Post receptor determinants of acute platelet response to clopidogrel in patients with symptomatic myocardial ischemia.

BACKGROUND: Clopidogrel resistance is more common in patients with loss-of-function CYP2C19 genotypes. Since adenylate cyclase (AC) and soluble guanylate cyclase (sGC) pathways are variably impaired in patients with ischaemic heart disease, we tested the relevance of these determinants in patients undergoing acute loading with clopidogrel (600 mg) prior to non-emergent coronary stenting. METHODS: Inhibitory effects of prostaglandin E1 (PGE1, an AC activator) and sodium nitroprusside (NP, a sGC activator) on platelet aggregation were determined at baseline and compared with platelet responses to clopidogrel (4 h after administration) assessed as ∆ADP, and Platelet Reactivity Index (∆PRI). Data were analysed according to CYP2C19 genotype. RESULTS: In patients without loss of function mutations (n=18), ∆ADP but not ∆PRI, was directly correlated with baseline PGE1 responsiveness (rs=0.62, p=0.005)). NP responsiveness did not predict ∆ADP. However there was no relationship between clopidogrel responses and either PGE1 or NP responsiveness in patients with loss of function mutations. Multivariate correlates of clopidogrel response were both the genotype status (ß=-0.609, p<0.001) and the baseline response to PGE1 (ß=0.303, p=0.03). CONCLUSIONS: While genetically impaired bio-activation markedly limits acute (4 h) clopidogrel response, impaired AC signalling provides an additional cause for clopidogrel resistance.

Clopidogrel "resistance": pre- vs post-receptor determinants.

The clinical efficacy of the P2Y12 receptor antagonist clopidogrel as an agent to prevent thrombotic events predominantly reflects its anti-aggregatory effects. Stent thrombosis in particular is more likely to occur in patients in whom clopidogrel effect is limited. "Resistance" to clopidogrel in general should theoretically arise either because of a reduction in plasma concentration of the active metabolite and/or of the downstream intracellular biochemical changes underlying antiplatelet effects. We therefore postulate that "resistance" to clopidogrel arises via a combination of pharmacogenetic, pharmacokinetic and intracellular biochemical mechanisms. Considerable attention has been so far directed to the finding that stent thrombosis occurs more frequently in patients with loss-of-function mutations of CYP2C19, thus limiting clopidogrel bioactivation. Furthermore, a number of drug-drug interactions may marginally impair responsiveness to clopidogrel, largely via impairment of bioactivation. However, population data also suggest that clopidogrel "resistance" occurs more frequently in patients with acute coronary syndromes than in normal subjects, and that "resistance" is particularly common in obese subjects and with diabetes. Here we critically review available literature and speculate on the possibility that non-genetic causes of clopidogrel "resistance" may arise from impairments of the intracellular signaling cascade initiated by P2Y12 receptor inhibition. In such cases, "resistance" to clopidogrel may also theoretically occur with other P2Y12 receptor antagonists, irrespective of the need for bioactivation. Delineation of this non-genetic component of "resistance" to P2Y12 inhibitors may facilitate the development of optimal therapeutic strategies for high-risk cardiovascular patients.

Renal nerves and postprandial renal excretion in the conscious monkey.

Experiments were performed in conscious macaque monkeys to determine if the renal nerves are important in mediating postprandial increases in renal fluid-electrolyte excretion in this species. Monkeys were given a high-sodium meal via a nasogastric tube. Consecutive 10-min urine samples were taken during the 30-min time of meal administration and then 180 min postprandially. The experiment was performed both before and 10-14 days after each animal underwent renal denervation. Diuresis and natriuresis occurred under both renal-innervated and -denervated conditions. However, the amounts of urine and sodium excreted were less after renal denervation. For the total 210 min of measurements obtained after the meal was started, cumulative urine output was 95.0 +/- 26.4 ml and sodium excretion 7.18 +/- 1.74 meq in innervated kidneys vs. 56.7 +/- 7.0 ml (a 40% decrease; P less than 0.005) and 4.84 +/- 0.99 meq (a 33% decrease; P less than 0.01) after denervation. These results demonstrate that the renal nerves are important in the nonhuman primate for eliciting the postprandial changes in urinary excretion secondary to intake of a high-sodium meal.

Renal nerves and renal responses to volume expansion in conscious monkeys.

Experiments were performed in conscious macaque monkeys to determine the effect of renal denervation on the diuresis and natriuresis of blood volume expansion. When the kidneys were innervated, expansion of estimated blood volume by 20% with 3% dextran in isotonic saline caused increases in urine flow (V), from 0.28 +/- 0.07 ml/min to a peak response of 1.08 +/- 0.20 ml/min, absolute sodium excretion (UNaV), from 30.0 +/- 11.2 to 99.8 +/- 11.7 mueq/min, and fractional sodium excretion (FENa+), from 1.24 +/- 0.51 to 3.19 +/- 0.56%. The animals then underwent bilateral renal denervation and were volume expanded a second time 6-13 days postdenervation. Under this condition, V increased from 0.32 +/- 0.05 to 0.64 +/- 0.08 ml/min, UNaV, from 22.2 +/- 4.6 to 46.2 +/- 8.0 mueq/min, and FENa+, from 0.91 +/- 0.26 to 1.92 +/- 0.41%, these increases being significantly less than when the kidneys were innervated. These results demonstrate that the renal nerves play an important role in the nonhuman primate in mediating increases in renal excretion during hypervolemia.

Effect of vagotomy and thoracic sympathectomy on responses of the monkey to water immersion.

