Intravenous basic fibroblast growth factor (bFGF) decreases DNA fragmentation and prevents downregulation of Bcl-2 expression in the ischemic brain following middle cerebral artery occlusion in rats.

In previous studies, we showed that basic fibroblast growth factor (bFGF) reduced infarct volume when infused intravenously in animal models of focal cerebral ischemia. In the current study, we examined the potential mechanism of infarct reduction by bFGF, especially effects on apoptosis within the ischemic brain. We found that bFGF decreased DNA fragmentation in the ischemic hemisphere, as assessed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) histochemical methods combined with morphological criteria. bFGF also prevented reduction of immunoreactivity of the anti-apoptotic protein Bcl-2 in the ischemic hemisphere, but did not alter immunoreactivity of the pro-apoptotic proteins Bax, Caspase-1, or Caspase-3. These changes in TUNEL histochemistry and Bcl-2 immunoreactivity were especially prominent in cortex at the borders ('penumbra') of infarcts, spared by bFGF treatment. We conclude that the infarct-reducing effects of bFGF may be due, in part, to prevention of downregulation of Bcl-2 expression and decreased apoptosis in the ischemic brain.

The relaxation induced by nicotine in the rat isolated renal artery.

The mechanism of nicotine-induced relaxation was investigated in the rat isolated renal artery. Nicotine (10(-3) M) produced a relaxation when preparations were precontracted by phenylephrine (3 x 10(-6) M). Nicotine-induced relaxation was 27.3 +/- 2.5% of phenylephrine contraction and was not affected by atropine (10(-5) M), guanethidine (10(-5) M), hexamethonium (10(-4) M), indomethacin (10(-5) M), N(G)-nitro-L-arginine (10(-4) M), methylene blue (10(-5) M), glibenclamide (10(-5) M), quinacrine (3 x 10(-6) M), tetrodotoxin (10(-6) M), capsaicin (10(-6) M), tetraethylammonium (10(-3) M), 4-aminopyridine (10(-3) M), and ouabain (10(-6) M) (n = 6, Mann-Whitney U-test). A calcium antagonizing effect of nicotine was not observed. Therefore, it appears that nicotine relaxes rat isolated renal artery by a nonspecific action on the vascular smooth muscle.

Vasodilatation induced by nicotine in the isolated perfused rat kidney.

1. In isolated perfused rat kidney, under a constant flow of 8-10 ml/min, mean basal perfusion pressure was found to be 82.57 +/- 8.96 mm Hg (n = 70). 2. After a bolus injection of 10 micrograms/0.1 ml phenylephrine (PE) which causes maximum vasopressor response, a 93.27 +/- 0.56 mm Hg increase in basal perfusion pressure was recorded (n = 70). In control experiments, a submaximum dose of PE (3 x 10(-6) M) caused a 68.37 +/- 0.47 mm Hg (n = 5) increase in perfusion pressure. 3. Nicotine, at a dose of 100 micrograms/0.1 ml, decreased the perfusion pressure raised by submaximum dose of PE. This nicotine-induced dilatation was 24.97 +/- 3.27% of maximum PE constriction (n = 5). 4. Nicotine-induced dilatation was not affected by atropine, guanethidine, hexamethonium, tetrodotoxin, capsaicin, indomethacin, quinacrine, NG-nitro-L-arginine, methylene blue, glibenclamide, tetraethylammonium, 4-aminopyridine and ouabain (n = 5).

Hypertension increases the contractions to sumatriptan in the human internal mammary artery.

BACKGROUND: The internal mammary artery is the graft of choice for myocardial revascularization. The tendency to spasm increases toward the distal end of the internal mammary artery, which is the portion generally used for anastomosis. The distal internal mammary artery is more pharmacologically responsive to 5-hydroxytryptamine and several other vasoconstrictor agents than its midsection. METHODS: We examined the effects of 5-hydroxytryptamine and a 5-hydroxytryptamine1-like receptor agonist sumatriptan on internal mammary artery segments (length, 3-4 mm) obtained from patients undergoing coronary artery bypass grafting. To unmask a 5-hydroxytryptamine1-like receptor-mediated contractile response, threshold concentrations of potassium chloride were used. RESULTS: 5-Hydroxytryptamine induced concentration-dependent contractions in all, quiescent and potassium chloride precontracted, preparations. Sumatriptan induced marked contraction in some of the quiescent internal mammary artery rings, whereas it elicited marked and concentration-dependent contractions in all of the preparations given a moderate tone by a threshold concentration of potassium chloride. The sensitivity to sumatriptan was higher in potassium chloride-precontracted distal arteries than it was for the quiescent distal segments. Additionally, the sensitivity to and the efficacy of sumatriptan were much more markedly potentiated by precontraction in the preparations taken from hypertensive patients. CONCLUSIONS: The more marked potentiation of the responses in arteries from hypertensive patients may be one of the factors influencing the patency rates.

5-HT1-like receptor-mediated contraction in the human internal mammary artery.

We wished to characterize the 5-hydroxytryptamine (5-HT) receptors mediating vasoconstriction in the human internal mammary artery (IMA). Segments of the IMA obtained from patients undergoing coronary by-pass surgery were suspended in an organ bath and exposed to 5-HT and sumatriptan (SUM), a 5-HT1-like receptor agonist, in the presence and absence of potassium chloride (KCl) and angiotensin II. 5-HT induced concentration-dependent contractions in all quiescent and pre-contracted preparations. SUM induced small contractions in 70% of quiescent IMA rings, whereas it elicited marked and concentration-dependent contractions in all of the preparations given a moderate tone by a threshold concentration of KCl and angiotensin II. The efficacy of SUM was higher in precontracted arteries. Concentration-effect curves (CEC) of 5-HT and SUM were not affected by the 5-HT3-receptor antagonist tropisetron (1 microM). The nonselective antagonist, methiothepin (30 nM), shifted the CEC of SUM to the right. 5-HT2A-receptor antagonist, ketanserin (1 microM) inhibited responses to 5-HT, whereas it affected only the responses to the smaller concentrations of SUM. When methiothepin (30 nM) was applied in the presence of ketanserin (1 microM), a further inhibition in the responses to 5-HT was observed. These results suggest that 5-HT1-like receptors mediate the contractile action of SUM and contribute to that of 5-HT in IMA.