PubMed Health⌕ Search

Biomedical subjects

M R Weir

Publications and source records attributed to M R Weir.

At least 19 recordsLinked to original sources
PubMed1992

Hypertensive nephropathy: is a more physiologic approach to blood pressure control an important concern for the preservation of renal function?

During the past 2 decades, there have been important reductions in stroke-related morbidity and mortality due to better control of hypertension. However, there has been a lesser effect on the reduction of coronary mortality and far less of an impact on all other forms of noncardiovascular disorders such as renal disease. This suggests that our ability to prevent hypertensive nephrosclerosis through traditional methods of lowering blood pressure may not be as effective as was once thought, particularly in high-risk patients such as blacks, diabetics, the elderly, and patients with preexisting renal disease. One reason that may partially explain the difficulty in protecting the renal circulation from hypertensive damage is the interaction between antihypertensive medications and the aged-related decline in renal perfusion. Depending on their mechanism of action, antihypertensive agents may impair renal blood flow (through plasma volume contraction or reduction) and further aggravate the age-related decline in renal perfusion. A worsening of renal perfusion may activate counterregulatory neurohormonal mechanisms, such as the renin-angiotensin-aldosterone system, which in turn may place the patient at increased risk for the development of glomerulosclerosis through promotion of vascular or mesangial hypertrophic changes or increased intraglomerular pressure, despite an associated reduction in systemic blood pressure. Since antihypertensive agents have such varied effects on systemic and renal hemodynamics, an understanding of the antihypertensive actions in a given patient may have significant influence on renal function. Thus, an improved understanding about the effects of aging and hypertension on the renal microcirculation will hopefully facilitate a more physiologically appropriate antihypertensive medication selection with the expectation that renal function will be benefitted over the long term.

Age Factors↗
PubMed1992

Risk for renal injury in diabetic hypertensive patients. The physiologic basis for blood pressure control.

In determining a therapeutic approach to coexistent adult-onset (type II) diabetes and hypertension in patients who are middle-aged, special attention must be given to the pathophysiology of the hypertensive disease and how it affects the kidneys. Diabetes and hypertension potentiate renal damage, which clearly leads to a reduced life span and increased morbidity. Nonpharmacologic measures (eg, exercise, weight control, glycemic control, protein-restricted diet) and pharmacologic approaches need to be combined so as to control systemic blood pressure yet maintain adequate renal perfusion. Clearly, preexisting accentuated vascular reactivity to vasoconstrictive growth factors in diabetic patients stimulates maladaptive compensatory responses in the kidney. This precipitates greater renal injury superimposed on the relative risk of the hypertension-diabetes combination itself.

Diabetes Mellitus, Type 2↗
PubMed1992

Risk for renal injury in diabetic hypertensive patients. Pharmacologic approaches.

In the first article of this pair (page 77), Drs Weir and Bakris discussed a physiologic approach to management of diabetic hypertensive patients. In this article, they discuss the latest findings regarding use of angiotensin-converting enzyme inhibitors and calcium channel blockers along with glycemic control and reduced protein intake.

Antihypertensive Agents↗
PubMed1992

Race- and rank-specific infant mortality in a US military population.

Mortality among black infants in the United States is approximately twice that among white infants. The disparity has been attributed in large part to the higher incidence of poverty and limited access to health care among black Americans. We investigated race- and rank-specific infant mortality rates among dependents of military officers and soldiers at Madigan Army Medical Center, Tacoma, Wash, between 1985 and 1990. The overall infant mortality rate was 9.3 deaths per 1000 live births compared with 10.1 deaths per 1000 live births in the United States in 1987. Mortality rates for infants born to families of junior enlisted soldiers were similar to those for infants born to families of noncommissioned and commissioned officers. The mortality rate among black infants was 11.1 deaths per 1000 live births compared with 17.9 deaths per 1000 live births among all black Americans in 1987. These lower rates of mortality among black infants may be due to guaranteed access to health care and higher levels of family education and income in the multiracial subpopulation served by our medical center compared with the nation as a whole.

Black or African American↗
PubMed1992

A dose-response trial of once-daily diltiazem.

