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Biomedical subjects

R A Keith

Publications and source records attributed to R A Keith.

At least 55 records · Page 3Linked to original sources
PubMed1989

Characterization of the effects of omega-conotoxin GVIA on the responses of voltage-sensitive calcium channels.

1. omega-conotoxin GVIA (omega-CT) caused a potent (IC50 approximately 2nM) but less than maximal (55%) inhibition of [3H]-noradrenaline release from cortical brain slices induced by K+. At 0.1 microM, omega-CT inhibited [3H] gamma-aminobutyric acid (GABA) and [3H]-acetylcholine release by approximately 40%. 2. K+-evoked [3H]-noradrenaline release from cortical brain slices was also characterized with respect to the effects of PN 200-110 (dihydropyridine L-channel antagonist), BAY K8644 (L-channel VSCC agonist), and Cd++ (an inorganic L- and N-channel antagonist). 10 microM Cd++ and 1 microM PN 200-110 inhibited K+-evoked [3H]-noradrenaline release by 52% and 17%, respectively. 10 microM Bay K 8644 enhanced K+-evoked [3H]-noradrenaline release by 22%, and this enhancement was blocked by 1 microM PN 200-110. 3. omega-CT caused a near-maximal inhibition of the electrically evoked twitch responses of the rat vas deferens (IC50 approximately 10 nM) and guinea-pig ileum (IC50 approximately 60 nM), but had no effect on the postjunctional contractile responses of noradrenaline (vas deferens) or carbachol (ileum). At concentrations as high as 1 microM, omega-CT had no effect on the K+-induced contraction of the rat aorta. 4. Neither the equilibrium binding of [3H]-(+)-PN 200-110 nor the allosteric regulation of [3H]-(+)-PN 200-110 binding by tiapamil or diltiazem were altered by omega-CT (0.1 microM). 5. These observations support the notion that the N-type voltage-sensitive calcium channel plays a major role in coupling neuronal excitation with neurotransmitter release.

Acetylcholine↗
PubMed1989

Inhibition of N-methyl-D-aspartate- and kainic acid-induced neurotransmitter release by omega-conotoxin GVIA.

1. The role of voltage-sensitive calcium channels (VSCC) in N-methyl-D-aspartate (NMDA)- and kainic acid (KA)-evoked neurotransmitter release from rat cortical and hippocampal brain slices was evaluated by determining the effects of omega-conotoxin GVIA, an inhibitor of neuronal L- and N-type VSCC, and PN 200-110, a selective inhibitor of L-type VSCC. 2. Selective antagonists of the NMDA receptor ionophore complex, Mg2+, CPP and MK-801, inhibited NMDA- but not KA-evoked release of [3H]-noradrenaline from hippocampal and cortical brain slices. This suggests that cortical and hippocampal receptors are similar and that NMDA and KA act at distinct excitatory amino acid receptor subtypes. 3. [3H]-noradrenaline release induced by both NMDA and KA was similarly inhibited (approximately 30%) by omega-conotoxin GVIA. In contrast, PN 200-110 had no significant effect, although there was a tendency towards inhibition. 4. The results suggest that although NMDA- and KA-receptors are pharmacologically distinct, the N-type, but not the L-type, VSCC plays a small but significant role in neurotransmitter release induced by both NMDA and KA. It remains to be determined whether the N-type VSCC are involved in the physiological and/or pathological manifestations of excitatory amino acid receptor stimulation.

Animals↗
PubMed1989

ICI 147,798: a slowly dissociable beta adrenoceptor antagonist that causes insurmountable beta-1 and surmountable beta-2 adrenoceptor antagonism in isolated tissues.

