oral hypoglycemic agents for diabetic patients. These drugs inhibit K+ channels in pancreatic cells, inducing sequential depolarization, Ca2+ influx through voltage-gated Ca2+ channels, and exocytosis of insulin (Hardman et al. The antihypertensive diazoxide acts in the opposite fashion on K+ channels and impairs insulin secretion. Whereas this effect is generally undesirable, it is exploited in the treatment of inoperable insulin-secreting pancreatic tumors. Toxic Alteration of Cellular Maintenance Numerous toxicants interfere with cellular maintenance functions. In a multicellular organism, cells must maintain their own structural and functional integrity as well as provide supportive functions for other cells. Execution of these functions may be disrupted by chemicals, resulting in a toxic response. Impairment of Internal Cellular Maintenance: Mechanisms of Toxic Cell Death For survival, all cells must synthesize endogenous molecules; assemble macromolecular complexes, membranes, and cell organelles; maintain the intracellular environment; and produce energy for operation. Chemicals that disrupt these functions, especially the energy-producing function of mitochondria and protein synthesis controlling function of the genome, jeopardize survival and may cause toxic cell death. In the following discussion, these events and the chemicals that may cause them are individually characterized. Then it is pointed out how their concerted action may induce a bioenergetic catastrophe, culminating in necrosis. Finally, there follows a discussion of the circumstances under which the cell can avoid this disordered decay and how it can execute death by activating catabolic processes that bring about an ordered disassembly and removal of the cell, called apoptosis. It is utilized in numerous biosynthetic reactions, activating endogenous compounds by phosphorylation and adenylation, and is incorporated into cofactors as well as nucleic acids. It is required for muscle contraction and polymerization of the cytoskeleton, fueling cellular motility, cell division, vesicular transport, and the maintenance of cell morphology. Coupled to oxidation of hydrogen to water, this process is termed oxidative phosphorylation. Substances in class A interfere with the delivery of hydrogen to the electron transport chain. For example, fluoroacetate inhibits the citric acid cycle and the production of reduced cofactors. Class B chemicals such as rotenone and cyanide inhibit the transfer of electrons along the electron transport chain to oxygen. Class C agents interfere with oxygen delivery to the terminal electron transporter, cytochrome oxidase. Arrows with letters A to D point to the ultimate sites of action of 4 categories of agents that interfere with oxidative phosphorylation (Table 3-6). For simplicity, this scheme does not indicate the outer mitochondrial membrane and that protons are extruded from the matrix space along the electron transport chain at 3 sites. Depletors of coenzyme A (CoA) (a) Thiol-reactive electrophiles: 4-(dimethylamino)phenol, p-benzoquinone (b) Drugs enzymatically conjugated with CoA: salicylic acid (the metabolite of aspirin), valproic acid 8. Multisite inhibitor drugs: phenformin, propofol, salicylic acid (when overdosed) E. Ca2+ transporter, they play a significant role in Ca2+ sequestration only when the cytoplasmic levels rise into the micromolar range. Under such conditions, a large amount of Ca2+ accumulates in the mitochondria, where it is deposited as calcium phosphate. Toxicants induce elevation of cytoplasmic Ca2+ levels by promoting Ca2+ influx into or inhibiting Ca2+ efflux from the cytoplasm (Table 3-7). Opening of the ligand- or voltage-gated Ca2+ channels Table 3-7 Agents Causing Sustained Elevation of Cytosolic Ca2+ A. Hydrolytic enzymes: phospholipases in snake venoms, endogenous phospholipase A2 3. The increased conversion of pyruvate to lactate also may contribute to the acidosis. The intracellular phosphoric acidosis is beneficial for the cells presumably because the released phosphoric acid forms insoluble calcium phosphate, preventing the rise of cytosolic Ca2+, with its deleterious consequences (see below). Terminally, the intracellular pH rises, increasing phospholipase activity, and this contributes to irreversible membrane damage (ie, rupture of the blebs) not only by degrading phospholipids but also by generating endogenous detergents such as lysophospholipids and free fatty acids. Sustained Rise of Intracellular Ca2+ Intracellular Ca2+ levels are highly regulated.