This trial was performed to determine the safe and effective dosage range of once daily diltiazem (diltiazem CD) capsules for treatment of essential hypertension. Patients with essential hypertension having supine diastolic blood pressure values greater than or equal to 95 mm Hg and less than or equal to 110 mm Hg were randomly assigned to receive placebo or one of four doses of diltiazem CD: 90, 180, 360, or 540 mg. Blood pressure was measured at trough, 24 hours after the dose, and at the time of peak effect, 10 hours after the dose. Diltiazem CD lowered both supine diastolic and systolic blood pressure. A linear dose response was seen with changes in diastolic and systolic blood pressure and heart rate for trough and peak measurements. Trough/peak ratios for the 180, 360, and 540 mg doses were all greater than 0.50. Adverse effects were dose related; those most commonly reported were headache (8.6%), bradycardia (8.1%), and edema (7%), with bradycardia and edema possibly dose related. It is therefore concluded that diltiazem CD is a safe and effective antihypertensive agent.

Adolescent↗
PubMed1992

Determinants of the renal response to ACE inhibition in patients with congestive heart failure.

The objective of the present study was to determine whether pretreatment neurohormonal and renal hemodynamic parameters predict the change in renal function with the administration of quinapril, a new angiotensin-converting enzyme (ACE) inhibitor. Twenty patients with New York Heart Association (NYHA) class III and IV heart failure were evaluated. Following pretreatment determination of renal function and plasma neurohormones, patients were treated daily with 10 mg of quinapril. Measurements of glomerular filtration rate (GFR) and renal plasma flow (RPF) were repeated after 7 weeks to assess changes in function (delta GFR and delta RPF). Mean GFR increased from 49 +/- 6 to 56 +/- 7 ml/min/1.73 m2 (p = 0.10), but decreased in five patients. Mean RPF increased from 235 +/- 23 to 252 +/- 23 ml/min/1.73 m2 (p = 0.08), but decreased in five patients. There was no relation between delta GFR and baseline determinations of GFR, RPF, plasma renin activity, plasma angiotensin II, or serum Na. Only a high filtration fraction (GFR/RPF) predicted a decreased GFR (r = 0.61, p less than 0.005). In contrast, no baseline renal hemodynamic parameter correlated with delta RPF. We conclude that poor renal function does not increase the risk of renal deterioration with quinapril. However, dependence of renal function upon the renin-angiotensin system may be predicted by a high filtration fraction.

Angiotensin II↗
PubMed1992

Evidence that the antiproliferative effect of verapamil on afferent and efferent immune responses is independent of calcium channel inhibition.

Calcium channel blockers are capable of inhibiting the afferent and efferent limbs of the immune responses of human peripheral blood mononuclear cells in in vitro systems. This effect is thought to be related to the ability of the calcium channel blocker to limit the transmembrane flux of calcium. We report herein that two optical enantiomers of verapamil, one (S-) which is capable of blocking the slow calcium channel and mitogen-stimulated 45Ca++ uptake into human lymphocytes, while the other (R+) is incapable of either activity, share almost identical capabilities of depressing both the afferent and efferent limbs of immunity. These observations suggest that the inhibitory effects of verapamil on various afferent and efferent immune events are, in part at least, unrelated to the inhibition of transmembrane calcium flux.

Adult↗
PubMed1992

A pilot study to assess the ability of an orally available selective thromboxane synthase inhibitor to improve renal function in cyclosporine-treated renal transplant recipients.

Six cyclosporine (cyclosporine A [CsA])-treated renal transplant patients (4.3 +/- 0.6 months posttransplantation) were studied to see if selective urinary thromboxane (TX) inhibition with CGS 12970 (TX synthase inhibitor) would improve renal function and lessen CsA-induced decrements in RPF and GFR as measured by [99Tc]DTPA and [131I]hippuran clearances. The baseline trough CsA levels of the patients were 208 +/- 92 ng/mL. Before treatment with CGS 12970 (100 mg twice a day for 7 days), all drugs known to affect renal function or CsA pharmacokinetics were stopped. CGS 12970 therapy did not alter RPF (203 +/- 17 pre versus 200 +/- 15 mL/min post), GFR (38.5 +/- 3.2 pre versus 38.2 +/- 3.9 mL/min post), or serum creatinine (creat) (1.9 +/- .06 pre versus 1.8 +/- 0.18 mg/dL post), despite an average of 81% suppression of urine TX (65 +/- 14 pg/mg of creat pre versus 12 +/- 4 pg/mg of creat post); P less than 0.01), as measured by gas chromatography/mass spectrometry. CGS 12970 had no significant effect on urinary 6-keto-prostaglandin F1 alpha levels (63 +/- 4 pg/mg of creat pre versus 85 +/- 25 pg/mg of creat post). CGS 12970 did not alter CsA pharmacokinetics or drug levels, blood pressure, weight, or serum electrolytes of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Simultaneous measurements of glomerular filtration rate by two radioisotopic methods in patients without renal impairment.