ICI 147,798 has been shown to exhibit both diuretic and beta-antagonist properties in vivo. The present study investigated the nature and selectivity of the beta-antagonism in a variety of isolated tissues. ICI 147,798 produced a concentration-dependent suppression of the maximum chronotropic response of norepinephrine in guinea pig right atria (beta-1 adrenoceptor). ICI 147,798 caused a concentration-dependent shift to the right of the salbutamol concentration-response curve in the guinea pig trachea (beta-2 adrenoceptor), and Schild analysis suggested competitive inhibition. Propranolol produced parallel shifts to the right of the norepinephrine concentration-response curve in guinea pig right atria, except at relatively high concentrations. The inhibitory effects of propranolol in guinea pig right atria were reversed by greater than 95%, whereas the effects of ICI 147,798 were only slightly reversed after a 6-hr washout period. Preincubation of propranolol with ICI 147,798 in guinea pig right atria prevented completely the suppression of the norepinephrine maximum chronotropic response. Postincubation of propranolol with ICI 147,798 partially reversed the suppression of the maximum chronotropic response. ICI 147,798 had no effect on the maximum chronotropic responses of either histamine (H2-receptor) or forskolin (adenylate cyclase activation) in guinea pig right atria and had no effect on agonist responses in a variety of other receptor systems. The insurmountable beta-1 adrenoceptor antagonism was evaluated based on the assumptions of irreversible competitive antagonism, mixed competitive and noncompetitive antagonism and slowly dissociating competitive antagonism ("hemi-equilibrium" conditions). Concentration-dependent changes in norepinephrine KA values suggested the first three possibilities were unlikely.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1989

Insurmountable beta receptor blockade by ICI 147,798 in rabbits.

In rabbits, the characteristics of cardiac beta-1 receptor blockade produced by ICI 147,798, a novel beta receptor blocking agent with diuretic properties, were evaluated and compared with those of propranolol. In conscious rabbits, i.v. injections of 0.31, 1.0 and 3.1 mg/kg of ICI 147,798 and 1.0 mg/kg of propranolol caused significant bradycardia. ICI 147,798 produced a dose-dependent shift to the right of the dose-response (chronotropic) curve of isoproterenol with suppression of the maximal tachycardia, an effect characteristic of insurmountable beta receptor blockade. Propranolol also produced a shift to the right of the dose-response curve of isoproterenol without affecting the maximal tachycardia. ICI 147,798-induced antagonism was specific for beta adrenoceptors as it failed to modify the effects of acetylcholine, angiotensin II, phenylephrine, adenosine, histamine and prostaglandin E2 on mean arterial pressure and heart rate. In rabbits with prior autonomic blockade, ICI 147,798, like propranolol, failed to inhibit the positive chronotropic effects of theophylline which are mediated by postreceptor mechanisms. In reserpinized rabbits, ICI 147,798 was found to have no intrinsic sympathomimetic activity. Unlike the effects of propranolol, which were attenuated by first-pass through the hepatic vascular bed, the effects of ICI 147,798 were unaffected suggesting an absence of first-pass metabolism. The effects of propranolol (1.0 mg/kg i.v.) were not detectable at 24 hr after injection, whereas significant beta receptor blocking activity was still present at 24 hr after ICI 147,798 (1.0 mg/kg i.v.). The results suggest that ICI 147,798 is a specific, long-acting, insurmountable beta-1 receptor blocking agent without intrinsic sympathomimetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1988

Observations in the rehabilitation hospital: twenty years of research.

For the past 20 years two research groups, one in Texas and one in California, have been making systematic observations of rehabilitation hospital activities. In both programs interest in recording behavior originated with an environmental psychology orientation. The Texas investigations focused primarily on individuals with spinal cord injury, both during rehabilitation and after discharge. In California, the study populations have been primarily those with strokes. Early work revealed that patients spent a relatively small portion of the day in therapeutic routines, their activities were restricted to a few hospital locations, and the opportunities for independent behavior were limited. Later research has shown a more intensive treatment schedule, but patients still spend a significant portion of the work-day alone and not in treatment. Observations in three different hospitals showed that patients experienced very similar treatment routines. Using both mechanical and human recording methods, it was found that measures of hospital behavior were sensitive to treatment progress and were robust predictors of postdischarge outcomes. Although this work has produced insights into the operation of rehabilitation hospitals, there is little evidence that it has influenced their operations. The current organization of treatment needs to be examined, however, in light of the findings presented here.

Behavior↗
PubMed1987

Inhibition of presynaptic alpha-2-adrenoceptor and opioid receptor agonist responses in the rat vas deferens by chronic imipramine treatment.

