Relationship between untreated and insulin-treated diabetes and vascular relaxation.

The effects of untreated and insulin-treated streptozotocin-induced diabetes on the ability of the rat aorta maximally contracted with either 10(-4) M phenylephrine (PE) or 70 mM KCl to relax in response to 10(-5) to 10(-2) M theophylline (Theo) were examined. No significant differences between Theo-induced relaxation of the PE-contracture in control, untreated diabetic and insulin-treated diabetic aortas were observed until 12 weeks after the induction of diabetes. Twelve weeks after the induction of diabetes, the untreated diabetic aortas exhibited less relaxation in response to Theo than did the controls. This diabetes-induced decrease in relaxation of the PE-contracture was not reversed by insulin-treatment. Diabetes increased the ability of the K-contracted aortas to relax in response to Theo 4 weeks after the induction of diabetes. This diabetes-induced increase in the Theo-induced relaxation of the K-contracture was reversed by insulin-treatment. Even though there was no difference in the sensitivity of the PE-contracted tissues to Theo, the K-stimulated tissues from the untreated diabetic animals were more susceptible to the relaxing effects of Theo than either the control or insulin-treated aortas. These results indicate that diabetes affects the ability of the vascular smooth muscle to relax in response to theophylline, depending on the length of time in the diabetic state, the type of stimulus (PE or KCl) and whether or not insulin-treatment is applied.

The effects of fructose-1,6-diphosphate on the isolated rabbit heart.

The effects of 0.1-100 mgm of fructose-1,6-diphosphate (FDP) were observed on the inotropic and chronotropic activity of the isolated, perfused rabbit heart, using a modified Langendorff technique. The preparations were treated with bolus injections of 0.1-100 mgm of FDP in gradually increasing concentrations following their recovery from previous injections. FDP produced a biphasic inotropic response with an initial decrease in contractility followed by an increase. The largest increases in contractility were observed at concentrations below 25 mgm while the greatest decreases occurred at the higher doses. The average maximal increase in contractility was 136.5 +/- 24% at an average dose of 1.53 +/- 0.6 mgm FDP. The average maximal decrease in the inotropic activity was 69 +/- 3% which was observed at an average dose of 92 +/- 8 mgm FDP. Recovery of the contractile activity following the observed effects of FDP was greater than or equal to pretreatment levels at all concentrations except 0.5 and 100 mgm FDP. The basal tone or tension of some hearts, especially after high doses of FDP, increased with some of these preparations contracting into a hard, putty-colored knot. FDP was also observed to exert an anti-arrhythmic effect on arrhythmic hearts. A negative chronotropic response was noted at all concentrations of FDP while a positive chronotropic response was observed only at the 0.1 mgm dose of FDP. The average increases and decreases in heart rate were 65 +/- 18 and 37 +/- 7%, respectively, at average respective doses of 9 +/- 6 and 40 +/- 15 mgm FDP. These data indicate that FDP exerts biphasic inotropic and chronotropic effects as well as an anti-arrhythmic effect on the isolated myocardium. They also indicate that FDP is toxic at higher cumulative doses.

Insulin reversal of diabetes-induced inhibition of vascular contractility in the rat.

Contractures induced by 10(-9)-10(-4) M phenylephrine (PE) or 10-70 mM KCl were observed in aortas isolated from untreated and insulin-treated streptozotocin-diabetic rats. The experiments were conducted at 2-wk intervals for a 12-wk period after the induction of diabetes. Diabetes caused an average decrease of 58 and 60% in the K and PE contractures, respectively. Although the PE contractures in aortas from the insulin-treated diabetic animals (81%) were significantly greater than those in aortas from the untreated diabetic animals (60%), they were significantly less than those in control tissues (100%). Insulin treatment completely reversed the diabetes-induced decrease in the K contracture (102%). It appears that the diabetes-induced decreases in tension may result from an altered sensitivity of the tissues to KCl but not PE. Histological examination of the tissues revealed that the diminished contractions were not due to any detectable change in mural structure. The data indicate that diabetes-induced inhibition of the mechanisms involved in mediating the K contracture are completely reversible by insulin treatment, whereas those mediating the PE contracture are only partially reversible.

Contractile and relaxing activity of arterial smooth muscle from streptozotocin-diabetic rats.