Isotopic clearance techniques have been widely used to measure GFR but may give variable results depending on the level of renal function and the technique used. GFR, measured by the technique of plasma disappearance of 99mTc-labeled diethylenetriaminopentacetic acid ([99mTc]DTPA) was compared with simultaneously obtained urinary clearance of [99mTc]DTPA. GFR was also measured by concurrent 24-h clearance of creatinine. Forty-six measurements of GFR were obtained in 12 patients who had no evidence of renal disease. Plasma disappearance was measured from three timed plasma samples collected 60 to 180 min after the bolus injection of 200 microCi of [99mTc]DTPA and was calculated as the product of the volume of distribution (milliliters) at time zero and the clearance rate (per minute) as determined by the regression of the monoexponential plot. Urinary clearance was measured as the average of 3 1-h urinary clearances collected after a water diuresis was established. GFR measured by plasma disappearance was significantly greater (P less than 0.001) than GFR measured simultaneously by urinary clearance. There was a linear correlation between GFR measured by urinary clearance and that measured by plasma clearance (r = 0.994). Plasma clearance exceeded urinary clearance by a constant factor of 1.3 over the range studied (urinary clearance range, 49 to 94 mL/min/1.73 m2). It was concluded that at relatively a normal GFR, the plasma clearance of [99mTc]DTPA consistently overestimates the urinary clearance of [99mTc]DTPA.

Animals↗
PubMed1992

A dose escalation trial comparing the combination of diltiazem SR and hydrochlorothiazide with the monotherapies in patients with essential hypertension.

A multicentre, randomised, placebo-controlled parallel group study comparing various doses of the combination diltiazem SR (DTZ SR)/hydrochlorothiazide (HCTZ) with the monotherapies was performed to delineate the optimal antihypertensive dosage of the two drug combinations. The study was carried out in 298 patients with mild to moderate essential hypertension (stable supine diastolic blood pressure, DBP, greater than or equal to 95 and less than or equal to 110 mmHg). After a single-blind placebo lead-in period lasting 4-6 weeks to establish stable baseline BP, the patients were randomised to receive either placebo (n = 75), HCTZ (n = 76), DTZ SR (n = 72), or the combination of DTZ SR/HCTZ (n = 75). There were three 4-week evaluation periods with forced escalation of therapy as follows: HCTZ (6.25, 6.25, 12.5 mg twice daily), DTZ SR (60, 90, 120 mg twice daily), and the combination of DTZ SR/HCTZ (60/6.25, 90/6.25, 120/12.5 mg twice daily). DTZ SR/HCTZ (120/12.5 mg) produced statistically significantly greater reductions in supine DBP compared with each monotherapy and placebo. The lower doses of DTZ SR/HCTZ (60/6.25 mg and 90/6.25 mg) produced statistically significantly greater supine DBP reductions compared with DTZ SR monotherapy and placebo, but not compared with HCTZ monotherapy. A comparison of reduction in supine DBP between evaluation periods demonstrated a dose-response relationship for the combination therapy in reducing BP over the dosage range studied. Adverse clinical and laboratory events were not significantly different between the therapies.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Impact of age, race, and obesity on hypertensive mechanisms and therapy.

Despite the demonstrated efficacy of traditional antihypertensive therapy in reducing blood pressure, hypertension continues to be a major cause of cardiovascular disease morbidity and mortality. Stepped-care therapy is a nonphysiologic approach that, due to potential metabolic derangements and stimulation of undesirable reflex responses, may not substantially reduce the cardiovascular and renal complications associated with hypertension or improve long-term survival in many hypertensive patients. Because of fundamental hemodynamic differences related to the age, race, and weight of hypertensive patients, drug treatment often elicits varying responses. Certain classes of drugs are not only more effective but also more appropriate from a physiologic standpoint in specific types of patients. Therapy selection based in part on hemodynamic mechanisms and demographic patterns is a more rational approach to patient management and may contribute to a better overall outcome than has been observed with conventional treatment.