The effects of chronic imipramine administration on agonist responses in rat isolated smooth muscle preparations were investigated. The administration of 20 mg/kg imipramine two times a day for 4 and 11 days resulted in an equivalent subsensitivity (approximately 8-fold) of clonidine-induced inhibition of electrically evoked contractions in the rat vas deferens (presynaptic alpha 2-adrenoceptor response). Imipramine (4 days) resulted in a marked inhibition of the ability of [D-Ala2, D-Leu5] enkephalin to decrease electrically evoked contractions of the vas deferens (presynaptic opioid receptor response) but did not significantly affect the carbachol-induced increase in electrically evoked contractions (muscarinic receptor response). In the absence of cocaine the contractile effects of norepinephrine and tyramine in the vas deferens were, respectively, potentiated and inhibited, following imipramine (4 days), suggesting a decrease in the activity of the neuronal uptake mechanism. When determined in the presence of cocaine, the potency of the postsynaptic effects of norepinephrine in the vas deferens (alpha 1-adrenoceptor response) was not significantly altered by imipramine (4 days). With regard to other postsynaptic receptors, imipramine (4 days) decreased slightly the potency of phenylephrine in the aorta (alpha 1-adrenoceptor response) and increased slightly the potency of carbachol in the trachea (muscarinic receptor response) and the potency of serotonin in the rat aorta (5HT2-receptor response). Thus, chronic imipramine administration decreased the potency of presynaptic alpha 2- and opioid agonist responses in the vas deferens but caused very little or no changes in the potencies of agonists at postsynaptic sites.

Adrenergic alpha-Antagonists↗
PubMed1987

Time use of stroke patients in three rehabilitation hospitals.

The active role of the patient in the rehabilitation hospital requires the efficient use of patient time. Previous work has found that such patients spend a relatively small portion of their day in treatment. In this study 63 stroke patients in three hospitals were observed for two work days each. Fifty observations were made during each day of the patient's location, activity and whom the patient was with. Treatment occupied an average of 31% of the day. Passive behavior took up 42% of patients' time. Discriminant analysis showed that patients in the hospital with a separate stroke unit spent more time in treatment. In spite of quantitative differences, the three hospitals had similar patterns of treatment activity and deployment of staff. Clinical norms for the treatment of stoke across the three hospitals resulted in similar treatment experiences for patients. A system of prospective payment which did not require specific billed treatment hours might allow more flexibility and efficiency in this type of specialty hospital.

Aged↗
PubMed1987

Individual variations of prostanoid agonist responses in rabbit aorta: evidence for the independent regulation of prostanoid receptor subtypes.

1 The frequency and selectivity of individual variations of prostanoid agonist responses in aortic strips from a population of male rabbits was studied. Three levels of responsiveness to the thromboxane mimetic U46619 occurred: responders (R), intermediate responders (IR), and non-responders (NR). R could be subdivided into R1 and R2 based on an enhanced potency of prostaglandin F2 alpha (PGF2 alpha) in R2. In the total population (n = 92), the phenotype frequency was: R, 69%; IR, 11%; and NR, 20%. In a subgroup of this population in which R1 and R2 phenotypes were determined (n = 63), the phenotype frequency was: R1, 54%; R2, 19%; IR, 6%; and NR, 21%. 2 The four rabbit aorta phenotypes, R1, R2, IR, and NR, were characterized with respect to the rank orders of prostanoid agonist potency, agonist intrinsic activities, and the effects of the thromboxane receptor antagonist SQ29548. The rank order of prostanoid agonist potency was U46619 greater than PGF2 alpha greater than PGE2 in R1 and R2, and PGF2 alpha greater than or equal to PGE2 greater than U46619 in IR and NR. For each prostanoid agonist, the intrinsic activity was highest in R (R1 congruent to R2), intermediate in IR, and lowest in NR. In R1, SQ29548 inhibited all prostanoid agonist responses equally. The contractile effects of PGF2 alpha and PGE2 were partially resistant to inhibition by SQ29548 in R2. Prostanoid agonist responses were not inhibited by SQ29548 in IR. 3 The potency of histamine was equivalent in R1, R2, IR, and NR. 4 It is concluded that there are individual variations in the functional expression of thromboxane receptor sensitivity, i.e., prostanoid agonist responses inhibited by SQ29548. Also, there are individual variations in the functional expression of the sensitivity of a non-thromboxane receptor or receptors, i.e., prostanoid agonist responses not inhibited by SQ29548. It has been proposed by others that prostanoid receptors be termed P-receptors and that the prostanoid agonist to which they are most sensitive be indicated by a preceding letter, e.g., TP- for thromboxane receptor and FP- for PGF2 alpha-selective receptor. Accordingly, we proposed a working hypothesis that suggests the four phenotypes could result from the independent regulation of the functional expression of TP- and FP-receptor subtypes with (a) R2 containing both the TP- and FP-receptor subtypes in a fully functional state; (b) R1 containing only the functional TP-receptor; (c) IR containing only the functional FP-receptor; and (d) NR containing only a low efficacy FP-receptor system. 5 The mechanisms underlying the observed individual variations are unknown but could include changes in receptor number or affinity, changes in receptor-effector coupling, changes in a second messenger system, or changes in tissue degradative or uptake processes. Further study is needed to differentiate between these possibilities.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1987

In vitro pharmacology of ICI 198,615: a novel, potent and selective peptide leukotriene antagonist.