Cardiopulmonary stretch receptors have been implicated as part of a reflex mechanism linking changes in blood volume to changes in renal excretion. Experiments were performed to determine whether total denervation of these receptors by combined cervical vagotomy and thoracic sympathectomy affects the renal responses of the monkey to head-out water immersion, a maneuver that translocates blood to the thorax and elicits an increase in renal salt and water excretion. Macaca fascicularis monkeys first underwent chronic bilateral thoracic sympathectomy or sham denervation performed in two stages a week apart. One to two weeks later, they were anesthetized with pentobarbital sodium, and the sympathectomized animals underwent bilateral cervical vagotomy. Control renal function did not differ between the two groups. Immersion of 90-min duration increased central venous and mean arterial pressures by similar amounts in both groups, but heart rate increased only in the sham-denervated animals. Denervation did not affect the magnitudes or delay the times of onset of the increases in urine flow, absolute and fractional sodium excretion, and osmolar and free water clearances occurring with immersion. These results demonstrate that in the anesthetized monkey cardiopulmonary receptors are not necessary for eliciting the renal responses to immersion.

Renal nerves and renal responses to head-up tilt in dogs.

Experiments were performed in anesthetized dogs to compare the effects of acute and chronic unilateral renal denervation on the renal responses to head-up tilt and to assess denervation hypersensitivity to infused norepinephrine (NE). Responses of the denervated kidney were compared with those of the contralateral innervated kidney in each animal. With acute denervation, 40 min of 45 degrees head-up tilt decreased urine flow (V) 37%, absolute sodium excretion (UNaV) 53%, and fractional sodium excretion (FENa+) 44% in the innervated kidneys, but no decreases occurred in the denervated kidneys. NE infusion (125 ng X kg-1 X min-1) increased arterial pressure by 11 mmHg and increased V, UNaV, and FENa+ in both kidneys. In the chronically denervated animals (2-4 wk prior to experiment) tilt decreased V by 32%, UNaV by 44%, and FENa+ by 21% in the innervated kidneys, but again no changes occurred in the denervated kidneys. NE infusion in this group also increased arterial pressure approximately 11 mmHg and caused V, UNaV, and FENa+ to increase in the innervated kidneys but decrease in the denervated kidneys. These results demonstrate that the renal responses to tilt are abolished by both acute and chronic renal denervation even though the chronically denervated kidney is hypersensitive to NE-stimulated fluid reabsorption. Therefore endogenous plasma NE levels must not increase enough during tilt such that this hypersensitivity phenomenon can compensate for chronic ablation of the renal nerves.

Cardiopulmonary and sinoaortic baroreceptors and volume expansion in the monkey.

Experiments were performed to determine the effect of combined cardiopulmonary and and sinoaortic baroreceptor denervation on the renal responses of the anesthetized nonhuman primate to acute intravascular volume expansion. Adult male Macaca fascicularis monkeys underwent chronic bilateral thoracic sympathectomy (middle cervical ganglion--T6) or sham surgery performed in two stages. After a 1-3 week recovery period, each animal was anesthetized with sodium pentobarbital and subjected to cervical vagotomy--sinoaortic denervation or further sham denervation. Estimated blood volume was then acutely expanded 20% with 6% dextran in isotonic saline. Control renal excretory function did not differ between the two groups, and both groups had similar increases in urine flow, sodium excretion, osmolar clearance, free water clearance and renal plasma flow after volume expansion. The patterns of the responses showed some group differences in that the increases in renal excretion after volume-loading had an earlier onset in the denervated animals. These results demonstrate that combined ablation of thoracic sympathetic, vagal and sinoaortic neural pathways does not compromise the ability of the nonhuman primate to increase salt and water excretion when blood volume is acutely expanded. Therefore, these neural mechanisms are not necessary for eliciting the renal responses to this hypervolemic stimulus in this species during the anesthetized state.

Renal nerves and initial excretory responses to recumbency: a species comparison.

Experiments were performed in anesthetized Macaca fascicularis monkeys and mongrel dogs to determine if there are species differences concerning the involvement of the renal nerves in mediating the initial renal effects occurring with the assumption of recumbency. All animals underwent acute unilateral renal denervation with the contralateral kidney serving as the innervated control. Renal perfusion pressure was controlled throughout each experiment. Control measurements were made with all animals tilted head up 45 degrees, and recumbent measurements were made 5-15 min after the animals were lowered to 0 degree. In the monkeys, similar increases in urine flow, absolute and fractional sodium excretion, and creatinine and p-aminohippurate clearances occurred in both the innervated and denervated kidneys during recumbency. In contrast, in the dogs, renal denervation abolished these responses in that increases in these parameters occurred in the innervated kidneys only. These results demonstrate that the initial diuresis and natriuresis of recumbency are dependent on the presence of the renal nerves in the dog but not in the monkey.

Computed axial tomography of the body with the EMI general purpose scanner. A preliminary assessment.

Computed axial tomography (CAT) of the brain has already proved itself to be the first line in the diagnosis of intracranial lesions. With the installation of the EMI (CT 5005) general purpose scanner at Garden City Clinic in mid-October 1977, we have been utilizing this technique not only on the cranium but on the rest of the body as well. It has proved an invaluable diagnostic tool, in that the diagnosis can often be made with this technique alone. It short-circuits many of the sophisticated routine X-ray studies which require hospitalization, an anaesthetic, and time lost to the patient and doctor. In many cases it has obviated the need for an exploratory laparotomy. In most cases the technique can be performed on outpatients; the patient is perfectly relaxed during the scan, and may be saved days in hospital. There are limitations, however, and patients should be carefully selected. A discussion of the indications for body scanning in both our own and overseas experience therefore seems in order.