Adolescent↗
PubMed1991

Therapeutic benefits of calcium channel blockers in cyclosporine-treated organ transplant recipients: blood pressure control and immunosuppression.

Cyclosporine has dramatically improved the success rates for all forms of organ transplantation. However, its use is complicated by the frequent occurrence of hypertension and reversible nephrotoxicity. The iatrogenic hypertension induced by cyclosporine resembles a low-renin, salt-sensitive form of essential hypertension, which is often controlled with salt restriction and therapies counteracting renal salt acquisition, e.g., diuretics and calcium channel blockers (CCBs). CCBs may also counteract the direct vasoconstrictive effects of cyclosporine, as well as the effects of other vasoconstrictors, such as endothelin or thromboxane, that may be stimulated by cyclosporine. Additionally, CCBs may potentiate the immunosuppression of cyclosporine, yet minimize nephrotoxicity. We demonstrated that the in vitro combination of verapamil and cyclosporine had an additive inhibitory effect on the activation and function of human peripheral blood mononuclear cells in several assays of the afferent and efferent limbs of immunologic responses. This additive immunosuppression was not likely to have been related to these drugs' effects on interleukin-2 (IL-2) circuitry, since no additive inhibition of IL-2 production or IL-2 responsiveness was found. There was some additive inhibition of IL-2 receptor expression at the higher concentrations of verapamil and cyclosporine that were tested. Although the combination of verapamil and cyclosporine additively inhibited mitogen-induced 45Ca uptake, the inhibitory effect of cyclosporine appears to be due to an inhibition of lymphocyte activation rather than direct inhibition of calcium flux through the slow calcium channel, suggesting that the two drugs do not have additive effects in depressing the transmembrane flux of calcium. More recently, we have demonstrated that the inactive enantiomer of verapamil, which does not block the slow calcium channel, has identical immunosuppressive capabilities as the active enantiomer. Thus, the antiproliferative effect of verapamil is probably slow-calcium-channel independent and may represent the ability of the drug to interfere with muscarinic, alpha 1-adrenergic, or even opiate receptors on lymphocytes or to block lymphocyte potassium channels. An even better possibility is that verapamil may diminish necessary precursor molecule uptake into lymphocytes, since both the inactive and active isomeric forms of verapamil are capable of diminishing thymidine, uridine, and leucine incorporation into stimulated lymphocytes--necessary for DNA, RNA, and protein synthesis, respectively. These in vitro observations may have clinical applicability, as early studies demonstrate reduced rejection rates of cyclosporine-treated transplant patients receiving CCBs. Consequently, CCBs are important medications to be considered for use in cyclosporine-treated organ transplant recipients.

Calcium Channel Blockers↗
PubMed1991

Minimization of indomethacin-induced reduction in renal function by misoprostol.

A prospective, randomized, open-label, triple crossover comparison of the effects of indomethacin, misoprostol, or the combination, on renal function was performed to assess the ability of an oral prostaglandin E analogue, misoprostol, to minimize indomethacin-induced decline in renal function in middle-aged women. Twelve healthy women (mean age: 60.5 +/- 1.6 yr) with normal renal function (serum creatinine: 81 +/- 9 umol/L) were studied; six women were normotensive, and six women were hypertensive with their blood pressure controlled with 50-mg hydrochlorothiazide daily. All patients were placed on a 2-g sodium daily diet for 2 weeks before initiation of the study. The subjects were prospectively randomized to receive each of three 4-day treatments of indomethacin (25 mg q 6hr), misoprostol (200 mcg q 6hr), or the combination of drugs with a 4-day washout between each treatment period. Measurements of GFR (urine accumulation of 99mTc-DTPA) and RPF (serum disappearance 131I-Hippuran), and urine collections for electrolytes were obtained before the first treatment period and on the fourth day of each treatment period. Three of the six hypertensive patients and three of the six normotensive patients had a decrease (greater than 10%) in GFR associated with indomethacin therapy. When misoprostol was given with the indomethacin, four of these six patients did not experience a decline in GFR (baseline GFR for six patients: 75.4 +/- 6.6 mL/min/1.73m2, GFR after indomethacin: 57.8 +/- 9.5 mL/min/1.73m2, GFR with combination of indomethacin and misoprostol: 69.7 +/- 3.5 mL/min/1.73m2. RPF was not consistently altered by subacute/chronic dosing of indomethacin, misoprostol, or the combination of the drugs. The authors conclude that misoprostol ameliorates indomethacin-induced renal dysfunction in salt-restricted and diuretic-treated middle-aged women with normal serum creatinine.