ICI 198,615 is a representative compound from a new class of peptide leukotriene (LT) receptor antagonists. In isolated guinea pig trachea and parenchymal lung strips, ICI 198,615 demonstrated competitive antagonism of the contractile activity of LTD4 and LTE4 with pA2 values of 10.1 to 9.5, respectively. The compound also appeared to antagonize the contractile activity of LTC4 in guinea pig trachea; however, in the presence of an inhibitor of the metabolism of LTC4 to LTD4, ICI 198, 615 provided a pKB value of 5.3, indicating weak antagonism at the LTC4 receptor. ICI 198,615 was also a potent antagonist of LTC4 and LTD4 in isolated human bronchi and pulmonary veins with pKa values of 9.75 +/- 0.32 to 9.20 +/- 0.24, respectively. When evaluated for activity on a broad variety of non-LT receptors, the compound displayed a minimal selectivity of 6310 and a maximal selectivity of greater than 125,000 for the LTE4 receptor. These in vitro studies indicate that ICI 198,615 is the most potent and selective peptide LT receptor antagonist described to date.

Acetophenones↗
PubMed1986

The effect of varying carbachol concentration on the slope of Schild plots of selective beta-adrenoceptor antagonists in the carbachol-contracted guinea-pig trachea.

The effect of varying the level of smooth muscle tone induced by carbachol on the Schild analysis of atenolol (beta 1-selective) and ICI 118,551 (beta 2-selective) with salbutamol as agonist, on the guinea-pig tracheal preparation has been examined. When 10(-6) M carbachol was used to induce near-maximal smooth muscle tone, Schild plot slopes for atenolol and ICI 118,551 were less than 1. Slopes of Schild plots for both drugs were equivalent to 1 when 10(-7) M carbachol was used to produce approximately half-maximal smooth muscle tone. Depletion of neuronal noradrenaline by prior treatment with reserpine had no effect on the Schild analysis. Salbutamol produced maximal relaxation and was more potent when tone was induced with 10(-7) M carbachol, but was less effective at 10(-6) M carbachol. Pretreatment with reserpine increased the potency of salbutamol at each concentration of carbachol. The results suggest that either the level of smooth muscle tone or an unknown effect associated with a high level of smooth muscle tone induced by carbachol may contribute to low slope values of Schild plots of selective beta-adrenoceptor antagonists in the carbachol-contracted guinea-pig trachea. The carbachol-contracted guinea-pig trachea can be used to determine theoretically valid pA2 values for selective beta-adrenoceptor antagonists as long as substantially less than a maximal level of smooth muscle tone is induced by carbachol.

Adrenergic beta-Antagonists↗
PubMed1986

Modulation of peripheral beta-1 and alpha-2 receptor sensitivities by the administration of the tricyclic antidepressant, imipramine, alone and in combination with alpha-2 antagonists to rats.

The purpose of the present investigation was to determine whether peripheral beta-1 and alpha-2 receptors are regulated by the tricyclic antidepressant, imipramine. The administration of imipramine alone decreased the sensitivity of peripheral beta-1 receptor activity in anesthetized rats (isoproterenol-induced positive chronotropy) after 11 days, but not after 4 days. The coadministration of the selective alpha-2 antagonists, yohimbine or idazoxan (RX 781094), with imipramine resulted in a decrease in beta-1 receptor sensitivity in anesthetized rats within only 4 days. In isolated spontaneously beating right atria taken from drug-treated rats, beta-1 receptor sensitivity (isoproterenol positive chronotrophy) was not affected by the administration of imipramine for 4 days; however, administration of imipramine for 11 days resulted in significant decrease in beta-1 receptor sensitivity. The coadministration of yohimbine or idazoxan with imipramine resulted in a decrease in beta-1 receptor function in only 4 days. Beta-2 receptor sensitivity (isoproterenol-induced hypotension in anesthetized rats) was not significantly altered under conditions in which beta-1 receptor sensitivity was decreased. The destruction of central catecholamine-containing neurons with 6-hydroxydopamine prevented the subsensitivity of peripheral beta-1 receptor function in anesthetized rats induced by the coadministration of imipramine plus yohimbine (4 days). The sensitivity of peripheral alpha-2 receptors (clonidine-induced inhibition of electrically stimulated rat vas deferens) was depressed after the administration of imipramine alone (4 days) and imipramine plus yohimbine or idazoxan (4 days).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1985

Thiopurine methyltransferase: mouse kidney and liver assay conditions, biochemical properties and strain variation.

