Biomedical subjects

M H McDonald

Publications and source records attributed to M H McDonald.

4 recordsLinked to original sources

PubMed1999

Paradoxically enhanced bradykinin-induced venodilation in young, healthy, short-term smokers.

Bradykinin is a nonapeptide, whose mechanism of vasodilation is mediated chiefly through the release of endothelium-derived relaxing factor (EDRF). Diminished vasodilatory response to EDRF has been demonstrated in many pathologic states such as hypertension, atherosclerosis, diabetes, and long-term, heavy smoking. We studied whether the diminished EDRF-mediated vasodilatory response seen in chronic diseases can be demonstrated in young, clinically healthy smokers. We used the dorsal hand-vein compliance technique, an in vivo technique used to measure response to local infusions of vasoactive substances. Full dose-response curves to bradykinin (dosing range, 0.5-500 ng/min) were generated in 11 young, healthy smokers and 11 young, healthy nonsmokers by using hand veins preconstricted with phenylephrine (dosing range, 20-6,800 ng/min). In addition, after a washout period, a single maximal dose of a non-endothelium-dependent vasodilator, isoproterenol (300 ng/min) was infused. Our results demonstrated that smokers had a greater maximal venodilation to bradykinin than did nonsmokers (106 +/- 40% vs. 69 +/- 49%; p < 0.05). The log of the dose that produced half-maximal response to bradykinin was smaller in smokers: -0.10 +/- 0.93 (0.79 ng/min) versus 0.75 +/- 0.84 (5.6 ng/min); p < 0.05. There was no difference in the maximal dilatory response to isoproterenol: 80 +/- 45% (smokers) versus 89 +/- 50% (nonsmokers), nor was there a difference in the log dose of phenylephrine necessary to produce 80% constriction of the hand vein (2.7 +/-0.7 vs. 2.7 +/- 0.9 ng/min) between the two groups. We conclude that young, otherwise healthy smokers have a paradoxic hyperactive response to the endothelium-dependent vasodilator, bradykinin, but maintain a similar response to the nonendothelium-dependent vasodilator, isoproterenol as compared with nonsmokers. Their reactivity to the alpha1-adrenergic agonist phenylephrine was found to be intact. It is possible that a hyperactive response to EDRF in young smokers contributes to endothelium damage seen in chronic disease. To our knowledge, this is the first report on increased reactivity to bradykinin in short-term smokers.

Adult↗

PubMed1996

Response of human artery, vein, and cultured smooth muscle cells to atrial and C-type natriuretic peptides.

OBJECTIVES: We determined the response of intracellular cyclic GMP in human arteries and veins and in smooth muscle cells cultured from these vessels to C-type natriuretic peptide in comparison with atrial natriuretic peptide. DESIGN: Repeated-measures analysis of concentration-response curves. SETTING: Anesthesia research laboratory. SUBJECTS: Vascular smooth muscle cells from human blood vessels obtained with Institutional Review Board approval and patient consent. MEASUREMENTS AND MAIN RESULTS: Segments of internal mammary artery and saphenous vein were obtained from patients undergoing coronary artery bypass surgery. Smooth muscle cells were cultured from these vessels. Concentration-response curves of intracellular cyclic GMP were determined and analyzed by two-way analysis of variance with repeated measures. In segments of intact saphenous vein, C-type natriuretic peptide was significantly more effective than atrial natriuretic peptide (16-fold increase in cyclic GMP in response to 1 microM of C-type natriuretic peptide vs. six-fold increase in cyclic GMP in response to 1 microM of atrial natriuretic peptide, p < .05). In rings of intact internal mammary artery, 1 microM of atrial natriuretic peptide (26-fold increase in cyclic GMP over basal value) was more effective than 1 microM of c-type natriuretic peptide (three-fold increase in cyclic GMP over basal value, p < .05). In cultured cells from these vessels, the pattern of response to C-type natriuretic peptide and atrial natriuretic peptide was the same as in the intact vessels. CONCLUSIONS: These results indicated that human smooth muscle cells in arteries and veins express both forms of natriuretic peptide receptors but that atrial natriuretic peptide acts primarily on the artery and C-type natriuretic peptide acts predominantly on the vein. Increased concentrations of C-type natriuretic peptide could contribute to venous pooling in septic shock.

Analysis of Variance↗

PubMed1995

Tolerance to nitroglycerin in vascular smooth muscle cells is not affected by the level of intracellular glutathione or L-cysteine.

A major hypothesis for the mechanism of tolerance to nitroglycerin (NTG) is that continued use causes a decrease in thiol donors within the vascular smooth muscle cell that are essential for the effect of NTG. We tested this idea directly in the target cell. NTG tolerance, measured as reduced formation of intracellular cyclic guanosine monophosphate (cGMP), was induced in pig coronary smooth muscle cells. The consequence of altering intracellular levels of the thiol donors, glutathione (GSH) and L-cysteine (L-cys), was determined. Incubating cells with 100 microM NTG for 1 h caused an 83% reduction in cGMP formation in response to acute readministration of 200 microM NTG for 2 min but was not associated with a reduction in intracellular GSH or L-cys. This result was not altered when intracellular GSH levels were increased three-fold by including 1 mM GSH in the incubation buffer. Also, recovery from tolerance was not affected by supplementation with GSH. Further, the response of cGMP to NTG was not altered by inhibiting the synthesis of GSH and lowering intracellular levels of GSH by 77%. Similar findings were made with supplemental L-cys or N-acetyl-L-cysteine. These results do not support the hypothesis that tolerance to NTG is the result of a reduction of the thiol donors GSH and L-cys within vascular smooth muscle cells.

Acetylcysteine↗

PubMed1979

Administration of gonadal steroids to the castrated male rat prevents a decrease in the release of gonadotropin-releasing hormone from the incubated hypothalamus.

The influence of testosterone on gonadotropin-releasing hormone (GnRH) secretion was assessed indirectly by altering the serum testosterone concentration of male rats and measuring GnRH release from their incubated hypothalami 1 wk later.GnRH release from hypothalami of castrated rats was 13.4+/-1.2 (SE) pg/h, compared to 35.3+/-3.8 pg/h from hypothalami of intact rats (P < 0.001). GnRH release from the hypothalami of castrated rats treated with testosterone propionate, 100 or 500 mug daily, was 25.0+/-3.4 pg/h and 27.9+/-3.6 pg/h, which is significantly greater (P < 0.05 and P < 0.01, respectively) than that from hypothalami of castrated rats treated only with sesame oil.A similar decrease in GnRH release from hypothalami of hypophysectomized rats and prevention of this decrease by treating the hypophysectomized rats with testosterone propionate is evidence that the observed effects of testosterone are not mediated via luteinizing hormone and(or) follicle-stimulating hormone secretion. Treatment of castrated rats with either dihydrotestosterone propionate or estradiol benzoate also prevented the decrease in GnRH release from the hypothalami of castrated rats. We conclude that testosterone, dihydrotestosterone, and estradiol all prevent the decrease in GnRH release from hypothalami of castrated rats treated with these steroids. The possibility exists that these steroids may also maintain GnRH secretion in vivo.

Animals↗