Alprostadil↗
PubMed1991

Additive inhibition of afferent and efferent immunological responses of human peripheral blood mononuclear cells by verapamil and cyclosporine.

We have studied the effects of verapamil (0-50 microM) on the in vitro immunological function of human peripheral blood mononuclear cells in the presence or absence of cyclosporine (0-600 ng/ml). The proliferative response to phytohemagglutinin, OKT3, and alloantigens, the generation of cytotoxic T lymphocytes following allogeneic stimulation, and mitogen-induced reduction of intracellular ATP were inhibited in a concentration-dependent fashion by verapamil alone and by cyclosporine alone. When the two drugs were added to the same culture, additive inhibition was observed. A verapamil concentration of 5 microM usually reduced by at least 50% the amount of cyclosporine necessary to cause the same level of inhibition seen when no verapamil was present. The additive inhibition of the two drugs was likely not due to additive inhibition of IL-2 responsiveness, since neither drug alone inhibited the response of an IL-2-dependent T cell clone (CTLL-2) to recombinant IL-2 except at the highest concentrations tested, where a mild additive effect was noted. Nor was the additive inhibition related to an additive effect on total IL-2 receptor expression since an additive inhibitory effect on PHA-induced IL-2 receptor expression was only seen with 50 microM verapamil, while additive functional effects on mitogen- and antigen-induced proliferation and alloantigen-induced CTL generation were seen with 5 microM verapamil doses. Verapamil or cyclosporine alone inhibited IL-2 production of PHA- and phorbol ester-stimulated peripheral blood mononuclear cells--however, no additive effect was seen when the two drugs were both added to culture, probably because of the very potent inhibition by cyclosporine alone. Natural killer cell activity of human peripheral blood mononuclear cells against K562 target cells was significantly inhibited by verapamil in a concentration-dependent fashion, while cyclosporine had a more modest concentration-dependent effect. The combination of both drugs demonstrated additive inhibition. Effector function of cytotoxic T lymphocytes was modestly inhibited by either verapamil or cyclosporine alone. A combination of the highest concentrations of verapamil and cyclosporine caused an additive inhibitory effect. In summary, these data demonstrate that verapamil and cyclosporine have concentration-dependent inhibitory activities on both the afferent and efferent limbs of immunity that were additive when verapamil was used in a concentration of at least 5 microM. The additive effects are probably not related to effects on IL-2 circuitry.

Adult↗
PubMed1991

Correlation of in vitro CD4+ T helper cell function with clinical graft status in immunosuppressed kidney transplant recipients.

We recently identified three distinct T helper pathways which contribute to interleukin-2 (IL-2) production by human peripheral blood lymphocytes following stimulation with HLA alloantigens. In two of these pathways, CD4+ T helper cells respond to alloantigen using either self antigen-presenting cells (sAPC)* or allogeneic antigen-presenting cells (aAPC). A third pathway involves CD8+ T helper cells using aAPC. Previous in vitro studies have shown that the T helper pathway dependent on CD4+ T helper cells and sAPC (CD4-sAPC) is the most susceptible to suppression by cyclosporine. In the present study, we measured alloantigen-stimulated IL-2 production by PBL from 42 kidney transplant recipients to characterize the strength of the three T helper-APC pathways. In 58% of patients, a loss of the CD4-sAPC pathway was identified and was correlated with cyclosporine treatment. However, several patients not receiving cyclosporine also exhibited a similar loss of T helper cell function, suggesting that cyclosporine is not the only factor involved. Of 27 patients exhibiting depressed CD4-sAPC function, none had evidence of ongoing/recent graft rejection. In contrast, of 11 patients with no defects in the three pathways of in vitro T helper cell function, 6 had evidence of chronic graft rejection. Of considerable interest are the data obtained from a separate group of 4 patients who had episodes of acute rejection during the study. In each case, at the time of the rejection episode, all exhibited an intact CD4-sAPC pathway. However, samples tested prior to the rejection episode or after successful treatment of the rejection episode showed a depressed CD4-sAPC pathway. These results suggest that depression of the CD4-sAPC pathway represents adequate immunosuppression for graft retention and that patients not exhibiting such suppression are at increased risk for both acute and chronic graft rejection. These data may have relevance for diagnosis and/or prediction of graft rejection and may provide an in vitro method of monitoring the functional degree of immunosuppression in transplant recipients.