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of aromatic and heterocyclic thiol compounds including drugs such as 6-mercaptopurine (6-MP) and 6-thioguanine. In humans, the level of TPMT activity is inherited in a monogenic fashion. It would be important to develop an experimental animal model in which the genetic regulation of TPMT could be studied. Therefore, TPMT activity was measured in kidney and liver homogenates from A/J inbred mice. Apparent Michaelis (Km) constants for the two cosubstrates for the reaction, 6-MP and S-adenosyl-L-methionine (Ado-Met), in mouse kidney were 7.0 X 10(-4) M and 2.4 X 10(-6) M respectively. Apparent Km constants for 6-MP and Ado-Met in mouse liver were 5.4 X 10(-4) M and 2.1 X 10(-6) M respectively. The pH optimum for the reaction was 6.7 in both tissues, and over 95% of the TPMT activity in both mouse liver and kidney was "soluble" after centrifugation at 100,000 g for 1 hr. 3,4-Dimethoxy-5-hydroxybenzoic acid, an inhibitor of human kidney TPMT, decreased mouse kidney and liver enzyme activities by more than 95% at a concentration of 1 mM. TPMT activities were then measured in liver and kidney tissue from nine additional inbred strains of mice aged 7-8 weeks. Six of the nine inbred strains had TPMT activities very similar to those found in A/J animals. However, three strains, the C57BL/6J, C57BL/6ByJ and AKR/J, had significantly lower levels of activity in both liver and kidney than did any of the seven other strains. Liver TPMT activities in these three strains were only 23-32% of the average activity in A/J mouse liver. Kidney enzyme activities in the same three strains averaged 49-62% of the average activity in A/J mouse kidneys. These striking differences in TPMT activity among inbred mouse strains will make it possible to test the hypothesis that inheritance regulates variations in TPMT activity in this experimental animal.

Animals↗
PubMed1985

Characteristics of patients from the Hospital Utilization Project Data System: 1980-1982.

The 1974-75 report of the Hospital Utilization Project (HUP) patient data system for rehabilitation hospitals contained 5,427 cases from 20 hospitals. This report is for the three years 1980-82 with 52,404 cases involving 1,911,531 patient days from 40 hospitals. Information is grouped into two sets. The first set includes age, sex, race, and primary payment source. The second set contains length of stay and discharge destination by diagnosis. Diagnostic codes have been grouped to conform as much as possible to the disabling conditions used by the Health Care Financing Administration to define a rehabilitation hospital. These conditions account for 78.5% of discharges. Additional analyses include first admissions versus readmissions, full program versus short-term admissions and region of the country. Length of stay and percentage discharged home for all patients are very similar to those of the 1981 American Hospital Association survey. Variations in case mix for different sections of the United States show that clinical practices and payment policies are not uniform across regions.

Adolescent↗
PubMed1984

Functional assessment measures in medical rehabilitation: current status.

A number of reviews of functional assessment instruments have focused primarily on the merits of individual scales. This examination of the status of functional measures looks at conceptual issues underlying scale usage, including the domains of measurement, the criterion problem and assumptions underlying treatment. Work on the properties of measures (standardization, scalability, reliability and validity) is also scrutinized. Because insufficient attention has been devoted to most of these issues, medical rehabilitation lacks a set of measures with widespread utility. Self-care and mobility are included in most functional assessment scales, so agreement on an instrument for measuring these functions would be an important step. Subsequent research could then be directed toward establishing measurement properties and relationships to external criteria. The result would improve communication among professionals and make it easier to relay the benefits of rehabilitation to the public.

Activities of Daily Living↗
PubMed1983

Correlation of low and high affinity thiol methyltransferase and phenol methyltransferase activities in human erythrocyte membranes.

