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Biomedical subjects

G Kunos

Publications and source records attributed to G Kunos.

At least 109 records · Page 6Linked to original sources
PubMed1984

Thyrotropin releasing hormone and naloxone attenuate the antihypertensive action of central alpha 2-adrenoceptor stimulation through different mechanisms.

In various forms of shock, TRH is equivalent to naloxone in reversing the hypotension and improving the survival rate. The present findings indicate that in spontaneously hypertensive rats (SHR), TRH has another naloxone-like effect in antagonizing the antihypertensive response to clonidine and alpha-methyldopa. When given during the hypotensive response to alpha-methyldopa, both naloxone and TRH produce a pressor response. While this effect of naloxone is blocked by prazosin, the effect of TRH is not influenced by prazosin or hexamethonium but is inhibited by a vasopressin pressor antagonist. This suggests that the pressor response to naloxone is mediated by the sympathetic nervous system, whereas the similar action of TRH is independent of sympatho-adrenomedullary functions and it is mediated by vasopressin.

Animals↗
PubMed1983

Diurnal rhythm of beta endorphin in normotensive and hypertensive patients: the effect of clonidine.

Diurnal rhythm of plasma beta endorphin was established with the highest level in the morning and the lowest one at midnight in normotensive subjects and also in patients with essential hypertension. Clonidine (300 micrograms daily) significantly increased plasma beta endorphin concentrations only in the hypertensive patients. The significant linear correlation between the increase in plasma beta endorphin concentration and the decrease in blood pressure (both systolic and diastolic) in these patients may point to the role of this endogenous opioid in the antihypertensive action of clonidine.

Circadian Rhythm↗
PubMed1983

Possible role of an endogenous opioid in the antihypertensive action of propranolol in spontaneously hypertensive rats.

The effect on systolic blood pressure and heart rate of the acute and chronic intraperitoneal (i.p.) administration of d- and dl-propranolol was investigated on unanesthetised spontaneously hypertensive rats. The effect of naloxone on the propranolol induced hypotension was also studied to test the hypothesis that the antihypertensive effect of propranolol involves the release of an endogenous opiate. On i.p. administration, 3 mg/kg d-propranolol was inactive; 3 and 30 mg/kg dl-propranolol decreased blood pressure and heart rate in a dose-dependent manner. When the rats were pretreated with 2 mg/kg naloxone i.p., the effect of propranolol on the blood pressure was nearly completely abolished, while that on the heart rate was only partially blocked. Chronic administration of dl-propranolol (30 mg/kg b.i.d.) to spontaneously hypertensive rats from the age of 6 weeks (prehypertensive phase) for 29 days prevented the development of hypertension while the rats treated with physiological saline for 29 days (control group) developed hypertension. Naloxone (2 mg/kg i.p.) administered on the 29th day to chronically treated rats induced a reversal of the propranolol action on systolic blood pressure and heart rate, i.e., blood pressure and heart rate increased. Naloxone had no such effect in the control group. We suggest that the release of an endogenous opioid contributes to the acute and chronic antihypertensive action of i.p. propranolol in spontaneously hypertensive rats and that the secretion of endogenous opioids participating in the control of cardiovascular functions is influenced by adrenergic mechanisms.

Animals↗
PubMed1982

Decreased alpha 1-adrenoceptor responsiveness and density in liver cells of thyroidectomized rats.

The effects of hypothyroidism on the hepatic alpha 1-receptor system were studied in isolated rat liver cells. Phenylephrine and vasopressin caused concentration-dependent activation of glycogen phosphorylase and release of 45Ca from 45Ca-loaded cells in either normal or thyroidectomized rats. However, the magnitude of both responses to phenylephrine was markedly suppressed after thyroidectomy and could be restored to near normal levels by in vivo treatment with 1-triiodothyronine (0.25 mg/kg/day) for 4 days. The potency of vasopressin to induce phosphorylase activation and 45Ca release was only slightly reduced by thyroidectomy. Binding of [3H]prazosin to putative alpha 1-receptors in purified liver plasma membranes revealed that the above changes were accompanied by a decrease in the density of binding sites from 567 +/- 51 fmol/mg of protein in controls to 326 +/- 51 fmol/mg in thyroidectomized rats and a return to 498 +/- 23 fmol/mg in thyroidectomized rats treated with 1-triiodothyronine. The affinity of binding sites for [3H]prazosin or for alpha-receptor agonists was the same in the three groups of rats and affinity for epinephrine was unaffected by the presence of guanyl-5'-yl imidodiphosphate (30-100 microM). From these findings, it appears that a reduction in the number of hepatic alpha 1-receptors is responsible for the selective decrease in alpha-adrenergic responses in the hypothyroid rat liver. These changes are opposite to those previously reported for hepatic beta-receptors.

