The spectra of a number of methylated xanthines have been determined in aqueous solution as a function of pH and have been found to fall into two distinct categories; that is, these derivatives may be placed into either of two spectral classes which are readily distinguishable regarding both the positions and the intensities of the bands. Correlation of the spectral shifts with pH has permitted an assignment for the sequence of ionization of the various hydrogen atoms.In the case of xanthine, for example, the first ionization is attributed to the removal of the 3-hydrogen while the second is due to the 7hydrogen. When the 3-position is substituted, the 7-hydrogen ionizes first; the 1-hydrogen next. When the l-position is substituted the order is identical to that of xanthine, and if the 7-position is substituted, the sequence is 3, 1. In general, the sequence of ionization of the three positions would be 3, 7, 1. The spectrally-determined apparent dissociation constants are found to be in good agreement with those obtained potentiometrically. Contrary to an earlier belief, it has been shown that xanthine, 7-methylxanthine and xanthosine each exhibit two dissociations in the pH range studied. The relative values of the various apparent dissociation constants are discussed in terms of structure.

Key points• In decerebrated rats, the exercise pressor reflex arising from a hindlimb whose femoral artery was occluded for 72 h was significantly higher than that arising from a hindlimb whose femoral artery was freely perfused.• Blockade of endoperoxide 4 receptors, but not blockade of endoperoxide 3 receptors, prevented the exaggerated exercise pressor reflex in rats with ligated femoral arteries.• Blockade of endoperoxide 3 or 4 receptors in rats with freely perfused femoral arteries had no effect on the exercise pressor reflex.• Western immunoblots showed that ligation of the femoral artery for 72 h increased the endoperoxide 4 receptor protein in the L4 and L5 dorsal root ganglia over their freely perfused counterparts by 24% (P < 0.05).Abstract Ligating the femoral artery for 72 h in decerebrated rats exaggerates the exercise pressor reflex. The sensory arm of this reflex is comprised of group III and IV afferents, which can be either sensitized or stimulated by PGE 2 . In vitro studies showed that endoperoxide (EP) 3 and 4 receptors were responsible for the PGE 2 -induced sensitization of rat dorsal root ganglion cells. This in vitro finding prompted us to test the hypothesis that blockade of EP3 and/or EP4 receptors attenuated the exaggerated exercise pressor reflex in rats with ligated femoral arteries. We measured the cardiovascular responses to static hindlimb contraction or tendon stretch before and after femoral arterial injection of L798106 (an EP3 antagonist) or L161982 (an EP4 antagonist). The pressor and cardioaccelerator responses to either contraction or tendon stretch were not attenuated by L798106 in either the ligated or freely perfused rats. Likewise in five rats whose hindlimb muscles were freely perfused, the pressor and cardioaccelerator responses to either contraction or tendon stretch were not attenuated by L161982. In the six ligated rats, however, the pressor response to contraction was attenuated by L161982, averaging 37 ± 3 mmHg before, 18 ± 2 mmHg afterward (P < 0.05). Western blotting analysis revealed that ligation of the femoral artery for 72 h increased the EP4 receptor protein in the L4 and L5 dorsal root ganglia over their freely perfused counterparts by 24% (P < 0.05). We conclude that EP4 receptors, but not EP3 receptors, play an important role in the exaggerated exercise pressor reflex found in rats with ligated femoral arteries. Abbreviations: HR, heart rate; MAP, mean arterial pressure; TTI, tension-time index.

Recent findings have shown that muscle contraction evokes an exaggerated pressor response in type 1 diabetes mellitus (T1DM) rats; however, it is not known whether the mechanoreflex, which is commonly stimulated by stretching the Achilles tendon, contributes to this abnormal response. Furthermore, the role of mechano-gated Piezo channels, found on thin-fiber afferent endings, in evoking the mechanoreflex in T1DM is also unknown. Therefore, in male and female streptozotocin (STZ, 50 mg/kg)-induced T1DM and healthy control (CTL) rats, we examined the pressor and cardioaccelerator responses to tendon stretch during the early stage of the disease. To determine the role of Piezo channels, GsMTx-4, a selective Piezo channel inhibitor, was injected into the arterial supply of the hindlimb. At 1 wk after STZ injection in unanesthetized, decerebrate rats, we stretched the Achilles tendon for 30 s and measured pressor and cardioaccelerator responses. We then compared pressor and cardioaccelerator responses to tendon stretch before and after GsMTx-4 injection (10 µg/100 ml). We found that the pressor (change in mean arterial pressure) response [41 ± 5 mmHg ( n = 15) for STZ and 18 ± 3 mmHg ( n = 11) for CTL ( P < 0.01)] and cardioaccelerator (change in heart rate) response [18 ± 4 beats/min for STZ ( n = 15) and 8 ± 2 beats/min ( n = 11) for CTL ( P < 0.05)] to tendon stretch were exaggerated in STZ rats. Local injection of GsMTx-4 attenuated the pressor [55 ± 7 mmHg ( n = 6) before and 27 ± 9 mmHg ( n = 6) after GsMTx-4 ( P < 0.01)], but not the cardioaccelerator, response to tendon stretch in STZ rats and had no effect on either response in CTL rats. These data suggest that T1DM exaggerates the mechanoreflex response to tendon stretch and that Piezo channels play a role in this exaggeration.

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The exercise pressor reflex contributes to increases in cardiovascular and ventilatory function during exercise. These reflexive increases are caused by both mechanical and metabolic stimulation of Group III and IV afferents with endings in contracting skeletal muscle. Patients with peripheral artery disease (PAD) have an augmented exercise pressor reflex. Recently, an animal model of PAD was established which allows further investigation of possible mechanisms involved in this augmented reflex. Earlier studies have identified ASIC3 channels, bradykinin receptors, P2X receptors, endoperoxide receptors, and thromboxane receptors as playing a role in evoking the exercise pressor reflex in healthy rats. This review focuses on recent studies using a rat model of PAD in order to determine possible mechanisms contributing to the exaggerated exercise pressor reflex seen in patients with this disease.