Human red blood cell (RBC) membranes have been reported to contain both high and low affinity 'forms' of the drug metabolizing enzyme thiol methyltransferase (TMT). The biochemical characteristics of the two 'forms' of human RBC TMT were compared. Apparent Km constants of the high affinity activity for 2-mercaptoethanol and S-adenosyl-L-methionine, cosubstrates for the TMT reaction, were 0.38 mumol/l and 2.6 mumol/l, respectively. These constants may be compared with values of 20 mmol/l and 43 mumol/l, respectively, previously reported for the low affinity form of RBC TMT activity. The properties and regulation of the two forms of TMT were then compared with each other and also with those of two 'control' enzymes, phenol methyltransferase (PMT) and beta-glucuronidase. When high and low affinity TMT, PMT and beta-glucuronidase activities were measured in RBC membranes from 22 individual subjects, there were highly significant correlations among all three methyltransferase activities (all r values greater than 0.95), but beta-glucuronidase activity did not correlate significantly with any of the methyltransferase activities (all r values less than 0.40). The thermal stabilities of the three methyltransferases were very similar. They were all inactivated approximately 50% by incubation at 48 degrees C for 15 min. beta-Glucuronidase activity was approximately 50% inactivated by incubation at 76 degrees C for 15 min. PMT and both TMT activities had similar subcellular distributions and similar responses to ions and to enzyme inhibitors. These results suggested that high and low affinity TMT and PMT activities might be catalyzed by the same enzyme. Alternatively, these three RBC membrane methyltransferase activities might be regulated in a parallel fashion.

Adult↗
PubMed1983

Thiol methylation pharmacogenetics: heritability of human erythrocyte thiol methyltransferase activity.

Thiol methylation of aliphatic sulfhydryl drugs is catalyzed by thiol methyltransferase (TMT), an enzyme activity that can be measured in the human erythrocyte (RBC) membrane. As a first step toward determining the possible role of inheritance in the regulation of individual variations in the S-methylation of drugs in man, the heritability of human RBC membrane TMT activity was determined. RBC TMT activity was measured in blood samples from 231 first-degree relatives in 47 randomly selected families. The frequency distribution of enzyme activities was unimodal, with a fivefold variation within +/- 2 SDs. RBC TMT activity did not correlate with either age or sex. Heritability in the "narrow" sense (h2) was estimated by comparing correlations of RBC TMT activities in first-degree relatives with theoretical values expected for a trait under total additive genetic control. The correlation between RBC TMT activities in mothers and fathers in these families was only 0.04, a finding that made shared environment a less likely explanation for significant correlations among other family members. However, sibling-sibling (S-S), parent-offspring (P-O), and midparent (average of two parental values)-offspring (M-O) correlations were 0.49, 0.49, and 0.69.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1983

Nitroglycerin tolerance and cyclic GMP generation in the longitudinal smooth muscle of the guinea-pig ileum.

The effects of in vitro nitroglycerin tolerance and methylene blue pretreatment on the ability of nitroglycerin and nitroprusside to promote relaxation and tissue accumulation of cyclic GMP were examined in the carbachol-contracted longitudinal smooth muscle of the guinea-pig ileum. Nitroglycerin and nitroprusside produced concentration-dependent increases in cyclic GMP levels. However, only nitroglycerin increased cyclic GMP levels before the onset of relaxation. Nitroglycerin tolerance produced approximately 200- and 5-fold shifts to the right of nitroglycerin and nitroprusside relaxation curves, respectively. Methylene blue pretreatment produced approximately 5-fold shifts to the right of both nitroglycerin and nitroprusside relaxation curves. Whenever there was an inhibition of nitroglycerin- or nitroprusside-induced relaxation, there was a corresponding reduction of cyclic GMP generation. Methylene blue inhibited the ability of 8-bromoguanosine 3',5'-monophosphoric acid to promote smooth muscle relaxation, suggesting that it also may impair the subsequent actions of cyclic GMP. This study provides the first demonstration of nitroglycerin tolerance in a nonvascular smooth muscle and provides evidence that cyclic GMP mediates the relaxant effects of nitroglycerin in the longitudinal smooth muscle of the guinea-pig ileum. However, because nitroprusside promoted tissue accumulation of cyclic GMP subsequent to relaxation, an exclusive role for cyclic GMP-mediated relaxation for this drug in the longitudinal smooth muscle appears unlikely.

Animals↗