Animals↗
PubMed1982

Possible involvement of an endogenous opioid in the antihypertensive effect of clonidine in patients with essential hypertension.

The effect of naloxone on the hypotensive and bradycardiac action of clonidine was studied in 27 hospitalized patients with uncomplicated mild-to-moderate essential hypertension. In a double-blind, crossover study, clonidine, 0.3 mg/day orally for 3 days, significantly reduced systolic and diastolic blood pressure and heart rate, whereas placebo was ineffective. Naloxone, 0.4 mg given intravenously on the third day of clonidine treatment, caused a rapid increase in blood pressure and heart rate in 14 patients (reacting group), but was ineffective in the remaining 13 patients (nonreacting group). Naloxone given during the placebo period was ineffective in all patients. Both the clonidine-induced hypotension and the rebound increase in blood pressure after cessation of clonidine were significantly greater in the reacting than in the nonreacting group. These observations suggest that release of an endogenous opioid contributes to the antihypertensive action of clonidine; this mechanism may be also involved in the discontinuation syndrome after cessation of clonidine.

Adult↗
PubMed1982

Selective desensitization of cardiac beta adrenoceptors by prolonged in vivo infusion of catecholamines in rats.

The effects of prolonged in vivo infusion of isoproterenol (400 micrograms/kg/hr) or norepinephrine (200 micrograms/kg/hr) from a minipump on the physiological reactivity and binding properties of cardiac beta and alpha-1 adrenoceptors were tested in rats. Infusion of either catecholamine significantly reduced the in vitro inotropic and chronotropic potency of isoproterenol in isolated left and right atria, respectively; desensitization was near maximal as early as after 2 hr of infusion. No significant change in the density of [3H]dihydroalprenolol-labeled beta receptors was evident at this time point in either atrial or ventricular tissue, although isoproterenol did decrease binding site density after 7 days of infusion. There was no change in the binding affinity or physiological blocking potency of dihydroalprenolol after isoproterenol infusion. The inotropic potency of phenylephrine in the presence of dihydroalprenolol was unaffected by infusion of either isoproterenol or norepinephrine and methoxamine failed to increase right atrial rate either in control or in isoproterenol-infused rats. There was also no change in the density and affinity of [3H]prazosin binding sites after isoproterenol infusion. These results indicate selective desensitization of cardiac beta receptors without changes in alpha-1 receptors by prolonged in vivo stimulation with catecholamines. This reaction pattern is different from the well documented effects of hypothyroidism, which include decreased sensitivity of cardiac beta and increased sensitivity of cardiac alpha-1 receptor-mediated responses in rats. Thus, the mechanisms responsible for altered receptor function in the two conditions appear to be different.

Animals↗
PubMed1981

beta-Endorphin: possible involvement in the antihypertensive effect of central alpha-receptor activation.

Clonidine and L-alpha-methylnoradrenaline (but not D-alpha-methylnoradrenaline) increase the release of a substance with beta-endorphin immunoreactivity from slices of brainstem of spontaneously hypertensive rats, but not that of normotensive rats. It was reported earlier that opiate antagonists inhibit the hypotensive action of clonidine and alpha-methyldopa in spontaneously hypertensive but not in normotensive rats and that beta-endorphin has hypotensive effects of its own. Together, these findings indicate that release of beta-endorphin by central alpha-receptor agonists may contribute to the antihypertensive action of these drugs.

Adrenergic alpha-Agonists↗
PubMed1980

The influence of hormonal and neuronal factors on rat heart adrenoceptors.

