In vitro studies on endothelial cells have noted that the benefits of creatine against atherosclerosis (via immune cell adhesion to the endothelial cell) are blocked with the pharmaceutical ZM241385, a high affintiy adenosine A2A receptor antagonist.[316] This particular receptor subset (A2A rather than other adenosine receptors) and its inhibition are similar to caffeine,[589] suggesting that caffeine may have an inhibitory effect on this mechanism of creatine.
1-3 Minutes Rest: Ideal for “tension and fatigue exercises,” which include most secondary compound exercises. This range is sort of the midpoint between being ideal for strength and being ideal for generating fatigue. So while it’s not entirely what’s best for either, it is what’s perfect for achieving an equal combination of the two… which is exactly what we want from these exercises.
Contrast loading is the alternation of heavy and light loads. Considered as sets, the heavy load is performed at about 85-95% 1 repetition max; the light load should be considerably lighter at about 30-60% 1RM. Both sets should be performed fast with the lighter set being performed as fast as possible. The joints should not be locked as this inhibits muscle fibre recruitment and reduces the speed at which the exercise can be performed. The lighter set may be a loaded plyometric exercise such as loaded squat jumps or jumps with a trap bar.
When looking specifically at human studies, there has been a failure of creatine supplementation to induce or exacerbate kidney damage in people with amyotrophic lateral sclerosis (ALS). Subjects do not experience kidney damage for up to or over a year’s worth of supplementation in the 5-10g range.[505][506][507] Postmenopausal women,[517] people with type II diabetes,[518] people on hemodialysis,[313] otherwise healthy elderly,[519] young people,[454][520][521] and athletes do not experience kidney damage either.[324] Moreover, numerous scientific reviews on both the long- and short-term safety of supplemental creatine have consistently found no adverse effects on kidney function in a wide range of doses.[522][523][524][452][525][451][526][527] However, while doses >10 g/day have been found not to impair kidney function, there are fewer long-term trials using such high chronic daily intakes.[527]

It is known that intracellular energy depletion (assessed by a depletion of ATP) stimulates AMPK activity in order to normalize the AMP:ATP ratio,[333][334] and when activated AMPK (active in states of low cellular energy[335] and colocalizes with creatine kinase in muscle tissue[336]) appears to inhibit creatine kinase via phosphorylation (preserving phosphocreatine stores but attenuating the rate that creatine buffers ATP). While phosphocreatine technically inhibits AMPK, this does not occur in the presence of creatine at a 2:1 ratio.[334] It seems that if the ratio of phosphocreatine:creatine increases (indicative of excess cellular energy status) that AMPK activity is then attenuated, since when a cell is in a high energy status, there is less AMP to directly activate AMPK.[334][336][337]