Adult↗
PubMed1991

The immunosuppressive properties of enisoprost and a 5-lipoxygenase inhibitor (SC-45662).

Metabolic derivatives of arachidonic acid such as prostaglandins and leukotrienes may alter immune responses. Enisoprost (ENO), a synthetic prostaglandin E analog, inhibited the response of human peripheral blood mononuclear cells to phytohemagglutinin in a concentration-dependent fashion: .1, 1.0, and 10 micrograms/ml yielding 4.0, 21.7, and 74.3% inhibition, respectively. ENO also potently inhibited both IL-2 production (measured by ELISA) and IL-2 responsiveness (measured by CTLL-2 response to IL-2) in a concentration-dependent manner, yet did not inhibit acquisition of IL-2 receptors. ENO similarly diminished efferent immune function in a concentration-dependent fashion, as measured by inhibition of cytotoxic T cell and natural killer effector function. A 5-lipoxygenase inhibitor (5-LO), SC-45662, also inhibited mononuclear cell response to PHA in a concentration-dependent manner: 0.1, 1.0, and 10 micrograms/ml yielding 5.0, 9.7, and 79.7% inhibition, respectively. Although 5-LO potently inhibited IL-2 production, it had no effect on IL-2 responsiveness or IL-2 receptor acquisition. Like ENO, 5-LO impaired CTL and NK effector function yet was not as potent in inhibiting CTL effector function. In summary, ENO and 5-LO inhibit afferent and efferent immune function. The inhibitory effects of these drugs are not related to cytotoxicity as cell viability is maintained for 72 hr in the presence of these drugs, and the inhibitory effect is reversible when the drugs are removed. The 5-LO does not inhibit mononuclear cell responses simply by shunting the formation of arachidonic acid precursors to form inhibitory prostaglandins, since it does not impair IL-2 responsiveness in a manner similar to ENO. These two compounds may prove to have clinical utility in organ transplantation if safely achieved serum concentrations of these drugs yield in vivo immunosuppression parallel to our in vitro results.

Acetates↗
PubMed1991

Nicardipine as antihypertensive monotherapy: positive effects on quality of life.

The effects of nicardipine and propranolol on patients' quality of life were compared during a double-blind, multicentre, parallel, randomised study of hypertension therapy. After a placebo run-in period, the doses for each patient were successfully titrated to reduce supine diastolic blood pressure to less than 90 mmHg with either nicardipine 60 or 90 mg/day (123 patients) or with propranolol 90-240 mg/day (120 patients). Both drugs demonstrated similar efficacy in reducing systolic and diastolic blood pressure. Total duration of therapy ranged from 6-12 weeks. The Nottingham Health Profile questionnaire was used to assess the effect of each treatment on the patients' quality of life. The overall quality of life score for patients on nicardipine showed a tendency toward improvement, while for those on propranolol, the trend was toward overall worsening. The differences between the two treatment groups were statistically significant for males (P = 0.02). The analysis of the separate components of this evaluation demonstrated that physical mobility was reported to be decreased more for the propranolol-treated patients than for the nicardipine-treated patients (P = 0.02). In contrast to the propranolol-treated patients, the nicardipine-treated patients reported improvements for sleep, social life, work, sex life, and for activities related to hobbies and interests. A second questionnaire was used to assess the effects of the therapies on work productivity. Among those patients who worked for pay, more patients treated with propranolol than those treated with nicardipine rated themselves as less productive at work (P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