Contractures induced by 10(-4)M phenylephrine (PE) and 70 mM KCl and their relaxation by 10(-2) M theophylline (theo) were observed in aortae isolated from untreated and insulin-treated streptozotocin-diabetic rats for 12 weeks after the induction of diabetes. Diabetes consistently caused an average decrease of 40% in the PE and K-contractures. Treatment of diabetic animals with 2.0-3.5 units (U) of Neutral Protamine Hagedorn (NPH) insulin/day/partially prevented diabetes-induced decreases in the PE contractures while completely preventing them in the K-contractures. Relaxation of the PE-contracture, which was more susceptible to theo than was the K-contracture in control tissues, was not affected by either untreated or insulin-treated diabetes until 12 weeks after the induction of diabetes. While in vivo insulin treatment did not reverse diabetes-induced decreases in the theo-induced relaxation of the PE contracture, it did prevent the diabetes-induced increase in the relaxation of the K-contracture which was observed after 4 weeks. The results indicate that while the mechanisms involved in mediating the PE and K-contractures are inhibited by diabetes, insulin is more effective at preventing the effects of diabetes on the K-contracture and its relaxation than on the induction and relaxation of the PE-contracture.

The effects of streptozotocin-induced diabetes and insulin-treatment on the cardiovascular system of the rat.

In this study the cardiovascular effects of diabetes consisted of a decrease in the heart rate 6 days and in the blood pressure 7 weeks after the induction of streptozotocin-diabetes in rats. The diabetes-induced decrease in heart rate was reversed within 4 days after the institution of insulin-treatment, which also prevented the fall in blood pressure. Maximal KC1 (70 mM) and phenylephrine (10(-4)M)-induced contractures in aortae from diabetic rats were 57 and 48%, respectively, of those from control animals, while tissues from insulin-treated diabetic rats did not differ from controls. Theophylline (10(-2)M)-induced relaxation of the phenylephrine contracture in diabetic tissues was less than in control aortae while relaxation of the K-contracture was greater in control than in diabetic tissues. Insulin-treatment reversed the effects of diabetes on theophylline-induced relaxation of the KC1, but not the phenylephrine contracture. These findings indicate that insulin-treatment will either prevent or reverse diabetes-induced decreases in blood pressure, heart rate and vascular responsiveness to phenylephrine and CK1.

Interaction between phenylephrine and prostaglandins E1 and F1 alpha on the contractile responses of vascular muscle.

Prostaglandins (PGs) E1 or F1 alpha (1.4--8.4 x 10(-8) M) contracted strips of rabbit aorta and increased the contractions produced by 1--6 x 10(-7) M phenylephrine (PE). The addition of the PGs simultaneously with PE or after a low concentration of PE (2 x 10(-7) M) significantly increased the PE-induced contractions. However, when the PGs were added after a higher concentration of PE (6 x 10(-7) M) an additional increase in the PE-induced contraction was produced with PGF1 alpha but not with PGE1. Isobolic plots of the data obtained from the simultaneous addition of PE and the PGs indicate that both PGs interact with PE in a synergistic or potentiative manner, suggesting that their effects are mediated through different receptor mechanisms. Addition of the PGs after a high dose of PE indicates that there may also be either qualitative or quantitative differences between PGE1 and PGF1 alpha.

Influence of prostaglandins E1 and F1alpha on K-induced responses in vascular smooth muscle.

The effects of PGE1 and PGF1alpha (1.4-8.4 X 10(-8)M) were studied on contractures induced by 10--60 mM KCl in the isolated rabbit aorta. The greatest PG-induced increases in the K-contractures were observed at the lower concentrations of KCl. Greater tension increases were noted, particularly at the higher K concentrations with the simultaneous addition of KCl and the PGs rather than with their sequential addition in which the PGs were added after KCl. For example, when the PGs were added to tissues contracted with 60 mM KCl, no additional tension increases occurred, while significant increases were observed when the PGs were added simultaneously with 50--60 mM KCl. Isobolic plots of the data indicate that PGE1 at lower concentrations and PGF1alpha at all concentrations interacted with KCl as competitive antagonists. At median doses PGE1 exhibited an additive effect with KCl, while higher doses interacted in a synergistic manner.

Relationship between theophylline-induced relaxation and excitation-contraction coupling in intestinal smooth muscle.

The effects of 1.0 to 10.0 mM theophylline on excitation-contraction (E-C) coupling in the taenia coli of the guinea-pig were observed with the sucrose-gap technique. Theophylline at all concentrations simultaneously inhibited spontaneous, calcium-dependent action potentials and muscle contractions. At the higher doses, theophylline depolarized the membrane in spontaneously active preparations. In the presence of high potassium (60 mM) the spike activity was blocked only by 10.0 mM theophylline. High potassium made the spikes more resistant to the drug than were those in spontaneously active preparations. The phasic and tonic components of the potassium-contracture were progressively decreased by increasing concentrations of theophylline and were completely blocked by the 10.0 mM concentration. The drug had no effect on the potassium-induced membrane depolarization observed during the potassium-contracture. On the basis of these observations, it is proposed that theophylline inhibits spike and contractile activity in taenia coli by interfering with the availability of calcium which has been postulated to be necessary for maintenance of these functions.