1 The influence of hormonal and neuronal factors on adrenoceptors mediating increased cardiac force and rate of contraction were studied in rat isolated atria. The pharmacological properties of these receptors were deduced from the relative potencies of agonists and from the effects of selective alpha- and beta-adrenoceptor antagonists. The numbers and affinities of alpha- and beta-adrenoceptors were also determined by radioligand binding to ventricular membrane fragments.2 Hypophysectomy reduced the inotropic potency of isoprenaline and increased the potency of phenylephrine and methoxamine in left atria. The effect of phenylephrine was inhibited by propranolol less effectively and by phentolamine or phenoxybenzamine more effectively in hypophysectomized than in control rats. The difference in block was smaller at low than at high antagonist concentrations. Similar but smaller changes were observed for chronotropic responses of right atria.3 The decreased beta- and increased alpha-receptor response after hypophysectomy was similar to that observed earlier in thyroidectomized rats (Kunos, 1977). These changes developed slowly after hypophysectomy (>2 weeks), they were both reversed within 2 days of thyroxine treatment (0.2 mg/kg daily), but were not affected by cortisone treatment (50 mg/kg every 12 h for 4 days).4 Treatment of hypophysectomized rats for 2 days with thyroxine increased the density of [(3)H]-dihydroalprenolol ([(3)H]-DHA) binding sites from 27.5 +/- 2.7 to 45.5 +/- 5.7 fmol/mg protein and decreased the density of [(3)H]-WB-4101 binding sites from 38.7 +/- 3.1 to 18.7 +/- 2.5 fmol/mg protein. The affinity of either type of binding site for agonists or antagonist was not significantly altered by thyroxine treatment and the sum total of alpha(1)- and beta-receptors remained the same.5 Sympathetic denervation of thyroidectomized rats by 6-hydroxydopamine increased the inotropic potency of isoprenaline and noradrenaline and the blocking effect of propranolol, and decreased the potency of phenylephrine and the blocking effect of phenoxybenzamine to or beyond values observed in euthyroid controls. The density of [(3)H]-DHA binding sites was higher and that of [(3)H]-WB-4101 binding sites was lower in the denervated than in the innervated hypothyroid myocardium. Depletion of endogenous noradrenaline stores by reserpine did not significantly alter the adrenoceptor response pattern of the hypothyroid preparations and did not influence the density or affinity of [(3)H]-DHA and [(3)H]-WB-4101 binding sites.6 These results indicate that thyrotropin or steroids do not contribute to the reciprocal changes in the sensitivity of cardiac alpha(1)- and beta-adrenoceptors in altered thyroid states. These thyroid hormone-dependent changes are probably due to a parallel, reciprocal change in the numbers but not the affinities of alpha(1)- and beta-adrenoceptors. Reciprocal regulation of cardiac alpha(1)- and beta-adrenoceptors by thyroid hormones requires intact sympathetic innervation but not the presence of normal stores of the neurotransmitter.

Adrenal Cortex Hormones↗
PubMed1980

Possible role of an endogenous opiate in the cardiovascular effects of central alpha adrenoceptor stimulation in spontaneously hypertensive rats.

In unanesthetized sponatneously hypertensive rats (SHR), naloxone (0.5--2 mg/kg ip.) or naltrexone (2 mg/kg) inhibited the hypotension and bradycardia produced by clonidine (5--20 micrograms/kg iv.). Chronic treatment of SHR with clonidine (3 x 20 micrograms/kg/day orally for 12 days) reduced blood pressure and heart rate and these effects were acutely reversed by a single injection of naloxone. Naloxone also reversed the hypotension produced by a single injection of alpha-methyldopa (50--300 mg/kg ip.). In pentobarbital-anesthetized SHR, the hypotension and bradycardia produced by 5 micrograms/kg of clonidine were inhibited either by naloxone (2 mg/kg) or by yohimbine (1 mg/kg ip.). Morphine (0.33 mg/kg iv.) also reduced blood pressure and heart rate in these animals but these effects were only antagonized by naloxone and not by yohimbine. In conscious and anesthetized normotensive Wistar Kyoto rats, the reduction in blood pressure and heart rate by clonidine or alpha-methyldopa were smaller than in SHR, and these effects were not influenced by naloxone. These results confirm and extend earlier observations and suggest the existence of an "opioidergic" component in the antihypertensive action of central alpha adrenoceptor stimulants in SHR. They also show that a similar mechanism is either absent or inactive in the normotensive Wistar Kyoto rats.

Anesthesia↗